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Slide 1 - Early And Long Term Treatment With Clopidogrel In Coronary Artery Disease פרופ’ יוסף רוזנמן מכון הלב, בי"ח וולפסון דצמבר 2005
Slide 2 - Early And Long Term Treatment With Clopidogrel In Coronary Artery Disease פרופ’ יוסף רוזנמן מכון הלב, בי"ח וולפסון דצמבר 2005 Acute Coronary Syndromes Acute Coronary Syndrome No ST Elevation ST Elevation Unstable Angina Myocardial Infarction Non Q MI Q wave MI Non ST Elevation MI Braunwald E et al. J Am Coll Cardiol 2000;36:970–1062.
Slide 3 - Early And Long Term Treatment With Clopidogrel In Coronary Artery Disease פרופ’ יוסף רוזנמן מכון הלב, בי"ח וולפסון דצמבר 2005 Acute Coronary Syndromes Acute Coronary Syndrome No ST Elevation ST Elevation Unstable Angina Myocardial Infarction Non Q MI Q wave MI Non ST Elevation MI Braunwald E et al. J Am Coll Cardiol 2000;36:970–1062. Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization
Slide 4 - Early And Long Term Treatment With Clopidogrel In Coronary Artery Disease פרופ’ יוסף רוזנמן מכון הלב, בי"ח וולפסון דצמבר 2005 Acute Coronary Syndromes Acute Coronary Syndrome No ST Elevation ST Elevation Unstable Angina Myocardial Infarction Non Q MI Q wave MI Non ST Elevation MI Braunwald E et al. J Am Coll Cardiol 2000;36:970–1062. Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term)
Slide 5 - Early And Long Term Treatment With Clopidogrel In Coronary Artery Disease פרופ’ יוסף רוזנמן מכון הלב, בי"ח וולפסון דצמבר 2005 Acute Coronary Syndromes Acute Coronary Syndrome No ST Elevation ST Elevation Unstable Angina Myocardial Infarction Non Q MI Q wave MI Non ST Elevation MI Braunwald E et al. J Am Coll Cardiol 2000;36:970–1062. Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When angiography / PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until angiography / PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month improving long-term outcome 1 2
Slide 6 - Early And Long Term Treatment With Clopidogrel In Coronary Artery Disease פרופ’ יוסף רוזנמן מכון הלב, בי"ח וולפסון דצמבר 2005 Acute Coronary Syndromes Acute Coronary Syndrome No ST Elevation ST Elevation Unstable Angina Myocardial Infarction Non Q MI Q wave MI Non ST Elevation MI Braunwald E et al. J Am Coll Cardiol 2000;36:970–1062. Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When angiography / PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until angiography / PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month improving long-term outcome 1 2 Goals of therapy Prevent ischemic events until coronary angiography / PCI Before plaque stabilization was achieved Prevent PCI / stent related ischemic complications Clopidogrel before coronary angiography - Patients with ACS 1
Slide 7 - Early And Long Term Treatment With Clopidogrel In Coronary Artery Disease פרופ’ יוסף רוזנמן מכון הלב, בי"ח וולפסון דצמבר 2005 Acute Coronary Syndromes Acute Coronary Syndrome No ST Elevation ST Elevation Unstable Angina Myocardial Infarction Non Q MI Q wave MI Non ST Elevation MI Braunwald E et al. J Am Coll Cardiol 2000;36:970–1062. Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When angiography / PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until angiography / PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month improving long-term outcome 1 2 Goals of therapy Prevent ischemic events until coronary angiography / PCI Before plaque stabilization was achieved Prevent PCI / stent related ischemic complications Clopidogrel before coronary angiography - Patients with ACS 1 Clopidogrel before coronary angiography - Patients with ACS ST Elevation CLARITY Non ST Elevation CURE 1
Slide 8 - Early And Long Term Treatment With Clopidogrel In Coronary Artery Disease פרופ’ יוסף רוזנמן מכון הלב, בי"ח וולפסון דצמבר 2005 Acute Coronary Syndromes Acute Coronary Syndrome No ST Elevation ST Elevation Unstable Angina Myocardial Infarction Non Q MI Q wave MI Non ST Elevation MI Braunwald E et al. J Am Coll Cardiol 2000;36:970–1062. Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When angiography / PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until angiography / PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month improving long-term outcome 1 2 Goals of therapy Prevent ischemic events until coronary angiography / PCI Before plaque stabilization was achieved Prevent PCI / stent related ischemic complications Clopidogrel before coronary angiography - Patients with ACS 1 Clopidogrel before coronary angiography - Patients with ACS ST Elevation CLARITY Non ST Elevation CURE 1 ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS
Slide 9 - Early And Long Term Treatment With Clopidogrel In Coronary Artery Disease פרופ’ יוסף רוזנמן מכון הלב, בי"ח וולפסון דצמבר 2005 Acute Coronary Syndromes Acute Coronary Syndrome No ST Elevation ST Elevation Unstable Angina Myocardial Infarction Non Q MI Q wave MI Non ST Elevation MI Braunwald E et al. J Am Coll Cardiol 2000;36:970–1062. Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When angiography / PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until angiography / PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month improving long-term outcome 1 2 Goals of therapy Prevent ischemic events until coronary angiography / PCI Before plaque stabilization was achieved Prevent PCI / stent related ischemic complications Clopidogrel before coronary angiography - Patients with ACS 1 Clopidogrel before coronary angiography - Patients with ACS ST Elevation CLARITY Non ST Elevation CURE 1 ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Study Design Fibrinolytic, ASA, Heparin Clopidogrel 300 mg + 75 mg qd Coronary Angiogram (2-8 days) Primary endpoint: Occluded artery (TIMI Flow Grade 0/1) or D/MI by time of angio randomize Placebo Double-blind, randomized, placebo-controlled trial in 3491 patients, age 18-75 yrs with STEMI < 12 hours Study Drug 30-day clinical follow-up Open-label clopidogrel per MD in both groups
Slide 10 - Early And Long Term Treatment With Clopidogrel In Coronary Artery Disease פרופ’ יוסף רוזנמן מכון הלב, בי"ח וולפסון דצמבר 2005 Acute Coronary Syndromes Acute Coronary Syndrome No ST Elevation ST Elevation Unstable Angina Myocardial Infarction Non Q MI Q wave MI Non ST Elevation MI Braunwald E et al. J Am Coll Cardiol 2000;36:970–1062. Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When angiography / PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until angiography / PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month improving long-term outcome 1 2 Goals of therapy Prevent ischemic events until coronary angiography / PCI Before plaque stabilization was achieved Prevent PCI / stent related ischemic complications Clopidogrel before coronary angiography - Patients with ACS 1 Clopidogrel before coronary angiography - Patients with ACS ST Elevation CLARITY Non ST Elevation CURE 1 ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Study Design Fibrinolytic, ASA, Heparin Clopidogrel 300 mg + 75 mg qd Coronary Angiogram (2-8 days) Primary endpoint: Occluded artery (TIMI Flow Grade 0/1) or D/MI by time of angio randomize Placebo Double-blind, randomized, placebo-controlled trial in 3491 patients, age 18-75 yrs with STEMI < 12 hours Study Drug 30-day clinical follow-up Open-label clopidogrel per MD in both groups Primary Endpoint: Occluded Artery (or D/MI by time of angio) Placebo Clopidogrel P=0.00000036 Odds Ratio 0.64 (95% CI 0.53-0.76) 1.0 0.4 0.6 0.8 1.2 1.6 Clopidogrel better Placebo better n=1752 n=1739 36% Odds Reduction
Slide 11 - Early And Long Term Treatment With Clopidogrel In Coronary Artery Disease פרופ’ יוסף רוזנמן מכון הלב, בי"ח וולפסון דצמבר 2005 Acute Coronary Syndromes Acute Coronary Syndrome No ST Elevation ST Elevation Unstable Angina Myocardial Infarction Non Q MI Q wave MI Non ST Elevation MI Braunwald E et al. J Am Coll Cardiol 2000;36:970–1062. Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When angiography / PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until angiography / PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month improving long-term outcome 1 2 Goals of therapy Prevent ischemic events until coronary angiography / PCI Before plaque stabilization was achieved Prevent PCI / stent related ischemic complications Clopidogrel before coronary angiography - Patients with ACS 1 Clopidogrel before coronary angiography - Patients with ACS ST Elevation CLARITY Non ST Elevation CURE 1 ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Study Design Fibrinolytic, ASA, Heparin Clopidogrel 300 mg + 75 mg qd Coronary Angiogram (2-8 days) Primary endpoint: Occluded artery (TIMI Flow Grade 0/1) or D/MI by time of angio randomize Placebo Double-blind, randomized, placebo-controlled trial in 3491 patients, age 18-75 yrs with STEMI < 12 hours Study Drug 30-day clinical follow-up Open-label clopidogrel per MD in both groups Primary Endpoint: Occluded Artery (or D/MI by time of angio) Placebo Clopidogrel P=0.00000036 Odds Ratio 0.64 (95% CI 0.53-0.76) 1.0 0.4 0.6 0.8 1.2 1.6 Clopidogrel better Placebo better n=1752 n=1739 36% Odds Reduction Primary & Angiographic Outcomes (median 3.5 days)
Slide 12 - Early And Long Term Treatment With Clopidogrel In Coronary Artery Disease פרופ’ יוסף רוזנמן מכון הלב, בי"ח וולפסון דצמבר 2005 Acute Coronary Syndromes Acute Coronary Syndrome No ST Elevation ST Elevation Unstable Angina Myocardial Infarction Non Q MI Q wave MI Non ST Elevation MI Braunwald E et al. J Am Coll Cardiol 2000;36:970–1062. Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When angiography / PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until angiography / PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month improving long-term outcome 1 2 Goals of therapy Prevent ischemic events until coronary angiography / PCI Before plaque stabilization was achieved Prevent PCI / stent related ischemic complications Clopidogrel before coronary angiography - Patients with ACS 1 Clopidogrel before coronary angiography - Patients with ACS ST Elevation CLARITY Non ST Elevation CURE 1 ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Study Design Fibrinolytic, ASA, Heparin Clopidogrel 300 mg + 75 mg qd Coronary Angiogram (2-8 days) Primary endpoint: Occluded artery (TIMI Flow Grade 0/1) or D/MI by time of angio randomize Placebo Double-blind, randomized, placebo-controlled trial in 3491 patients, age 18-75 yrs with STEMI < 12 hours Study Drug 30-day clinical follow-up Open-label clopidogrel per MD in both groups Primary Endpoint: Occluded Artery (or D/MI by time of angio) Placebo Clopidogrel P=0.00000036 Odds Ratio 0.64 (95% CI 0.53-0.76) 1.0 0.4 0.6 0.8 1.2 1.6 Clopidogrel better Placebo better n=1752 n=1739 36% Odds Reduction Primary & Angiographic Outcomes (median 3.5 days) Need for Urgent or Additional Treatment 21%  P=0.01 21%  P=0.005 16%  P=0.07 Early Angio (w/in 48 hrs) Urgent Revasc (index hosp) GP IIb/IIIa if PCI
Slide 13 - Early And Long Term Treatment With Clopidogrel In Coronary Artery Disease פרופ’ יוסף רוזנמן מכון הלב, בי"ח וולפסון דצמבר 2005 Acute Coronary Syndromes Acute Coronary Syndrome No ST Elevation ST Elevation Unstable Angina Myocardial Infarction Non Q MI Q wave MI Non ST Elevation MI Braunwald E et al. J Am Coll Cardiol 2000;36:970–1062. Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When angiography / PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until angiography / PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month improving long-term outcome 1 2 Goals of therapy Prevent ischemic events until coronary angiography / PCI Before plaque stabilization was achieved Prevent PCI / stent related ischemic complications Clopidogrel before coronary angiography - Patients with ACS 1 Clopidogrel before coronary angiography - Patients with ACS ST Elevation CLARITY Non ST Elevation CURE 1 ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Study Design Fibrinolytic, ASA, Heparin Clopidogrel 300 mg + 75 mg qd Coronary Angiogram (2-8 days) Primary endpoint: Occluded artery (TIMI Flow Grade 0/1) or D/MI by time of angio randomize Placebo Double-blind, randomized, placebo-controlled trial in 3491 patients, age 18-75 yrs with STEMI < 12 hours Study Drug 30-day clinical follow-up Open-label clopidogrel per MD in both groups Primary Endpoint: Occluded Artery (or D/MI by time of angio) Placebo Clopidogrel P=0.00000036 Odds Ratio 0.64 (95% CI 0.53-0.76) 1.0 0.4 0.6 0.8 1.2 1.6 Clopidogrel better Placebo better n=1752 n=1739 36% Odds Reduction Primary & Angiographic Outcomes (median 3.5 days) Need for Urgent or Additional Treatment 21%  P=0.01 21%  P=0.005 16%  P=0.07 Early Angio (w/in 48 hrs) Urgent Revasc (index hosp) GP IIb/IIIa if PCI CV Death, MI, RI  Urg Revasc days Percentage with endpoint (%) 0 5 10 15 0 5 10 15 20 25 30 Placebo Clopidogrel Odds Ratio 0.80 (95% CI 0.65-0.97) P=0.026 20% 1
Slide 14 - Early And Long Term Treatment With Clopidogrel In Coronary Artery Disease פרופ’ יוסף רוזנמן מכון הלב, בי"ח וולפסון דצמבר 2005 Acute Coronary Syndromes Acute Coronary Syndrome No ST Elevation ST Elevation Unstable Angina Myocardial Infarction Non Q MI Q wave MI Non ST Elevation MI Braunwald E et al. J Am Coll Cardiol 2000;36:970–1062. Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When angiography / PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until angiography / PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month improving long-term outcome 1 2 Goals of therapy Prevent ischemic events until coronary angiography / PCI Before plaque stabilization was achieved Prevent PCI / stent related ischemic complications Clopidogrel before coronary angiography - Patients with ACS 1 Clopidogrel before coronary angiography - Patients with ACS ST Elevation CLARITY Non ST Elevation CURE 1 ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Study Design Fibrinolytic, ASA, Heparin Clopidogrel 300 mg + 75 mg qd Coronary Angiogram (2-8 days) Primary endpoint: Occluded artery (TIMI Flow Grade 0/1) or D/MI by time of angio randomize Placebo Double-blind, randomized, placebo-controlled trial in 3491 patients, age 18-75 yrs with STEMI < 12 hours Study Drug 30-day clinical follow-up Open-label clopidogrel per MD in both groups Primary Endpoint: Occluded Artery (or D/MI by time of angio) Placebo Clopidogrel P=0.00000036 Odds Ratio 0.64 (95% CI 0.53-0.76) 1.0 0.4 0.6 0.8 1.2 1.6 Clopidogrel better Placebo better n=1752 n=1739 36% Odds Reduction Primary & Angiographic Outcomes (median 3.5 days) Need for Urgent or Additional Treatment 21%  P=0.01 21%  P=0.005 16%  P=0.07 Early Angio (w/in 48 hrs) Urgent Revasc (index hosp) GP IIb/IIIa if PCI CV Death, MI, RI  Urg Revasc days Percentage with endpoint (%) 0 5 10 15 0 5 10 15 20 25 30 Placebo Clopidogrel Odds Ratio 0.80 (95% CI 0.65-0.97) P=0.026 20% 1 CLARITY: Patient Management Clopidogrel Placebo Parameter (n=1,752) (n=1,739) Symptom onset to fibrinolytic (hours) 2.7 2.6 Fibrinolytic to study drug (minutes) 10 10 Median doses of study medication 4 4 Angiography performed (%) 94 94 Study drug to angiography (hours) 84 84 Coronary revascularization (%): 63 63 PCI 57.2 56.6 CABG 5.9 6.0 Sabatine M et al. New Engl J Med 2005; 352: 1179–1189.
Slide 15 - Early And Long Term Treatment With Clopidogrel In Coronary Artery Disease פרופ’ יוסף רוזנמן מכון הלב, בי"ח וולפסון דצמבר 2005 Acute Coronary Syndromes Acute Coronary Syndrome No ST Elevation ST Elevation Unstable Angina Myocardial Infarction Non Q MI Q wave MI Non ST Elevation MI Braunwald E et al. J Am Coll Cardiol 2000;36:970–1062. Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When angiography / PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until angiography / PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month improving long-term outcome 1 2 Goals of therapy Prevent ischemic events until coronary angiography / PCI Before plaque stabilization was achieved Prevent PCI / stent related ischemic complications Clopidogrel before coronary angiography - Patients with ACS 1 Clopidogrel before coronary angiography - Patients with ACS ST Elevation CLARITY Non ST Elevation CURE 1 ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Study Design Fibrinolytic, ASA, Heparin Clopidogrel 300 mg + 75 mg qd Coronary Angiogram (2-8 days) Primary endpoint: Occluded artery (TIMI Flow Grade 0/1) or D/MI by time of angio randomize Placebo Double-blind, randomized, placebo-controlled trial in 3491 patients, age 18-75 yrs with STEMI < 12 hours Study Drug 30-day clinical follow-up Open-label clopidogrel per MD in both groups Primary Endpoint: Occluded Artery (or D/MI by time of angio) Placebo Clopidogrel P=0.00000036 Odds Ratio 0.64 (95% CI 0.53-0.76) 1.0 0.4 0.6 0.8 1.2 1.6 Clopidogrel better Placebo better n=1752 n=1739 36% Odds Reduction Primary & Angiographic Outcomes (median 3.5 days) Need for Urgent or Additional Treatment 21%  P=0.01 21%  P=0.005 16%  P=0.07 Early Angio (w/in 48 hrs) Urgent Revasc (index hosp) GP IIb/IIIa if PCI CV Death, MI, RI  Urg Revasc days Percentage with endpoint (%) 0 5 10 15 0 5 10 15 20 25 30 Placebo Clopidogrel Odds Ratio 0.80 (95% CI 0.65-0.97) P=0.026 20% 1 CLARITY: Patient Management Clopidogrel Placebo Parameter (n=1,752) (n=1,739) Symptom onset to fibrinolytic (hours) 2.7 2.6 Fibrinolytic to study drug (minutes) 10 10 Median doses of study medication 4 4 Angiography performed (%) 94 94 Study drug to angiography (hours) 84 84 Coronary revascularization (%): 63 63 PCI 57.2 56.6 CABG 5.9 6.0 Sabatine M et al. New Engl J Med 2005; 352: 1179–1189. PCI-CLARITY: Reduction in CV Death, MI, Stroke from PCI to 30 Days Days Post PCI Percentage with Outcome (%) 0 2 0 5 10 15 20 25 30 46%* p=0.008 Clopidogrel Pretreatment (3.6%) No Pretreatment (6.2%) 4 6 8 M Sabatine, et al. JAMA 2005
Slide 16 - Early And Long Term Treatment With Clopidogrel In Coronary Artery Disease פרופ’ יוסף רוזנמן מכון הלב, בי"ח וולפסון דצמבר 2005 Acute Coronary Syndromes Acute Coronary Syndrome No ST Elevation ST Elevation Unstable Angina Myocardial Infarction Non Q MI Q wave MI Non ST Elevation MI Braunwald E et al. J Am Coll Cardiol 2000;36:970–1062. Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When angiography / PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until angiography / PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month improving long-term outcome 1 2 Goals of therapy Prevent ischemic events until coronary angiography / PCI Before plaque stabilization was achieved Prevent PCI / stent related ischemic complications Clopidogrel before coronary angiography - Patients with ACS 1 Clopidogrel before coronary angiography - Patients with ACS ST Elevation CLARITY Non ST Elevation CURE 1 ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Study Design Fibrinolytic, ASA, Heparin Clopidogrel 300 mg + 75 mg qd Coronary Angiogram (2-8 days) Primary endpoint: Occluded artery (TIMI Flow Grade 0/1) or D/MI by time of angio randomize Placebo Double-blind, randomized, placebo-controlled trial in 3491 patients, age 18-75 yrs with STEMI < 12 hours Study Drug 30-day clinical follow-up Open-label clopidogrel per MD in both groups Primary Endpoint: Occluded Artery (or D/MI by time of angio) Placebo Clopidogrel P=0.00000036 Odds Ratio 0.64 (95% CI 0.53-0.76) 1.0 0.4 0.6 0.8 1.2 1.6 Clopidogrel better Placebo better n=1752 n=1739 36% Odds Reduction Primary & Angiographic Outcomes (median 3.5 days) Need for Urgent or Additional Treatment 21%  P=0.01 21%  P=0.005 16%  P=0.07 Early Angio (w/in 48 hrs) Urgent Revasc (index hosp) GP IIb/IIIa if PCI CV Death, MI, RI  Urg Revasc days Percentage with endpoint (%) 0 5 10 15 0 5 10 15 20 25 30 Placebo Clopidogrel Odds Ratio 0.80 (95% CI 0.65-0.97) P=0.026 20% 1 CLARITY: Patient Management Clopidogrel Placebo Parameter (n=1,752) (n=1,739) Symptom onset to fibrinolytic (hours) 2.7 2.6 Fibrinolytic to study drug (minutes) 10 10 Median doses of study medication 4 4 Angiography performed (%) 94 94 Study drug to angiography (hours) 84 84 Coronary revascularization (%): 63 63 PCI 57.2 56.6 CABG 5.9 6.0 Sabatine M et al. New Engl J Med 2005; 352: 1179–1189. PCI-CLARITY: Reduction in CV Death, MI, Stroke from PCI to 30 Days Days Post PCI Percentage with Outcome (%) 0 2 0 5 10 15 20 25 30 46%* p=0.008 Clopidogrel Pretreatment (3.6%) No Pretreatment (6.2%) 4 6 8 M Sabatine, et al. JAMA 2005 PCI-CLARITY: MI, Stroke, or CV Death Events pre and post PCI ***MI or Stroke M Sabatine, et al. JAMA 2005,
Slide 17 - Early And Long Term Treatment With Clopidogrel In Coronary Artery Disease פרופ’ יוסף רוזנמן מכון הלב, בי"ח וולפסון דצמבר 2005 Acute Coronary Syndromes Acute Coronary Syndrome No ST Elevation ST Elevation Unstable Angina Myocardial Infarction Non Q MI Q wave MI Non ST Elevation MI Braunwald E et al. J Am Coll Cardiol 2000;36:970–1062. Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When angiography / PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until angiography / PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month improving long-term outcome 1 2 Goals of therapy Prevent ischemic events until coronary angiography / PCI Before plaque stabilization was achieved Prevent PCI / stent related ischemic complications Clopidogrel before coronary angiography - Patients with ACS 1 Clopidogrel before coronary angiography - Patients with ACS ST Elevation CLARITY Non ST Elevation CURE 1 ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Study Design Fibrinolytic, ASA, Heparin Clopidogrel 300 mg + 75 mg qd Coronary Angiogram (2-8 days) Primary endpoint: Occluded artery (TIMI Flow Grade 0/1) or D/MI by time of angio randomize Placebo Double-blind, randomized, placebo-controlled trial in 3491 patients, age 18-75 yrs with STEMI < 12 hours Study Drug 30-day clinical follow-up Open-label clopidogrel per MD in both groups Primary Endpoint: Occluded Artery (or D/MI by time of angio) Placebo Clopidogrel P=0.00000036 Odds Ratio 0.64 (95% CI 0.53-0.76) 1.0 0.4 0.6 0.8 1.2 1.6 Clopidogrel better Placebo better n=1752 n=1739 36% Odds Reduction Primary & Angiographic Outcomes (median 3.5 days) Need for Urgent or Additional Treatment 21%  P=0.01 21%  P=0.005 16%  P=0.07 Early Angio (w/in 48 hrs) Urgent Revasc (index hosp) GP IIb/IIIa if PCI CV Death, MI, RI  Urg Revasc days Percentage with endpoint (%) 0 5 10 15 0 5 10 15 20 25 30 Placebo Clopidogrel Odds Ratio 0.80 (95% CI 0.65-0.97) P=0.026 20% 1 CLARITY: Patient Management Clopidogrel Placebo Parameter (n=1,752) (n=1,739) Symptom onset to fibrinolytic (hours) 2.7 2.6 Fibrinolytic to study drug (minutes) 10 10 Median doses of study medication 4 4 Angiography performed (%) 94 94 Study drug to angiography (hours) 84 84 Coronary revascularization (%): 63 63 PCI 57.2 56.6 CABG 5.9 6.0 Sabatine M et al. New Engl J Med 2005; 352: 1179–1189. PCI-CLARITY: Reduction in CV Death, MI, Stroke from PCI to 30 Days Days Post PCI Percentage with Outcome (%) 0 2 0 5 10 15 20 25 30 46%* p=0.008 Clopidogrel Pretreatment (3.6%) No Pretreatment (6.2%) 4 6 8 M Sabatine, et al. JAMA 2005 PCI-CLARITY: MI, Stroke, or CV Death Events pre and post PCI ***MI or Stroke M Sabatine, et al. JAMA 2005, Prehospital Fibrinolysis with Double Antiplatelet Therapy in Acute ST-Elevation Myocardial Infarction: The Clarity Ambulance Substudy
Slide 18 - Early And Long Term Treatment With Clopidogrel In Coronary Artery Disease פרופ’ יוסף רוזנמן מכון הלב, בי"ח וולפסון דצמבר 2005 Acute Coronary Syndromes Acute Coronary Syndrome No ST Elevation ST Elevation Unstable Angina Myocardial Infarction Non Q MI Q wave MI Non ST Elevation MI Braunwald E et al. J Am Coll Cardiol 2000;36:970–1062. Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When angiography / PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until angiography / PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month improving long-term outcome 1 2 Goals of therapy Prevent ischemic events until coronary angiography / PCI Before plaque stabilization was achieved Prevent PCI / stent related ischemic complications Clopidogrel before coronary angiography - Patients with ACS 1 Clopidogrel before coronary angiography - Patients with ACS ST Elevation CLARITY Non ST Elevation CURE 1 ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Study Design Fibrinolytic, ASA, Heparin Clopidogrel 300 mg + 75 mg qd Coronary Angiogram (2-8 days) Primary endpoint: Occluded artery (TIMI Flow Grade 0/1) or D/MI by time of angio randomize Placebo Double-blind, randomized, placebo-controlled trial in 3491 patients, age 18-75 yrs with STEMI < 12 hours Study Drug 30-day clinical follow-up Open-label clopidogrel per MD in both groups Primary Endpoint: Occluded Artery (or D/MI by time of angio) Placebo Clopidogrel P=0.00000036 Odds Ratio 0.64 (95% CI 0.53-0.76) 1.0 0.4 0.6 0.8 1.2 1.6 Clopidogrel better Placebo better n=1752 n=1739 36% Odds Reduction Primary & Angiographic Outcomes (median 3.5 days) Need for Urgent or Additional Treatment 21%  P=0.01 21%  P=0.005 16%  P=0.07 Early Angio (w/in 48 hrs) Urgent Revasc (index hosp) GP IIb/IIIa if PCI CV Death, MI, RI  Urg Revasc days Percentage with endpoint (%) 0 5 10 15 0 5 10 15 20 25 30 Placebo Clopidogrel Odds Ratio 0.80 (95% CI 0.65-0.97) P=0.026 20% 1 CLARITY: Patient Management Clopidogrel Placebo Parameter (n=1,752) (n=1,739) Symptom onset to fibrinolytic (hours) 2.7 2.6 Fibrinolytic to study drug (minutes) 10 10 Median doses of study medication 4 4 Angiography performed (%) 94 94 Study drug to angiography (hours) 84 84 Coronary revascularization (%): 63 63 PCI 57.2 56.6 CABG 5.9 6.0 Sabatine M et al. New Engl J Med 2005; 352: 1179–1189. PCI-CLARITY: Reduction in CV Death, MI, Stroke from PCI to 30 Days Days Post PCI Percentage with Outcome (%) 0 2 0 5 10 15 20 25 30 46%* p=0.008 Clopidogrel Pretreatment (3.6%) No Pretreatment (6.2%) 4 6 8 M Sabatine, et al. JAMA 2005 PCI-CLARITY: MI, Stroke, or CV Death Events pre and post PCI ***MI or Stroke M Sabatine, et al. JAMA 2005, Prehospital Fibrinolysis with Double Antiplatelet Therapy in Acute ST-Elevation Myocardial Infarction: The Clarity Ambulance Substudy Substudy Sites and Patient Numbers France: 172 patients L Soulat: 57 Y Lambert: 48 F Lapostolle: 28 F Thieuleux: 21 C Gully: 10 D Pollet: 5 D Galley: 2 L Olliver: 1 UK: 40 patients J Adgey: 27 J Purvis: 13 Sweden: 5 patients J-E Karlsson: 5 217 patients in total
Slide 19 - Early And Long Term Treatment With Clopidogrel In Coronary Artery Disease פרופ’ יוסף רוזנמן מכון הלב, בי"ח וולפסון דצמבר 2005 Acute Coronary Syndromes Acute Coronary Syndrome No ST Elevation ST Elevation Unstable Angina Myocardial Infarction Non Q MI Q wave MI Non ST Elevation MI Braunwald E et al. J Am Coll Cardiol 2000;36:970–1062. Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When angiography / PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until angiography / PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month improving long-term outcome 1 2 Goals of therapy Prevent ischemic events until coronary angiography / PCI Before plaque stabilization was achieved Prevent PCI / stent related ischemic complications Clopidogrel before coronary angiography - Patients with ACS 1 Clopidogrel before coronary angiography - Patients with ACS ST Elevation CLARITY Non ST Elevation CURE 1 ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Study Design Fibrinolytic, ASA, Heparin Clopidogrel 300 mg + 75 mg qd Coronary Angiogram (2-8 days) Primary endpoint: Occluded artery (TIMI Flow Grade 0/1) or D/MI by time of angio randomize Placebo Double-blind, randomized, placebo-controlled trial in 3491 patients, age 18-75 yrs with STEMI < 12 hours Study Drug 30-day clinical follow-up Open-label clopidogrel per MD in both groups Primary Endpoint: Occluded Artery (or D/MI by time of angio) Placebo Clopidogrel P=0.00000036 Odds Ratio 0.64 (95% CI 0.53-0.76) 1.0 0.4 0.6 0.8 1.2 1.6 Clopidogrel better Placebo better n=1752 n=1739 36% Odds Reduction Primary & Angiographic Outcomes (median 3.5 days) Need for Urgent or Additional Treatment 21%  P=0.01 21%  P=0.005 16%  P=0.07 Early Angio (w/in 48 hrs) Urgent Revasc (index hosp) GP IIb/IIIa if PCI CV Death, MI, RI  Urg Revasc days Percentage with endpoint (%) 0 5 10 15 0 5 10 15 20 25 30 Placebo Clopidogrel Odds Ratio 0.80 (95% CI 0.65-0.97) P=0.026 20% 1 CLARITY: Patient Management Clopidogrel Placebo Parameter (n=1,752) (n=1,739) Symptom onset to fibrinolytic (hours) 2.7 2.6 Fibrinolytic to study drug (minutes) 10 10 Median doses of study medication 4 4 Angiography performed (%) 94 94 Study drug to angiography (hours) 84 84 Coronary revascularization (%): 63 63 PCI 57.2 56.6 CABG 5.9 6.0 Sabatine M et al. New Engl J Med 2005; 352: 1179–1189. PCI-CLARITY: Reduction in CV Death, MI, Stroke from PCI to 30 Days Days Post PCI Percentage with Outcome (%) 0 2 0 5 10 15 20 25 30 46%* p=0.008 Clopidogrel Pretreatment (3.6%) No Pretreatment (6.2%) 4 6 8 M Sabatine, et al. JAMA 2005 PCI-CLARITY: MI, Stroke, or CV Death Events pre and post PCI ***MI or Stroke M Sabatine, et al. JAMA 2005, Prehospital Fibrinolysis with Double Antiplatelet Therapy in Acute ST-Elevation Myocardial Infarction: The Clarity Ambulance Substudy Substudy Sites and Patient Numbers France: 172 patients L Soulat: 57 Y Lambert: 48 F Lapostolle: 28 F Thieuleux: 21 C Gully: 10 D Pollet: 5 D Galley: 2 L Olliver: 1 UK: 40 patients J Adgey: 27 J Purvis: 13 Sweden: 5 patients J-E Karlsson: 5 217 patients in total Angiographic & ECG Parameters: Ambulance vs. Non-Ambulance *Complete considered to be >70%; ECG=electrocardiogram p value Event rate (%) Ambulance Non- ambulance Non-ambulance better Ambulance better Odds ratio (95% CI)
Slide 20 - Early And Long Term Treatment With Clopidogrel In Coronary Artery Disease פרופ’ יוסף רוזנמן מכון הלב, בי"ח וולפסון דצמבר 2005 Acute Coronary Syndromes Acute Coronary Syndrome No ST Elevation ST Elevation Unstable Angina Myocardial Infarction Non Q MI Q wave MI Non ST Elevation MI Braunwald E et al. J Am Coll Cardiol 2000;36:970–1062. Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When angiography / PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until angiography / PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month improving long-term outcome 1 2 Goals of therapy Prevent ischemic events until coronary angiography / PCI Before plaque stabilization was achieved Prevent PCI / stent related ischemic complications Clopidogrel before coronary angiography - Patients with ACS 1 Clopidogrel before coronary angiography - Patients with ACS ST Elevation CLARITY Non ST Elevation CURE 1 ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Study Design Fibrinolytic, ASA, Heparin Clopidogrel 300 mg + 75 mg qd Coronary Angiogram (2-8 days) Primary endpoint: Occluded artery (TIMI Flow Grade 0/1) or D/MI by time of angio randomize Placebo Double-blind, randomized, placebo-controlled trial in 3491 patients, age 18-75 yrs with STEMI < 12 hours Study Drug 30-day clinical follow-up Open-label clopidogrel per MD in both groups Primary Endpoint: Occluded Artery (or D/MI by time of angio) Placebo Clopidogrel P=0.00000036 Odds Ratio 0.64 (95% CI 0.53-0.76) 1.0 0.4 0.6 0.8 1.2 1.6 Clopidogrel better Placebo better n=1752 n=1739 36% Odds Reduction Primary & Angiographic Outcomes (median 3.5 days) Need for Urgent or Additional Treatment 21%  P=0.01 21%  P=0.005 16%  P=0.07 Early Angio (w/in 48 hrs) Urgent Revasc (index hosp) GP IIb/IIIa if PCI CV Death, MI, RI  Urg Revasc days Percentage with endpoint (%) 0 5 10 15 0 5 10 15 20 25 30 Placebo Clopidogrel Odds Ratio 0.80 (95% CI 0.65-0.97) P=0.026 20% 1 CLARITY: Patient Management Clopidogrel Placebo Parameter (n=1,752) (n=1,739) Symptom onset to fibrinolytic (hours) 2.7 2.6 Fibrinolytic to study drug (minutes) 10 10 Median doses of study medication 4 4 Angiography performed (%) 94 94 Study drug to angiography (hours) 84 84 Coronary revascularization (%): 63 63 PCI 57.2 56.6 CABG 5.9 6.0 Sabatine M et al. New Engl J Med 2005; 352: 1179–1189. PCI-CLARITY: Reduction in CV Death, MI, Stroke from PCI to 30 Days Days Post PCI Percentage with Outcome (%) 0 2 0 5 10 15 20 25 30 46%* p=0.008 Clopidogrel Pretreatment (3.6%) No Pretreatment (6.2%) 4 6 8 M Sabatine, et al. JAMA 2005 PCI-CLARITY: MI, Stroke, or CV Death Events pre and post PCI ***MI or Stroke M Sabatine, et al. JAMA 2005, Prehospital Fibrinolysis with Double Antiplatelet Therapy in Acute ST-Elevation Myocardial Infarction: The Clarity Ambulance Substudy Substudy Sites and Patient Numbers France: 172 patients L Soulat: 57 Y Lambert: 48 F Lapostolle: 28 F Thieuleux: 21 C Gully: 10 D Pollet: 5 D Galley: 2 L Olliver: 1 UK: 40 patients J Adgey: 27 J Purvis: 13 Sweden: 5 patients J-E Karlsson: 5 217 patients in total Angiographic & ECG Parameters: Ambulance vs. Non-Ambulance *Complete considered to be >70%; ECG=electrocardiogram p value Event rate (%) Ambulance Non- ambulance Non-ambulance better Ambulance better Odds ratio (95% CI) 0 0.5 1.0 1.5 2.0 Ambulance Non-ambulance Overall Clopidogrel better Placebo better Odds ratio (95% CI) Primary Endpoint of TIMI Flow Grade 0/1, MI or Death 0.60 (0.301.17) 0.64 (0.530.76) 0.65 (0.540.77)
Slide 21 - Early And Long Term Treatment With Clopidogrel In Coronary Artery Disease פרופ’ יוסף רוזנמן מכון הלב, בי"ח וולפסון דצמבר 2005 Acute Coronary Syndromes Acute Coronary Syndrome No ST Elevation ST Elevation Unstable Angina Myocardial Infarction Non Q MI Q wave MI Non ST Elevation MI Braunwald E et al. J Am Coll Cardiol 2000;36:970–1062. Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When angiography / PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until angiography / PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month improving long-term outcome 1 2 Goals of therapy Prevent ischemic events until coronary angiography / PCI Before plaque stabilization was achieved Prevent PCI / stent related ischemic complications Clopidogrel before coronary angiography - Patients with ACS 1 Clopidogrel before coronary angiography - Patients with ACS ST Elevation CLARITY Non ST Elevation CURE 1 ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Study Design Fibrinolytic, ASA, Heparin Clopidogrel 300 mg + 75 mg qd Coronary Angiogram (2-8 days) Primary endpoint: Occluded artery (TIMI Flow Grade 0/1) or D/MI by time of angio randomize Placebo Double-blind, randomized, placebo-controlled trial in 3491 patients, age 18-75 yrs with STEMI < 12 hours Study Drug 30-day clinical follow-up Open-label clopidogrel per MD in both groups Primary Endpoint: Occluded Artery (or D/MI by time of angio) Placebo Clopidogrel P=0.00000036 Odds Ratio 0.64 (95% CI 0.53-0.76) 1.0 0.4 0.6 0.8 1.2 1.6 Clopidogrel better Placebo better n=1752 n=1739 36% Odds Reduction Primary & Angiographic Outcomes (median 3.5 days) Need for Urgent or Additional Treatment 21%  P=0.01 21%  P=0.005 16%  P=0.07 Early Angio (w/in 48 hrs) Urgent Revasc (index hosp) GP IIb/IIIa if PCI CV Death, MI, RI  Urg Revasc days Percentage with endpoint (%) 0 5 10 15 0 5 10 15 20 25 30 Placebo Clopidogrel Odds Ratio 0.80 (95% CI 0.65-0.97) P=0.026 20% 1 CLARITY: Patient Management Clopidogrel Placebo Parameter (n=1,752) (n=1,739) Symptom onset to fibrinolytic (hours) 2.7 2.6 Fibrinolytic to study drug (minutes) 10 10 Median doses of study medication 4 4 Angiography performed (%) 94 94 Study drug to angiography (hours) 84 84 Coronary revascularization (%): 63 63 PCI 57.2 56.6 CABG 5.9 6.0 Sabatine M et al. New Engl J Med 2005; 352: 1179–1189. PCI-CLARITY: Reduction in CV Death, MI, Stroke from PCI to 30 Days Days Post PCI Percentage with Outcome (%) 0 2 0 5 10 15 20 25 30 46%* p=0.008 Clopidogrel Pretreatment (3.6%) No Pretreatment (6.2%) 4 6 8 M Sabatine, et al. JAMA 2005 PCI-CLARITY: MI, Stroke, or CV Death Events pre and post PCI ***MI or Stroke M Sabatine, et al. JAMA 2005, Prehospital Fibrinolysis with Double Antiplatelet Therapy in Acute ST-Elevation Myocardial Infarction: The Clarity Ambulance Substudy Substudy Sites and Patient Numbers France: 172 patients L Soulat: 57 Y Lambert: 48 F Lapostolle: 28 F Thieuleux: 21 C Gully: 10 D Pollet: 5 D Galley: 2 L Olliver: 1 UK: 40 patients J Adgey: 27 J Purvis: 13 Sweden: 5 patients J-E Karlsson: 5 217 patients in total Angiographic & ECG Parameters: Ambulance vs. Non-Ambulance *Complete considered to be >70%; ECG=electrocardiogram p value Event rate (%) Ambulance Non- ambulance Non-ambulance better Ambulance better Odds ratio (95% CI) 0 0.5 1.0 1.5 2.0 Ambulance Non-ambulance Overall Clopidogrel better Placebo better Odds ratio (95% CI) Primary Endpoint of TIMI Flow Grade 0/1, MI or Death 0.60 (0.301.17) 0.64 (0.530.76) 0.65 (0.540.77) ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS
Slide 22 - Early And Long Term Treatment With Clopidogrel In Coronary Artery Disease פרופ’ יוסף רוזנמן מכון הלב, בי"ח וולפסון דצמבר 2005 Acute Coronary Syndromes Acute Coronary Syndrome No ST Elevation ST Elevation Unstable Angina Myocardial Infarction Non Q MI Q wave MI Non ST Elevation MI Braunwald E et al. J Am Coll Cardiol 2000;36:970–1062. Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When angiography / PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until angiography / PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month improving long-term outcome 1 2 Goals of therapy Prevent ischemic events until coronary angiography / PCI Before plaque stabilization was achieved Prevent PCI / stent related ischemic complications Clopidogrel before coronary angiography - Patients with ACS 1 Clopidogrel before coronary angiography - Patients with ACS ST Elevation CLARITY Non ST Elevation CURE 1 ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Study Design Fibrinolytic, ASA, Heparin Clopidogrel 300 mg + 75 mg qd Coronary Angiogram (2-8 days) Primary endpoint: Occluded artery (TIMI Flow Grade 0/1) or D/MI by time of angio randomize Placebo Double-blind, randomized, placebo-controlled trial in 3491 patients, age 18-75 yrs with STEMI < 12 hours Study Drug 30-day clinical follow-up Open-label clopidogrel per MD in both groups Primary Endpoint: Occluded Artery (or D/MI by time of angio) Placebo Clopidogrel P=0.00000036 Odds Ratio 0.64 (95% CI 0.53-0.76) 1.0 0.4 0.6 0.8 1.2 1.6 Clopidogrel better Placebo better n=1752 n=1739 36% Odds Reduction Primary & Angiographic Outcomes (median 3.5 days) Need for Urgent or Additional Treatment 21%  P=0.01 21%  P=0.005 16%  P=0.07 Early Angio (w/in 48 hrs) Urgent Revasc (index hosp) GP IIb/IIIa if PCI CV Death, MI, RI  Urg Revasc days Percentage with endpoint (%) 0 5 10 15 0 5 10 15 20 25 30 Placebo Clopidogrel Odds Ratio 0.80 (95% CI 0.65-0.97) P=0.026 20% 1 CLARITY: Patient Management Clopidogrel Placebo Parameter (n=1,752) (n=1,739) Symptom onset to fibrinolytic (hours) 2.7 2.6 Fibrinolytic to study drug (minutes) 10 10 Median doses of study medication 4 4 Angiography performed (%) 94 94 Study drug to angiography (hours) 84 84 Coronary revascularization (%): 63 63 PCI 57.2 56.6 CABG 5.9 6.0 Sabatine M et al. New Engl J Med 2005; 352: 1179–1189. PCI-CLARITY: Reduction in CV Death, MI, Stroke from PCI to 30 Days Days Post PCI Percentage with Outcome (%) 0 2 0 5 10 15 20 25 30 46%* p=0.008 Clopidogrel Pretreatment (3.6%) No Pretreatment (6.2%) 4 6 8 M Sabatine, et al. JAMA 2005 PCI-CLARITY: MI, Stroke, or CV Death Events pre and post PCI ***MI or Stroke M Sabatine, et al. JAMA 2005, Prehospital Fibrinolysis with Double Antiplatelet Therapy in Acute ST-Elevation Myocardial Infarction: The Clarity Ambulance Substudy Substudy Sites and Patient Numbers France: 172 patients L Soulat: 57 Y Lambert: 48 F Lapostolle: 28 F Thieuleux: 21 C Gully: 10 D Pollet: 5 D Galley: 2 L Olliver: 1 UK: 40 patients J Adgey: 27 J Purvis: 13 Sweden: 5 patients J-E Karlsson: 5 217 patients in total Angiographic & ECG Parameters: Ambulance vs. Non-Ambulance *Complete considered to be >70%; ECG=electrocardiogram p value Event rate (%) Ambulance Non- ambulance Non-ambulance better Ambulance better Odds ratio (95% CI) 0 0.5 1.0 1.5 2.0 Ambulance Non-ambulance Overall Clopidogrel better Placebo better Odds ratio (95% CI) Primary Endpoint of TIMI Flow Grade 0/1, MI or Death 0.60 (0.301.17) 0.64 (0.530.76) 0.65 (0.540.77) ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Clopidogrel 75mg q.d. + ASA 75-325 mg q.d.* (6259 patients) Placebo + ASA 75-325 mg q.d.* (6303 patients) Day 1 6 m. Visit 9 m. Visit 12 m. or Final Visit 3 m. Visit Discharge Visit 1 m. Visit Patients with Acute Coronary Syndrome (unstable angina or non-ST-segment elevation MI) R Placebo loading dose R = Randomization * In combination with other standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Study Design 3 months £ double-blind treatment £ 12 months Clopidogrel 300 mg loading dose CURE
Slide 23 - Early And Long Term Treatment With Clopidogrel In Coronary Artery Disease פרופ’ יוסף רוזנמן מכון הלב, בי"ח וולפסון דצמבר 2005 Acute Coronary Syndromes Acute Coronary Syndrome No ST Elevation ST Elevation Unstable Angina Myocardial Infarction Non Q MI Q wave MI Non ST Elevation MI Braunwald E et al. J Am Coll Cardiol 2000;36:970–1062. Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When angiography / PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until angiography / PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month improving long-term outcome 1 2 Goals of therapy Prevent ischemic events until coronary angiography / PCI Before plaque stabilization was achieved Prevent PCI / stent related ischemic complications Clopidogrel before coronary angiography - Patients with ACS 1 Clopidogrel before coronary angiography - Patients with ACS ST Elevation CLARITY Non ST Elevation CURE 1 ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Study Design Fibrinolytic, ASA, Heparin Clopidogrel 300 mg + 75 mg qd Coronary Angiogram (2-8 days) Primary endpoint: Occluded artery (TIMI Flow Grade 0/1) or D/MI by time of angio randomize Placebo Double-blind, randomized, placebo-controlled trial in 3491 patients, age 18-75 yrs with STEMI < 12 hours Study Drug 30-day clinical follow-up Open-label clopidogrel per MD in both groups Primary Endpoint: Occluded Artery (or D/MI by time of angio) Placebo Clopidogrel P=0.00000036 Odds Ratio 0.64 (95% CI 0.53-0.76) 1.0 0.4 0.6 0.8 1.2 1.6 Clopidogrel better Placebo better n=1752 n=1739 36% Odds Reduction Primary & Angiographic Outcomes (median 3.5 days) Need for Urgent or Additional Treatment 21%  P=0.01 21%  P=0.005 16%  P=0.07 Early Angio (w/in 48 hrs) Urgent Revasc (index hosp) GP IIb/IIIa if PCI CV Death, MI, RI  Urg Revasc days Percentage with endpoint (%) 0 5 10 15 0 5 10 15 20 25 30 Placebo Clopidogrel Odds Ratio 0.80 (95% CI 0.65-0.97) P=0.026 20% 1 CLARITY: Patient Management Clopidogrel Placebo Parameter (n=1,752) (n=1,739) Symptom onset to fibrinolytic (hours) 2.7 2.6 Fibrinolytic to study drug (minutes) 10 10 Median doses of study medication 4 4 Angiography performed (%) 94 94 Study drug to angiography (hours) 84 84 Coronary revascularization (%): 63 63 PCI 57.2 56.6 CABG 5.9 6.0 Sabatine M et al. New Engl J Med 2005; 352: 1179–1189. PCI-CLARITY: Reduction in CV Death, MI, Stroke from PCI to 30 Days Days Post PCI Percentage with Outcome (%) 0 2 0 5 10 15 20 25 30 46%* p=0.008 Clopidogrel Pretreatment (3.6%) No Pretreatment (6.2%) 4 6 8 M Sabatine, et al. JAMA 2005 PCI-CLARITY: MI, Stroke, or CV Death Events pre and post PCI ***MI or Stroke M Sabatine, et al. JAMA 2005, Prehospital Fibrinolysis with Double Antiplatelet Therapy in Acute ST-Elevation Myocardial Infarction: The Clarity Ambulance Substudy Substudy Sites and Patient Numbers France: 172 patients L Soulat: 57 Y Lambert: 48 F Lapostolle: 28 F Thieuleux: 21 C Gully: 10 D Pollet: 5 D Galley: 2 L Olliver: 1 UK: 40 patients J Adgey: 27 J Purvis: 13 Sweden: 5 patients J-E Karlsson: 5 217 patients in total Angiographic & ECG Parameters: Ambulance vs. Non-Ambulance *Complete considered to be >70%; ECG=electrocardiogram p value Event rate (%) Ambulance Non- ambulance Non-ambulance better Ambulance better Odds ratio (95% CI) 0 0.5 1.0 1.5 2.0 Ambulance Non-ambulance Overall Clopidogrel better Placebo better Odds ratio (95% CI) Primary Endpoint of TIMI Flow Grade 0/1, MI or Death 0.60 (0.301.17) 0.64 (0.530.76) 0.65 (0.540.77) ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Clopidogrel 75mg q.d. + ASA 75-325 mg q.d.* (6259 patients) Placebo + ASA 75-325 mg q.d.* (6303 patients) Day 1 6 m. Visit 9 m. Visit 12 m. or Final Visit 3 m. Visit Discharge Visit 1 m. Visit Patients with Acute Coronary Syndrome (unstable angina or non-ST-segment elevation MI) R Placebo loading dose R = Randomization * In combination with other standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Study Design 3 months £ double-blind treatment £ 12 months Clopidogrel 300 mg loading dose CURE Clopidogrel + ASA* 3 6 9 Placebo + ASA* Months of Follow-Up 11.4% 9.3% 20% RRR P < 0.001 N = 12,562 0 12 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Primary End Point - MI/Stroke/CV Death CURE
Slide 24 - Early And Long Term Treatment With Clopidogrel In Coronary Artery Disease פרופ’ יוסף רוזנמן מכון הלב, בי"ח וולפסון דצמבר 2005 Acute Coronary Syndromes Acute Coronary Syndrome No ST Elevation ST Elevation Unstable Angina Myocardial Infarction Non Q MI Q wave MI Non ST Elevation MI Braunwald E et al. J Am Coll Cardiol 2000;36:970–1062. Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When angiography / PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until angiography / PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month improving long-term outcome 1 2 Goals of therapy Prevent ischemic events until coronary angiography / PCI Before plaque stabilization was achieved Prevent PCI / stent related ischemic complications Clopidogrel before coronary angiography - Patients with ACS 1 Clopidogrel before coronary angiography - Patients with ACS ST Elevation CLARITY Non ST Elevation CURE 1 ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Study Design Fibrinolytic, ASA, Heparin Clopidogrel 300 mg + 75 mg qd Coronary Angiogram (2-8 days) Primary endpoint: Occluded artery (TIMI Flow Grade 0/1) or D/MI by time of angio randomize Placebo Double-blind, randomized, placebo-controlled trial in 3491 patients, age 18-75 yrs with STEMI < 12 hours Study Drug 30-day clinical follow-up Open-label clopidogrel per MD in both groups Primary Endpoint: Occluded Artery (or D/MI by time of angio) Placebo Clopidogrel P=0.00000036 Odds Ratio 0.64 (95% CI 0.53-0.76) 1.0 0.4 0.6 0.8 1.2 1.6 Clopidogrel better Placebo better n=1752 n=1739 36% Odds Reduction Primary & Angiographic Outcomes (median 3.5 days) Need for Urgent or Additional Treatment 21%  P=0.01 21%  P=0.005 16%  P=0.07 Early Angio (w/in 48 hrs) Urgent Revasc (index hosp) GP IIb/IIIa if PCI CV Death, MI, RI  Urg Revasc days Percentage with endpoint (%) 0 5 10 15 0 5 10 15 20 25 30 Placebo Clopidogrel Odds Ratio 0.80 (95% CI 0.65-0.97) P=0.026 20% 1 CLARITY: Patient Management Clopidogrel Placebo Parameter (n=1,752) (n=1,739) Symptom onset to fibrinolytic (hours) 2.7 2.6 Fibrinolytic to study drug (minutes) 10 10 Median doses of study medication 4 4 Angiography performed (%) 94 94 Study drug to angiography (hours) 84 84 Coronary revascularization (%): 63 63 PCI 57.2 56.6 CABG 5.9 6.0 Sabatine M et al. New Engl J Med 2005; 352: 1179–1189. PCI-CLARITY: Reduction in CV Death, MI, Stroke from PCI to 30 Days Days Post PCI Percentage with Outcome (%) 0 2 0 5 10 15 20 25 30 46%* p=0.008 Clopidogrel Pretreatment (3.6%) No Pretreatment (6.2%) 4 6 8 M Sabatine, et al. JAMA 2005 PCI-CLARITY: MI, Stroke, or CV Death Events pre and post PCI ***MI or Stroke M Sabatine, et al. JAMA 2005, Prehospital Fibrinolysis with Double Antiplatelet Therapy in Acute ST-Elevation Myocardial Infarction: The Clarity Ambulance Substudy Substudy Sites and Patient Numbers France: 172 patients L Soulat: 57 Y Lambert: 48 F Lapostolle: 28 F Thieuleux: 21 C Gully: 10 D Pollet: 5 D Galley: 2 L Olliver: 1 UK: 40 patients J Adgey: 27 J Purvis: 13 Sweden: 5 patients J-E Karlsson: 5 217 patients in total Angiographic & ECG Parameters: Ambulance vs. Non-Ambulance *Complete considered to be >70%; ECG=electrocardiogram p value Event rate (%) Ambulance Non- ambulance Non-ambulance better Ambulance better Odds ratio (95% CI) 0 0.5 1.0 1.5 2.0 Ambulance Non-ambulance Overall Clopidogrel better Placebo better Odds ratio (95% CI) Primary Endpoint of TIMI Flow Grade 0/1, MI or Death 0.60 (0.301.17) 0.64 (0.530.76) 0.65 (0.540.77) ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Clopidogrel 75mg q.d. + ASA 75-325 mg q.d.* (6259 patients) Placebo + ASA 75-325 mg q.d.* (6303 patients) Day 1 6 m. Visit 9 m. Visit 12 m. or Final Visit 3 m. Visit Discharge Visit 1 m. Visit Patients with Acute Coronary Syndrome (unstable angina or non-ST-segment elevation MI) R Placebo loading dose R = Randomization * In combination with other standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Study Design 3 months £ double-blind treatment £ 12 months Clopidogrel 300 mg loading dose CURE Clopidogrel + ASA* 3 6 9 Placebo + ASA* Months of Follow-Up 11.4% 9.3% 20% RRR P < 0.001 N = 12,562 0 12 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Primary End Point - MI/Stroke/CV Death CURE Clopidogrel + ASA* 10 20 30 Placebo + ASA* Days of Follow-Up 0 21% RRR P = 0.003 N = 12,562 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. MI/Stroke/CV Death within 30 Days CURE 1
Slide 25 - Early And Long Term Treatment With Clopidogrel In Coronary Artery Disease פרופ’ יוסף רוזנמן מכון הלב, בי"ח וולפסון דצמבר 2005 Acute Coronary Syndromes Acute Coronary Syndrome No ST Elevation ST Elevation Unstable Angina Myocardial Infarction Non Q MI Q wave MI Non ST Elevation MI Braunwald E et al. J Am Coll Cardiol 2000;36:970–1062. Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When angiography / PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until angiography / PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month improving long-term outcome 1 2 Goals of therapy Prevent ischemic events until coronary angiography / PCI Before plaque stabilization was achieved Prevent PCI / stent related ischemic complications Clopidogrel before coronary angiography - Patients with ACS 1 Clopidogrel before coronary angiography - Patients with ACS ST Elevation CLARITY Non ST Elevation CURE 1 ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Study Design Fibrinolytic, ASA, Heparin Clopidogrel 300 mg + 75 mg qd Coronary Angiogram (2-8 days) Primary endpoint: Occluded artery (TIMI Flow Grade 0/1) or D/MI by time of angio randomize Placebo Double-blind, randomized, placebo-controlled trial in 3491 patients, age 18-75 yrs with STEMI < 12 hours Study Drug 30-day clinical follow-up Open-label clopidogrel per MD in both groups Primary Endpoint: Occluded Artery (or D/MI by time of angio) Placebo Clopidogrel P=0.00000036 Odds Ratio 0.64 (95% CI 0.53-0.76) 1.0 0.4 0.6 0.8 1.2 1.6 Clopidogrel better Placebo better n=1752 n=1739 36% Odds Reduction Primary & Angiographic Outcomes (median 3.5 days) Need for Urgent or Additional Treatment 21%  P=0.01 21%  P=0.005 16%  P=0.07 Early Angio (w/in 48 hrs) Urgent Revasc (index hosp) GP IIb/IIIa if PCI CV Death, MI, RI  Urg Revasc days Percentage with endpoint (%) 0 5 10 15 0 5 10 15 20 25 30 Placebo Clopidogrel Odds Ratio 0.80 (95% CI 0.65-0.97) P=0.026 20% 1 CLARITY: Patient Management Clopidogrel Placebo Parameter (n=1,752) (n=1,739) Symptom onset to fibrinolytic (hours) 2.7 2.6 Fibrinolytic to study drug (minutes) 10 10 Median doses of study medication 4 4 Angiography performed (%) 94 94 Study drug to angiography (hours) 84 84 Coronary revascularization (%): 63 63 PCI 57.2 56.6 CABG 5.9 6.0 Sabatine M et al. New Engl J Med 2005; 352: 1179–1189. PCI-CLARITY: Reduction in CV Death, MI, Stroke from PCI to 30 Days Days Post PCI Percentage with Outcome (%) 0 2 0 5 10 15 20 25 30 46%* p=0.008 Clopidogrel Pretreatment (3.6%) No Pretreatment (6.2%) 4 6 8 M Sabatine, et al. JAMA 2005 PCI-CLARITY: MI, Stroke, or CV Death Events pre and post PCI ***MI or Stroke M Sabatine, et al. JAMA 2005, Prehospital Fibrinolysis with Double Antiplatelet Therapy in Acute ST-Elevation Myocardial Infarction: The Clarity Ambulance Substudy Substudy Sites and Patient Numbers France: 172 patients L Soulat: 57 Y Lambert: 48 F Lapostolle: 28 F Thieuleux: 21 C Gully: 10 D Pollet: 5 D Galley: 2 L Olliver: 1 UK: 40 patients J Adgey: 27 J Purvis: 13 Sweden: 5 patients J-E Karlsson: 5 217 patients in total Angiographic & ECG Parameters: Ambulance vs. Non-Ambulance *Complete considered to be >70%; ECG=electrocardiogram p value Event rate (%) Ambulance Non- ambulance Non-ambulance better Ambulance better Odds ratio (95% CI) 0 0.5 1.0 1.5 2.0 Ambulance Non-ambulance Overall Clopidogrel better Placebo better Odds ratio (95% CI) Primary Endpoint of TIMI Flow Grade 0/1, MI or Death 0.60 (0.301.17) 0.64 (0.530.76) 0.65 (0.540.77) ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Clopidogrel 75mg q.d. + ASA 75-325 mg q.d.* (6259 patients) Placebo + ASA 75-325 mg q.d.* (6303 patients) Day 1 6 m. Visit 9 m. Visit 12 m. or Final Visit 3 m. Visit Discharge Visit 1 m. Visit Patients with Acute Coronary Syndrome (unstable angina or non-ST-segment elevation MI) R Placebo loading dose R = Randomization * In combination with other standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Study Design 3 months £ double-blind treatment £ 12 months Clopidogrel 300 mg loading dose CURE Clopidogrel + ASA* 3 6 9 Placebo + ASA* Months of Follow-Up 11.4% 9.3% 20% RRR P < 0.001 N = 12,562 0 12 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Primary End Point - MI/Stroke/CV Death CURE Clopidogrel + ASA* 10 20 30 Placebo + ASA* Days of Follow-Up 0 21% RRR P = 0.003 N = 12,562 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. MI/Stroke/CV Death within 30 Days CURE 1 CV death, nonfatal MI, stroke or refractory or severe ischemia 34% NEJM 2001; 345:495-502 MI/Stroke/CV Death or severe Ischemia at 24 hours CURE 1
Slide 26 - Early And Long Term Treatment With Clopidogrel In Coronary Artery Disease פרופ’ יוסף רוזנמן מכון הלב, בי"ח וולפסון דצמבר 2005 Acute Coronary Syndromes Acute Coronary Syndrome No ST Elevation ST Elevation Unstable Angina Myocardial Infarction Non Q MI Q wave MI Non ST Elevation MI Braunwald E et al. J Am Coll Cardiol 2000;36:970–1062. Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When angiography / PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until angiography / PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month improving long-term outcome 1 2 Goals of therapy Prevent ischemic events until coronary angiography / PCI Before plaque stabilization was achieved Prevent PCI / stent related ischemic complications Clopidogrel before coronary angiography - Patients with ACS 1 Clopidogrel before coronary angiography - Patients with ACS ST Elevation CLARITY Non ST Elevation CURE 1 ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Study Design Fibrinolytic, ASA, Heparin Clopidogrel 300 mg + 75 mg qd Coronary Angiogram (2-8 days) Primary endpoint: Occluded artery (TIMI Flow Grade 0/1) or D/MI by time of angio randomize Placebo Double-blind, randomized, placebo-controlled trial in 3491 patients, age 18-75 yrs with STEMI < 12 hours Study Drug 30-day clinical follow-up Open-label clopidogrel per MD in both groups Primary Endpoint: Occluded Artery (or D/MI by time of angio) Placebo Clopidogrel P=0.00000036 Odds Ratio 0.64 (95% CI 0.53-0.76) 1.0 0.4 0.6 0.8 1.2 1.6 Clopidogrel better Placebo better n=1752 n=1739 36% Odds Reduction Primary & Angiographic Outcomes (median 3.5 days) Need for Urgent or Additional Treatment 21%  P=0.01 21%  P=0.005 16%  P=0.07 Early Angio (w/in 48 hrs) Urgent Revasc (index hosp) GP IIb/IIIa if PCI CV Death, MI, RI  Urg Revasc days Percentage with endpoint (%) 0 5 10 15 0 5 10 15 20 25 30 Placebo Clopidogrel Odds Ratio 0.80 (95% CI 0.65-0.97) P=0.026 20% 1 CLARITY: Patient Management Clopidogrel Placebo Parameter (n=1,752) (n=1,739) Symptom onset to fibrinolytic (hours) 2.7 2.6 Fibrinolytic to study drug (minutes) 10 10 Median doses of study medication 4 4 Angiography performed (%) 94 94 Study drug to angiography (hours) 84 84 Coronary revascularization (%): 63 63 PCI 57.2 56.6 CABG 5.9 6.0 Sabatine M et al. New Engl J Med 2005; 352: 1179–1189. PCI-CLARITY: Reduction in CV Death, MI, Stroke from PCI to 30 Days Days Post PCI Percentage with Outcome (%) 0 2 0 5 10 15 20 25 30 46%* p=0.008 Clopidogrel Pretreatment (3.6%) No Pretreatment (6.2%) 4 6 8 M Sabatine, et al. JAMA 2005 PCI-CLARITY: MI, Stroke, or CV Death Events pre and post PCI ***MI or Stroke M Sabatine, et al. JAMA 2005, Prehospital Fibrinolysis with Double Antiplatelet Therapy in Acute ST-Elevation Myocardial Infarction: The Clarity Ambulance Substudy Substudy Sites and Patient Numbers France: 172 patients L Soulat: 57 Y Lambert: 48 F Lapostolle: 28 F Thieuleux: 21 C Gully: 10 D Pollet: 5 D Galley: 2 L Olliver: 1 UK: 40 patients J Adgey: 27 J Purvis: 13 Sweden: 5 patients J-E Karlsson: 5 217 patients in total Angiographic & ECG Parameters: Ambulance vs. Non-Ambulance *Complete considered to be >70%; ECG=electrocardiogram p value Event rate (%) Ambulance Non- ambulance Non-ambulance better Ambulance better Odds ratio (95% CI) 0 0.5 1.0 1.5 2.0 Ambulance Non-ambulance Overall Clopidogrel better Placebo better Odds ratio (95% CI) Primary Endpoint of TIMI Flow Grade 0/1, MI or Death 0.60 (0.301.17) 0.64 (0.530.76) 0.65 (0.540.77) ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Clopidogrel 75mg q.d. + ASA 75-325 mg q.d.* (6259 patients) Placebo + ASA 75-325 mg q.d.* (6303 patients) Day 1 6 m. Visit 9 m. Visit 12 m. or Final Visit 3 m. Visit Discharge Visit 1 m. Visit Patients with Acute Coronary Syndrome (unstable angina or non-ST-segment elevation MI) R Placebo loading dose R = Randomization * In combination with other standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Study Design 3 months £ double-blind treatment £ 12 months Clopidogrel 300 mg loading dose CURE Clopidogrel + ASA* 3 6 9 Placebo + ASA* Months of Follow-Up 11.4% 9.3% 20% RRR P < 0.001 N = 12,562 0 12 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Primary End Point - MI/Stroke/CV Death CURE Clopidogrel + ASA* 10 20 30 Placebo + ASA* Days of Follow-Up 0 21% RRR P = 0.003 N = 12,562 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. MI/Stroke/CV Death within 30 Days CURE 1 CV death, nonfatal MI, stroke or refractory or severe ischemia 34% NEJM 2001; 345:495-502 MI/Stroke/CV Death or severe Ischemia at 24 hours CURE 1 % patients requiring thrombolytic therapy 43% % patients requiring GP IIb/IIIa inhibitors 18% NEJM 2001; 345:495-502 Need for Additional Anti-Thrombotic After Randomization P< 0.001 P= 0.003 Thrombolysis GP IIb/IIIa Inhibitor CURE 1
Slide 27 - Early And Long Term Treatment With Clopidogrel In Coronary Artery Disease פרופ’ יוסף רוזנמן מכון הלב, בי"ח וולפסון דצמבר 2005 Acute Coronary Syndromes Acute Coronary Syndrome No ST Elevation ST Elevation Unstable Angina Myocardial Infarction Non Q MI Q wave MI Non ST Elevation MI Braunwald E et al. J Am Coll Cardiol 2000;36:970–1062. Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When angiography / PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until angiography / PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month improving long-term outcome 1 2 Goals of therapy Prevent ischemic events until coronary angiography / PCI Before plaque stabilization was achieved Prevent PCI / stent related ischemic complications Clopidogrel before coronary angiography - Patients with ACS 1 Clopidogrel before coronary angiography - Patients with ACS ST Elevation CLARITY Non ST Elevation CURE 1 ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Study Design Fibrinolytic, ASA, Heparin Clopidogrel 300 mg + 75 mg qd Coronary Angiogram (2-8 days) Primary endpoint: Occluded artery (TIMI Flow Grade 0/1) or D/MI by time of angio randomize Placebo Double-blind, randomized, placebo-controlled trial in 3491 patients, age 18-75 yrs with STEMI < 12 hours Study Drug 30-day clinical follow-up Open-label clopidogrel per MD in both groups Primary Endpoint: Occluded Artery (or D/MI by time of angio) Placebo Clopidogrel P=0.00000036 Odds Ratio 0.64 (95% CI 0.53-0.76) 1.0 0.4 0.6 0.8 1.2 1.6 Clopidogrel better Placebo better n=1752 n=1739 36% Odds Reduction Primary & Angiographic Outcomes (median 3.5 days) Need for Urgent or Additional Treatment 21%  P=0.01 21%  P=0.005 16%  P=0.07 Early Angio (w/in 48 hrs) Urgent Revasc (index hosp) GP IIb/IIIa if PCI CV Death, MI, RI  Urg Revasc days Percentage with endpoint (%) 0 5 10 15 0 5 10 15 20 25 30 Placebo Clopidogrel Odds Ratio 0.80 (95% CI 0.65-0.97) P=0.026 20% 1 CLARITY: Patient Management Clopidogrel Placebo Parameter (n=1,752) (n=1,739) Symptom onset to fibrinolytic (hours) 2.7 2.6 Fibrinolytic to study drug (minutes) 10 10 Median doses of study medication 4 4 Angiography performed (%) 94 94 Study drug to angiography (hours) 84 84 Coronary revascularization (%): 63 63 PCI 57.2 56.6 CABG 5.9 6.0 Sabatine M et al. New Engl J Med 2005; 352: 1179–1189. PCI-CLARITY: Reduction in CV Death, MI, Stroke from PCI to 30 Days Days Post PCI Percentage with Outcome (%) 0 2 0 5 10 15 20 25 30 46%* p=0.008 Clopidogrel Pretreatment (3.6%) No Pretreatment (6.2%) 4 6 8 M Sabatine, et al. JAMA 2005 PCI-CLARITY: MI, Stroke, or CV Death Events pre and post PCI ***MI or Stroke M Sabatine, et al. JAMA 2005, Prehospital Fibrinolysis with Double Antiplatelet Therapy in Acute ST-Elevation Myocardial Infarction: The Clarity Ambulance Substudy Substudy Sites and Patient Numbers France: 172 patients L Soulat: 57 Y Lambert: 48 F Lapostolle: 28 F Thieuleux: 21 C Gully: 10 D Pollet: 5 D Galley: 2 L Olliver: 1 UK: 40 patients J Adgey: 27 J Purvis: 13 Sweden: 5 patients J-E Karlsson: 5 217 patients in total Angiographic & ECG Parameters: Ambulance vs. Non-Ambulance *Complete considered to be >70%; ECG=electrocardiogram p value Event rate (%) Ambulance Non- ambulance Non-ambulance better Ambulance better Odds ratio (95% CI) 0 0.5 1.0 1.5 2.0 Ambulance Non-ambulance Overall Clopidogrel better Placebo better Odds ratio (95% CI) Primary Endpoint of TIMI Flow Grade 0/1, MI or Death 0.60 (0.301.17) 0.64 (0.530.76) 0.65 (0.540.77) ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Clopidogrel 75mg q.d. + ASA 75-325 mg q.d.* (6259 patients) Placebo + ASA 75-325 mg q.d.* (6303 patients) Day 1 6 m. Visit 9 m. Visit 12 m. or Final Visit 3 m. Visit Discharge Visit 1 m. Visit Patients with Acute Coronary Syndrome (unstable angina or non-ST-segment elevation MI) R Placebo loading dose R = Randomization * In combination with other standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Study Design 3 months £ double-blind treatment £ 12 months Clopidogrel 300 mg loading dose CURE Clopidogrel + ASA* 3 6 9 Placebo + ASA* Months of Follow-Up 11.4% 9.3% 20% RRR P < 0.001 N = 12,562 0 12 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Primary End Point - MI/Stroke/CV Death CURE Clopidogrel + ASA* 10 20 30 Placebo + ASA* Days of Follow-Up 0 21% RRR P = 0.003 N = 12,562 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. MI/Stroke/CV Death within 30 Days CURE 1 CV death, nonfatal MI, stroke or refractory or severe ischemia 34% NEJM 2001; 345:495-502 MI/Stroke/CV Death or severe Ischemia at 24 hours CURE 1 % patients requiring thrombolytic therapy 43% % patients requiring GP IIb/IIIa inhibitors 18% NEJM 2001; 345:495-502 Need for Additional Anti-Thrombotic After Randomization P< 0.001 P= 0.003 Thrombolysis GP IIb/IIIa Inhibitor CURE 1 Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? GP IIb/IIIa receptor is the final common pathway in platelet aggregation. GP IIb/IIIa blockade is the most effective antiplatelet aggregation therapy. Bleeding risk is not increased if therapy is stopped 2-4 hours prior to CABG. Bleeding risk is markedly increased unless clopidogrel is stopped 3-5 days prior to CABG.
Slide 28 - Early And Long Term Treatment With Clopidogrel In Coronary Artery Disease פרופ’ יוסף רוזנמן מכון הלב, בי"ח וולפסון דצמבר 2005 Acute Coronary Syndromes Acute Coronary Syndrome No ST Elevation ST Elevation Unstable Angina Myocardial Infarction Non Q MI Q wave MI Non ST Elevation MI Braunwald E et al. J Am Coll Cardiol 2000;36:970–1062. Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When angiography / PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until angiography / PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month improving long-term outcome 1 2 Goals of therapy Prevent ischemic events until coronary angiography / PCI Before plaque stabilization was achieved Prevent PCI / stent related ischemic complications Clopidogrel before coronary angiography - Patients with ACS 1 Clopidogrel before coronary angiography - Patients with ACS ST Elevation CLARITY Non ST Elevation CURE 1 ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Study Design Fibrinolytic, ASA, Heparin Clopidogrel 300 mg + 75 mg qd Coronary Angiogram (2-8 days) Primary endpoint: Occluded artery (TIMI Flow Grade 0/1) or D/MI by time of angio randomize Placebo Double-blind, randomized, placebo-controlled trial in 3491 patients, age 18-75 yrs with STEMI < 12 hours Study Drug 30-day clinical follow-up Open-label clopidogrel per MD in both groups Primary Endpoint: Occluded Artery (or D/MI by time of angio) Placebo Clopidogrel P=0.00000036 Odds Ratio 0.64 (95% CI 0.53-0.76) 1.0 0.4 0.6 0.8 1.2 1.6 Clopidogrel better Placebo better n=1752 n=1739 36% Odds Reduction Primary & Angiographic Outcomes (median 3.5 days) Need for Urgent or Additional Treatment 21%  P=0.01 21%  P=0.005 16%  P=0.07 Early Angio (w/in 48 hrs) Urgent Revasc (index hosp) GP IIb/IIIa if PCI CV Death, MI, RI  Urg Revasc days Percentage with endpoint (%) 0 5 10 15 0 5 10 15 20 25 30 Placebo Clopidogrel Odds Ratio 0.80 (95% CI 0.65-0.97) P=0.026 20% 1 CLARITY: Patient Management Clopidogrel Placebo Parameter (n=1,752) (n=1,739) Symptom onset to fibrinolytic (hours) 2.7 2.6 Fibrinolytic to study drug (minutes) 10 10 Median doses of study medication 4 4 Angiography performed (%) 94 94 Study drug to angiography (hours) 84 84 Coronary revascularization (%): 63 63 PCI 57.2 56.6 CABG 5.9 6.0 Sabatine M et al. New Engl J Med 2005; 352: 1179–1189. PCI-CLARITY: Reduction in CV Death, MI, Stroke from PCI to 30 Days Days Post PCI Percentage with Outcome (%) 0 2 0 5 10 15 20 25 30 46%* p=0.008 Clopidogrel Pretreatment (3.6%) No Pretreatment (6.2%) 4 6 8 M Sabatine, et al. JAMA 2005 PCI-CLARITY: MI, Stroke, or CV Death Events pre and post PCI ***MI or Stroke M Sabatine, et al. JAMA 2005, Prehospital Fibrinolysis with Double Antiplatelet Therapy in Acute ST-Elevation Myocardial Infarction: The Clarity Ambulance Substudy Substudy Sites and Patient Numbers France: 172 patients L Soulat: 57 Y Lambert: 48 F Lapostolle: 28 F Thieuleux: 21 C Gully: 10 D Pollet: 5 D Galley: 2 L Olliver: 1 UK: 40 patients J Adgey: 27 J Purvis: 13 Sweden: 5 patients J-E Karlsson: 5 217 patients in total Angiographic & ECG Parameters: Ambulance vs. Non-Ambulance *Complete considered to be >70%; ECG=electrocardiogram p value Event rate (%) Ambulance Non- ambulance Non-ambulance better Ambulance better Odds ratio (95% CI) 0 0.5 1.0 1.5 2.0 Ambulance Non-ambulance Overall Clopidogrel better Placebo better Odds ratio (95% CI) Primary Endpoint of TIMI Flow Grade 0/1, MI or Death 0.60 (0.301.17) 0.64 (0.530.76) 0.65 (0.540.77) ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Clopidogrel 75mg q.d. + ASA 75-325 mg q.d.* (6259 patients) Placebo + ASA 75-325 mg q.d.* (6303 patients) Day 1 6 m. Visit 9 m. Visit 12 m. or Final Visit 3 m. Visit Discharge Visit 1 m. Visit Patients with Acute Coronary Syndrome (unstable angina or non-ST-segment elevation MI) R Placebo loading dose R = Randomization * In combination with other standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Study Design 3 months £ double-blind treatment £ 12 months Clopidogrel 300 mg loading dose CURE Clopidogrel + ASA* 3 6 9 Placebo + ASA* Months of Follow-Up 11.4% 9.3% 20% RRR P < 0.001 N = 12,562 0 12 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Primary End Point - MI/Stroke/CV Death CURE Clopidogrel + ASA* 10 20 30 Placebo + ASA* Days of Follow-Up 0 21% RRR P = 0.003 N = 12,562 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. MI/Stroke/CV Death within 30 Days CURE 1 CV death, nonfatal MI, stroke or refractory or severe ischemia 34% NEJM 2001; 345:495-502 MI/Stroke/CV Death or severe Ischemia at 24 hours CURE 1 % patients requiring thrombolytic therapy 43% % patients requiring GP IIb/IIIa inhibitors 18% NEJM 2001; 345:495-502 Need for Additional Anti-Thrombotic After Randomization P< 0.001 P= 0.003 Thrombolysis GP IIb/IIIa Inhibitor CURE 1 Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? GP IIb/IIIa receptor is the final common pathway in platelet aggregation. GP IIb/IIIa blockade is the most effective antiplatelet aggregation therapy. Bleeding risk is not increased if therapy is stopped 2-4 hours prior to CABG. Bleeding risk is markedly increased unless clopidogrel is stopped 3-5 days prior to CABG. Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? Is there additional benefit to clopidogrel that would justify: Increased CABG bleeding or alternatively Need to postpone CABG for 3-5 days No data in the literature however
Slide 29 - Early And Long Term Treatment With Clopidogrel In Coronary Artery Disease פרופ’ יוסף רוזנמן מכון הלב, בי"ח וולפסון דצמבר 2005 Acute Coronary Syndromes Acute Coronary Syndrome No ST Elevation ST Elevation Unstable Angina Myocardial Infarction Non Q MI Q wave MI Non ST Elevation MI Braunwald E et al. J Am Coll Cardiol 2000;36:970–1062. Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When angiography / PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until angiography / PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month improving long-term outcome 1 2 Goals of therapy Prevent ischemic events until coronary angiography / PCI Before plaque stabilization was achieved Prevent PCI / stent related ischemic complications Clopidogrel before coronary angiography - Patients with ACS 1 Clopidogrel before coronary angiography - Patients with ACS ST Elevation CLARITY Non ST Elevation CURE 1 ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Study Design Fibrinolytic, ASA, Heparin Clopidogrel 300 mg + 75 mg qd Coronary Angiogram (2-8 days) Primary endpoint: Occluded artery (TIMI Flow Grade 0/1) or D/MI by time of angio randomize Placebo Double-blind, randomized, placebo-controlled trial in 3491 patients, age 18-75 yrs with STEMI < 12 hours Study Drug 30-day clinical follow-up Open-label clopidogrel per MD in both groups Primary Endpoint: Occluded Artery (or D/MI by time of angio) Placebo Clopidogrel P=0.00000036 Odds Ratio 0.64 (95% CI 0.53-0.76) 1.0 0.4 0.6 0.8 1.2 1.6 Clopidogrel better Placebo better n=1752 n=1739 36% Odds Reduction Primary & Angiographic Outcomes (median 3.5 days) Need for Urgent or Additional Treatment 21%  P=0.01 21%  P=0.005 16%  P=0.07 Early Angio (w/in 48 hrs) Urgent Revasc (index hosp) GP IIb/IIIa if PCI CV Death, MI, RI  Urg Revasc days Percentage with endpoint (%) 0 5 10 15 0 5 10 15 20 25 30 Placebo Clopidogrel Odds Ratio 0.80 (95% CI 0.65-0.97) P=0.026 20% 1 CLARITY: Patient Management Clopidogrel Placebo Parameter (n=1,752) (n=1,739) Symptom onset to fibrinolytic (hours) 2.7 2.6 Fibrinolytic to study drug (minutes) 10 10 Median doses of study medication 4 4 Angiography performed (%) 94 94 Study drug to angiography (hours) 84 84 Coronary revascularization (%): 63 63 PCI 57.2 56.6 CABG 5.9 6.0 Sabatine M et al. New Engl J Med 2005; 352: 1179–1189. PCI-CLARITY: Reduction in CV Death, MI, Stroke from PCI to 30 Days Days Post PCI Percentage with Outcome (%) 0 2 0 5 10 15 20 25 30 46%* p=0.008 Clopidogrel Pretreatment (3.6%) No Pretreatment (6.2%) 4 6 8 M Sabatine, et al. JAMA 2005 PCI-CLARITY: MI, Stroke, or CV Death Events pre and post PCI ***MI or Stroke M Sabatine, et al. JAMA 2005, Prehospital Fibrinolysis with Double Antiplatelet Therapy in Acute ST-Elevation Myocardial Infarction: The Clarity Ambulance Substudy Substudy Sites and Patient Numbers France: 172 patients L Soulat: 57 Y Lambert: 48 F Lapostolle: 28 F Thieuleux: 21 C Gully: 10 D Pollet: 5 D Galley: 2 L Olliver: 1 UK: 40 patients J Adgey: 27 J Purvis: 13 Sweden: 5 patients J-E Karlsson: 5 217 patients in total Angiographic & ECG Parameters: Ambulance vs. Non-Ambulance *Complete considered to be >70%; ECG=electrocardiogram p value Event rate (%) Ambulance Non- ambulance Non-ambulance better Ambulance better Odds ratio (95% CI) 0 0.5 1.0 1.5 2.0 Ambulance Non-ambulance Overall Clopidogrel better Placebo better Odds ratio (95% CI) Primary Endpoint of TIMI Flow Grade 0/1, MI or Death 0.60 (0.301.17) 0.64 (0.530.76) 0.65 (0.540.77) ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Clopidogrel 75mg q.d. + ASA 75-325 mg q.d.* (6259 patients) Placebo + ASA 75-325 mg q.d.* (6303 patients) Day 1 6 m. Visit 9 m. Visit 12 m. or Final Visit 3 m. Visit Discharge Visit 1 m. Visit Patients with Acute Coronary Syndrome (unstable angina or non-ST-segment elevation MI) R Placebo loading dose R = Randomization * In combination with other standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Study Design 3 months £ double-blind treatment £ 12 months Clopidogrel 300 mg loading dose CURE Clopidogrel + ASA* 3 6 9 Placebo + ASA* Months of Follow-Up 11.4% 9.3% 20% RRR P < 0.001 N = 12,562 0 12 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Primary End Point - MI/Stroke/CV Death CURE Clopidogrel + ASA* 10 20 30 Placebo + ASA* Days of Follow-Up 0 21% RRR P = 0.003 N = 12,562 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. MI/Stroke/CV Death within 30 Days CURE 1 CV death, nonfatal MI, stroke or refractory or severe ischemia 34% NEJM 2001; 345:495-502 MI/Stroke/CV Death or severe Ischemia at 24 hours CURE 1 % patients requiring thrombolytic therapy 43% % patients requiring GP IIb/IIIa inhibitors 18% NEJM 2001; 345:495-502 Need for Additional Anti-Thrombotic After Randomization P< 0.001 P= 0.003 Thrombolysis GP IIb/IIIa Inhibitor CURE 1 Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? GP IIb/IIIa receptor is the final common pathway in platelet aggregation. GP IIb/IIIa blockade is the most effective antiplatelet aggregation therapy. Bleeding risk is not increased if therapy is stopped 2-4 hours prior to CABG. Bleeding risk is markedly increased unless clopidogrel is stopped 3-5 days prior to CABG. Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? Is there additional benefit to clopidogrel that would justify: Increased CABG bleeding or alternatively Need to postpone CABG for 3-5 days No data in the literature however Adhesion The Role of Platelets in Atherothrombosis Aggregation 3 Reproduced with permission from Cannon CP. Atherothrombosis slide compendium. Available at: www.theheart.org. 1 Activation 2
Slide 30 - Early And Long Term Treatment With Clopidogrel In Coronary Artery Disease פרופ’ יוסף רוזנמן מכון הלב, בי"ח וולפסון דצמבר 2005 Acute Coronary Syndromes Acute Coronary Syndrome No ST Elevation ST Elevation Unstable Angina Myocardial Infarction Non Q MI Q wave MI Non ST Elevation MI Braunwald E et al. J Am Coll Cardiol 2000;36:970–1062. Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When angiography / PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until angiography / PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month improving long-term outcome 1 2 Goals of therapy Prevent ischemic events until coronary angiography / PCI Before plaque stabilization was achieved Prevent PCI / stent related ischemic complications Clopidogrel before coronary angiography - Patients with ACS 1 Clopidogrel before coronary angiography - Patients with ACS ST Elevation CLARITY Non ST Elevation CURE 1 ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Study Design Fibrinolytic, ASA, Heparin Clopidogrel 300 mg + 75 mg qd Coronary Angiogram (2-8 days) Primary endpoint: Occluded artery (TIMI Flow Grade 0/1) or D/MI by time of angio randomize Placebo Double-blind, randomized, placebo-controlled trial in 3491 patients, age 18-75 yrs with STEMI < 12 hours Study Drug 30-day clinical follow-up Open-label clopidogrel per MD in both groups Primary Endpoint: Occluded Artery (or D/MI by time of angio) Placebo Clopidogrel P=0.00000036 Odds Ratio 0.64 (95% CI 0.53-0.76) 1.0 0.4 0.6 0.8 1.2 1.6 Clopidogrel better Placebo better n=1752 n=1739 36% Odds Reduction Primary & Angiographic Outcomes (median 3.5 days) Need for Urgent or Additional Treatment 21%  P=0.01 21%  P=0.005 16%  P=0.07 Early Angio (w/in 48 hrs) Urgent Revasc (index hosp) GP IIb/IIIa if PCI CV Death, MI, RI  Urg Revasc days Percentage with endpoint (%) 0 5 10 15 0 5 10 15 20 25 30 Placebo Clopidogrel Odds Ratio 0.80 (95% CI 0.65-0.97) P=0.026 20% 1 CLARITY: Patient Management Clopidogrel Placebo Parameter (n=1,752) (n=1,739) Symptom onset to fibrinolytic (hours) 2.7 2.6 Fibrinolytic to study drug (minutes) 10 10 Median doses of study medication 4 4 Angiography performed (%) 94 94 Study drug to angiography (hours) 84 84 Coronary revascularization (%): 63 63 PCI 57.2 56.6 CABG 5.9 6.0 Sabatine M et al. New Engl J Med 2005; 352: 1179–1189. PCI-CLARITY: Reduction in CV Death, MI, Stroke from PCI to 30 Days Days Post PCI Percentage with Outcome (%) 0 2 0 5 10 15 20 25 30 46%* p=0.008 Clopidogrel Pretreatment (3.6%) No Pretreatment (6.2%) 4 6 8 M Sabatine, et al. JAMA 2005 PCI-CLARITY: MI, Stroke, or CV Death Events pre and post PCI ***MI or Stroke M Sabatine, et al. JAMA 2005, Prehospital Fibrinolysis with Double Antiplatelet Therapy in Acute ST-Elevation Myocardial Infarction: The Clarity Ambulance Substudy Substudy Sites and Patient Numbers France: 172 patients L Soulat: 57 Y Lambert: 48 F Lapostolle: 28 F Thieuleux: 21 C Gully: 10 D Pollet: 5 D Galley: 2 L Olliver: 1 UK: 40 patients J Adgey: 27 J Purvis: 13 Sweden: 5 patients J-E Karlsson: 5 217 patients in total Angiographic & ECG Parameters: Ambulance vs. Non-Ambulance *Complete considered to be >70%; ECG=electrocardiogram p value Event rate (%) Ambulance Non- ambulance Non-ambulance better Ambulance better Odds ratio (95% CI) 0 0.5 1.0 1.5 2.0 Ambulance Non-ambulance Overall Clopidogrel better Placebo better Odds ratio (95% CI) Primary Endpoint of TIMI Flow Grade 0/1, MI or Death 0.60 (0.301.17) 0.64 (0.530.76) 0.65 (0.540.77) ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Clopidogrel 75mg q.d. + ASA 75-325 mg q.d.* (6259 patients) Placebo + ASA 75-325 mg q.d.* (6303 patients) Day 1 6 m. Visit 9 m. Visit 12 m. or Final Visit 3 m. Visit Discharge Visit 1 m. Visit Patients with Acute Coronary Syndrome (unstable angina or non-ST-segment elevation MI) R Placebo loading dose R = Randomization * In combination with other standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Study Design 3 months £ double-blind treatment £ 12 months Clopidogrel 300 mg loading dose CURE Clopidogrel + ASA* 3 6 9 Placebo + ASA* Months of Follow-Up 11.4% 9.3% 20% RRR P < 0.001 N = 12,562 0 12 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Primary End Point - MI/Stroke/CV Death CURE Clopidogrel + ASA* 10 20 30 Placebo + ASA* Days of Follow-Up 0 21% RRR P = 0.003 N = 12,562 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. MI/Stroke/CV Death within 30 Days CURE 1 CV death, nonfatal MI, stroke or refractory or severe ischemia 34% NEJM 2001; 345:495-502 MI/Stroke/CV Death or severe Ischemia at 24 hours CURE 1 % patients requiring thrombolytic therapy 43% % patients requiring GP IIb/IIIa inhibitors 18% NEJM 2001; 345:495-502 Need for Additional Anti-Thrombotic After Randomization P< 0.001 P= 0.003 Thrombolysis GP IIb/IIIa Inhibitor CURE 1 Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? GP IIb/IIIa receptor is the final common pathway in platelet aggregation. GP IIb/IIIa blockade is the most effective antiplatelet aggregation therapy. Bleeding risk is not increased if therapy is stopped 2-4 hours prior to CABG. Bleeding risk is markedly increased unless clopidogrel is stopped 3-5 days prior to CABG. Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? Is there additional benefit to clopidogrel that would justify: Increased CABG bleeding or alternatively Need to postpone CABG for 3-5 days No data in the literature however Adhesion The Role of Platelets in Atherothrombosis Aggregation 3 Reproduced with permission from Cannon CP. Atherothrombosis slide compendium. Available at: www.theheart.org. 1 Activation 2
Slide 31 - Early And Long Term Treatment With Clopidogrel In Coronary Artery Disease פרופ’ יוסף רוזנמן מכון הלב, בי"ח וולפסון דצמבר 2005 Acute Coronary Syndromes Acute Coronary Syndrome No ST Elevation ST Elevation Unstable Angina Myocardial Infarction Non Q MI Q wave MI Non ST Elevation MI Braunwald E et al. J Am Coll Cardiol 2000;36:970–1062. Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When angiography / PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until angiography / PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month improving long-term outcome 1 2 Goals of therapy Prevent ischemic events until coronary angiography / PCI Before plaque stabilization was achieved Prevent PCI / stent related ischemic complications Clopidogrel before coronary angiography - Patients with ACS 1 Clopidogrel before coronary angiography - Patients with ACS ST Elevation CLARITY Non ST Elevation CURE 1 ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Study Design Fibrinolytic, ASA, Heparin Clopidogrel 300 mg + 75 mg qd Coronary Angiogram (2-8 days) Primary endpoint: Occluded artery (TIMI Flow Grade 0/1) or D/MI by time of angio randomize Placebo Double-blind, randomized, placebo-controlled trial in 3491 patients, age 18-75 yrs with STEMI < 12 hours Study Drug 30-day clinical follow-up Open-label clopidogrel per MD in both groups Primary Endpoint: Occluded Artery (or D/MI by time of angio) Placebo Clopidogrel P=0.00000036 Odds Ratio 0.64 (95% CI 0.53-0.76) 1.0 0.4 0.6 0.8 1.2 1.6 Clopidogrel better Placebo better n=1752 n=1739 36% Odds Reduction Primary & Angiographic Outcomes (median 3.5 days) Need for Urgent or Additional Treatment 21%  P=0.01 21%  P=0.005 16%  P=0.07 Early Angio (w/in 48 hrs) Urgent Revasc (index hosp) GP IIb/IIIa if PCI CV Death, MI, RI  Urg Revasc days Percentage with endpoint (%) 0 5 10 15 0 5 10 15 20 25 30 Placebo Clopidogrel Odds Ratio 0.80 (95% CI 0.65-0.97) P=0.026 20% 1 CLARITY: Patient Management Clopidogrel Placebo Parameter (n=1,752) (n=1,739) Symptom onset to fibrinolytic (hours) 2.7 2.6 Fibrinolytic to study drug (minutes) 10 10 Median doses of study medication 4 4 Angiography performed (%) 94 94 Study drug to angiography (hours) 84 84 Coronary revascularization (%): 63 63 PCI 57.2 56.6 CABG 5.9 6.0 Sabatine M et al. New Engl J Med 2005; 352: 1179–1189. PCI-CLARITY: Reduction in CV Death, MI, Stroke from PCI to 30 Days Days Post PCI Percentage with Outcome (%) 0 2 0 5 10 15 20 25 30 46%* p=0.008 Clopidogrel Pretreatment (3.6%) No Pretreatment (6.2%) 4 6 8 M Sabatine, et al. JAMA 2005 PCI-CLARITY: MI, Stroke, or CV Death Events pre and post PCI ***MI or Stroke M Sabatine, et al. JAMA 2005, Prehospital Fibrinolysis with Double Antiplatelet Therapy in Acute ST-Elevation Myocardial Infarction: The Clarity Ambulance Substudy Substudy Sites and Patient Numbers France: 172 patients L Soulat: 57 Y Lambert: 48 F Lapostolle: 28 F Thieuleux: 21 C Gully: 10 D Pollet: 5 D Galley: 2 L Olliver: 1 UK: 40 patients J Adgey: 27 J Purvis: 13 Sweden: 5 patients J-E Karlsson: 5 217 patients in total Angiographic & ECG Parameters: Ambulance vs. Non-Ambulance *Complete considered to be >70%; ECG=electrocardiogram p value Event rate (%) Ambulance Non- ambulance Non-ambulance better Ambulance better Odds ratio (95% CI) 0 0.5 1.0 1.5 2.0 Ambulance Non-ambulance Overall Clopidogrel better Placebo better Odds ratio (95% CI) Primary Endpoint of TIMI Flow Grade 0/1, MI or Death 0.60 (0.301.17) 0.64 (0.530.76) 0.65 (0.540.77) ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Clopidogrel 75mg q.d. + ASA 75-325 mg q.d.* (6259 patients) Placebo + ASA 75-325 mg q.d.* (6303 patients) Day 1 6 m. Visit 9 m. Visit 12 m. or Final Visit 3 m. Visit Discharge Visit 1 m. Visit Patients with Acute Coronary Syndrome (unstable angina or non-ST-segment elevation MI) R Placebo loading dose R = Randomization * In combination with other standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Study Design 3 months £ double-blind treatment £ 12 months Clopidogrel 300 mg loading dose CURE Clopidogrel + ASA* 3 6 9 Placebo + ASA* Months of Follow-Up 11.4% 9.3% 20% RRR P < 0.001 N = 12,562 0 12 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Primary End Point - MI/Stroke/CV Death CURE Clopidogrel + ASA* 10 20 30 Placebo + ASA* Days of Follow-Up 0 21% RRR P = 0.003 N = 12,562 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. MI/Stroke/CV Death within 30 Days CURE 1 CV death, nonfatal MI, stroke or refractory or severe ischemia 34% NEJM 2001; 345:495-502 MI/Stroke/CV Death or severe Ischemia at 24 hours CURE 1 % patients requiring thrombolytic therapy 43% % patients requiring GP IIb/IIIa inhibitors 18% NEJM 2001; 345:495-502 Need for Additional Anti-Thrombotic After Randomization P< 0.001 P= 0.003 Thrombolysis GP IIb/IIIa Inhibitor CURE 1 Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? GP IIb/IIIa receptor is the final common pathway in platelet aggregation. GP IIb/IIIa blockade is the most effective antiplatelet aggregation therapy. Bleeding risk is not increased if therapy is stopped 2-4 hours prior to CABG. Bleeding risk is markedly increased unless clopidogrel is stopped 3-5 days prior to CABG. Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? Is there additional benefit to clopidogrel that would justify: Increased CABG bleeding or alternatively Need to postpone CABG for 3-5 days No data in the literature however Adhesion The Role of Platelets in Atherothrombosis Aggregation 3 Reproduced with permission from Cannon CP. Atherothrombosis slide compendium. Available at: www.theheart.org. 1 Activation 2
Slide 32 - Early And Long Term Treatment With Clopidogrel In Coronary Artery Disease פרופ’ יוסף רוזנמן מכון הלב, בי"ח וולפסון דצמבר 2005 Acute Coronary Syndromes Acute Coronary Syndrome No ST Elevation ST Elevation Unstable Angina Myocardial Infarction Non Q MI Q wave MI Non ST Elevation MI Braunwald E et al. J Am Coll Cardiol 2000;36:970–1062. Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When angiography / PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until angiography / PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month improving long-term outcome 1 2 Goals of therapy Prevent ischemic events until coronary angiography / PCI Before plaque stabilization was achieved Prevent PCI / stent related ischemic complications Clopidogrel before coronary angiography - Patients with ACS 1 Clopidogrel before coronary angiography - Patients with ACS ST Elevation CLARITY Non ST Elevation CURE 1 ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Study Design Fibrinolytic, ASA, Heparin Clopidogrel 300 mg + 75 mg qd Coronary Angiogram (2-8 days) Primary endpoint: Occluded artery (TIMI Flow Grade 0/1) or D/MI by time of angio randomize Placebo Double-blind, randomized, placebo-controlled trial in 3491 patients, age 18-75 yrs with STEMI < 12 hours Study Drug 30-day clinical follow-up Open-label clopidogrel per MD in both groups Primary Endpoint: Occluded Artery (or D/MI by time of angio) Placebo Clopidogrel P=0.00000036 Odds Ratio 0.64 (95% CI 0.53-0.76) 1.0 0.4 0.6 0.8 1.2 1.6 Clopidogrel better Placebo better n=1752 n=1739 36% Odds Reduction Primary & Angiographic Outcomes (median 3.5 days) Need for Urgent or Additional Treatment 21%  P=0.01 21%  P=0.005 16%  P=0.07 Early Angio (w/in 48 hrs) Urgent Revasc (index hosp) GP IIb/IIIa if PCI CV Death, MI, RI  Urg Revasc days Percentage with endpoint (%) 0 5 10 15 0 5 10 15 20 25 30 Placebo Clopidogrel Odds Ratio 0.80 (95% CI 0.65-0.97) P=0.026 20% 1 CLARITY: Patient Management Clopidogrel Placebo Parameter (n=1,752) (n=1,739) Symptom onset to fibrinolytic (hours) 2.7 2.6 Fibrinolytic to study drug (minutes) 10 10 Median doses of study medication 4 4 Angiography performed (%) 94 94 Study drug to angiography (hours) 84 84 Coronary revascularization (%): 63 63 PCI 57.2 56.6 CABG 5.9 6.0 Sabatine M et al. New Engl J Med 2005; 352: 1179–1189. PCI-CLARITY: Reduction in CV Death, MI, Stroke from PCI to 30 Days Days Post PCI Percentage with Outcome (%) 0 2 0 5 10 15 20 25 30 46%* p=0.008 Clopidogrel Pretreatment (3.6%) No Pretreatment (6.2%) 4 6 8 M Sabatine, et al. JAMA 2005 PCI-CLARITY: MI, Stroke, or CV Death Events pre and post PCI ***MI or Stroke M Sabatine, et al. JAMA 2005, Prehospital Fibrinolysis with Double Antiplatelet Therapy in Acute ST-Elevation Myocardial Infarction: The Clarity Ambulance Substudy Substudy Sites and Patient Numbers France: 172 patients L Soulat: 57 Y Lambert: 48 F Lapostolle: 28 F Thieuleux: 21 C Gully: 10 D Pollet: 5 D Galley: 2 L Olliver: 1 UK: 40 patients J Adgey: 27 J Purvis: 13 Sweden: 5 patients J-E Karlsson: 5 217 patients in total Angiographic & ECG Parameters: Ambulance vs. Non-Ambulance *Complete considered to be >70%; ECG=electrocardiogram p value Event rate (%) Ambulance Non- ambulance Non-ambulance better Ambulance better Odds ratio (95% CI) 0 0.5 1.0 1.5 2.0 Ambulance Non-ambulance Overall Clopidogrel better Placebo better Odds ratio (95% CI) Primary Endpoint of TIMI Flow Grade 0/1, MI or Death 0.60 (0.301.17) 0.64 (0.530.76) 0.65 (0.540.77) ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Clopidogrel 75mg q.d. + ASA 75-325 mg q.d.* (6259 patients) Placebo + ASA 75-325 mg q.d.* (6303 patients) Day 1 6 m. Visit 9 m. Visit 12 m. or Final Visit 3 m. Visit Discharge Visit 1 m. Visit Patients with Acute Coronary Syndrome (unstable angina or non-ST-segment elevation MI) R Placebo loading dose R = Randomization * In combination with other standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Study Design 3 months £ double-blind treatment £ 12 months Clopidogrel 300 mg loading dose CURE Clopidogrel + ASA* 3 6 9 Placebo + ASA* Months of Follow-Up 11.4% 9.3% 20% RRR P < 0.001 N = 12,562 0 12 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Primary End Point - MI/Stroke/CV Death CURE Clopidogrel + ASA* 10 20 30 Placebo + ASA* Days of Follow-Up 0 21% RRR P = 0.003 N = 12,562 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. MI/Stroke/CV Death within 30 Days CURE 1 CV death, nonfatal MI, stroke or refractory or severe ischemia 34% NEJM 2001; 345:495-502 MI/Stroke/CV Death or severe Ischemia at 24 hours CURE 1 % patients requiring thrombolytic therapy 43% % patients requiring GP IIb/IIIa inhibitors 18% NEJM 2001; 345:495-502 Need for Additional Anti-Thrombotic After Randomization P< 0.001 P= 0.003 Thrombolysis GP IIb/IIIa Inhibitor CURE 1 Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? GP IIb/IIIa receptor is the final common pathway in platelet aggregation. GP IIb/IIIa blockade is the most effective antiplatelet aggregation therapy. Bleeding risk is not increased if therapy is stopped 2-4 hours prior to CABG. Bleeding risk is markedly increased unless clopidogrel is stopped 3-5 days prior to CABG. Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? Is there additional benefit to clopidogrel that would justify: Increased CABG bleeding or alternatively Need to postpone CABG for 3-5 days No data in the literature however Adhesion The Role of Platelets in Atherothrombosis Aggregation 3 Reproduced with permission from Cannon CP. Atherothrombosis slide compendium. Available at: www.theheart.org. 1 Activation 2 Conclusions: Early Clopidogrel Therapy Treatment with clopidogrel is indicated as soon as possible in patients with acute coronary syndrome ST elevation and non ST elevation Treatment is effective to reduce ischemic complications Before coronay angiography During and after PCI 1
Slide 33 - Early And Long Term Treatment With Clopidogrel In Coronary Artery Disease פרופ’ יוסף רוזנמן מכון הלב, בי"ח וולפסון דצמבר 2005 Acute Coronary Syndromes Acute Coronary Syndrome No ST Elevation ST Elevation Unstable Angina Myocardial Infarction Non Q MI Q wave MI Non ST Elevation MI Braunwald E et al. J Am Coll Cardiol 2000;36:970–1062. Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When angiography / PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until angiography / PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month improving long-term outcome 1 2 Goals of therapy Prevent ischemic events until coronary angiography / PCI Before plaque stabilization was achieved Prevent PCI / stent related ischemic complications Clopidogrel before coronary angiography - Patients with ACS 1 Clopidogrel before coronary angiography - Patients with ACS ST Elevation CLARITY Non ST Elevation CURE 1 ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Study Design Fibrinolytic, ASA, Heparin Clopidogrel 300 mg + 75 mg qd Coronary Angiogram (2-8 days) Primary endpoint: Occluded artery (TIMI Flow Grade 0/1) or D/MI by time of angio randomize Placebo Double-blind, randomized, placebo-controlled trial in 3491 patients, age 18-75 yrs with STEMI < 12 hours Study Drug 30-day clinical follow-up Open-label clopidogrel per MD in both groups Primary Endpoint: Occluded Artery (or D/MI by time of angio) Placebo Clopidogrel P=0.00000036 Odds Ratio 0.64 (95% CI 0.53-0.76) 1.0 0.4 0.6 0.8 1.2 1.6 Clopidogrel better Placebo better n=1752 n=1739 36% Odds Reduction Primary & Angiographic Outcomes (median 3.5 days) Need for Urgent or Additional Treatment 21%  P=0.01 21%  P=0.005 16%  P=0.07 Early Angio (w/in 48 hrs) Urgent Revasc (index hosp) GP IIb/IIIa if PCI CV Death, MI, RI  Urg Revasc days Percentage with endpoint (%) 0 5 10 15 0 5 10 15 20 25 30 Placebo Clopidogrel Odds Ratio 0.80 (95% CI 0.65-0.97) P=0.026 20% 1 CLARITY: Patient Management Clopidogrel Placebo Parameter (n=1,752) (n=1,739) Symptom onset to fibrinolytic (hours) 2.7 2.6 Fibrinolytic to study drug (minutes) 10 10 Median doses of study medication 4 4 Angiography performed (%) 94 94 Study drug to angiography (hours) 84 84 Coronary revascularization (%): 63 63 PCI 57.2 56.6 CABG 5.9 6.0 Sabatine M et al. New Engl J Med 2005; 352: 1179–1189. PCI-CLARITY: Reduction in CV Death, MI, Stroke from PCI to 30 Days Days Post PCI Percentage with Outcome (%) 0 2 0 5 10 15 20 25 30 46%* p=0.008 Clopidogrel Pretreatment (3.6%) No Pretreatment (6.2%) 4 6 8 M Sabatine, et al. JAMA 2005 PCI-CLARITY: MI, Stroke, or CV Death Events pre and post PCI ***MI or Stroke M Sabatine, et al. JAMA 2005, Prehospital Fibrinolysis with Double Antiplatelet Therapy in Acute ST-Elevation Myocardial Infarction: The Clarity Ambulance Substudy Substudy Sites and Patient Numbers France: 172 patients L Soulat: 57 Y Lambert: 48 F Lapostolle: 28 F Thieuleux: 21 C Gully: 10 D Pollet: 5 D Galley: 2 L Olliver: 1 UK: 40 patients J Adgey: 27 J Purvis: 13 Sweden: 5 patients J-E Karlsson: 5 217 patients in total Angiographic & ECG Parameters: Ambulance vs. Non-Ambulance *Complete considered to be >70%; ECG=electrocardiogram p value Event rate (%) Ambulance Non- ambulance Non-ambulance better Ambulance better Odds ratio (95% CI) 0 0.5 1.0 1.5 2.0 Ambulance Non-ambulance Overall Clopidogrel better Placebo better Odds ratio (95% CI) Primary Endpoint of TIMI Flow Grade 0/1, MI or Death 0.60 (0.301.17) 0.64 (0.530.76) 0.65 (0.540.77) ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Clopidogrel 75mg q.d. + ASA 75-325 mg q.d.* (6259 patients) Placebo + ASA 75-325 mg q.d.* (6303 patients) Day 1 6 m. Visit 9 m. Visit 12 m. or Final Visit 3 m. Visit Discharge Visit 1 m. Visit Patients with Acute Coronary Syndrome (unstable angina or non-ST-segment elevation MI) R Placebo loading dose R = Randomization * In combination with other standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Study Design 3 months £ double-blind treatment £ 12 months Clopidogrel 300 mg loading dose CURE Clopidogrel + ASA* 3 6 9 Placebo + ASA* Months of Follow-Up 11.4% 9.3% 20% RRR P < 0.001 N = 12,562 0 12 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Primary End Point - MI/Stroke/CV Death CURE Clopidogrel + ASA* 10 20 30 Placebo + ASA* Days of Follow-Up 0 21% RRR P = 0.003 N = 12,562 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. MI/Stroke/CV Death within 30 Days CURE 1 CV death, nonfatal MI, stroke or refractory or severe ischemia 34% NEJM 2001; 345:495-502 MI/Stroke/CV Death or severe Ischemia at 24 hours CURE 1 % patients requiring thrombolytic therapy 43% % patients requiring GP IIb/IIIa inhibitors 18% NEJM 2001; 345:495-502 Need for Additional Anti-Thrombotic After Randomization P< 0.001 P= 0.003 Thrombolysis GP IIb/IIIa Inhibitor CURE 1 Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? GP IIb/IIIa receptor is the final common pathway in platelet aggregation. GP IIb/IIIa blockade is the most effective antiplatelet aggregation therapy. Bleeding risk is not increased if therapy is stopped 2-4 hours prior to CABG. Bleeding risk is markedly increased unless clopidogrel is stopped 3-5 days prior to CABG. Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? Is there additional benefit to clopidogrel that would justify: Increased CABG bleeding or alternatively Need to postpone CABG for 3-5 days No data in the literature however Adhesion The Role of Platelets in Atherothrombosis Aggregation 3 Reproduced with permission from Cannon CP. Atherothrombosis slide compendium. Available at: www.theheart.org. 1 Activation 2 Conclusions: Early Clopidogrel Therapy Treatment with clopidogrel is indicated as soon as possible in patients with acute coronary syndrome ST elevation and non ST elevation Treatment is effective to reduce ischemic complications Before coronay angiography During and after PCI 1 Conclusions: Early Clopidogrel Therapy Loading dose should be 600mg to achieve early optimal antiplatelet effect ?? 300mg in patients after fibrinolytic therapy It is unclear whether therapy should be added to “upstream” GP IIb/IIIa antagonists Especially in high risk patients in whom the likelihood for CABG is high 1
Slide 34 - Early And Long Term Treatment With Clopidogrel In Coronary Artery Disease פרופ’ יוסף רוזנמן מכון הלב, בי"ח וולפסון דצמבר 2005 Acute Coronary Syndromes Acute Coronary Syndrome No ST Elevation ST Elevation Unstable Angina Myocardial Infarction Non Q MI Q wave MI Non ST Elevation MI Braunwald E et al. J Am Coll Cardiol 2000;36:970–1062. Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When angiography / PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until angiography / PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month improving long-term outcome 1 2 Goals of therapy Prevent ischemic events until coronary angiography / PCI Before plaque stabilization was achieved Prevent PCI / stent related ischemic complications Clopidogrel before coronary angiography - Patients with ACS 1 Clopidogrel before coronary angiography - Patients with ACS ST Elevation CLARITY Non ST Elevation CURE 1 ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Study Design Fibrinolytic, ASA, Heparin Clopidogrel 300 mg + 75 mg qd Coronary Angiogram (2-8 days) Primary endpoint: Occluded artery (TIMI Flow Grade 0/1) or D/MI by time of angio randomize Placebo Double-blind, randomized, placebo-controlled trial in 3491 patients, age 18-75 yrs with STEMI < 12 hours Study Drug 30-day clinical follow-up Open-label clopidogrel per MD in both groups Primary Endpoint: Occluded Artery (or D/MI by time of angio) Placebo Clopidogrel P=0.00000036 Odds Ratio 0.64 (95% CI 0.53-0.76) 1.0 0.4 0.6 0.8 1.2 1.6 Clopidogrel better Placebo better n=1752 n=1739 36% Odds Reduction Primary & Angiographic Outcomes (median 3.5 days) Need for Urgent or Additional Treatment 21%  P=0.01 21%  P=0.005 16%  P=0.07 Early Angio (w/in 48 hrs) Urgent Revasc (index hosp) GP IIb/IIIa if PCI CV Death, MI, RI  Urg Revasc days Percentage with endpoint (%) 0 5 10 15 0 5 10 15 20 25 30 Placebo Clopidogrel Odds Ratio 0.80 (95% CI 0.65-0.97) P=0.026 20% 1 CLARITY: Patient Management Clopidogrel Placebo Parameter (n=1,752) (n=1,739) Symptom onset to fibrinolytic (hours) 2.7 2.6 Fibrinolytic to study drug (minutes) 10 10 Median doses of study medication 4 4 Angiography performed (%) 94 94 Study drug to angiography (hours) 84 84 Coronary revascularization (%): 63 63 PCI 57.2 56.6 CABG 5.9 6.0 Sabatine M et al. New Engl J Med 2005; 352: 1179–1189. PCI-CLARITY: Reduction in CV Death, MI, Stroke from PCI to 30 Days Days Post PCI Percentage with Outcome (%) 0 2 0 5 10 15 20 25 30 46%* p=0.008 Clopidogrel Pretreatment (3.6%) No Pretreatment (6.2%) 4 6 8 M Sabatine, et al. JAMA 2005 PCI-CLARITY: MI, Stroke, or CV Death Events pre and post PCI ***MI or Stroke M Sabatine, et al. JAMA 2005, Prehospital Fibrinolysis with Double Antiplatelet Therapy in Acute ST-Elevation Myocardial Infarction: The Clarity Ambulance Substudy Substudy Sites and Patient Numbers France: 172 patients L Soulat: 57 Y Lambert: 48 F Lapostolle: 28 F Thieuleux: 21 C Gully: 10 D Pollet: 5 D Galley: 2 L Olliver: 1 UK: 40 patients J Adgey: 27 J Purvis: 13 Sweden: 5 patients J-E Karlsson: 5 217 patients in total Angiographic & ECG Parameters: Ambulance vs. Non-Ambulance *Complete considered to be >70%; ECG=electrocardiogram p value Event rate (%) Ambulance Non- ambulance Non-ambulance better Ambulance better Odds ratio (95% CI) 0 0.5 1.0 1.5 2.0 Ambulance Non-ambulance Overall Clopidogrel better Placebo better Odds ratio (95% CI) Primary Endpoint of TIMI Flow Grade 0/1, MI or Death 0.60 (0.301.17) 0.64 (0.530.76) 0.65 (0.540.77) ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Clopidogrel 75mg q.d. + ASA 75-325 mg q.d.* (6259 patients) Placebo + ASA 75-325 mg q.d.* (6303 patients) Day 1 6 m. Visit 9 m. Visit 12 m. or Final Visit 3 m. Visit Discharge Visit 1 m. Visit Patients with Acute Coronary Syndrome (unstable angina or non-ST-segment elevation MI) R Placebo loading dose R = Randomization * In combination with other standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Study Design 3 months £ double-blind treatment £ 12 months Clopidogrel 300 mg loading dose CURE Clopidogrel + ASA* 3 6 9 Placebo + ASA* Months of Follow-Up 11.4% 9.3% 20% RRR P < 0.001 N = 12,562 0 12 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Primary End Point - MI/Stroke/CV Death CURE Clopidogrel + ASA* 10 20 30 Placebo + ASA* Days of Follow-Up 0 21% RRR P = 0.003 N = 12,562 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. MI/Stroke/CV Death within 30 Days CURE 1 CV death, nonfatal MI, stroke or refractory or severe ischemia 34% NEJM 2001; 345:495-502 MI/Stroke/CV Death or severe Ischemia at 24 hours CURE 1 % patients requiring thrombolytic therapy 43% % patients requiring GP IIb/IIIa inhibitors 18% NEJM 2001; 345:495-502 Need for Additional Anti-Thrombotic After Randomization P< 0.001 P= 0.003 Thrombolysis GP IIb/IIIa Inhibitor CURE 1 Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? GP IIb/IIIa receptor is the final common pathway in platelet aggregation. GP IIb/IIIa blockade is the most effective antiplatelet aggregation therapy. Bleeding risk is not increased if therapy is stopped 2-4 hours prior to CABG. Bleeding risk is markedly increased unless clopidogrel is stopped 3-5 days prior to CABG. Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? Is there additional benefit to clopidogrel that would justify: Increased CABG bleeding or alternatively Need to postpone CABG for 3-5 days No data in the literature however Adhesion The Role of Platelets in Atherothrombosis Aggregation 3 Reproduced with permission from Cannon CP. Atherothrombosis slide compendium. Available at: www.theheart.org. 1 Activation 2 Conclusions: Early Clopidogrel Therapy Treatment with clopidogrel is indicated as soon as possible in patients with acute coronary syndrome ST elevation and non ST elevation Treatment is effective to reduce ischemic complications Before coronay angiography During and after PCI 1 Conclusions: Early Clopidogrel Therapy Loading dose should be 600mg to achieve early optimal antiplatelet effect ?? 300mg in patients after fibrinolytic therapy It is unclear whether therapy should be added to “upstream” GP IIb/IIIa antagonists Especially in high risk patients in whom the likelihood for CABG is high 1 Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term)
Slide 35 - Early And Long Term Treatment With Clopidogrel In Coronary Artery Disease פרופ’ יוסף רוזנמן מכון הלב, בי"ח וולפסון דצמבר 2005 Acute Coronary Syndromes Acute Coronary Syndrome No ST Elevation ST Elevation Unstable Angina Myocardial Infarction Non Q MI Q wave MI Non ST Elevation MI Braunwald E et al. J Am Coll Cardiol 2000;36:970–1062. Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When angiography / PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until angiography / PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month improving long-term outcome 1 2 Goals of therapy Prevent ischemic events until coronary angiography / PCI Before plaque stabilization was achieved Prevent PCI / stent related ischemic complications Clopidogrel before coronary angiography - Patients with ACS 1 Clopidogrel before coronary angiography - Patients with ACS ST Elevation CLARITY Non ST Elevation CURE 1 ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Study Design Fibrinolytic, ASA, Heparin Clopidogrel 300 mg + 75 mg qd Coronary Angiogram (2-8 days) Primary endpoint: Occluded artery (TIMI Flow Grade 0/1) or D/MI by time of angio randomize Placebo Double-blind, randomized, placebo-controlled trial in 3491 patients, age 18-75 yrs with STEMI < 12 hours Study Drug 30-day clinical follow-up Open-label clopidogrel per MD in both groups Primary Endpoint: Occluded Artery (or D/MI by time of angio) Placebo Clopidogrel P=0.00000036 Odds Ratio 0.64 (95% CI 0.53-0.76) 1.0 0.4 0.6 0.8 1.2 1.6 Clopidogrel better Placebo better n=1752 n=1739 36% Odds Reduction Primary & Angiographic Outcomes (median 3.5 days) Need for Urgent or Additional Treatment 21%  P=0.01 21%  P=0.005 16%  P=0.07 Early Angio (w/in 48 hrs) Urgent Revasc (index hosp) GP IIb/IIIa if PCI CV Death, MI, RI  Urg Revasc days Percentage with endpoint (%) 0 5 10 15 0 5 10 15 20 25 30 Placebo Clopidogrel Odds Ratio 0.80 (95% CI 0.65-0.97) P=0.026 20% 1 CLARITY: Patient Management Clopidogrel Placebo Parameter (n=1,752) (n=1,739) Symptom onset to fibrinolytic (hours) 2.7 2.6 Fibrinolytic to study drug (minutes) 10 10 Median doses of study medication 4 4 Angiography performed (%) 94 94 Study drug to angiography (hours) 84 84 Coronary revascularization (%): 63 63 PCI 57.2 56.6 CABG 5.9 6.0 Sabatine M et al. New Engl J Med 2005; 352: 1179–1189. PCI-CLARITY: Reduction in CV Death, MI, Stroke from PCI to 30 Days Days Post PCI Percentage with Outcome (%) 0 2 0 5 10 15 20 25 30 46%* p=0.008 Clopidogrel Pretreatment (3.6%) No Pretreatment (6.2%) 4 6 8 M Sabatine, et al. JAMA 2005 PCI-CLARITY: MI, Stroke, or CV Death Events pre and post PCI ***MI or Stroke M Sabatine, et al. JAMA 2005, Prehospital Fibrinolysis with Double Antiplatelet Therapy in Acute ST-Elevation Myocardial Infarction: The Clarity Ambulance Substudy Substudy Sites and Patient Numbers France: 172 patients L Soulat: 57 Y Lambert: 48 F Lapostolle: 28 F Thieuleux: 21 C Gully: 10 D Pollet: 5 D Galley: 2 L Olliver: 1 UK: 40 patients J Adgey: 27 J Purvis: 13 Sweden: 5 patients J-E Karlsson: 5 217 patients in total Angiographic & ECG Parameters: Ambulance vs. Non-Ambulance *Complete considered to be >70%; ECG=electrocardiogram p value Event rate (%) Ambulance Non- ambulance Non-ambulance better Ambulance better Odds ratio (95% CI) 0 0.5 1.0 1.5 2.0 Ambulance Non-ambulance Overall Clopidogrel better Placebo better Odds ratio (95% CI) Primary Endpoint of TIMI Flow Grade 0/1, MI or Death 0.60 (0.301.17) 0.64 (0.530.76) 0.65 (0.540.77) ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Clopidogrel 75mg q.d. + ASA 75-325 mg q.d.* (6259 patients) Placebo + ASA 75-325 mg q.d.* (6303 patients) Day 1 6 m. Visit 9 m. Visit 12 m. or Final Visit 3 m. Visit Discharge Visit 1 m. Visit Patients with Acute Coronary Syndrome (unstable angina or non-ST-segment elevation MI) R Placebo loading dose R = Randomization * In combination with other standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Study Design 3 months £ double-blind treatment £ 12 months Clopidogrel 300 mg loading dose CURE Clopidogrel + ASA* 3 6 9 Placebo + ASA* Months of Follow-Up 11.4% 9.3% 20% RRR P < 0.001 N = 12,562 0 12 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Primary End Point - MI/Stroke/CV Death CURE Clopidogrel + ASA* 10 20 30 Placebo + ASA* Days of Follow-Up 0 21% RRR P = 0.003 N = 12,562 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. MI/Stroke/CV Death within 30 Days CURE 1 CV death, nonfatal MI, stroke or refractory or severe ischemia 34% NEJM 2001; 345:495-502 MI/Stroke/CV Death or severe Ischemia at 24 hours CURE 1 % patients requiring thrombolytic therapy 43% % patients requiring GP IIb/IIIa inhibitors 18% NEJM 2001; 345:495-502 Need for Additional Anti-Thrombotic After Randomization P< 0.001 P= 0.003 Thrombolysis GP IIb/IIIa Inhibitor CURE 1 Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? GP IIb/IIIa receptor is the final common pathway in platelet aggregation. GP IIb/IIIa blockade is the most effective antiplatelet aggregation therapy. Bleeding risk is not increased if therapy is stopped 2-4 hours prior to CABG. Bleeding risk is markedly increased unless clopidogrel is stopped 3-5 days prior to CABG. Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? Is there additional benefit to clopidogrel that would justify: Increased CABG bleeding or alternatively Need to postpone CABG for 3-5 days No data in the literature however Adhesion The Role of Platelets in Atherothrombosis Aggregation 3 Reproduced with permission from Cannon CP. Atherothrombosis slide compendium. Available at: www.theheart.org. 1 Activation 2 Conclusions: Early Clopidogrel Therapy Treatment with clopidogrel is indicated as soon as possible in patients with acute coronary syndrome ST elevation and non ST elevation Treatment is effective to reduce ischemic complications Before coronay angiography During and after PCI 1 Conclusions: Early Clopidogrel Therapy Loading dose should be 600mg to achieve early optimal antiplatelet effect ?? 300mg in patients after fibrinolytic therapy It is unclear whether therapy should be added to “upstream” GP IIb/IIIa antagonists Especially in high risk patients in whom the likelihood for CABG is high 1 Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month after PCI / stent improving long-term outcome 1 2
Slide 36 - Early And Long Term Treatment With Clopidogrel In Coronary Artery Disease פרופ’ יוסף רוזנמן מכון הלב, בי"ח וולפסון דצמבר 2005 Acute Coronary Syndromes Acute Coronary Syndrome No ST Elevation ST Elevation Unstable Angina Myocardial Infarction Non Q MI Q wave MI Non ST Elevation MI Braunwald E et al. J Am Coll Cardiol 2000;36:970–1062. Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When angiography / PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until angiography / PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month improving long-term outcome 1 2 Goals of therapy Prevent ischemic events until coronary angiography / PCI Before plaque stabilization was achieved Prevent PCI / stent related ischemic complications Clopidogrel before coronary angiography - Patients with ACS 1 Clopidogrel before coronary angiography - Patients with ACS ST Elevation CLARITY Non ST Elevation CURE 1 ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Study Design Fibrinolytic, ASA, Heparin Clopidogrel 300 mg + 75 mg qd Coronary Angiogram (2-8 days) Primary endpoint: Occluded artery (TIMI Flow Grade 0/1) or D/MI by time of angio randomize Placebo Double-blind, randomized, placebo-controlled trial in 3491 patients, age 18-75 yrs with STEMI < 12 hours Study Drug 30-day clinical follow-up Open-label clopidogrel per MD in both groups Primary Endpoint: Occluded Artery (or D/MI by time of angio) Placebo Clopidogrel P=0.00000036 Odds Ratio 0.64 (95% CI 0.53-0.76) 1.0 0.4 0.6 0.8 1.2 1.6 Clopidogrel better Placebo better n=1752 n=1739 36% Odds Reduction Primary & Angiographic Outcomes (median 3.5 days) Need for Urgent or Additional Treatment 21%  P=0.01 21%  P=0.005 16%  P=0.07 Early Angio (w/in 48 hrs) Urgent Revasc (index hosp) GP IIb/IIIa if PCI CV Death, MI, RI  Urg Revasc days Percentage with endpoint (%) 0 5 10 15 0 5 10 15 20 25 30 Placebo Clopidogrel Odds Ratio 0.80 (95% CI 0.65-0.97) P=0.026 20% 1 CLARITY: Patient Management Clopidogrel Placebo Parameter (n=1,752) (n=1,739) Symptom onset to fibrinolytic (hours) 2.7 2.6 Fibrinolytic to study drug (minutes) 10 10 Median doses of study medication 4 4 Angiography performed (%) 94 94 Study drug to angiography (hours) 84 84 Coronary revascularization (%): 63 63 PCI 57.2 56.6 CABG 5.9 6.0 Sabatine M et al. New Engl J Med 2005; 352: 1179–1189. PCI-CLARITY: Reduction in CV Death, MI, Stroke from PCI to 30 Days Days Post PCI Percentage with Outcome (%) 0 2 0 5 10 15 20 25 30 46%* p=0.008 Clopidogrel Pretreatment (3.6%) No Pretreatment (6.2%) 4 6 8 M Sabatine, et al. JAMA 2005 PCI-CLARITY: MI, Stroke, or CV Death Events pre and post PCI ***MI or Stroke M Sabatine, et al. JAMA 2005, Prehospital Fibrinolysis with Double Antiplatelet Therapy in Acute ST-Elevation Myocardial Infarction: The Clarity Ambulance Substudy Substudy Sites and Patient Numbers France: 172 patients L Soulat: 57 Y Lambert: 48 F Lapostolle: 28 F Thieuleux: 21 C Gully: 10 D Pollet: 5 D Galley: 2 L Olliver: 1 UK: 40 patients J Adgey: 27 J Purvis: 13 Sweden: 5 patients J-E Karlsson: 5 217 patients in total Angiographic & ECG Parameters: Ambulance vs. Non-Ambulance *Complete considered to be >70%; ECG=electrocardiogram p value Event rate (%) Ambulance Non- ambulance Non-ambulance better Ambulance better Odds ratio (95% CI) 0 0.5 1.0 1.5 2.0 Ambulance Non-ambulance Overall Clopidogrel better Placebo better Odds ratio (95% CI) Primary Endpoint of TIMI Flow Grade 0/1, MI or Death 0.60 (0.301.17) 0.64 (0.530.76) 0.65 (0.540.77) ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Clopidogrel 75mg q.d. + ASA 75-325 mg q.d.* (6259 patients) Placebo + ASA 75-325 mg q.d.* (6303 patients) Day 1 6 m. Visit 9 m. Visit 12 m. or Final Visit 3 m. Visit Discharge Visit 1 m. Visit Patients with Acute Coronary Syndrome (unstable angina or non-ST-segment elevation MI) R Placebo loading dose R = Randomization * In combination with other standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Study Design 3 months £ double-blind treatment £ 12 months Clopidogrel 300 mg loading dose CURE Clopidogrel + ASA* 3 6 9 Placebo + ASA* Months of Follow-Up 11.4% 9.3% 20% RRR P < 0.001 N = 12,562 0 12 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Primary End Point - MI/Stroke/CV Death CURE Clopidogrel + ASA* 10 20 30 Placebo + ASA* Days of Follow-Up 0 21% RRR P = 0.003 N = 12,562 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. MI/Stroke/CV Death within 30 Days CURE 1 CV death, nonfatal MI, stroke or refractory or severe ischemia 34% NEJM 2001; 345:495-502 MI/Stroke/CV Death or severe Ischemia at 24 hours CURE 1 % patients requiring thrombolytic therapy 43% % patients requiring GP IIb/IIIa inhibitors 18% NEJM 2001; 345:495-502 Need for Additional Anti-Thrombotic After Randomization P< 0.001 P= 0.003 Thrombolysis GP IIb/IIIa Inhibitor CURE 1 Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? GP IIb/IIIa receptor is the final common pathway in platelet aggregation. GP IIb/IIIa blockade is the most effective antiplatelet aggregation therapy. Bleeding risk is not increased if therapy is stopped 2-4 hours prior to CABG. Bleeding risk is markedly increased unless clopidogrel is stopped 3-5 days prior to CABG. Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? Is there additional benefit to clopidogrel that would justify: Increased CABG bleeding or alternatively Need to postpone CABG for 3-5 days No data in the literature however Adhesion The Role of Platelets in Atherothrombosis Aggregation 3 Reproduced with permission from Cannon CP. Atherothrombosis slide compendium. Available at: www.theheart.org. 1 Activation 2 Conclusions: Early Clopidogrel Therapy Treatment with clopidogrel is indicated as soon as possible in patients with acute coronary syndrome ST elevation and non ST elevation Treatment is effective to reduce ischemic complications Before coronay angiography During and after PCI 1 Conclusions: Early Clopidogrel Therapy Loading dose should be 600mg to achieve early optimal antiplatelet effect ?? 300mg in patients after fibrinolytic therapy It is unclear whether therapy should be added to “upstream” GP IIb/IIIa antagonists Especially in high risk patients in whom the likelihood for CABG is high 1 Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month after PCI / stent improving long-term outcome 1 2 Discharge/Post-Discharge Medications - Guidelines ASA, if not contraindicated Clopidogrel, when ASA contraindicated Aspirin + Clopidogrel for up to 9 months -blocker, if not contraindicated Lipid  agents + diet, if LDL >130 mg/dL ACE Inhibitor: CHF, EF < 40%, DM, or HTN I IIa IIb III 2
Slide 37 - Early And Long Term Treatment With Clopidogrel In Coronary Artery Disease פרופ’ יוסף רוזנמן מכון הלב, בי"ח וולפסון דצמבר 2005 Acute Coronary Syndromes Acute Coronary Syndrome No ST Elevation ST Elevation Unstable Angina Myocardial Infarction Non Q MI Q wave MI Non ST Elevation MI Braunwald E et al. J Am Coll Cardiol 2000;36:970–1062. Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When angiography / PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until angiography / PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month improving long-term outcome 1 2 Goals of therapy Prevent ischemic events until coronary angiography / PCI Before plaque stabilization was achieved Prevent PCI / stent related ischemic complications Clopidogrel before coronary angiography - Patients with ACS 1 Clopidogrel before coronary angiography - Patients with ACS ST Elevation CLARITY Non ST Elevation CURE 1 ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Study Design Fibrinolytic, ASA, Heparin Clopidogrel 300 mg + 75 mg qd Coronary Angiogram (2-8 days) Primary endpoint: Occluded artery (TIMI Flow Grade 0/1) or D/MI by time of angio randomize Placebo Double-blind, randomized, placebo-controlled trial in 3491 patients, age 18-75 yrs with STEMI < 12 hours Study Drug 30-day clinical follow-up Open-label clopidogrel per MD in both groups Primary Endpoint: Occluded Artery (or D/MI by time of angio) Placebo Clopidogrel P=0.00000036 Odds Ratio 0.64 (95% CI 0.53-0.76) 1.0 0.4 0.6 0.8 1.2 1.6 Clopidogrel better Placebo better n=1752 n=1739 36% Odds Reduction Primary & Angiographic Outcomes (median 3.5 days) Need for Urgent or Additional Treatment 21%  P=0.01 21%  P=0.005 16%  P=0.07 Early Angio (w/in 48 hrs) Urgent Revasc (index hosp) GP IIb/IIIa if PCI CV Death, MI, RI  Urg Revasc days Percentage with endpoint (%) 0 5 10 15 0 5 10 15 20 25 30 Placebo Clopidogrel Odds Ratio 0.80 (95% CI 0.65-0.97) P=0.026 20% 1 CLARITY: Patient Management Clopidogrel Placebo Parameter (n=1,752) (n=1,739) Symptom onset to fibrinolytic (hours) 2.7 2.6 Fibrinolytic to study drug (minutes) 10 10 Median doses of study medication 4 4 Angiography performed (%) 94 94 Study drug to angiography (hours) 84 84 Coronary revascularization (%): 63 63 PCI 57.2 56.6 CABG 5.9 6.0 Sabatine M et al. New Engl J Med 2005; 352: 1179–1189. PCI-CLARITY: Reduction in CV Death, MI, Stroke from PCI to 30 Days Days Post PCI Percentage with Outcome (%) 0 2 0 5 10 15 20 25 30 46%* p=0.008 Clopidogrel Pretreatment (3.6%) No Pretreatment (6.2%) 4 6 8 M Sabatine, et al. JAMA 2005 PCI-CLARITY: MI, Stroke, or CV Death Events pre and post PCI ***MI or Stroke M Sabatine, et al. JAMA 2005, Prehospital Fibrinolysis with Double Antiplatelet Therapy in Acute ST-Elevation Myocardial Infarction: The Clarity Ambulance Substudy Substudy Sites and Patient Numbers France: 172 patients L Soulat: 57 Y Lambert: 48 F Lapostolle: 28 F Thieuleux: 21 C Gully: 10 D Pollet: 5 D Galley: 2 L Olliver: 1 UK: 40 patients J Adgey: 27 J Purvis: 13 Sweden: 5 patients J-E Karlsson: 5 217 patients in total Angiographic & ECG Parameters: Ambulance vs. Non-Ambulance *Complete considered to be >70%; ECG=electrocardiogram p value Event rate (%) Ambulance Non- ambulance Non-ambulance better Ambulance better Odds ratio (95% CI) 0 0.5 1.0 1.5 2.0 Ambulance Non-ambulance Overall Clopidogrel better Placebo better Odds ratio (95% CI) Primary Endpoint of TIMI Flow Grade 0/1, MI or Death 0.60 (0.301.17) 0.64 (0.530.76) 0.65 (0.540.77) ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Clopidogrel 75mg q.d. + ASA 75-325 mg q.d.* (6259 patients) Placebo + ASA 75-325 mg q.d.* (6303 patients) Day 1 6 m. Visit 9 m. Visit 12 m. or Final Visit 3 m. Visit Discharge Visit 1 m. Visit Patients with Acute Coronary Syndrome (unstable angina or non-ST-segment elevation MI) R Placebo loading dose R = Randomization * In combination with other standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Study Design 3 months £ double-blind treatment £ 12 months Clopidogrel 300 mg loading dose CURE Clopidogrel + ASA* 3 6 9 Placebo + ASA* Months of Follow-Up 11.4% 9.3% 20% RRR P < 0.001 N = 12,562 0 12 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Primary End Point - MI/Stroke/CV Death CURE Clopidogrel + ASA* 10 20 30 Placebo + ASA* Days of Follow-Up 0 21% RRR P = 0.003 N = 12,562 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. MI/Stroke/CV Death within 30 Days CURE 1 CV death, nonfatal MI, stroke or refractory or severe ischemia 34% NEJM 2001; 345:495-502 MI/Stroke/CV Death or severe Ischemia at 24 hours CURE 1 % patients requiring thrombolytic therapy 43% % patients requiring GP IIb/IIIa inhibitors 18% NEJM 2001; 345:495-502 Need for Additional Anti-Thrombotic After Randomization P< 0.001 P= 0.003 Thrombolysis GP IIb/IIIa Inhibitor CURE 1 Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? GP IIb/IIIa receptor is the final common pathway in platelet aggregation. GP IIb/IIIa blockade is the most effective antiplatelet aggregation therapy. Bleeding risk is not increased if therapy is stopped 2-4 hours prior to CABG. Bleeding risk is markedly increased unless clopidogrel is stopped 3-5 days prior to CABG. Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? Is there additional benefit to clopidogrel that would justify: Increased CABG bleeding or alternatively Need to postpone CABG for 3-5 days No data in the literature however Adhesion The Role of Platelets in Atherothrombosis Aggregation 3 Reproduced with permission from Cannon CP. Atherothrombosis slide compendium. Available at: www.theheart.org. 1 Activation 2 Conclusions: Early Clopidogrel Therapy Treatment with clopidogrel is indicated as soon as possible in patients with acute coronary syndrome ST elevation and non ST elevation Treatment is effective to reduce ischemic complications Before coronay angiography During and after PCI 1 Conclusions: Early Clopidogrel Therapy Loading dose should be 600mg to achieve early optimal antiplatelet effect ?? 300mg in patients after fibrinolytic therapy It is unclear whether therapy should be added to “upstream” GP IIb/IIIa antagonists Especially in high risk patients in whom the likelihood for CABG is high 1 Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month after PCI / stent improving long-term outcome 1 2 Discharge/Post-Discharge Medications - Guidelines ASA, if not contraindicated Clopidogrel, when ASA contraindicated Aspirin + Clopidogrel for up to 9 months -blocker, if not contraindicated Lipid  agents + diet, if LDL >130 mg/dL ACE Inhibitor: CHF, EF < 40%, DM, or HTN I IIa IIb III 2 Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization
Slide 38 - Early And Long Term Treatment With Clopidogrel In Coronary Artery Disease פרופ’ יוסף רוזנמן מכון הלב, בי"ח וולפסון דצמבר 2005 Acute Coronary Syndromes Acute Coronary Syndrome No ST Elevation ST Elevation Unstable Angina Myocardial Infarction Non Q MI Q wave MI Non ST Elevation MI Braunwald E et al. J Am Coll Cardiol 2000;36:970–1062. Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When angiography / PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until angiography / PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month improving long-term outcome 1 2 Goals of therapy Prevent ischemic events until coronary angiography / PCI Before plaque stabilization was achieved Prevent PCI / stent related ischemic complications Clopidogrel before coronary angiography - Patients with ACS 1 Clopidogrel before coronary angiography - Patients with ACS ST Elevation CLARITY Non ST Elevation CURE 1 ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Study Design Fibrinolytic, ASA, Heparin Clopidogrel 300 mg + 75 mg qd Coronary Angiogram (2-8 days) Primary endpoint: Occluded artery (TIMI Flow Grade 0/1) or D/MI by time of angio randomize Placebo Double-blind, randomized, placebo-controlled trial in 3491 patients, age 18-75 yrs with STEMI < 12 hours Study Drug 30-day clinical follow-up Open-label clopidogrel per MD in both groups Primary Endpoint: Occluded Artery (or D/MI by time of angio) Placebo Clopidogrel P=0.00000036 Odds Ratio 0.64 (95% CI 0.53-0.76) 1.0 0.4 0.6 0.8 1.2 1.6 Clopidogrel better Placebo better n=1752 n=1739 36% Odds Reduction Primary & Angiographic Outcomes (median 3.5 days) Need for Urgent or Additional Treatment 21%  P=0.01 21%  P=0.005 16%  P=0.07 Early Angio (w/in 48 hrs) Urgent Revasc (index hosp) GP IIb/IIIa if PCI CV Death, MI, RI  Urg Revasc days Percentage with endpoint (%) 0 5 10 15 0 5 10 15 20 25 30 Placebo Clopidogrel Odds Ratio 0.80 (95% CI 0.65-0.97) P=0.026 20% 1 CLARITY: Patient Management Clopidogrel Placebo Parameter (n=1,752) (n=1,739) Symptom onset to fibrinolytic (hours) 2.7 2.6 Fibrinolytic to study drug (minutes) 10 10 Median doses of study medication 4 4 Angiography performed (%) 94 94 Study drug to angiography (hours) 84 84 Coronary revascularization (%): 63 63 PCI 57.2 56.6 CABG 5.9 6.0 Sabatine M et al. New Engl J Med 2005; 352: 1179–1189. PCI-CLARITY: Reduction in CV Death, MI, Stroke from PCI to 30 Days Days Post PCI Percentage with Outcome (%) 0 2 0 5 10 15 20 25 30 46%* p=0.008 Clopidogrel Pretreatment (3.6%) No Pretreatment (6.2%) 4 6 8 M Sabatine, et al. JAMA 2005 PCI-CLARITY: MI, Stroke, or CV Death Events pre and post PCI ***MI or Stroke M Sabatine, et al. JAMA 2005, Prehospital Fibrinolysis with Double Antiplatelet Therapy in Acute ST-Elevation Myocardial Infarction: The Clarity Ambulance Substudy Substudy Sites and Patient Numbers France: 172 patients L Soulat: 57 Y Lambert: 48 F Lapostolle: 28 F Thieuleux: 21 C Gully: 10 D Pollet: 5 D Galley: 2 L Olliver: 1 UK: 40 patients J Adgey: 27 J Purvis: 13 Sweden: 5 patients J-E Karlsson: 5 217 patients in total Angiographic & ECG Parameters: Ambulance vs. Non-Ambulance *Complete considered to be >70%; ECG=electrocardiogram p value Event rate (%) Ambulance Non- ambulance Non-ambulance better Ambulance better Odds ratio (95% CI) 0 0.5 1.0 1.5 2.0 Ambulance Non-ambulance Overall Clopidogrel better Placebo better Odds ratio (95% CI) Primary Endpoint of TIMI Flow Grade 0/1, MI or Death 0.60 (0.301.17) 0.64 (0.530.76) 0.65 (0.540.77) ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Clopidogrel 75mg q.d. + ASA 75-325 mg q.d.* (6259 patients) Placebo + ASA 75-325 mg q.d.* (6303 patients) Day 1 6 m. Visit 9 m. Visit 12 m. or Final Visit 3 m. Visit Discharge Visit 1 m. Visit Patients with Acute Coronary Syndrome (unstable angina or non-ST-segment elevation MI) R Placebo loading dose R = Randomization * In combination with other standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Study Design 3 months £ double-blind treatment £ 12 months Clopidogrel 300 mg loading dose CURE Clopidogrel + ASA* 3 6 9 Placebo + ASA* Months of Follow-Up 11.4% 9.3% 20% RRR P < 0.001 N = 12,562 0 12 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Primary End Point - MI/Stroke/CV Death CURE Clopidogrel + ASA* 10 20 30 Placebo + ASA* Days of Follow-Up 0 21% RRR P = 0.003 N = 12,562 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. MI/Stroke/CV Death within 30 Days CURE 1 CV death, nonfatal MI, stroke or refractory or severe ischemia 34% NEJM 2001; 345:495-502 MI/Stroke/CV Death or severe Ischemia at 24 hours CURE 1 % patients requiring thrombolytic therapy 43% % patients requiring GP IIb/IIIa inhibitors 18% NEJM 2001; 345:495-502 Need for Additional Anti-Thrombotic After Randomization P< 0.001 P= 0.003 Thrombolysis GP IIb/IIIa Inhibitor CURE 1 Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? GP IIb/IIIa receptor is the final common pathway in platelet aggregation. GP IIb/IIIa blockade is the most effective antiplatelet aggregation therapy. Bleeding risk is not increased if therapy is stopped 2-4 hours prior to CABG. Bleeding risk is markedly increased unless clopidogrel is stopped 3-5 days prior to CABG. Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? Is there additional benefit to clopidogrel that would justify: Increased CABG bleeding or alternatively Need to postpone CABG for 3-5 days No data in the literature however Adhesion The Role of Platelets in Atherothrombosis Aggregation 3 Reproduced with permission from Cannon CP. Atherothrombosis slide compendium. Available at: www.theheart.org. 1 Activation 2 Conclusions: Early Clopidogrel Therapy Treatment with clopidogrel is indicated as soon as possible in patients with acute coronary syndrome ST elevation and non ST elevation Treatment is effective to reduce ischemic complications Before coronay angiography During and after PCI 1 Conclusions: Early Clopidogrel Therapy Loading dose should be 600mg to achieve early optimal antiplatelet effect ?? 300mg in patients after fibrinolytic therapy It is unclear whether therapy should be added to “upstream” GP IIb/IIIa antagonists Especially in high risk patients in whom the likelihood for CABG is high 1 Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month after PCI / stent improving long-term outcome 1 2 Discharge/Post-Discharge Medications - Guidelines ASA, if not contraindicated Clopidogrel, when ASA contraindicated Aspirin + Clopidogrel for up to 9 months -blocker, if not contraindicated Lipid  agents + diet, if LDL >130 mg/dL ACE Inhibitor: CHF, EF < 40%, DM, or HTN I IIa IIb III 2 Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization PCI PLACEBO + ASA * CLOPIDOGREL + ASA * 30 days post PCI End of follow-up Up to 12 months after randomization Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 2,658 patients undergoing PCI N = 1345 N = 1313 PCI-CURE Overall Study Design: PCI-CURE R Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE Question 1 Question 2
Slide 39 - Early And Long Term Treatment With Clopidogrel In Coronary Artery Disease פרופ’ יוסף רוזנמן מכון הלב, בי"ח וולפסון דצמבר 2005 Acute Coronary Syndromes Acute Coronary Syndrome No ST Elevation ST Elevation Unstable Angina Myocardial Infarction Non Q MI Q wave MI Non ST Elevation MI Braunwald E et al. J Am Coll Cardiol 2000;36:970–1062. Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When angiography / PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until angiography / PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month improving long-term outcome 1 2 Goals of therapy Prevent ischemic events until coronary angiography / PCI Before plaque stabilization was achieved Prevent PCI / stent related ischemic complications Clopidogrel before coronary angiography - Patients with ACS 1 Clopidogrel before coronary angiography - Patients with ACS ST Elevation CLARITY Non ST Elevation CURE 1 ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Study Design Fibrinolytic, ASA, Heparin Clopidogrel 300 mg + 75 mg qd Coronary Angiogram (2-8 days) Primary endpoint: Occluded artery (TIMI Flow Grade 0/1) or D/MI by time of angio randomize Placebo Double-blind, randomized, placebo-controlled trial in 3491 patients, age 18-75 yrs with STEMI < 12 hours Study Drug 30-day clinical follow-up Open-label clopidogrel per MD in both groups Primary Endpoint: Occluded Artery (or D/MI by time of angio) Placebo Clopidogrel P=0.00000036 Odds Ratio 0.64 (95% CI 0.53-0.76) 1.0 0.4 0.6 0.8 1.2 1.6 Clopidogrel better Placebo better n=1752 n=1739 36% Odds Reduction Primary & Angiographic Outcomes (median 3.5 days) Need for Urgent or Additional Treatment 21%  P=0.01 21%  P=0.005 16%  P=0.07 Early Angio (w/in 48 hrs) Urgent Revasc (index hosp) GP IIb/IIIa if PCI CV Death, MI, RI  Urg Revasc days Percentage with endpoint (%) 0 5 10 15 0 5 10 15 20 25 30 Placebo Clopidogrel Odds Ratio 0.80 (95% CI 0.65-0.97) P=0.026 20% 1 CLARITY: Patient Management Clopidogrel Placebo Parameter (n=1,752) (n=1,739) Symptom onset to fibrinolytic (hours) 2.7 2.6 Fibrinolytic to study drug (minutes) 10 10 Median doses of study medication 4 4 Angiography performed (%) 94 94 Study drug to angiography (hours) 84 84 Coronary revascularization (%): 63 63 PCI 57.2 56.6 CABG 5.9 6.0 Sabatine M et al. New Engl J Med 2005; 352: 1179–1189. PCI-CLARITY: Reduction in CV Death, MI, Stroke from PCI to 30 Days Days Post PCI Percentage with Outcome (%) 0 2 0 5 10 15 20 25 30 46%* p=0.008 Clopidogrel Pretreatment (3.6%) No Pretreatment (6.2%) 4 6 8 M Sabatine, et al. JAMA 2005 PCI-CLARITY: MI, Stroke, or CV Death Events pre and post PCI ***MI or Stroke M Sabatine, et al. JAMA 2005, Prehospital Fibrinolysis with Double Antiplatelet Therapy in Acute ST-Elevation Myocardial Infarction: The Clarity Ambulance Substudy Substudy Sites and Patient Numbers France: 172 patients L Soulat: 57 Y Lambert: 48 F Lapostolle: 28 F Thieuleux: 21 C Gully: 10 D Pollet: 5 D Galley: 2 L Olliver: 1 UK: 40 patients J Adgey: 27 J Purvis: 13 Sweden: 5 patients J-E Karlsson: 5 217 patients in total Angiographic & ECG Parameters: Ambulance vs. Non-Ambulance *Complete considered to be >70%; ECG=electrocardiogram p value Event rate (%) Ambulance Non- ambulance Non-ambulance better Ambulance better Odds ratio (95% CI) 0 0.5 1.0 1.5 2.0 Ambulance Non-ambulance Overall Clopidogrel better Placebo better Odds ratio (95% CI) Primary Endpoint of TIMI Flow Grade 0/1, MI or Death 0.60 (0.301.17) 0.64 (0.530.76) 0.65 (0.540.77) ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Clopidogrel 75mg q.d. + ASA 75-325 mg q.d.* (6259 patients) Placebo + ASA 75-325 mg q.d.* (6303 patients) Day 1 6 m. Visit 9 m. Visit 12 m. or Final Visit 3 m. Visit Discharge Visit 1 m. Visit Patients with Acute Coronary Syndrome (unstable angina or non-ST-segment elevation MI) R Placebo loading dose R = Randomization * In combination with other standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Study Design 3 months £ double-blind treatment £ 12 months Clopidogrel 300 mg loading dose CURE Clopidogrel + ASA* 3 6 9 Placebo + ASA* Months of Follow-Up 11.4% 9.3% 20% RRR P < 0.001 N = 12,562 0 12 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Primary End Point - MI/Stroke/CV Death CURE Clopidogrel + ASA* 10 20 30 Placebo + ASA* Days of Follow-Up 0 21% RRR P = 0.003 N = 12,562 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. MI/Stroke/CV Death within 30 Days CURE 1 CV death, nonfatal MI, stroke or refractory or severe ischemia 34% NEJM 2001; 345:495-502 MI/Stroke/CV Death or severe Ischemia at 24 hours CURE 1 % patients requiring thrombolytic therapy 43% % patients requiring GP IIb/IIIa inhibitors 18% NEJM 2001; 345:495-502 Need for Additional Anti-Thrombotic After Randomization P< 0.001 P= 0.003 Thrombolysis GP IIb/IIIa Inhibitor CURE 1 Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? GP IIb/IIIa receptor is the final common pathway in platelet aggregation. GP IIb/IIIa blockade is the most effective antiplatelet aggregation therapy. Bleeding risk is not increased if therapy is stopped 2-4 hours prior to CABG. Bleeding risk is markedly increased unless clopidogrel is stopped 3-5 days prior to CABG. Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? Is there additional benefit to clopidogrel that would justify: Increased CABG bleeding or alternatively Need to postpone CABG for 3-5 days No data in the literature however Adhesion The Role of Platelets in Atherothrombosis Aggregation 3 Reproduced with permission from Cannon CP. Atherothrombosis slide compendium. Available at: www.theheart.org. 1 Activation 2 Conclusions: Early Clopidogrel Therapy Treatment with clopidogrel is indicated as soon as possible in patients with acute coronary syndrome ST elevation and non ST elevation Treatment is effective to reduce ischemic complications Before coronay angiography During and after PCI 1 Conclusions: Early Clopidogrel Therapy Loading dose should be 600mg to achieve early optimal antiplatelet effect ?? 300mg in patients after fibrinolytic therapy It is unclear whether therapy should be added to “upstream” GP IIb/IIIa antagonists Especially in high risk patients in whom the likelihood for CABG is high 1 Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month after PCI / stent improving long-term outcome 1 2 Discharge/Post-Discharge Medications - Guidelines ASA, if not contraindicated Clopidogrel, when ASA contraindicated Aspirin + Clopidogrel for up to 9 months -blocker, if not contraindicated Lipid  agents + diet, if LDL >130 mg/dL ACE Inhibitor: CHF, EF < 40%, DM, or HTN I IIa IIb III 2 Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization PCI PLACEBO + ASA * CLOPIDOGREL + ASA * 30 days post PCI End of follow-up Up to 12 months after randomization Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 2,658 patients undergoing PCI N = 1345 N = 1313 PCI-CURE Overall Study Design: PCI-CURE R Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE Question 1 Question 2 Clopidogrel Arm Placebo Arm PCI* 28 Days Placebo + ASA† (325 mg) Randomization - Pre-treatment Clopidogrel 300 mg + ASA† (325 mg) Clopidogrel 75 mg QD + ASA† 325 mg QD Clopidogrel 75 mg QD + ASA† 325 mg QD R 12 Months Steinhubl S, Berger P, Tift Mann III J et al. JAMA. 2002;Vol 288,No 19:2411-2420. Placebo QD + ASA† (81-325 mg) QD Clopidogrel 75 mg QD + ASA† (81-325 mg) QD Overall Study Design: CREDO Question 1 Question 2 1 2 Open label clopidogrel continuation
Slide 40 - Early And Long Term Treatment With Clopidogrel In Coronary Artery Disease פרופ’ יוסף רוזנמן מכון הלב, בי"ח וולפסון דצמבר 2005 Acute Coronary Syndromes Acute Coronary Syndrome No ST Elevation ST Elevation Unstable Angina Myocardial Infarction Non Q MI Q wave MI Non ST Elevation MI Braunwald E et al. J Am Coll Cardiol 2000;36:970–1062. Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When angiography / PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until angiography / PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month improving long-term outcome 1 2 Goals of therapy Prevent ischemic events until coronary angiography / PCI Before plaque stabilization was achieved Prevent PCI / stent related ischemic complications Clopidogrel before coronary angiography - Patients with ACS 1 Clopidogrel before coronary angiography - Patients with ACS ST Elevation CLARITY Non ST Elevation CURE 1 ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Study Design Fibrinolytic, ASA, Heparin Clopidogrel 300 mg + 75 mg qd Coronary Angiogram (2-8 days) Primary endpoint: Occluded artery (TIMI Flow Grade 0/1) or D/MI by time of angio randomize Placebo Double-blind, randomized, placebo-controlled trial in 3491 patients, age 18-75 yrs with STEMI < 12 hours Study Drug 30-day clinical follow-up Open-label clopidogrel per MD in both groups Primary Endpoint: Occluded Artery (or D/MI by time of angio) Placebo Clopidogrel P=0.00000036 Odds Ratio 0.64 (95% CI 0.53-0.76) 1.0 0.4 0.6 0.8 1.2 1.6 Clopidogrel better Placebo better n=1752 n=1739 36% Odds Reduction Primary & Angiographic Outcomes (median 3.5 days) Need for Urgent or Additional Treatment 21%  P=0.01 21%  P=0.005 16%  P=0.07 Early Angio (w/in 48 hrs) Urgent Revasc (index hosp) GP IIb/IIIa if PCI CV Death, MI, RI  Urg Revasc days Percentage with endpoint (%) 0 5 10 15 0 5 10 15 20 25 30 Placebo Clopidogrel Odds Ratio 0.80 (95% CI 0.65-0.97) P=0.026 20% 1 CLARITY: Patient Management Clopidogrel Placebo Parameter (n=1,752) (n=1,739) Symptom onset to fibrinolytic (hours) 2.7 2.6 Fibrinolytic to study drug (minutes) 10 10 Median doses of study medication 4 4 Angiography performed (%) 94 94 Study drug to angiography (hours) 84 84 Coronary revascularization (%): 63 63 PCI 57.2 56.6 CABG 5.9 6.0 Sabatine M et al. New Engl J Med 2005; 352: 1179–1189. PCI-CLARITY: Reduction in CV Death, MI, Stroke from PCI to 30 Days Days Post PCI Percentage with Outcome (%) 0 2 0 5 10 15 20 25 30 46%* p=0.008 Clopidogrel Pretreatment (3.6%) No Pretreatment (6.2%) 4 6 8 M Sabatine, et al. JAMA 2005 PCI-CLARITY: MI, Stroke, or CV Death Events pre and post PCI ***MI or Stroke M Sabatine, et al. JAMA 2005, Prehospital Fibrinolysis with Double Antiplatelet Therapy in Acute ST-Elevation Myocardial Infarction: The Clarity Ambulance Substudy Substudy Sites and Patient Numbers France: 172 patients L Soulat: 57 Y Lambert: 48 F Lapostolle: 28 F Thieuleux: 21 C Gully: 10 D Pollet: 5 D Galley: 2 L Olliver: 1 UK: 40 patients J Adgey: 27 J Purvis: 13 Sweden: 5 patients J-E Karlsson: 5 217 patients in total Angiographic & ECG Parameters: Ambulance vs. Non-Ambulance *Complete considered to be >70%; ECG=electrocardiogram p value Event rate (%) Ambulance Non- ambulance Non-ambulance better Ambulance better Odds ratio (95% CI) 0 0.5 1.0 1.5 2.0 Ambulance Non-ambulance Overall Clopidogrel better Placebo better Odds ratio (95% CI) Primary Endpoint of TIMI Flow Grade 0/1, MI or Death 0.60 (0.301.17) 0.64 (0.530.76) 0.65 (0.540.77) ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Clopidogrel 75mg q.d. + ASA 75-325 mg q.d.* (6259 patients) Placebo + ASA 75-325 mg q.d.* (6303 patients) Day 1 6 m. Visit 9 m. Visit 12 m. or Final Visit 3 m. Visit Discharge Visit 1 m. Visit Patients with Acute Coronary Syndrome (unstable angina or non-ST-segment elevation MI) R Placebo loading dose R = Randomization * In combination with other standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Study Design 3 months £ double-blind treatment £ 12 months Clopidogrel 300 mg loading dose CURE Clopidogrel + ASA* 3 6 9 Placebo + ASA* Months of Follow-Up 11.4% 9.3% 20% RRR P < 0.001 N = 12,562 0 12 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Primary End Point - MI/Stroke/CV Death CURE Clopidogrel + ASA* 10 20 30 Placebo + ASA* Days of Follow-Up 0 21% RRR P = 0.003 N = 12,562 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. MI/Stroke/CV Death within 30 Days CURE 1 CV death, nonfatal MI, stroke or refractory or severe ischemia 34% NEJM 2001; 345:495-502 MI/Stroke/CV Death or severe Ischemia at 24 hours CURE 1 % patients requiring thrombolytic therapy 43% % patients requiring GP IIb/IIIa inhibitors 18% NEJM 2001; 345:495-502 Need for Additional Anti-Thrombotic After Randomization P< 0.001 P= 0.003 Thrombolysis GP IIb/IIIa Inhibitor CURE 1 Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? GP IIb/IIIa receptor is the final common pathway in platelet aggregation. GP IIb/IIIa blockade is the most effective antiplatelet aggregation therapy. Bleeding risk is not increased if therapy is stopped 2-4 hours prior to CABG. Bleeding risk is markedly increased unless clopidogrel is stopped 3-5 days prior to CABG. Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? Is there additional benefit to clopidogrel that would justify: Increased CABG bleeding or alternatively Need to postpone CABG for 3-5 days No data in the literature however Adhesion The Role of Platelets in Atherothrombosis Aggregation 3 Reproduced with permission from Cannon CP. Atherothrombosis slide compendium. Available at: www.theheart.org. 1 Activation 2 Conclusions: Early Clopidogrel Therapy Treatment with clopidogrel is indicated as soon as possible in patients with acute coronary syndrome ST elevation and non ST elevation Treatment is effective to reduce ischemic complications Before coronay angiography During and after PCI 1 Conclusions: Early Clopidogrel Therapy Loading dose should be 600mg to achieve early optimal antiplatelet effect ?? 300mg in patients after fibrinolytic therapy It is unclear whether therapy should be added to “upstream” GP IIb/IIIa antagonists Especially in high risk patients in whom the likelihood for CABG is high 1 Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month after PCI / stent improving long-term outcome 1 2 Discharge/Post-Discharge Medications - Guidelines ASA, if not contraindicated Clopidogrel, when ASA contraindicated Aspirin + Clopidogrel for up to 9 months -blocker, if not contraindicated Lipid  agents + diet, if LDL >130 mg/dL ACE Inhibitor: CHF, EF < 40%, DM, or HTN I IIa IIb III 2 Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization PCI PLACEBO + ASA * CLOPIDOGREL + ASA * 30 days post PCI End of follow-up Up to 12 months after randomization Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 2,658 patients undergoing PCI N = 1345 N = 1313 PCI-CURE Overall Study Design: PCI-CURE R Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE Question 1 Question 2 Clopidogrel Arm Placebo Arm PCI* 28 Days Placebo + ASA† (325 mg) Randomization - Pre-treatment Clopidogrel 300 mg + ASA† (325 mg) Clopidogrel 75 mg QD + ASA† 325 mg QD Clopidogrel 75 mg QD + ASA† 325 mg QD R 12 Months Steinhubl S, Berger P, Tift Mann III J et al. JAMA. 2002;Vol 288,No 19:2411-2420. Placebo QD + ASA† (81-325 mg) QD Clopidogrel 75 mg QD + ASA† (81-325 mg) QD Overall Study Design: CREDO Question 1 Question 2 1 2 Open label clopidogrel continuation Methodological Pitfall Can a study with a single randomization provide an answer to two questions? Alternatively Should a second randomization be done in order to answer the second question?
Slide 41 - Early And Long Term Treatment With Clopidogrel In Coronary Artery Disease פרופ’ יוסף רוזנמן מכון הלב, בי"ח וולפסון דצמבר 2005 Acute Coronary Syndromes Acute Coronary Syndrome No ST Elevation ST Elevation Unstable Angina Myocardial Infarction Non Q MI Q wave MI Non ST Elevation MI Braunwald E et al. J Am Coll Cardiol 2000;36:970–1062. Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When angiography / PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until angiography / PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month improving long-term outcome 1 2 Goals of therapy Prevent ischemic events until coronary angiography / PCI Before plaque stabilization was achieved Prevent PCI / stent related ischemic complications Clopidogrel before coronary angiography - Patients with ACS 1 Clopidogrel before coronary angiography - Patients with ACS ST Elevation CLARITY Non ST Elevation CURE 1 ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Study Design Fibrinolytic, ASA, Heparin Clopidogrel 300 mg + 75 mg qd Coronary Angiogram (2-8 days) Primary endpoint: Occluded artery (TIMI Flow Grade 0/1) or D/MI by time of angio randomize Placebo Double-blind, randomized, placebo-controlled trial in 3491 patients, age 18-75 yrs with STEMI < 12 hours Study Drug 30-day clinical follow-up Open-label clopidogrel per MD in both groups Primary Endpoint: Occluded Artery (or D/MI by time of angio) Placebo Clopidogrel P=0.00000036 Odds Ratio 0.64 (95% CI 0.53-0.76) 1.0 0.4 0.6 0.8 1.2 1.6 Clopidogrel better Placebo better n=1752 n=1739 36% Odds Reduction Primary & Angiographic Outcomes (median 3.5 days) Need for Urgent or Additional Treatment 21%  P=0.01 21%  P=0.005 16%  P=0.07 Early Angio (w/in 48 hrs) Urgent Revasc (index hosp) GP IIb/IIIa if PCI CV Death, MI, RI  Urg Revasc days Percentage with endpoint (%) 0 5 10 15 0 5 10 15 20 25 30 Placebo Clopidogrel Odds Ratio 0.80 (95% CI 0.65-0.97) P=0.026 20% 1 CLARITY: Patient Management Clopidogrel Placebo Parameter (n=1,752) (n=1,739) Symptom onset to fibrinolytic (hours) 2.7 2.6 Fibrinolytic to study drug (minutes) 10 10 Median doses of study medication 4 4 Angiography performed (%) 94 94 Study drug to angiography (hours) 84 84 Coronary revascularization (%): 63 63 PCI 57.2 56.6 CABG 5.9 6.0 Sabatine M et al. New Engl J Med 2005; 352: 1179–1189. PCI-CLARITY: Reduction in CV Death, MI, Stroke from PCI to 30 Days Days Post PCI Percentage with Outcome (%) 0 2 0 5 10 15 20 25 30 46%* p=0.008 Clopidogrel Pretreatment (3.6%) No Pretreatment (6.2%) 4 6 8 M Sabatine, et al. JAMA 2005 PCI-CLARITY: MI, Stroke, or CV Death Events pre and post PCI ***MI or Stroke M Sabatine, et al. JAMA 2005, Prehospital Fibrinolysis with Double Antiplatelet Therapy in Acute ST-Elevation Myocardial Infarction: The Clarity Ambulance Substudy Substudy Sites and Patient Numbers France: 172 patients L Soulat: 57 Y Lambert: 48 F Lapostolle: 28 F Thieuleux: 21 C Gully: 10 D Pollet: 5 D Galley: 2 L Olliver: 1 UK: 40 patients J Adgey: 27 J Purvis: 13 Sweden: 5 patients J-E Karlsson: 5 217 patients in total Angiographic & ECG Parameters: Ambulance vs. Non-Ambulance *Complete considered to be >70%; ECG=electrocardiogram p value Event rate (%) Ambulance Non- ambulance Non-ambulance better Ambulance better Odds ratio (95% CI) 0 0.5 1.0 1.5 2.0 Ambulance Non-ambulance Overall Clopidogrel better Placebo better Odds ratio (95% CI) Primary Endpoint of TIMI Flow Grade 0/1, MI or Death 0.60 (0.301.17) 0.64 (0.530.76) 0.65 (0.540.77) ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Clopidogrel 75mg q.d. + ASA 75-325 mg q.d.* (6259 patients) Placebo + ASA 75-325 mg q.d.* (6303 patients) Day 1 6 m. Visit 9 m. Visit 12 m. or Final Visit 3 m. Visit Discharge Visit 1 m. Visit Patients with Acute Coronary Syndrome (unstable angina or non-ST-segment elevation MI) R Placebo loading dose R = Randomization * In combination with other standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Study Design 3 months £ double-blind treatment £ 12 months Clopidogrel 300 mg loading dose CURE Clopidogrel + ASA* 3 6 9 Placebo + ASA* Months of Follow-Up 11.4% 9.3% 20% RRR P < 0.001 N = 12,562 0 12 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Primary End Point - MI/Stroke/CV Death CURE Clopidogrel + ASA* 10 20 30 Placebo + ASA* Days of Follow-Up 0 21% RRR P = 0.003 N = 12,562 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. MI/Stroke/CV Death within 30 Days CURE 1 CV death, nonfatal MI, stroke or refractory or severe ischemia 34% NEJM 2001; 345:495-502 MI/Stroke/CV Death or severe Ischemia at 24 hours CURE 1 % patients requiring thrombolytic therapy 43% % patients requiring GP IIb/IIIa inhibitors 18% NEJM 2001; 345:495-502 Need for Additional Anti-Thrombotic After Randomization P< 0.001 P= 0.003 Thrombolysis GP IIb/IIIa Inhibitor CURE 1 Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? GP IIb/IIIa receptor is the final common pathway in platelet aggregation. GP IIb/IIIa blockade is the most effective antiplatelet aggregation therapy. Bleeding risk is not increased if therapy is stopped 2-4 hours prior to CABG. Bleeding risk is markedly increased unless clopidogrel is stopped 3-5 days prior to CABG. Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? Is there additional benefit to clopidogrel that would justify: Increased CABG bleeding or alternatively Need to postpone CABG for 3-5 days No data in the literature however Adhesion The Role of Platelets in Atherothrombosis Aggregation 3 Reproduced with permission from Cannon CP. Atherothrombosis slide compendium. Available at: www.theheart.org. 1 Activation 2 Conclusions: Early Clopidogrel Therapy Treatment with clopidogrel is indicated as soon as possible in patients with acute coronary syndrome ST elevation and non ST elevation Treatment is effective to reduce ischemic complications Before coronay angiography During and after PCI 1 Conclusions: Early Clopidogrel Therapy Loading dose should be 600mg to achieve early optimal antiplatelet effect ?? 300mg in patients after fibrinolytic therapy It is unclear whether therapy should be added to “upstream” GP IIb/IIIa antagonists Especially in high risk patients in whom the likelihood for CABG is high 1 Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month after PCI / stent improving long-term outcome 1 2 Discharge/Post-Discharge Medications - Guidelines ASA, if not contraindicated Clopidogrel, when ASA contraindicated Aspirin + Clopidogrel for up to 9 months -blocker, if not contraindicated Lipid  agents + diet, if LDL >130 mg/dL ACE Inhibitor: CHF, EF < 40%, DM, or HTN I IIa IIb III 2 Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization PCI PLACEBO + ASA * CLOPIDOGREL + ASA * 30 days post PCI End of follow-up Up to 12 months after randomization Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 2,658 patients undergoing PCI N = 1345 N = 1313 PCI-CURE Overall Study Design: PCI-CURE R Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE Question 1 Question 2 Clopidogrel Arm Placebo Arm PCI* 28 Days Placebo + ASA† (325 mg) Randomization - Pre-treatment Clopidogrel 300 mg + ASA† (325 mg) Clopidogrel 75 mg QD + ASA† 325 mg QD Clopidogrel 75 mg QD + ASA† 325 mg QD R 12 Months Steinhubl S, Berger P, Tift Mann III J et al. JAMA. 2002;Vol 288,No 19:2411-2420. Placebo QD + ASA† (81-325 mg) QD Clopidogrel 75 mg QD + ASA† (81-325 mg) QD Overall Study Design: CREDO Question 1 Question 2 1 2 Open label clopidogrel continuation Methodological Pitfall Can a study with a single randomization provide an answer to two questions? Alternatively Should a second randomization be done in order to answer the second question? PCI PLACEBO + ASA * CLOPIDOGREL + ASA * 30 days post PCI End of follow-up Up to 12 months after randomization Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 1345 N = 1313 PCI-CURE Study Design single randomization R Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE Continuation Continuation
Slide 42 - Early And Long Term Treatment With Clopidogrel In Coronary Artery Disease פרופ’ יוסף רוזנמן מכון הלב, בי"ח וולפסון דצמבר 2005 Acute Coronary Syndromes Acute Coronary Syndrome No ST Elevation ST Elevation Unstable Angina Myocardial Infarction Non Q MI Q wave MI Non ST Elevation MI Braunwald E et al. J Am Coll Cardiol 2000;36:970–1062. Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When angiography / PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until angiography / PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month improving long-term outcome 1 2 Goals of therapy Prevent ischemic events until coronary angiography / PCI Before plaque stabilization was achieved Prevent PCI / stent related ischemic complications Clopidogrel before coronary angiography - Patients with ACS 1 Clopidogrel before coronary angiography - Patients with ACS ST Elevation CLARITY Non ST Elevation CURE 1 ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Study Design Fibrinolytic, ASA, Heparin Clopidogrel 300 mg + 75 mg qd Coronary Angiogram (2-8 days) Primary endpoint: Occluded artery (TIMI Flow Grade 0/1) or D/MI by time of angio randomize Placebo Double-blind, randomized, placebo-controlled trial in 3491 patients, age 18-75 yrs with STEMI < 12 hours Study Drug 30-day clinical follow-up Open-label clopidogrel per MD in both groups Primary Endpoint: Occluded Artery (or D/MI by time of angio) Placebo Clopidogrel P=0.00000036 Odds Ratio 0.64 (95% CI 0.53-0.76) 1.0 0.4 0.6 0.8 1.2 1.6 Clopidogrel better Placebo better n=1752 n=1739 36% Odds Reduction Primary & Angiographic Outcomes (median 3.5 days) Need for Urgent or Additional Treatment 21%  P=0.01 21%  P=0.005 16%  P=0.07 Early Angio (w/in 48 hrs) Urgent Revasc (index hosp) GP IIb/IIIa if PCI CV Death, MI, RI  Urg Revasc days Percentage with endpoint (%) 0 5 10 15 0 5 10 15 20 25 30 Placebo Clopidogrel Odds Ratio 0.80 (95% CI 0.65-0.97) P=0.026 20% 1 CLARITY: Patient Management Clopidogrel Placebo Parameter (n=1,752) (n=1,739) Symptom onset to fibrinolytic (hours) 2.7 2.6 Fibrinolytic to study drug (minutes) 10 10 Median doses of study medication 4 4 Angiography performed (%) 94 94 Study drug to angiography (hours) 84 84 Coronary revascularization (%): 63 63 PCI 57.2 56.6 CABG 5.9 6.0 Sabatine M et al. New Engl J Med 2005; 352: 1179–1189. PCI-CLARITY: Reduction in CV Death, MI, Stroke from PCI to 30 Days Days Post PCI Percentage with Outcome (%) 0 2 0 5 10 15 20 25 30 46%* p=0.008 Clopidogrel Pretreatment (3.6%) No Pretreatment (6.2%) 4 6 8 M Sabatine, et al. JAMA 2005 PCI-CLARITY: MI, Stroke, or CV Death Events pre and post PCI ***MI or Stroke M Sabatine, et al. JAMA 2005, Prehospital Fibrinolysis with Double Antiplatelet Therapy in Acute ST-Elevation Myocardial Infarction: The Clarity Ambulance Substudy Substudy Sites and Patient Numbers France: 172 patients L Soulat: 57 Y Lambert: 48 F Lapostolle: 28 F Thieuleux: 21 C Gully: 10 D Pollet: 5 D Galley: 2 L Olliver: 1 UK: 40 patients J Adgey: 27 J Purvis: 13 Sweden: 5 patients J-E Karlsson: 5 217 patients in total Angiographic & ECG Parameters: Ambulance vs. Non-Ambulance *Complete considered to be >70%; ECG=electrocardiogram p value Event rate (%) Ambulance Non- ambulance Non-ambulance better Ambulance better Odds ratio (95% CI) 0 0.5 1.0 1.5 2.0 Ambulance Non-ambulance Overall Clopidogrel better Placebo better Odds ratio (95% CI) Primary Endpoint of TIMI Flow Grade 0/1, MI or Death 0.60 (0.301.17) 0.64 (0.530.76) 0.65 (0.540.77) ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Clopidogrel 75mg q.d. + ASA 75-325 mg q.d.* (6259 patients) Placebo + ASA 75-325 mg q.d.* (6303 patients) Day 1 6 m. Visit 9 m. Visit 12 m. or Final Visit 3 m. Visit Discharge Visit 1 m. Visit Patients with Acute Coronary Syndrome (unstable angina or non-ST-segment elevation MI) R Placebo loading dose R = Randomization * In combination with other standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Study Design 3 months £ double-blind treatment £ 12 months Clopidogrel 300 mg loading dose CURE Clopidogrel + ASA* 3 6 9 Placebo + ASA* Months of Follow-Up 11.4% 9.3% 20% RRR P < 0.001 N = 12,562 0 12 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Primary End Point - MI/Stroke/CV Death CURE Clopidogrel + ASA* 10 20 30 Placebo + ASA* Days of Follow-Up 0 21% RRR P = 0.003 N = 12,562 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. MI/Stroke/CV Death within 30 Days CURE 1 CV death, nonfatal MI, stroke or refractory or severe ischemia 34% NEJM 2001; 345:495-502 MI/Stroke/CV Death or severe Ischemia at 24 hours CURE 1 % patients requiring thrombolytic therapy 43% % patients requiring GP IIb/IIIa inhibitors 18% NEJM 2001; 345:495-502 Need for Additional Anti-Thrombotic After Randomization P< 0.001 P= 0.003 Thrombolysis GP IIb/IIIa Inhibitor CURE 1 Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? GP IIb/IIIa receptor is the final common pathway in platelet aggregation. GP IIb/IIIa blockade is the most effective antiplatelet aggregation therapy. Bleeding risk is not increased if therapy is stopped 2-4 hours prior to CABG. Bleeding risk is markedly increased unless clopidogrel is stopped 3-5 days prior to CABG. Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? Is there additional benefit to clopidogrel that would justify: Increased CABG bleeding or alternatively Need to postpone CABG for 3-5 days No data in the literature however Adhesion The Role of Platelets in Atherothrombosis Aggregation 3 Reproduced with permission from Cannon CP. Atherothrombosis slide compendium. Available at: www.theheart.org. 1 Activation 2 Conclusions: Early Clopidogrel Therapy Treatment with clopidogrel is indicated as soon as possible in patients with acute coronary syndrome ST elevation and non ST elevation Treatment is effective to reduce ischemic complications Before coronay angiography During and after PCI 1 Conclusions: Early Clopidogrel Therapy Loading dose should be 600mg to achieve early optimal antiplatelet effect ?? 300mg in patients after fibrinolytic therapy It is unclear whether therapy should be added to “upstream” GP IIb/IIIa antagonists Especially in high risk patients in whom the likelihood for CABG is high 1 Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month after PCI / stent improving long-term outcome 1 2 Discharge/Post-Discharge Medications - Guidelines ASA, if not contraindicated Clopidogrel, when ASA contraindicated Aspirin + Clopidogrel for up to 9 months -blocker, if not contraindicated Lipid  agents + diet, if LDL >130 mg/dL ACE Inhibitor: CHF, EF < 40%, DM, or HTN I IIa IIb III 2 Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization PCI PLACEBO + ASA * CLOPIDOGREL + ASA * 30 days post PCI End of follow-up Up to 12 months after randomization Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 2,658 patients undergoing PCI N = 1345 N = 1313 PCI-CURE Overall Study Design: PCI-CURE R Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE Question 1 Question 2 Clopidogrel Arm Placebo Arm PCI* 28 Days Placebo + ASA† (325 mg) Randomization - Pre-treatment Clopidogrel 300 mg + ASA† (325 mg) Clopidogrel 75 mg QD + ASA† 325 mg QD Clopidogrel 75 mg QD + ASA† 325 mg QD R 12 Months Steinhubl S, Berger P, Tift Mann III J et al. JAMA. 2002;Vol 288,No 19:2411-2420. Placebo QD + ASA† (81-325 mg) QD Clopidogrel 75 mg QD + ASA† (81-325 mg) QD Overall Study Design: CREDO Question 1 Question 2 1 2 Open label clopidogrel continuation Methodological Pitfall Can a study with a single randomization provide an answer to two questions? Alternatively Should a second randomization be done in order to answer the second question? PCI PLACEBO + ASA * CLOPIDOGREL + ASA * 30 days post PCI End of follow-up Up to 12 months after randomization Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 1345 N = 1313 PCI-CURE Study Design single randomization R Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE Continuation Continuation PCI PLACEBO + ASA * CLOPIDOGREL + ASA * Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 1345 N = 1313 PCI-CURE Alternative Study Design two randomizations R1 Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE R2 R2 Clop. Placebo Continuation Continuation Question 2 2
Slide 43 - Early And Long Term Treatment With Clopidogrel In Coronary Artery Disease פרופ’ יוסף רוזנמן מכון הלב, בי"ח וולפסון דצמבר 2005 Acute Coronary Syndromes Acute Coronary Syndrome No ST Elevation ST Elevation Unstable Angina Myocardial Infarction Non Q MI Q wave MI Non ST Elevation MI Braunwald E et al. J Am Coll Cardiol 2000;36:970–1062. Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When angiography / PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until angiography / PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month improving long-term outcome 1 2 Goals of therapy Prevent ischemic events until coronary angiography / PCI Before plaque stabilization was achieved Prevent PCI / stent related ischemic complications Clopidogrel before coronary angiography - Patients with ACS 1 Clopidogrel before coronary angiography - Patients with ACS ST Elevation CLARITY Non ST Elevation CURE 1 ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Study Design Fibrinolytic, ASA, Heparin Clopidogrel 300 mg + 75 mg qd Coronary Angiogram (2-8 days) Primary endpoint: Occluded artery (TIMI Flow Grade 0/1) or D/MI by time of angio randomize Placebo Double-blind, randomized, placebo-controlled trial in 3491 patients, age 18-75 yrs with STEMI < 12 hours Study Drug 30-day clinical follow-up Open-label clopidogrel per MD in both groups Primary Endpoint: Occluded Artery (or D/MI by time of angio) Placebo Clopidogrel P=0.00000036 Odds Ratio 0.64 (95% CI 0.53-0.76) 1.0 0.4 0.6 0.8 1.2 1.6 Clopidogrel better Placebo better n=1752 n=1739 36% Odds Reduction Primary & Angiographic Outcomes (median 3.5 days) Need for Urgent or Additional Treatment 21%  P=0.01 21%  P=0.005 16%  P=0.07 Early Angio (w/in 48 hrs) Urgent Revasc (index hosp) GP IIb/IIIa if PCI CV Death, MI, RI  Urg Revasc days Percentage with endpoint (%) 0 5 10 15 0 5 10 15 20 25 30 Placebo Clopidogrel Odds Ratio 0.80 (95% CI 0.65-0.97) P=0.026 20% 1 CLARITY: Patient Management Clopidogrel Placebo Parameter (n=1,752) (n=1,739) Symptom onset to fibrinolytic (hours) 2.7 2.6 Fibrinolytic to study drug (minutes) 10 10 Median doses of study medication 4 4 Angiography performed (%) 94 94 Study drug to angiography (hours) 84 84 Coronary revascularization (%): 63 63 PCI 57.2 56.6 CABG 5.9 6.0 Sabatine M et al. New Engl J Med 2005; 352: 1179–1189. PCI-CLARITY: Reduction in CV Death, MI, Stroke from PCI to 30 Days Days Post PCI Percentage with Outcome (%) 0 2 0 5 10 15 20 25 30 46%* p=0.008 Clopidogrel Pretreatment (3.6%) No Pretreatment (6.2%) 4 6 8 M Sabatine, et al. JAMA 2005 PCI-CLARITY: MI, Stroke, or CV Death Events pre and post PCI ***MI or Stroke M Sabatine, et al. JAMA 2005, Prehospital Fibrinolysis with Double Antiplatelet Therapy in Acute ST-Elevation Myocardial Infarction: The Clarity Ambulance Substudy Substudy Sites and Patient Numbers France: 172 patients L Soulat: 57 Y Lambert: 48 F Lapostolle: 28 F Thieuleux: 21 C Gully: 10 D Pollet: 5 D Galley: 2 L Olliver: 1 UK: 40 patients J Adgey: 27 J Purvis: 13 Sweden: 5 patients J-E Karlsson: 5 217 patients in total Angiographic & ECG Parameters: Ambulance vs. Non-Ambulance *Complete considered to be >70%; ECG=electrocardiogram p value Event rate (%) Ambulance Non- ambulance Non-ambulance better Ambulance better Odds ratio (95% CI) 0 0.5 1.0 1.5 2.0 Ambulance Non-ambulance Overall Clopidogrel better Placebo better Odds ratio (95% CI) Primary Endpoint of TIMI Flow Grade 0/1, MI or Death 0.60 (0.301.17) 0.64 (0.530.76) 0.65 (0.540.77) ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Clopidogrel 75mg q.d. + ASA 75-325 mg q.d.* (6259 patients) Placebo + ASA 75-325 mg q.d.* (6303 patients) Day 1 6 m. Visit 9 m. Visit 12 m. or Final Visit 3 m. Visit Discharge Visit 1 m. Visit Patients with Acute Coronary Syndrome (unstable angina or non-ST-segment elevation MI) R Placebo loading dose R = Randomization * In combination with other standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Study Design 3 months £ double-blind treatment £ 12 months Clopidogrel 300 mg loading dose CURE Clopidogrel + ASA* 3 6 9 Placebo + ASA* Months of Follow-Up 11.4% 9.3% 20% RRR P < 0.001 N = 12,562 0 12 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Primary End Point - MI/Stroke/CV Death CURE Clopidogrel + ASA* 10 20 30 Placebo + ASA* Days of Follow-Up 0 21% RRR P = 0.003 N = 12,562 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. MI/Stroke/CV Death within 30 Days CURE 1 CV death, nonfatal MI, stroke or refractory or severe ischemia 34% NEJM 2001; 345:495-502 MI/Stroke/CV Death or severe Ischemia at 24 hours CURE 1 % patients requiring thrombolytic therapy 43% % patients requiring GP IIb/IIIa inhibitors 18% NEJM 2001; 345:495-502 Need for Additional Anti-Thrombotic After Randomization P< 0.001 P= 0.003 Thrombolysis GP IIb/IIIa Inhibitor CURE 1 Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? GP IIb/IIIa receptor is the final common pathway in platelet aggregation. GP IIb/IIIa blockade is the most effective antiplatelet aggregation therapy. Bleeding risk is not increased if therapy is stopped 2-4 hours prior to CABG. Bleeding risk is markedly increased unless clopidogrel is stopped 3-5 days prior to CABG. Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? Is there additional benefit to clopidogrel that would justify: Increased CABG bleeding or alternatively Need to postpone CABG for 3-5 days No data in the literature however Adhesion The Role of Platelets in Atherothrombosis Aggregation 3 Reproduced with permission from Cannon CP. Atherothrombosis slide compendium. Available at: www.theheart.org. 1 Activation 2 Conclusions: Early Clopidogrel Therapy Treatment with clopidogrel is indicated as soon as possible in patients with acute coronary syndrome ST elevation and non ST elevation Treatment is effective to reduce ischemic complications Before coronay angiography During and after PCI 1 Conclusions: Early Clopidogrel Therapy Loading dose should be 600mg to achieve early optimal antiplatelet effect ?? 300mg in patients after fibrinolytic therapy It is unclear whether therapy should be added to “upstream” GP IIb/IIIa antagonists Especially in high risk patients in whom the likelihood for CABG is high 1 Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month after PCI / stent improving long-term outcome 1 2 Discharge/Post-Discharge Medications - Guidelines ASA, if not contraindicated Clopidogrel, when ASA contraindicated Aspirin + Clopidogrel for up to 9 months -blocker, if not contraindicated Lipid  agents + diet, if LDL >130 mg/dL ACE Inhibitor: CHF, EF < 40%, DM, or HTN I IIa IIb III 2 Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization PCI PLACEBO + ASA * CLOPIDOGREL + ASA * 30 days post PCI End of follow-up Up to 12 months after randomization Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 2,658 patients undergoing PCI N = 1345 N = 1313 PCI-CURE Overall Study Design: PCI-CURE R Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE Question 1 Question 2 Clopidogrel Arm Placebo Arm PCI* 28 Days Placebo + ASA† (325 mg) Randomization - Pre-treatment Clopidogrel 300 mg + ASA† (325 mg) Clopidogrel 75 mg QD + ASA† 325 mg QD Clopidogrel 75 mg QD + ASA† 325 mg QD R 12 Months Steinhubl S, Berger P, Tift Mann III J et al. JAMA. 2002;Vol 288,No 19:2411-2420. Placebo QD + ASA† (81-325 mg) QD Clopidogrel 75 mg QD + ASA† (81-325 mg) QD Overall Study Design: CREDO Question 1 Question 2 1 2 Open label clopidogrel continuation Methodological Pitfall Can a study with a single randomization provide an answer to two questions? Alternatively Should a second randomization be done in order to answer the second question? PCI PLACEBO + ASA * CLOPIDOGREL + ASA * 30 days post PCI End of follow-up Up to 12 months after randomization Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 1345 N = 1313 PCI-CURE Study Design single randomization R Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE Continuation Continuation PCI PLACEBO + ASA * CLOPIDOGREL + ASA * Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 1345 N = 1313 PCI-CURE Alternative Study Design two randomizations R1 Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE R2 R2 Clop. Placebo Continuation Continuation Question 2 2 Is it just methodology? Can we really expect long term benefit from early antiplatelet therapy?
Slide 44 - Early And Long Term Treatment With Clopidogrel In Coronary Artery Disease פרופ’ יוסף רוזנמן מכון הלב, בי"ח וולפסון דצמבר 2005 Acute Coronary Syndromes Acute Coronary Syndrome No ST Elevation ST Elevation Unstable Angina Myocardial Infarction Non Q MI Q wave MI Non ST Elevation MI Braunwald E et al. J Am Coll Cardiol 2000;36:970–1062. Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When angiography / PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until angiography / PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month improving long-term outcome 1 2 Goals of therapy Prevent ischemic events until coronary angiography / PCI Before plaque stabilization was achieved Prevent PCI / stent related ischemic complications Clopidogrel before coronary angiography - Patients with ACS 1 Clopidogrel before coronary angiography - Patients with ACS ST Elevation CLARITY Non ST Elevation CURE 1 ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Study Design Fibrinolytic, ASA, Heparin Clopidogrel 300 mg + 75 mg qd Coronary Angiogram (2-8 days) Primary endpoint: Occluded artery (TIMI Flow Grade 0/1) or D/MI by time of angio randomize Placebo Double-blind, randomized, placebo-controlled trial in 3491 patients, age 18-75 yrs with STEMI < 12 hours Study Drug 30-day clinical follow-up Open-label clopidogrel per MD in both groups Primary Endpoint: Occluded Artery (or D/MI by time of angio) Placebo Clopidogrel P=0.00000036 Odds Ratio 0.64 (95% CI 0.53-0.76) 1.0 0.4 0.6 0.8 1.2 1.6 Clopidogrel better Placebo better n=1752 n=1739 36% Odds Reduction Primary & Angiographic Outcomes (median 3.5 days) Need for Urgent or Additional Treatment 21%  P=0.01 21%  P=0.005 16%  P=0.07 Early Angio (w/in 48 hrs) Urgent Revasc (index hosp) GP IIb/IIIa if PCI CV Death, MI, RI  Urg Revasc days Percentage with endpoint (%) 0 5 10 15 0 5 10 15 20 25 30 Placebo Clopidogrel Odds Ratio 0.80 (95% CI 0.65-0.97) P=0.026 20% 1 CLARITY: Patient Management Clopidogrel Placebo Parameter (n=1,752) (n=1,739) Symptom onset to fibrinolytic (hours) 2.7 2.6 Fibrinolytic to study drug (minutes) 10 10 Median doses of study medication 4 4 Angiography performed (%) 94 94 Study drug to angiography (hours) 84 84 Coronary revascularization (%): 63 63 PCI 57.2 56.6 CABG 5.9 6.0 Sabatine M et al. New Engl J Med 2005; 352: 1179–1189. PCI-CLARITY: Reduction in CV Death, MI, Stroke from PCI to 30 Days Days Post PCI Percentage with Outcome (%) 0 2 0 5 10 15 20 25 30 46%* p=0.008 Clopidogrel Pretreatment (3.6%) No Pretreatment (6.2%) 4 6 8 M Sabatine, et al. JAMA 2005 PCI-CLARITY: MI, Stroke, or CV Death Events pre and post PCI ***MI or Stroke M Sabatine, et al. JAMA 2005, Prehospital Fibrinolysis with Double Antiplatelet Therapy in Acute ST-Elevation Myocardial Infarction: The Clarity Ambulance Substudy Substudy Sites and Patient Numbers France: 172 patients L Soulat: 57 Y Lambert: 48 F Lapostolle: 28 F Thieuleux: 21 C Gully: 10 D Pollet: 5 D Galley: 2 L Olliver: 1 UK: 40 patients J Adgey: 27 J Purvis: 13 Sweden: 5 patients J-E Karlsson: 5 217 patients in total Angiographic & ECG Parameters: Ambulance vs. Non-Ambulance *Complete considered to be >70%; ECG=electrocardiogram p value Event rate (%) Ambulance Non- ambulance Non-ambulance better Ambulance better Odds ratio (95% CI) 0 0.5 1.0 1.5 2.0 Ambulance Non-ambulance Overall Clopidogrel better Placebo better Odds ratio (95% CI) Primary Endpoint of TIMI Flow Grade 0/1, MI or Death 0.60 (0.301.17) 0.64 (0.530.76) 0.65 (0.540.77) ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Clopidogrel 75mg q.d. + ASA 75-325 mg q.d.* (6259 patients) Placebo + ASA 75-325 mg q.d.* (6303 patients) Day 1 6 m. Visit 9 m. Visit 12 m. or Final Visit 3 m. Visit Discharge Visit 1 m. Visit Patients with Acute Coronary Syndrome (unstable angina or non-ST-segment elevation MI) R Placebo loading dose R = Randomization * In combination with other standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Study Design 3 months £ double-blind treatment £ 12 months Clopidogrel 300 mg loading dose CURE Clopidogrel + ASA* 3 6 9 Placebo + ASA* Months of Follow-Up 11.4% 9.3% 20% RRR P < 0.001 N = 12,562 0 12 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Primary End Point - MI/Stroke/CV Death CURE Clopidogrel + ASA* 10 20 30 Placebo + ASA* Days of Follow-Up 0 21% RRR P = 0.003 N = 12,562 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. MI/Stroke/CV Death within 30 Days CURE 1 CV death, nonfatal MI, stroke or refractory or severe ischemia 34% NEJM 2001; 345:495-502 MI/Stroke/CV Death or severe Ischemia at 24 hours CURE 1 % patients requiring thrombolytic therapy 43% % patients requiring GP IIb/IIIa inhibitors 18% NEJM 2001; 345:495-502 Need for Additional Anti-Thrombotic After Randomization P< 0.001 P= 0.003 Thrombolysis GP IIb/IIIa Inhibitor CURE 1 Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? GP IIb/IIIa receptor is the final common pathway in platelet aggregation. GP IIb/IIIa blockade is the most effective antiplatelet aggregation therapy. Bleeding risk is not increased if therapy is stopped 2-4 hours prior to CABG. Bleeding risk is markedly increased unless clopidogrel is stopped 3-5 days prior to CABG. Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? Is there additional benefit to clopidogrel that would justify: Increased CABG bleeding or alternatively Need to postpone CABG for 3-5 days No data in the literature however Adhesion The Role of Platelets in Atherothrombosis Aggregation 3 Reproduced with permission from Cannon CP. Atherothrombosis slide compendium. Available at: www.theheart.org. 1 Activation 2 Conclusions: Early Clopidogrel Therapy Treatment with clopidogrel is indicated as soon as possible in patients with acute coronary syndrome ST elevation and non ST elevation Treatment is effective to reduce ischemic complications Before coronay angiography During and after PCI 1 Conclusions: Early Clopidogrel Therapy Loading dose should be 600mg to achieve early optimal antiplatelet effect ?? 300mg in patients after fibrinolytic therapy It is unclear whether therapy should be added to “upstream” GP IIb/IIIa antagonists Especially in high risk patients in whom the likelihood for CABG is high 1 Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month after PCI / stent improving long-term outcome 1 2 Discharge/Post-Discharge Medications - Guidelines ASA, if not contraindicated Clopidogrel, when ASA contraindicated Aspirin + Clopidogrel for up to 9 months -blocker, if not contraindicated Lipid  agents + diet, if LDL >130 mg/dL ACE Inhibitor: CHF, EF < 40%, DM, or HTN I IIa IIb III 2 Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization PCI PLACEBO + ASA * CLOPIDOGREL + ASA * 30 days post PCI End of follow-up Up to 12 months after randomization Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 2,658 patients undergoing PCI N = 1345 N = 1313 PCI-CURE Overall Study Design: PCI-CURE R Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE Question 1 Question 2 Clopidogrel Arm Placebo Arm PCI* 28 Days Placebo + ASA† (325 mg) Randomization - Pre-treatment Clopidogrel 300 mg + ASA† (325 mg) Clopidogrel 75 mg QD + ASA† 325 mg QD Clopidogrel 75 mg QD + ASA† 325 mg QD R 12 Months Steinhubl S, Berger P, Tift Mann III J et al. JAMA. 2002;Vol 288,No 19:2411-2420. Placebo QD + ASA† (81-325 mg) QD Clopidogrel 75 mg QD + ASA† (81-325 mg) QD Overall Study Design: CREDO Question 1 Question 2 1 2 Open label clopidogrel continuation Methodological Pitfall Can a study with a single randomization provide an answer to two questions? Alternatively Should a second randomization be done in order to answer the second question? PCI PLACEBO + ASA * CLOPIDOGREL + ASA * 30 days post PCI End of follow-up Up to 12 months after randomization Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 1345 N = 1313 PCI-CURE Study Design single randomization R Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE Continuation Continuation PCI PLACEBO + ASA * CLOPIDOGREL + ASA * Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 1345 N = 1313 PCI-CURE Alternative Study Design two randomizations R1 Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE R2 R2 Clop. Placebo Continuation Continuation Question 2 2 Is it just methodology? Can we really expect long term benefit from early antiplatelet therapy? Adjunct antiplatelet therapy for PCI EPISTENT Randomized study designed to determine the effect of treatment with abciximab TARGET Randomized study designed to show that tirofiban is not inferior to abciximab Post-hoc nonrandomized comparison among those who were or were not pre-treated with clopidogrel PCI-CURE Subgroup of CURE patients who underwent PCI Randomized comparison of pre-treatment and continued clopidogrel therapy vs. placebo
Slide 45 - Early And Long Term Treatment With Clopidogrel In Coronary Artery Disease פרופ’ יוסף רוזנמן מכון הלב, בי"ח וולפסון דצמבר 2005 Acute Coronary Syndromes Acute Coronary Syndrome No ST Elevation ST Elevation Unstable Angina Myocardial Infarction Non Q MI Q wave MI Non ST Elevation MI Braunwald E et al. J Am Coll Cardiol 2000;36:970–1062. Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When angiography / PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until angiography / PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month improving long-term outcome 1 2 Goals of therapy Prevent ischemic events until coronary angiography / PCI Before plaque stabilization was achieved Prevent PCI / stent related ischemic complications Clopidogrel before coronary angiography - Patients with ACS 1 Clopidogrel before coronary angiography - Patients with ACS ST Elevation CLARITY Non ST Elevation CURE 1 ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Study Design Fibrinolytic, ASA, Heparin Clopidogrel 300 mg + 75 mg qd Coronary Angiogram (2-8 days) Primary endpoint: Occluded artery (TIMI Flow Grade 0/1) or D/MI by time of angio randomize Placebo Double-blind, randomized, placebo-controlled trial in 3491 patients, age 18-75 yrs with STEMI < 12 hours Study Drug 30-day clinical follow-up Open-label clopidogrel per MD in both groups Primary Endpoint: Occluded Artery (or D/MI by time of angio) Placebo Clopidogrel P=0.00000036 Odds Ratio 0.64 (95% CI 0.53-0.76) 1.0 0.4 0.6 0.8 1.2 1.6 Clopidogrel better Placebo better n=1752 n=1739 36% Odds Reduction Primary & Angiographic Outcomes (median 3.5 days) Need for Urgent or Additional Treatment 21%  P=0.01 21%  P=0.005 16%  P=0.07 Early Angio (w/in 48 hrs) Urgent Revasc (index hosp) GP IIb/IIIa if PCI CV Death, MI, RI  Urg Revasc days Percentage with endpoint (%) 0 5 10 15 0 5 10 15 20 25 30 Placebo Clopidogrel Odds Ratio 0.80 (95% CI 0.65-0.97) P=0.026 20% 1 CLARITY: Patient Management Clopidogrel Placebo Parameter (n=1,752) (n=1,739) Symptom onset to fibrinolytic (hours) 2.7 2.6 Fibrinolytic to study drug (minutes) 10 10 Median doses of study medication 4 4 Angiography performed (%) 94 94 Study drug to angiography (hours) 84 84 Coronary revascularization (%): 63 63 PCI 57.2 56.6 CABG 5.9 6.0 Sabatine M et al. New Engl J Med 2005; 352: 1179–1189. PCI-CLARITY: Reduction in CV Death, MI, Stroke from PCI to 30 Days Days Post PCI Percentage with Outcome (%) 0 2 0 5 10 15 20 25 30 46%* p=0.008 Clopidogrel Pretreatment (3.6%) No Pretreatment (6.2%) 4 6 8 M Sabatine, et al. JAMA 2005 PCI-CLARITY: MI, Stroke, or CV Death Events pre and post PCI ***MI or Stroke M Sabatine, et al. JAMA 2005, Prehospital Fibrinolysis with Double Antiplatelet Therapy in Acute ST-Elevation Myocardial Infarction: The Clarity Ambulance Substudy Substudy Sites and Patient Numbers France: 172 patients L Soulat: 57 Y Lambert: 48 F Lapostolle: 28 F Thieuleux: 21 C Gully: 10 D Pollet: 5 D Galley: 2 L Olliver: 1 UK: 40 patients J Adgey: 27 J Purvis: 13 Sweden: 5 patients J-E Karlsson: 5 217 patients in total Angiographic & ECG Parameters: Ambulance vs. Non-Ambulance *Complete considered to be >70%; ECG=electrocardiogram p value Event rate (%) Ambulance Non- ambulance Non-ambulance better Ambulance better Odds ratio (95% CI) 0 0.5 1.0 1.5 2.0 Ambulance Non-ambulance Overall Clopidogrel better Placebo better Odds ratio (95% CI) Primary Endpoint of TIMI Flow Grade 0/1, MI or Death 0.60 (0.301.17) 0.64 (0.530.76) 0.65 (0.540.77) ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Clopidogrel 75mg q.d. + ASA 75-325 mg q.d.* (6259 patients) Placebo + ASA 75-325 mg q.d.* (6303 patients) Day 1 6 m. Visit 9 m. Visit 12 m. or Final Visit 3 m. Visit Discharge Visit 1 m. Visit Patients with Acute Coronary Syndrome (unstable angina or non-ST-segment elevation MI) R Placebo loading dose R = Randomization * In combination with other standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Study Design 3 months £ double-blind treatment £ 12 months Clopidogrel 300 mg loading dose CURE Clopidogrel + ASA* 3 6 9 Placebo + ASA* Months of Follow-Up 11.4% 9.3% 20% RRR P < 0.001 N = 12,562 0 12 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Primary End Point - MI/Stroke/CV Death CURE Clopidogrel + ASA* 10 20 30 Placebo + ASA* Days of Follow-Up 0 21% RRR P = 0.003 N = 12,562 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. MI/Stroke/CV Death within 30 Days CURE 1 CV death, nonfatal MI, stroke or refractory or severe ischemia 34% NEJM 2001; 345:495-502 MI/Stroke/CV Death or severe Ischemia at 24 hours CURE 1 % patients requiring thrombolytic therapy 43% % patients requiring GP IIb/IIIa inhibitors 18% NEJM 2001; 345:495-502 Need for Additional Anti-Thrombotic After Randomization P< 0.001 P= 0.003 Thrombolysis GP IIb/IIIa Inhibitor CURE 1 Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? GP IIb/IIIa receptor is the final common pathway in platelet aggregation. GP IIb/IIIa blockade is the most effective antiplatelet aggregation therapy. Bleeding risk is not increased if therapy is stopped 2-4 hours prior to CABG. Bleeding risk is markedly increased unless clopidogrel is stopped 3-5 days prior to CABG. Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? Is there additional benefit to clopidogrel that would justify: Increased CABG bleeding or alternatively Need to postpone CABG for 3-5 days No data in the literature however Adhesion The Role of Platelets in Atherothrombosis Aggregation 3 Reproduced with permission from Cannon CP. Atherothrombosis slide compendium. Available at: www.theheart.org. 1 Activation 2 Conclusions: Early Clopidogrel Therapy Treatment with clopidogrel is indicated as soon as possible in patients with acute coronary syndrome ST elevation and non ST elevation Treatment is effective to reduce ischemic complications Before coronay angiography During and after PCI 1 Conclusions: Early Clopidogrel Therapy Loading dose should be 600mg to achieve early optimal antiplatelet effect ?? 300mg in patients after fibrinolytic therapy It is unclear whether therapy should be added to “upstream” GP IIb/IIIa antagonists Especially in high risk patients in whom the likelihood for CABG is high 1 Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month after PCI / stent improving long-term outcome 1 2 Discharge/Post-Discharge Medications - Guidelines ASA, if not contraindicated Clopidogrel, when ASA contraindicated Aspirin + Clopidogrel for up to 9 months -blocker, if not contraindicated Lipid  agents + diet, if LDL >130 mg/dL ACE Inhibitor: CHF, EF < 40%, DM, or HTN I IIa IIb III 2 Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization PCI PLACEBO + ASA * CLOPIDOGREL + ASA * 30 days post PCI End of follow-up Up to 12 months after randomization Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 2,658 patients undergoing PCI N = 1345 N = 1313 PCI-CURE Overall Study Design: PCI-CURE R Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE Question 1 Question 2 Clopidogrel Arm Placebo Arm PCI* 28 Days Placebo + ASA† (325 mg) Randomization - Pre-treatment Clopidogrel 300 mg + ASA† (325 mg) Clopidogrel 75 mg QD + ASA† 325 mg QD Clopidogrel 75 mg QD + ASA† 325 mg QD R 12 Months Steinhubl S, Berger P, Tift Mann III J et al. JAMA. 2002;Vol 288,No 19:2411-2420. Placebo QD + ASA† (81-325 mg) QD Clopidogrel 75 mg QD + ASA† (81-325 mg) QD Overall Study Design: CREDO Question 1 Question 2 1 2 Open label clopidogrel continuation Methodological Pitfall Can a study with a single randomization provide an answer to two questions? Alternatively Should a second randomization be done in order to answer the second question? PCI PLACEBO + ASA * CLOPIDOGREL + ASA * 30 days post PCI End of follow-up Up to 12 months after randomization Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 1345 N = 1313 PCI-CURE Study Design single randomization R Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE Continuation Continuation PCI PLACEBO + ASA * CLOPIDOGREL + ASA * Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 1345 N = 1313 PCI-CURE Alternative Study Design two randomizations R1 Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE R2 R2 Clop. Placebo Continuation Continuation Question 2 2 Is it just methodology? Can we really expect long term benefit from early antiplatelet therapy? Adjunct antiplatelet therapy for PCI EPISTENT Randomized study designed to determine the effect of treatment with abciximab TARGET Randomized study designed to show that tirofiban is not inferior to abciximab Post-hoc nonrandomized comparison among those who were or were not pre-treated with clopidogrel PCI-CURE Subgroup of CURE patients who underwent PCI Randomized comparison of pre-treatment and continued clopidogrel therapy vs. placebo Absolute reduction of Death or MI at 1 month and 1 year Abciximab Early clopidogrel Early and continued clopidogrel % reduction * * 6 month data in TARGET Early and long term reduction of death or MI from antiplatelet therapy in patients with ACS
Slide 46 - Early And Long Term Treatment With Clopidogrel In Coronary Artery Disease פרופ’ יוסף רוזנמן מכון הלב, בי"ח וולפסון דצמבר 2005 Acute Coronary Syndromes Acute Coronary Syndrome No ST Elevation ST Elevation Unstable Angina Myocardial Infarction Non Q MI Q wave MI Non ST Elevation MI Braunwald E et al. J Am Coll Cardiol 2000;36:970–1062. Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When angiography / PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until angiography / PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month improving long-term outcome 1 2 Goals of therapy Prevent ischemic events until coronary angiography / PCI Before plaque stabilization was achieved Prevent PCI / stent related ischemic complications Clopidogrel before coronary angiography - Patients with ACS 1 Clopidogrel before coronary angiography - Patients with ACS ST Elevation CLARITY Non ST Elevation CURE 1 ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Study Design Fibrinolytic, ASA, Heparin Clopidogrel 300 mg + 75 mg qd Coronary Angiogram (2-8 days) Primary endpoint: Occluded artery (TIMI Flow Grade 0/1) or D/MI by time of angio randomize Placebo Double-blind, randomized, placebo-controlled trial in 3491 patients, age 18-75 yrs with STEMI < 12 hours Study Drug 30-day clinical follow-up Open-label clopidogrel per MD in both groups Primary Endpoint: Occluded Artery (or D/MI by time of angio) Placebo Clopidogrel P=0.00000036 Odds Ratio 0.64 (95% CI 0.53-0.76) 1.0 0.4 0.6 0.8 1.2 1.6 Clopidogrel better Placebo better n=1752 n=1739 36% Odds Reduction Primary & Angiographic Outcomes (median 3.5 days) Need for Urgent or Additional Treatment 21%  P=0.01 21%  P=0.005 16%  P=0.07 Early Angio (w/in 48 hrs) Urgent Revasc (index hosp) GP IIb/IIIa if PCI CV Death, MI, RI  Urg Revasc days Percentage with endpoint (%) 0 5 10 15 0 5 10 15 20 25 30 Placebo Clopidogrel Odds Ratio 0.80 (95% CI 0.65-0.97) P=0.026 20% 1 CLARITY: Patient Management Clopidogrel Placebo Parameter (n=1,752) (n=1,739) Symptom onset to fibrinolytic (hours) 2.7 2.6 Fibrinolytic to study drug (minutes) 10 10 Median doses of study medication 4 4 Angiography performed (%) 94 94 Study drug to angiography (hours) 84 84 Coronary revascularization (%): 63 63 PCI 57.2 56.6 CABG 5.9 6.0 Sabatine M et al. New Engl J Med 2005; 352: 1179–1189. PCI-CLARITY: Reduction in CV Death, MI, Stroke from PCI to 30 Days Days Post PCI Percentage with Outcome (%) 0 2 0 5 10 15 20 25 30 46%* p=0.008 Clopidogrel Pretreatment (3.6%) No Pretreatment (6.2%) 4 6 8 M Sabatine, et al. JAMA 2005 PCI-CLARITY: MI, Stroke, or CV Death Events pre and post PCI ***MI or Stroke M Sabatine, et al. JAMA 2005, Prehospital Fibrinolysis with Double Antiplatelet Therapy in Acute ST-Elevation Myocardial Infarction: The Clarity Ambulance Substudy Substudy Sites and Patient Numbers France: 172 patients L Soulat: 57 Y Lambert: 48 F Lapostolle: 28 F Thieuleux: 21 C Gully: 10 D Pollet: 5 D Galley: 2 L Olliver: 1 UK: 40 patients J Adgey: 27 J Purvis: 13 Sweden: 5 patients J-E Karlsson: 5 217 patients in total Angiographic & ECG Parameters: Ambulance vs. Non-Ambulance *Complete considered to be >70%; ECG=electrocardiogram p value Event rate (%) Ambulance Non- ambulance Non-ambulance better Ambulance better Odds ratio (95% CI) 0 0.5 1.0 1.5 2.0 Ambulance Non-ambulance Overall Clopidogrel better Placebo better Odds ratio (95% CI) Primary Endpoint of TIMI Flow Grade 0/1, MI or Death 0.60 (0.301.17) 0.64 (0.530.76) 0.65 (0.540.77) ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Clopidogrel 75mg q.d. + ASA 75-325 mg q.d.* (6259 patients) Placebo + ASA 75-325 mg q.d.* (6303 patients) Day 1 6 m. Visit 9 m. Visit 12 m. or Final Visit 3 m. Visit Discharge Visit 1 m. Visit Patients with Acute Coronary Syndrome (unstable angina or non-ST-segment elevation MI) R Placebo loading dose R = Randomization * In combination with other standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Study Design 3 months £ double-blind treatment £ 12 months Clopidogrel 300 mg loading dose CURE Clopidogrel + ASA* 3 6 9 Placebo + ASA* Months of Follow-Up 11.4% 9.3% 20% RRR P < 0.001 N = 12,562 0 12 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Primary End Point - MI/Stroke/CV Death CURE Clopidogrel + ASA* 10 20 30 Placebo + ASA* Days of Follow-Up 0 21% RRR P = 0.003 N = 12,562 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. MI/Stroke/CV Death within 30 Days CURE 1 CV death, nonfatal MI, stroke or refractory or severe ischemia 34% NEJM 2001; 345:495-502 MI/Stroke/CV Death or severe Ischemia at 24 hours CURE 1 % patients requiring thrombolytic therapy 43% % patients requiring GP IIb/IIIa inhibitors 18% NEJM 2001; 345:495-502 Need for Additional Anti-Thrombotic After Randomization P< 0.001 P= 0.003 Thrombolysis GP IIb/IIIa Inhibitor CURE 1 Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? GP IIb/IIIa receptor is the final common pathway in platelet aggregation. GP IIb/IIIa blockade is the most effective antiplatelet aggregation therapy. Bleeding risk is not increased if therapy is stopped 2-4 hours prior to CABG. Bleeding risk is markedly increased unless clopidogrel is stopped 3-5 days prior to CABG. Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? Is there additional benefit to clopidogrel that would justify: Increased CABG bleeding or alternatively Need to postpone CABG for 3-5 days No data in the literature however Adhesion The Role of Platelets in Atherothrombosis Aggregation 3 Reproduced with permission from Cannon CP. Atherothrombosis slide compendium. Available at: www.theheart.org. 1 Activation 2 Conclusions: Early Clopidogrel Therapy Treatment with clopidogrel is indicated as soon as possible in patients with acute coronary syndrome ST elevation and non ST elevation Treatment is effective to reduce ischemic complications Before coronay angiography During and after PCI 1 Conclusions: Early Clopidogrel Therapy Loading dose should be 600mg to achieve early optimal antiplatelet effect ?? 300mg in patients after fibrinolytic therapy It is unclear whether therapy should be added to “upstream” GP IIb/IIIa antagonists Especially in high risk patients in whom the likelihood for CABG is high 1 Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month after PCI / stent improving long-term outcome 1 2 Discharge/Post-Discharge Medications - Guidelines ASA, if not contraindicated Clopidogrel, when ASA contraindicated Aspirin + Clopidogrel for up to 9 months -blocker, if not contraindicated Lipid  agents + diet, if LDL >130 mg/dL ACE Inhibitor: CHF, EF < 40%, DM, or HTN I IIa IIb III 2 Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization PCI PLACEBO + ASA * CLOPIDOGREL + ASA * 30 days post PCI End of follow-up Up to 12 months after randomization Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 2,658 patients undergoing PCI N = 1345 N = 1313 PCI-CURE Overall Study Design: PCI-CURE R Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE Question 1 Question 2 Clopidogrel Arm Placebo Arm PCI* 28 Days Placebo + ASA† (325 mg) Randomization - Pre-treatment Clopidogrel 300 mg + ASA† (325 mg) Clopidogrel 75 mg QD + ASA† 325 mg QD Clopidogrel 75 mg QD + ASA† 325 mg QD R 12 Months Steinhubl S, Berger P, Tift Mann III J et al. JAMA. 2002;Vol 288,No 19:2411-2420. Placebo QD + ASA† (81-325 mg) QD Clopidogrel 75 mg QD + ASA† (81-325 mg) QD Overall Study Design: CREDO Question 1 Question 2 1 2 Open label clopidogrel continuation Methodological Pitfall Can a study with a single randomization provide an answer to two questions? Alternatively Should a second randomization be done in order to answer the second question? PCI PLACEBO + ASA * CLOPIDOGREL + ASA * 30 days post PCI End of follow-up Up to 12 months after randomization Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 1345 N = 1313 PCI-CURE Study Design single randomization R Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE Continuation Continuation PCI PLACEBO + ASA * CLOPIDOGREL + ASA * Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 1345 N = 1313 PCI-CURE Alternative Study Design two randomizations R1 Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE R2 R2 Clop. Placebo Continuation Continuation Question 2 2 Is it just methodology? Can we really expect long term benefit from early antiplatelet therapy? Adjunct antiplatelet therapy for PCI EPISTENT Randomized study designed to determine the effect of treatment with abciximab TARGET Randomized study designed to show that tirofiban is not inferior to abciximab Post-hoc nonrandomized comparison among those who were or were not pre-treated with clopidogrel PCI-CURE Subgroup of CURE patients who underwent PCI Randomized comparison of pre-treatment and continued clopidogrel therapy vs. placebo Absolute reduction of Death or MI at 1 month and 1 year Abciximab Early clopidogrel Early and continued clopidogrel % reduction * * 6 month data in TARGET Early and long term reduction of death or MI from antiplatelet therapy in patients with ACS Long Term Clopidogrel Post PCI Clinical guidelines: 9 months to 1 year in patients with ACS However, current data does not fully support this recommendation What should we do? 2
Slide 47 - Early And Long Term Treatment With Clopidogrel In Coronary Artery Disease פרופ’ יוסף רוזנמן מכון הלב, בי"ח וולפסון דצמבר 2005 Acute Coronary Syndromes Acute Coronary Syndrome No ST Elevation ST Elevation Unstable Angina Myocardial Infarction Non Q MI Q wave MI Non ST Elevation MI Braunwald E et al. J Am Coll Cardiol 2000;36:970–1062. Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When angiography / PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until angiography / PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month improving long-term outcome 1 2 Goals of therapy Prevent ischemic events until coronary angiography / PCI Before plaque stabilization was achieved Prevent PCI / stent related ischemic complications Clopidogrel before coronary angiography - Patients with ACS 1 Clopidogrel before coronary angiography - Patients with ACS ST Elevation CLARITY Non ST Elevation CURE 1 ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Study Design Fibrinolytic, ASA, Heparin Clopidogrel 300 mg + 75 mg qd Coronary Angiogram (2-8 days) Primary endpoint: Occluded artery (TIMI Flow Grade 0/1) or D/MI by time of angio randomize Placebo Double-blind, randomized, placebo-controlled trial in 3491 patients, age 18-75 yrs with STEMI < 12 hours Study Drug 30-day clinical follow-up Open-label clopidogrel per MD in both groups Primary Endpoint: Occluded Artery (or D/MI by time of angio) Placebo Clopidogrel P=0.00000036 Odds Ratio 0.64 (95% CI 0.53-0.76) 1.0 0.4 0.6 0.8 1.2 1.6 Clopidogrel better Placebo better n=1752 n=1739 36% Odds Reduction Primary & Angiographic Outcomes (median 3.5 days) Need for Urgent or Additional Treatment 21%  P=0.01 21%  P=0.005 16%  P=0.07 Early Angio (w/in 48 hrs) Urgent Revasc (index hosp) GP IIb/IIIa if PCI CV Death, MI, RI  Urg Revasc days Percentage with endpoint (%) 0 5 10 15 0 5 10 15 20 25 30 Placebo Clopidogrel Odds Ratio 0.80 (95% CI 0.65-0.97) P=0.026 20% 1 CLARITY: Patient Management Clopidogrel Placebo Parameter (n=1,752) (n=1,739) Symptom onset to fibrinolytic (hours) 2.7 2.6 Fibrinolytic to study drug (minutes) 10 10 Median doses of study medication 4 4 Angiography performed (%) 94 94 Study drug to angiography (hours) 84 84 Coronary revascularization (%): 63 63 PCI 57.2 56.6 CABG 5.9 6.0 Sabatine M et al. New Engl J Med 2005; 352: 1179–1189. PCI-CLARITY: Reduction in CV Death, MI, Stroke from PCI to 30 Days Days Post PCI Percentage with Outcome (%) 0 2 0 5 10 15 20 25 30 46%* p=0.008 Clopidogrel Pretreatment (3.6%) No Pretreatment (6.2%) 4 6 8 M Sabatine, et al. JAMA 2005 PCI-CLARITY: MI, Stroke, or CV Death Events pre and post PCI ***MI or Stroke M Sabatine, et al. JAMA 2005, Prehospital Fibrinolysis with Double Antiplatelet Therapy in Acute ST-Elevation Myocardial Infarction: The Clarity Ambulance Substudy Substudy Sites and Patient Numbers France: 172 patients L Soulat: 57 Y Lambert: 48 F Lapostolle: 28 F Thieuleux: 21 C Gully: 10 D Pollet: 5 D Galley: 2 L Olliver: 1 UK: 40 patients J Adgey: 27 J Purvis: 13 Sweden: 5 patients J-E Karlsson: 5 217 patients in total Angiographic & ECG Parameters: Ambulance vs. Non-Ambulance *Complete considered to be >70%; ECG=electrocardiogram p value Event rate (%) Ambulance Non- ambulance Non-ambulance better Ambulance better Odds ratio (95% CI) 0 0.5 1.0 1.5 2.0 Ambulance Non-ambulance Overall Clopidogrel better Placebo better Odds ratio (95% CI) Primary Endpoint of TIMI Flow Grade 0/1, MI or Death 0.60 (0.301.17) 0.64 (0.530.76) 0.65 (0.540.77) ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Clopidogrel 75mg q.d. + ASA 75-325 mg q.d.* (6259 patients) Placebo + ASA 75-325 mg q.d.* (6303 patients) Day 1 6 m. Visit 9 m. Visit 12 m. or Final Visit 3 m. Visit Discharge Visit 1 m. Visit Patients with Acute Coronary Syndrome (unstable angina or non-ST-segment elevation MI) R Placebo loading dose R = Randomization * In combination with other standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Study Design 3 months £ double-blind treatment £ 12 months Clopidogrel 300 mg loading dose CURE Clopidogrel + ASA* 3 6 9 Placebo + ASA* Months of Follow-Up 11.4% 9.3% 20% RRR P < 0.001 N = 12,562 0 12 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Primary End Point - MI/Stroke/CV Death CURE Clopidogrel + ASA* 10 20 30 Placebo + ASA* Days of Follow-Up 0 21% RRR P = 0.003 N = 12,562 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. MI/Stroke/CV Death within 30 Days CURE 1 CV death, nonfatal MI, stroke or refractory or severe ischemia 34% NEJM 2001; 345:495-502 MI/Stroke/CV Death or severe Ischemia at 24 hours CURE 1 % patients requiring thrombolytic therapy 43% % patients requiring GP IIb/IIIa inhibitors 18% NEJM 2001; 345:495-502 Need for Additional Anti-Thrombotic After Randomization P< 0.001 P= 0.003 Thrombolysis GP IIb/IIIa Inhibitor CURE 1 Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? GP IIb/IIIa receptor is the final common pathway in platelet aggregation. GP IIb/IIIa blockade is the most effective antiplatelet aggregation therapy. Bleeding risk is not increased if therapy is stopped 2-4 hours prior to CABG. Bleeding risk is markedly increased unless clopidogrel is stopped 3-5 days prior to CABG. Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? Is there additional benefit to clopidogrel that would justify: Increased CABG bleeding or alternatively Need to postpone CABG for 3-5 days No data in the literature however Adhesion The Role of Platelets in Atherothrombosis Aggregation 3 Reproduced with permission from Cannon CP. Atherothrombosis slide compendium. Available at: www.theheart.org. 1 Activation 2 Conclusions: Early Clopidogrel Therapy Treatment with clopidogrel is indicated as soon as possible in patients with acute coronary syndrome ST elevation and non ST elevation Treatment is effective to reduce ischemic complications Before coronay angiography During and after PCI 1 Conclusions: Early Clopidogrel Therapy Loading dose should be 600mg to achieve early optimal antiplatelet effect ?? 300mg in patients after fibrinolytic therapy It is unclear whether therapy should be added to “upstream” GP IIb/IIIa antagonists Especially in high risk patients in whom the likelihood for CABG is high 1 Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month after PCI / stent improving long-term outcome 1 2 Discharge/Post-Discharge Medications - Guidelines ASA, if not contraindicated Clopidogrel, when ASA contraindicated Aspirin + Clopidogrel for up to 9 months -blocker, if not contraindicated Lipid  agents + diet, if LDL >130 mg/dL ACE Inhibitor: CHF, EF < 40%, DM, or HTN I IIa IIb III 2 Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization PCI PLACEBO + ASA * CLOPIDOGREL + ASA * 30 days post PCI End of follow-up Up to 12 months after randomization Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 2,658 patients undergoing PCI N = 1345 N = 1313 PCI-CURE Overall Study Design: PCI-CURE R Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE Question 1 Question 2 Clopidogrel Arm Placebo Arm PCI* 28 Days Placebo + ASA† (325 mg) Randomization - Pre-treatment Clopidogrel 300 mg + ASA† (325 mg) Clopidogrel 75 mg QD + ASA† 325 mg QD Clopidogrel 75 mg QD + ASA† 325 mg QD R 12 Months Steinhubl S, Berger P, Tift Mann III J et al. JAMA. 2002;Vol 288,No 19:2411-2420. Placebo QD + ASA† (81-325 mg) QD Clopidogrel 75 mg QD + ASA† (81-325 mg) QD Overall Study Design: CREDO Question 1 Question 2 1 2 Open label clopidogrel continuation Methodological Pitfall Can a study with a single randomization provide an answer to two questions? Alternatively Should a second randomization be done in order to answer the second question? PCI PLACEBO + ASA * CLOPIDOGREL + ASA * 30 days post PCI End of follow-up Up to 12 months after randomization Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 1345 N = 1313 PCI-CURE Study Design single randomization R Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE Continuation Continuation PCI PLACEBO + ASA * CLOPIDOGREL + ASA * Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 1345 N = 1313 PCI-CURE Alternative Study Design two randomizations R1 Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE R2 R2 Clop. Placebo Continuation Continuation Question 2 2 Is it just methodology? Can we really expect long term benefit from early antiplatelet therapy? Adjunct antiplatelet therapy for PCI EPISTENT Randomized study designed to determine the effect of treatment with abciximab TARGET Randomized study designed to show that tirofiban is not inferior to abciximab Post-hoc nonrandomized comparison among those who were or were not pre-treated with clopidogrel PCI-CURE Subgroup of CURE patients who underwent PCI Randomized comparison of pre-treatment and continued clopidogrel therapy vs. placebo Absolute reduction of Death or MI at 1 month and 1 year Abciximab Early clopidogrel Early and continued clopidogrel % reduction * * 6 month data in TARGET Early and long term reduction of death or MI from antiplatelet therapy in patients with ACS Long Term Clopidogrel Post PCI Clinical guidelines: 9 months to 1 year in patients with ACS However, current data does not fully support this recommendation What should we do? 2 Comulative event rate in primary prevention stable CAD and ACS ACS Stable Primary
Slide 48 - Early And Long Term Treatment With Clopidogrel In Coronary Artery Disease פרופ’ יוסף רוזנמן מכון הלב, בי"ח וולפסון דצמבר 2005 Acute Coronary Syndromes Acute Coronary Syndrome No ST Elevation ST Elevation Unstable Angina Myocardial Infarction Non Q MI Q wave MI Non ST Elevation MI Braunwald E et al. J Am Coll Cardiol 2000;36:970–1062. Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When angiography / PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until angiography / PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month improving long-term outcome 1 2 Goals of therapy Prevent ischemic events until coronary angiography / PCI Before plaque stabilization was achieved Prevent PCI / stent related ischemic complications Clopidogrel before coronary angiography - Patients with ACS 1 Clopidogrel before coronary angiography - Patients with ACS ST Elevation CLARITY Non ST Elevation CURE 1 ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Study Design Fibrinolytic, ASA, Heparin Clopidogrel 300 mg + 75 mg qd Coronary Angiogram (2-8 days) Primary endpoint: Occluded artery (TIMI Flow Grade 0/1) or D/MI by time of angio randomize Placebo Double-blind, randomized, placebo-controlled trial in 3491 patients, age 18-75 yrs with STEMI < 12 hours Study Drug 30-day clinical follow-up Open-label clopidogrel per MD in both groups Primary Endpoint: Occluded Artery (or D/MI by time of angio) Placebo Clopidogrel P=0.00000036 Odds Ratio 0.64 (95% CI 0.53-0.76) 1.0 0.4 0.6 0.8 1.2 1.6 Clopidogrel better Placebo better n=1752 n=1739 36% Odds Reduction Primary & Angiographic Outcomes (median 3.5 days) Need for Urgent or Additional Treatment 21%  P=0.01 21%  P=0.005 16%  P=0.07 Early Angio (w/in 48 hrs) Urgent Revasc (index hosp) GP IIb/IIIa if PCI CV Death, MI, RI  Urg Revasc days Percentage with endpoint (%) 0 5 10 15 0 5 10 15 20 25 30 Placebo Clopidogrel Odds Ratio 0.80 (95% CI 0.65-0.97) P=0.026 20% 1 CLARITY: Patient Management Clopidogrel Placebo Parameter (n=1,752) (n=1,739) Symptom onset to fibrinolytic (hours) 2.7 2.6 Fibrinolytic to study drug (minutes) 10 10 Median doses of study medication 4 4 Angiography performed (%) 94 94 Study drug to angiography (hours) 84 84 Coronary revascularization (%): 63 63 PCI 57.2 56.6 CABG 5.9 6.0 Sabatine M et al. New Engl J Med 2005; 352: 1179–1189. PCI-CLARITY: Reduction in CV Death, MI, Stroke from PCI to 30 Days Days Post PCI Percentage with Outcome (%) 0 2 0 5 10 15 20 25 30 46%* p=0.008 Clopidogrel Pretreatment (3.6%) No Pretreatment (6.2%) 4 6 8 M Sabatine, et al. JAMA 2005 PCI-CLARITY: MI, Stroke, or CV Death Events pre and post PCI ***MI or Stroke M Sabatine, et al. JAMA 2005, Prehospital Fibrinolysis with Double Antiplatelet Therapy in Acute ST-Elevation Myocardial Infarction: The Clarity Ambulance Substudy Substudy Sites and Patient Numbers France: 172 patients L Soulat: 57 Y Lambert: 48 F Lapostolle: 28 F Thieuleux: 21 C Gully: 10 D Pollet: 5 D Galley: 2 L Olliver: 1 UK: 40 patients J Adgey: 27 J Purvis: 13 Sweden: 5 patients J-E Karlsson: 5 217 patients in total Angiographic & ECG Parameters: Ambulance vs. Non-Ambulance *Complete considered to be >70%; ECG=electrocardiogram p value Event rate (%) Ambulance Non- ambulance Non-ambulance better Ambulance better Odds ratio (95% CI) 0 0.5 1.0 1.5 2.0 Ambulance Non-ambulance Overall Clopidogrel better Placebo better Odds ratio (95% CI) Primary Endpoint of TIMI Flow Grade 0/1, MI or Death 0.60 (0.301.17) 0.64 (0.530.76) 0.65 (0.540.77) ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Clopidogrel 75mg q.d. + ASA 75-325 mg q.d.* (6259 patients) Placebo + ASA 75-325 mg q.d.* (6303 patients) Day 1 6 m. Visit 9 m. Visit 12 m. or Final Visit 3 m. Visit Discharge Visit 1 m. Visit Patients with Acute Coronary Syndrome (unstable angina or non-ST-segment elevation MI) R Placebo loading dose R = Randomization * In combination with other standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Study Design 3 months £ double-blind treatment £ 12 months Clopidogrel 300 mg loading dose CURE Clopidogrel + ASA* 3 6 9 Placebo + ASA* Months of Follow-Up 11.4% 9.3% 20% RRR P < 0.001 N = 12,562 0 12 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Primary End Point - MI/Stroke/CV Death CURE Clopidogrel + ASA* 10 20 30 Placebo + ASA* Days of Follow-Up 0 21% RRR P = 0.003 N = 12,562 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. MI/Stroke/CV Death within 30 Days CURE 1 CV death, nonfatal MI, stroke or refractory or severe ischemia 34% NEJM 2001; 345:495-502 MI/Stroke/CV Death or severe Ischemia at 24 hours CURE 1 % patients requiring thrombolytic therapy 43% % patients requiring GP IIb/IIIa inhibitors 18% NEJM 2001; 345:495-502 Need for Additional Anti-Thrombotic After Randomization P< 0.001 P= 0.003 Thrombolysis GP IIb/IIIa Inhibitor CURE 1 Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? GP IIb/IIIa receptor is the final common pathway in platelet aggregation. GP IIb/IIIa blockade is the most effective antiplatelet aggregation therapy. Bleeding risk is not increased if therapy is stopped 2-4 hours prior to CABG. Bleeding risk is markedly increased unless clopidogrel is stopped 3-5 days prior to CABG. Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? Is there additional benefit to clopidogrel that would justify: Increased CABG bleeding or alternatively Need to postpone CABG for 3-5 days No data in the literature however Adhesion The Role of Platelets in Atherothrombosis Aggregation 3 Reproduced with permission from Cannon CP. Atherothrombosis slide compendium. Available at: www.theheart.org. 1 Activation 2 Conclusions: Early Clopidogrel Therapy Treatment with clopidogrel is indicated as soon as possible in patients with acute coronary syndrome ST elevation and non ST elevation Treatment is effective to reduce ischemic complications Before coronay angiography During and after PCI 1 Conclusions: Early Clopidogrel Therapy Loading dose should be 600mg to achieve early optimal antiplatelet effect ?? 300mg in patients after fibrinolytic therapy It is unclear whether therapy should be added to “upstream” GP IIb/IIIa antagonists Especially in high risk patients in whom the likelihood for CABG is high 1 Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month after PCI / stent improving long-term outcome 1 2 Discharge/Post-Discharge Medications - Guidelines ASA, if not contraindicated Clopidogrel, when ASA contraindicated Aspirin + Clopidogrel for up to 9 months -blocker, if not contraindicated Lipid  agents + diet, if LDL >130 mg/dL ACE Inhibitor: CHF, EF < 40%, DM, or HTN I IIa IIb III 2 Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization PCI PLACEBO + ASA * CLOPIDOGREL + ASA * 30 days post PCI End of follow-up Up to 12 months after randomization Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 2,658 patients undergoing PCI N = 1345 N = 1313 PCI-CURE Overall Study Design: PCI-CURE R Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE Question 1 Question 2 Clopidogrel Arm Placebo Arm PCI* 28 Days Placebo + ASA† (325 mg) Randomization - Pre-treatment Clopidogrel 300 mg + ASA† (325 mg) Clopidogrel 75 mg QD + ASA† 325 mg QD Clopidogrel 75 mg QD + ASA† 325 mg QD R 12 Months Steinhubl S, Berger P, Tift Mann III J et al. JAMA. 2002;Vol 288,No 19:2411-2420. Placebo QD + ASA† (81-325 mg) QD Clopidogrel 75 mg QD + ASA† (81-325 mg) QD Overall Study Design: CREDO Question 1 Question 2 1 2 Open label clopidogrel continuation Methodological Pitfall Can a study with a single randomization provide an answer to two questions? Alternatively Should a second randomization be done in order to answer the second question? PCI PLACEBO + ASA * CLOPIDOGREL + ASA * 30 days post PCI End of follow-up Up to 12 months after randomization Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 1345 N = 1313 PCI-CURE Study Design single randomization R Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE Continuation Continuation PCI PLACEBO + ASA * CLOPIDOGREL + ASA * Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 1345 N = 1313 PCI-CURE Alternative Study Design two randomizations R1 Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE R2 R2 Clop. Placebo Continuation Continuation Question 2 2 Is it just methodology? Can we really expect long term benefit from early antiplatelet therapy? Adjunct antiplatelet therapy for PCI EPISTENT Randomized study designed to determine the effect of treatment with abciximab TARGET Randomized study designed to show that tirofiban is not inferior to abciximab Post-hoc nonrandomized comparison among those who were or were not pre-treated with clopidogrel PCI-CURE Subgroup of CURE patients who underwent PCI Randomized comparison of pre-treatment and continued clopidogrel therapy vs. placebo Absolute reduction of Death or MI at 1 month and 1 year Abciximab Early clopidogrel Early and continued clopidogrel % reduction * * 6 month data in TARGET Early and long term reduction of death or MI from antiplatelet therapy in patients with ACS Long Term Clopidogrel Post PCI Clinical guidelines: 9 months to 1 year in patients with ACS However, current data does not fully support this recommendation What should we do? 2 Comulative event rate in primary prevention stable CAD and ACS ACS Stable Primary Risk of vascular event after ACS Risk of event Time after ACS Stable CAD Commulative risk Risk per time
Slide 49 - Early And Long Term Treatment With Clopidogrel In Coronary Artery Disease פרופ’ יוסף רוזנמן מכון הלב, בי"ח וולפסון דצמבר 2005 Acute Coronary Syndromes Acute Coronary Syndrome No ST Elevation ST Elevation Unstable Angina Myocardial Infarction Non Q MI Q wave MI Non ST Elevation MI Braunwald E et al. J Am Coll Cardiol 2000;36:970–1062. Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When angiography / PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until angiography / PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month improving long-term outcome 1 2 Goals of therapy Prevent ischemic events until coronary angiography / PCI Before plaque stabilization was achieved Prevent PCI / stent related ischemic complications Clopidogrel before coronary angiography - Patients with ACS 1 Clopidogrel before coronary angiography - Patients with ACS ST Elevation CLARITY Non ST Elevation CURE 1 ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Study Design Fibrinolytic, ASA, Heparin Clopidogrel 300 mg + 75 mg qd Coronary Angiogram (2-8 days) Primary endpoint: Occluded artery (TIMI Flow Grade 0/1) or D/MI by time of angio randomize Placebo Double-blind, randomized, placebo-controlled trial in 3491 patients, age 18-75 yrs with STEMI < 12 hours Study Drug 30-day clinical follow-up Open-label clopidogrel per MD in both groups Primary Endpoint: Occluded Artery (or D/MI by time of angio) Placebo Clopidogrel P=0.00000036 Odds Ratio 0.64 (95% CI 0.53-0.76) 1.0 0.4 0.6 0.8 1.2 1.6 Clopidogrel better Placebo better n=1752 n=1739 36% Odds Reduction Primary & Angiographic Outcomes (median 3.5 days) Need for Urgent or Additional Treatment 21%  P=0.01 21%  P=0.005 16%  P=0.07 Early Angio (w/in 48 hrs) Urgent Revasc (index hosp) GP IIb/IIIa if PCI CV Death, MI, RI  Urg Revasc days Percentage with endpoint (%) 0 5 10 15 0 5 10 15 20 25 30 Placebo Clopidogrel Odds Ratio 0.80 (95% CI 0.65-0.97) P=0.026 20% 1 CLARITY: Patient Management Clopidogrel Placebo Parameter (n=1,752) (n=1,739) Symptom onset to fibrinolytic (hours) 2.7 2.6 Fibrinolytic to study drug (minutes) 10 10 Median doses of study medication 4 4 Angiography performed (%) 94 94 Study drug to angiography (hours) 84 84 Coronary revascularization (%): 63 63 PCI 57.2 56.6 CABG 5.9 6.0 Sabatine M et al. New Engl J Med 2005; 352: 1179–1189. PCI-CLARITY: Reduction in CV Death, MI, Stroke from PCI to 30 Days Days Post PCI Percentage with Outcome (%) 0 2 0 5 10 15 20 25 30 46%* p=0.008 Clopidogrel Pretreatment (3.6%) No Pretreatment (6.2%) 4 6 8 M Sabatine, et al. JAMA 2005 PCI-CLARITY: MI, Stroke, or CV Death Events pre and post PCI ***MI or Stroke M Sabatine, et al. JAMA 2005, Prehospital Fibrinolysis with Double Antiplatelet Therapy in Acute ST-Elevation Myocardial Infarction: The Clarity Ambulance Substudy Substudy Sites and Patient Numbers France: 172 patients L Soulat: 57 Y Lambert: 48 F Lapostolle: 28 F Thieuleux: 21 C Gully: 10 D Pollet: 5 D Galley: 2 L Olliver: 1 UK: 40 patients J Adgey: 27 J Purvis: 13 Sweden: 5 patients J-E Karlsson: 5 217 patients in total Angiographic & ECG Parameters: Ambulance vs. Non-Ambulance *Complete considered to be >70%; ECG=electrocardiogram p value Event rate (%) Ambulance Non- ambulance Non-ambulance better Ambulance better Odds ratio (95% CI) 0 0.5 1.0 1.5 2.0 Ambulance Non-ambulance Overall Clopidogrel better Placebo better Odds ratio (95% CI) Primary Endpoint of TIMI Flow Grade 0/1, MI or Death 0.60 (0.301.17) 0.64 (0.530.76) 0.65 (0.540.77) ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Clopidogrel 75mg q.d. + ASA 75-325 mg q.d.* (6259 patients) Placebo + ASA 75-325 mg q.d.* (6303 patients) Day 1 6 m. Visit 9 m. Visit 12 m. or Final Visit 3 m. Visit Discharge Visit 1 m. Visit Patients with Acute Coronary Syndrome (unstable angina or non-ST-segment elevation MI) R Placebo loading dose R = Randomization * In combination with other standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Study Design 3 months £ double-blind treatment £ 12 months Clopidogrel 300 mg loading dose CURE Clopidogrel + ASA* 3 6 9 Placebo + ASA* Months of Follow-Up 11.4% 9.3% 20% RRR P < 0.001 N = 12,562 0 12 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Primary End Point - MI/Stroke/CV Death CURE Clopidogrel + ASA* 10 20 30 Placebo + ASA* Days of Follow-Up 0 21% RRR P = 0.003 N = 12,562 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. MI/Stroke/CV Death within 30 Days CURE 1 CV death, nonfatal MI, stroke or refractory or severe ischemia 34% NEJM 2001; 345:495-502 MI/Stroke/CV Death or severe Ischemia at 24 hours CURE 1 % patients requiring thrombolytic therapy 43% % patients requiring GP IIb/IIIa inhibitors 18% NEJM 2001; 345:495-502 Need for Additional Anti-Thrombotic After Randomization P< 0.001 P= 0.003 Thrombolysis GP IIb/IIIa Inhibitor CURE 1 Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? GP IIb/IIIa receptor is the final common pathway in platelet aggregation. GP IIb/IIIa blockade is the most effective antiplatelet aggregation therapy. Bleeding risk is not increased if therapy is stopped 2-4 hours prior to CABG. Bleeding risk is markedly increased unless clopidogrel is stopped 3-5 days prior to CABG. Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? Is there additional benefit to clopidogrel that would justify: Increased CABG bleeding or alternatively Need to postpone CABG for 3-5 days No data in the literature however Adhesion The Role of Platelets in Atherothrombosis Aggregation 3 Reproduced with permission from Cannon CP. Atherothrombosis slide compendium. Available at: www.theheart.org. 1 Activation 2 Conclusions: Early Clopidogrel Therapy Treatment with clopidogrel is indicated as soon as possible in patients with acute coronary syndrome ST elevation and non ST elevation Treatment is effective to reduce ischemic complications Before coronay angiography During and after PCI 1 Conclusions: Early Clopidogrel Therapy Loading dose should be 600mg to achieve early optimal antiplatelet effect ?? 300mg in patients after fibrinolytic therapy It is unclear whether therapy should be added to “upstream” GP IIb/IIIa antagonists Especially in high risk patients in whom the likelihood for CABG is high 1 Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month after PCI / stent improving long-term outcome 1 2 Discharge/Post-Discharge Medications - Guidelines ASA, if not contraindicated Clopidogrel, when ASA contraindicated Aspirin + Clopidogrel for up to 9 months -blocker, if not contraindicated Lipid  agents + diet, if LDL >130 mg/dL ACE Inhibitor: CHF, EF < 40%, DM, or HTN I IIa IIb III 2 Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization PCI PLACEBO + ASA * CLOPIDOGREL + ASA * 30 days post PCI End of follow-up Up to 12 months after randomization Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 2,658 patients undergoing PCI N = 1345 N = 1313 PCI-CURE Overall Study Design: PCI-CURE R Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE Question 1 Question 2 Clopidogrel Arm Placebo Arm PCI* 28 Days Placebo + ASA† (325 mg) Randomization - Pre-treatment Clopidogrel 300 mg + ASA† (325 mg) Clopidogrel 75 mg QD + ASA† 325 mg QD Clopidogrel 75 mg QD + ASA† 325 mg QD R 12 Months Steinhubl S, Berger P, Tift Mann III J et al. JAMA. 2002;Vol 288,No 19:2411-2420. Placebo QD + ASA† (81-325 mg) QD Clopidogrel 75 mg QD + ASA† (81-325 mg) QD Overall Study Design: CREDO Question 1 Question 2 1 2 Open label clopidogrel continuation Methodological Pitfall Can a study with a single randomization provide an answer to two questions? Alternatively Should a second randomization be done in order to answer the second question? PCI PLACEBO + ASA * CLOPIDOGREL + ASA * 30 days post PCI End of follow-up Up to 12 months after randomization Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 1345 N = 1313 PCI-CURE Study Design single randomization R Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE Continuation Continuation PCI PLACEBO + ASA * CLOPIDOGREL + ASA * Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 1345 N = 1313 PCI-CURE Alternative Study Design two randomizations R1 Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE R2 R2 Clop. Placebo Continuation Continuation Question 2 2 Is it just methodology? Can we really expect long term benefit from early antiplatelet therapy? Adjunct antiplatelet therapy for PCI EPISTENT Randomized study designed to determine the effect of treatment with abciximab TARGET Randomized study designed to show that tirofiban is not inferior to abciximab Post-hoc nonrandomized comparison among those who were or were not pre-treated with clopidogrel PCI-CURE Subgroup of CURE patients who underwent PCI Randomized comparison of pre-treatment and continued clopidogrel therapy vs. placebo Absolute reduction of Death or MI at 1 month and 1 year Abciximab Early clopidogrel Early and continued clopidogrel % reduction * * 6 month data in TARGET Early and long term reduction of death or MI from antiplatelet therapy in patients with ACS Long Term Clopidogrel Post PCI Clinical guidelines: 9 months to 1 year in patients with ACS However, current data does not fully support this recommendation What should we do? 2 Comulative event rate in primary prevention stable CAD and ACS ACS Stable Primary Risk of vascular event after ACS Risk of event Time after ACS Stable CAD Commulative risk Risk per time Risk of vascular event after ACS high and low risk Risk of event Time after ACS High risk Low risk
Slide 50 - Early And Long Term Treatment With Clopidogrel In Coronary Artery Disease פרופ’ יוסף רוזנמן מכון הלב, בי"ח וולפסון דצמבר 2005 Acute Coronary Syndromes Acute Coronary Syndrome No ST Elevation ST Elevation Unstable Angina Myocardial Infarction Non Q MI Q wave MI Non ST Elevation MI Braunwald E et al. J Am Coll Cardiol 2000;36:970–1062. Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When angiography / PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until angiography / PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month improving long-term outcome 1 2 Goals of therapy Prevent ischemic events until coronary angiography / PCI Before plaque stabilization was achieved Prevent PCI / stent related ischemic complications Clopidogrel before coronary angiography - Patients with ACS 1 Clopidogrel before coronary angiography - Patients with ACS ST Elevation CLARITY Non ST Elevation CURE 1 ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Study Design Fibrinolytic, ASA, Heparin Clopidogrel 300 mg + 75 mg qd Coronary Angiogram (2-8 days) Primary endpoint: Occluded artery (TIMI Flow Grade 0/1) or D/MI by time of angio randomize Placebo Double-blind, randomized, placebo-controlled trial in 3491 patients, age 18-75 yrs with STEMI < 12 hours Study Drug 30-day clinical follow-up Open-label clopidogrel per MD in both groups Primary Endpoint: Occluded Artery (or D/MI by time of angio) Placebo Clopidogrel P=0.00000036 Odds Ratio 0.64 (95% CI 0.53-0.76) 1.0 0.4 0.6 0.8 1.2 1.6 Clopidogrel better Placebo better n=1752 n=1739 36% Odds Reduction Primary & Angiographic Outcomes (median 3.5 days) Need for Urgent or Additional Treatment 21%  P=0.01 21%  P=0.005 16%  P=0.07 Early Angio (w/in 48 hrs) Urgent Revasc (index hosp) GP IIb/IIIa if PCI CV Death, MI, RI  Urg Revasc days Percentage with endpoint (%) 0 5 10 15 0 5 10 15 20 25 30 Placebo Clopidogrel Odds Ratio 0.80 (95% CI 0.65-0.97) P=0.026 20% 1 CLARITY: Patient Management Clopidogrel Placebo Parameter (n=1,752) (n=1,739) Symptom onset to fibrinolytic (hours) 2.7 2.6 Fibrinolytic to study drug (minutes) 10 10 Median doses of study medication 4 4 Angiography performed (%) 94 94 Study drug to angiography (hours) 84 84 Coronary revascularization (%): 63 63 PCI 57.2 56.6 CABG 5.9 6.0 Sabatine M et al. New Engl J Med 2005; 352: 1179–1189. PCI-CLARITY: Reduction in CV Death, MI, Stroke from PCI to 30 Days Days Post PCI Percentage with Outcome (%) 0 2 0 5 10 15 20 25 30 46%* p=0.008 Clopidogrel Pretreatment (3.6%) No Pretreatment (6.2%) 4 6 8 M Sabatine, et al. JAMA 2005 PCI-CLARITY: MI, Stroke, or CV Death Events pre and post PCI ***MI or Stroke M Sabatine, et al. JAMA 2005, Prehospital Fibrinolysis with Double Antiplatelet Therapy in Acute ST-Elevation Myocardial Infarction: The Clarity Ambulance Substudy Substudy Sites and Patient Numbers France: 172 patients L Soulat: 57 Y Lambert: 48 F Lapostolle: 28 F Thieuleux: 21 C Gully: 10 D Pollet: 5 D Galley: 2 L Olliver: 1 UK: 40 patients J Adgey: 27 J Purvis: 13 Sweden: 5 patients J-E Karlsson: 5 217 patients in total Angiographic & ECG Parameters: Ambulance vs. Non-Ambulance *Complete considered to be >70%; ECG=electrocardiogram p value Event rate (%) Ambulance Non- ambulance Non-ambulance better Ambulance better Odds ratio (95% CI) 0 0.5 1.0 1.5 2.0 Ambulance Non-ambulance Overall Clopidogrel better Placebo better Odds ratio (95% CI) Primary Endpoint of TIMI Flow Grade 0/1, MI or Death 0.60 (0.301.17) 0.64 (0.530.76) 0.65 (0.540.77) ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Clopidogrel 75mg q.d. + ASA 75-325 mg q.d.* (6259 patients) Placebo + ASA 75-325 mg q.d.* (6303 patients) Day 1 6 m. Visit 9 m. Visit 12 m. or Final Visit 3 m. Visit Discharge Visit 1 m. Visit Patients with Acute Coronary Syndrome (unstable angina or non-ST-segment elevation MI) R Placebo loading dose R = Randomization * In combination with other standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Study Design 3 months £ double-blind treatment £ 12 months Clopidogrel 300 mg loading dose CURE Clopidogrel + ASA* 3 6 9 Placebo + ASA* Months of Follow-Up 11.4% 9.3% 20% RRR P < 0.001 N = 12,562 0 12 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Primary End Point - MI/Stroke/CV Death CURE Clopidogrel + ASA* 10 20 30 Placebo + ASA* Days of Follow-Up 0 21% RRR P = 0.003 N = 12,562 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. MI/Stroke/CV Death within 30 Days CURE 1 CV death, nonfatal MI, stroke or refractory or severe ischemia 34% NEJM 2001; 345:495-502 MI/Stroke/CV Death or severe Ischemia at 24 hours CURE 1 % patients requiring thrombolytic therapy 43% % patients requiring GP IIb/IIIa inhibitors 18% NEJM 2001; 345:495-502 Need for Additional Anti-Thrombotic After Randomization P< 0.001 P= 0.003 Thrombolysis GP IIb/IIIa Inhibitor CURE 1 Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? GP IIb/IIIa receptor is the final common pathway in platelet aggregation. GP IIb/IIIa blockade is the most effective antiplatelet aggregation therapy. Bleeding risk is not increased if therapy is stopped 2-4 hours prior to CABG. Bleeding risk is markedly increased unless clopidogrel is stopped 3-5 days prior to CABG. Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? Is there additional benefit to clopidogrel that would justify: Increased CABG bleeding or alternatively Need to postpone CABG for 3-5 days No data in the literature however Adhesion The Role of Platelets in Atherothrombosis Aggregation 3 Reproduced with permission from Cannon CP. Atherothrombosis slide compendium. Available at: www.theheart.org. 1 Activation 2 Conclusions: Early Clopidogrel Therapy Treatment with clopidogrel is indicated as soon as possible in patients with acute coronary syndrome ST elevation and non ST elevation Treatment is effective to reduce ischemic complications Before coronay angiography During and after PCI 1 Conclusions: Early Clopidogrel Therapy Loading dose should be 600mg to achieve early optimal antiplatelet effect ?? 300mg in patients after fibrinolytic therapy It is unclear whether therapy should be added to “upstream” GP IIb/IIIa antagonists Especially in high risk patients in whom the likelihood for CABG is high 1 Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month after PCI / stent improving long-term outcome 1 2 Discharge/Post-Discharge Medications - Guidelines ASA, if not contraindicated Clopidogrel, when ASA contraindicated Aspirin + Clopidogrel for up to 9 months -blocker, if not contraindicated Lipid  agents + diet, if LDL >130 mg/dL ACE Inhibitor: CHF, EF < 40%, DM, or HTN I IIa IIb III 2 Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization PCI PLACEBO + ASA * CLOPIDOGREL + ASA * 30 days post PCI End of follow-up Up to 12 months after randomization Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 2,658 patients undergoing PCI N = 1345 N = 1313 PCI-CURE Overall Study Design: PCI-CURE R Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE Question 1 Question 2 Clopidogrel Arm Placebo Arm PCI* 28 Days Placebo + ASA† (325 mg) Randomization - Pre-treatment Clopidogrel 300 mg + ASA† (325 mg) Clopidogrel 75 mg QD + ASA† 325 mg QD Clopidogrel 75 mg QD + ASA† 325 mg QD R 12 Months Steinhubl S, Berger P, Tift Mann III J et al. JAMA. 2002;Vol 288,No 19:2411-2420. Placebo QD + ASA† (81-325 mg) QD Clopidogrel 75 mg QD + ASA† (81-325 mg) QD Overall Study Design: CREDO Question 1 Question 2 1 2 Open label clopidogrel continuation Methodological Pitfall Can a study with a single randomization provide an answer to two questions? Alternatively Should a second randomization be done in order to answer the second question? PCI PLACEBO + ASA * CLOPIDOGREL + ASA * 30 days post PCI End of follow-up Up to 12 months after randomization Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 1345 N = 1313 PCI-CURE Study Design single randomization R Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE Continuation Continuation PCI PLACEBO + ASA * CLOPIDOGREL + ASA * Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 1345 N = 1313 PCI-CURE Alternative Study Design two randomizations R1 Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE R2 R2 Clop. Placebo Continuation Continuation Question 2 2 Is it just methodology? Can we really expect long term benefit from early antiplatelet therapy? Adjunct antiplatelet therapy for PCI EPISTENT Randomized study designed to determine the effect of treatment with abciximab TARGET Randomized study designed to show that tirofiban is not inferior to abciximab Post-hoc nonrandomized comparison among those who were or were not pre-treated with clopidogrel PCI-CURE Subgroup of CURE patients who underwent PCI Randomized comparison of pre-treatment and continued clopidogrel therapy vs. placebo Absolute reduction of Death or MI at 1 month and 1 year Abciximab Early clopidogrel Early and continued clopidogrel % reduction * * 6 month data in TARGET Early and long term reduction of death or MI from antiplatelet therapy in patients with ACS Long Term Clopidogrel Post PCI Clinical guidelines: 9 months to 1 year in patients with ACS However, current data does not fully support this recommendation What should we do? 2 Comulative event rate in primary prevention stable CAD and ACS ACS Stable Primary Risk of vascular event after ACS Risk of event Time after ACS Stable CAD Commulative risk Risk per time Risk of vascular event after ACS high and low risk Risk of event Time after ACS High risk Low risk Risk of bleeding after initiation of clopidogrel (high and low risk) Risk of event Time after clopidogrel High risk Low risk Fixed, except for the initial few days heparin, catheterization
Slide 51 - Early And Long Term Treatment With Clopidogrel In Coronary Artery Disease פרופ’ יוסף רוזנמן מכון הלב, בי"ח וולפסון דצמבר 2005 Acute Coronary Syndromes Acute Coronary Syndrome No ST Elevation ST Elevation Unstable Angina Myocardial Infarction Non Q MI Q wave MI Non ST Elevation MI Braunwald E et al. J Am Coll Cardiol 2000;36:970–1062. Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When angiography / PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until angiography / PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month improving long-term outcome 1 2 Goals of therapy Prevent ischemic events until coronary angiography / PCI Before plaque stabilization was achieved Prevent PCI / stent related ischemic complications Clopidogrel before coronary angiography - Patients with ACS 1 Clopidogrel before coronary angiography - Patients with ACS ST Elevation CLARITY Non ST Elevation CURE 1 ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Study Design Fibrinolytic, ASA, Heparin Clopidogrel 300 mg + 75 mg qd Coronary Angiogram (2-8 days) Primary endpoint: Occluded artery (TIMI Flow Grade 0/1) or D/MI by time of angio randomize Placebo Double-blind, randomized, placebo-controlled trial in 3491 patients, age 18-75 yrs with STEMI < 12 hours Study Drug 30-day clinical follow-up Open-label clopidogrel per MD in both groups Primary Endpoint: Occluded Artery (or D/MI by time of angio) Placebo Clopidogrel P=0.00000036 Odds Ratio 0.64 (95% CI 0.53-0.76) 1.0 0.4 0.6 0.8 1.2 1.6 Clopidogrel better Placebo better n=1752 n=1739 36% Odds Reduction Primary & Angiographic Outcomes (median 3.5 days) Need for Urgent or Additional Treatment 21%  P=0.01 21%  P=0.005 16%  P=0.07 Early Angio (w/in 48 hrs) Urgent Revasc (index hosp) GP IIb/IIIa if PCI CV Death, MI, RI  Urg Revasc days Percentage with endpoint (%) 0 5 10 15 0 5 10 15 20 25 30 Placebo Clopidogrel Odds Ratio 0.80 (95% CI 0.65-0.97) P=0.026 20% 1 CLARITY: Patient Management Clopidogrel Placebo Parameter (n=1,752) (n=1,739) Symptom onset to fibrinolytic (hours) 2.7 2.6 Fibrinolytic to study drug (minutes) 10 10 Median doses of study medication 4 4 Angiography performed (%) 94 94 Study drug to angiography (hours) 84 84 Coronary revascularization (%): 63 63 PCI 57.2 56.6 CABG 5.9 6.0 Sabatine M et al. New Engl J Med 2005; 352: 1179–1189. PCI-CLARITY: Reduction in CV Death, MI, Stroke from PCI to 30 Days Days Post PCI Percentage with Outcome (%) 0 2 0 5 10 15 20 25 30 46%* p=0.008 Clopidogrel Pretreatment (3.6%) No Pretreatment (6.2%) 4 6 8 M Sabatine, et al. JAMA 2005 PCI-CLARITY: MI, Stroke, or CV Death Events pre and post PCI ***MI or Stroke M Sabatine, et al. JAMA 2005, Prehospital Fibrinolysis with Double Antiplatelet Therapy in Acute ST-Elevation Myocardial Infarction: The Clarity Ambulance Substudy Substudy Sites and Patient Numbers France: 172 patients L Soulat: 57 Y Lambert: 48 F Lapostolle: 28 F Thieuleux: 21 C Gully: 10 D Pollet: 5 D Galley: 2 L Olliver: 1 UK: 40 patients J Adgey: 27 J Purvis: 13 Sweden: 5 patients J-E Karlsson: 5 217 patients in total Angiographic & ECG Parameters: Ambulance vs. Non-Ambulance *Complete considered to be >70%; ECG=electrocardiogram p value Event rate (%) Ambulance Non- ambulance Non-ambulance better Ambulance better Odds ratio (95% CI) 0 0.5 1.0 1.5 2.0 Ambulance Non-ambulance Overall Clopidogrel better Placebo better Odds ratio (95% CI) Primary Endpoint of TIMI Flow Grade 0/1, MI or Death 0.60 (0.301.17) 0.64 (0.530.76) 0.65 (0.540.77) ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Clopidogrel 75mg q.d. + ASA 75-325 mg q.d.* (6259 patients) Placebo + ASA 75-325 mg q.d.* (6303 patients) Day 1 6 m. Visit 9 m. Visit 12 m. or Final Visit 3 m. Visit Discharge Visit 1 m. Visit Patients with Acute Coronary Syndrome (unstable angina or non-ST-segment elevation MI) R Placebo loading dose R = Randomization * In combination with other standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Study Design 3 months £ double-blind treatment £ 12 months Clopidogrel 300 mg loading dose CURE Clopidogrel + ASA* 3 6 9 Placebo + ASA* Months of Follow-Up 11.4% 9.3% 20% RRR P < 0.001 N = 12,562 0 12 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Primary End Point - MI/Stroke/CV Death CURE Clopidogrel + ASA* 10 20 30 Placebo + ASA* Days of Follow-Up 0 21% RRR P = 0.003 N = 12,562 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. MI/Stroke/CV Death within 30 Days CURE 1 CV death, nonfatal MI, stroke or refractory or severe ischemia 34% NEJM 2001; 345:495-502 MI/Stroke/CV Death or severe Ischemia at 24 hours CURE 1 % patients requiring thrombolytic therapy 43% % patients requiring GP IIb/IIIa inhibitors 18% NEJM 2001; 345:495-502 Need for Additional Anti-Thrombotic After Randomization P< 0.001 P= 0.003 Thrombolysis GP IIb/IIIa Inhibitor CURE 1 Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? GP IIb/IIIa receptor is the final common pathway in platelet aggregation. GP IIb/IIIa blockade is the most effective antiplatelet aggregation therapy. Bleeding risk is not increased if therapy is stopped 2-4 hours prior to CABG. Bleeding risk is markedly increased unless clopidogrel is stopped 3-5 days prior to CABG. Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? Is there additional benefit to clopidogrel that would justify: Increased CABG bleeding or alternatively Need to postpone CABG for 3-5 days No data in the literature however Adhesion The Role of Platelets in Atherothrombosis Aggregation 3 Reproduced with permission from Cannon CP. Atherothrombosis slide compendium. Available at: www.theheart.org. 1 Activation 2 Conclusions: Early Clopidogrel Therapy Treatment with clopidogrel is indicated as soon as possible in patients with acute coronary syndrome ST elevation and non ST elevation Treatment is effective to reduce ischemic complications Before coronay angiography During and after PCI 1 Conclusions: Early Clopidogrel Therapy Loading dose should be 600mg to achieve early optimal antiplatelet effect ?? 300mg in patients after fibrinolytic therapy It is unclear whether therapy should be added to “upstream” GP IIb/IIIa antagonists Especially in high risk patients in whom the likelihood for CABG is high 1 Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month after PCI / stent improving long-term outcome 1 2 Discharge/Post-Discharge Medications - Guidelines ASA, if not contraindicated Clopidogrel, when ASA contraindicated Aspirin + Clopidogrel for up to 9 months -blocker, if not contraindicated Lipid  agents + diet, if LDL >130 mg/dL ACE Inhibitor: CHF, EF < 40%, DM, or HTN I IIa IIb III 2 Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization PCI PLACEBO + ASA * CLOPIDOGREL + ASA * 30 days post PCI End of follow-up Up to 12 months after randomization Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 2,658 patients undergoing PCI N = 1345 N = 1313 PCI-CURE Overall Study Design: PCI-CURE R Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE Question 1 Question 2 Clopidogrel Arm Placebo Arm PCI* 28 Days Placebo + ASA† (325 mg) Randomization - Pre-treatment Clopidogrel 300 mg + ASA† (325 mg) Clopidogrel 75 mg QD + ASA† 325 mg QD Clopidogrel 75 mg QD + ASA† 325 mg QD R 12 Months Steinhubl S, Berger P, Tift Mann III J et al. JAMA. 2002;Vol 288,No 19:2411-2420. Placebo QD + ASA† (81-325 mg) QD Clopidogrel 75 mg QD + ASA† (81-325 mg) QD Overall Study Design: CREDO Question 1 Question 2 1 2 Open label clopidogrel continuation Methodological Pitfall Can a study with a single randomization provide an answer to two questions? Alternatively Should a second randomization be done in order to answer the second question? PCI PLACEBO + ASA * CLOPIDOGREL + ASA * 30 days post PCI End of follow-up Up to 12 months after randomization Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 1345 N = 1313 PCI-CURE Study Design single randomization R Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE Continuation Continuation PCI PLACEBO + ASA * CLOPIDOGREL + ASA * Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 1345 N = 1313 PCI-CURE Alternative Study Design two randomizations R1 Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE R2 R2 Clop. Placebo Continuation Continuation Question 2 2 Is it just methodology? Can we really expect long term benefit from early antiplatelet therapy? Adjunct antiplatelet therapy for PCI EPISTENT Randomized study designed to determine the effect of treatment with abciximab TARGET Randomized study designed to show that tirofiban is not inferior to abciximab Post-hoc nonrandomized comparison among those who were or were not pre-treated with clopidogrel PCI-CURE Subgroup of CURE patients who underwent PCI Randomized comparison of pre-treatment and continued clopidogrel therapy vs. placebo Absolute reduction of Death or MI at 1 month and 1 year Abciximab Early clopidogrel Early and continued clopidogrel % reduction * * 6 month data in TARGET Early and long term reduction of death or MI from antiplatelet therapy in patients with ACS Long Term Clopidogrel Post PCI Clinical guidelines: 9 months to 1 year in patients with ACS However, current data does not fully support this recommendation What should we do? 2 Comulative event rate in primary prevention stable CAD and ACS ACS Stable Primary Risk of vascular event after ACS Risk of event Time after ACS Stable CAD Commulative risk Risk per time Risk of vascular event after ACS high and low risk Risk of event Time after ACS High risk Low risk Risk of bleeding after initiation of clopidogrel (high and low risk) Risk of event Time after clopidogrel High risk Low risk Fixed, except for the initial few days heparin, catheterization Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? vascular bleeding
Slide 52 - Early And Long Term Treatment With Clopidogrel In Coronary Artery Disease פרופ’ יוסף רוזנמן מכון הלב, בי"ח וולפסון דצמבר 2005 Acute Coronary Syndromes Acute Coronary Syndrome No ST Elevation ST Elevation Unstable Angina Myocardial Infarction Non Q MI Q wave MI Non ST Elevation MI Braunwald E et al. J Am Coll Cardiol 2000;36:970–1062. Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When angiography / PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until angiography / PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month improving long-term outcome 1 2 Goals of therapy Prevent ischemic events until coronary angiography / PCI Before plaque stabilization was achieved Prevent PCI / stent related ischemic complications Clopidogrel before coronary angiography - Patients with ACS 1 Clopidogrel before coronary angiography - Patients with ACS ST Elevation CLARITY Non ST Elevation CURE 1 ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Study Design Fibrinolytic, ASA, Heparin Clopidogrel 300 mg + 75 mg qd Coronary Angiogram (2-8 days) Primary endpoint: Occluded artery (TIMI Flow Grade 0/1) or D/MI by time of angio randomize Placebo Double-blind, randomized, placebo-controlled trial in 3491 patients, age 18-75 yrs with STEMI < 12 hours Study Drug 30-day clinical follow-up Open-label clopidogrel per MD in both groups Primary Endpoint: Occluded Artery (or D/MI by time of angio) Placebo Clopidogrel P=0.00000036 Odds Ratio 0.64 (95% CI 0.53-0.76) 1.0 0.4 0.6 0.8 1.2 1.6 Clopidogrel better Placebo better n=1752 n=1739 36% Odds Reduction Primary & Angiographic Outcomes (median 3.5 days) Need for Urgent or Additional Treatment 21%  P=0.01 21%  P=0.005 16%  P=0.07 Early Angio (w/in 48 hrs) Urgent Revasc (index hosp) GP IIb/IIIa if PCI CV Death, MI, RI  Urg Revasc days Percentage with endpoint (%) 0 5 10 15 0 5 10 15 20 25 30 Placebo Clopidogrel Odds Ratio 0.80 (95% CI 0.65-0.97) P=0.026 20% 1 CLARITY: Patient Management Clopidogrel Placebo Parameter (n=1,752) (n=1,739) Symptom onset to fibrinolytic (hours) 2.7 2.6 Fibrinolytic to study drug (minutes) 10 10 Median doses of study medication 4 4 Angiography performed (%) 94 94 Study drug to angiography (hours) 84 84 Coronary revascularization (%): 63 63 PCI 57.2 56.6 CABG 5.9 6.0 Sabatine M et al. New Engl J Med 2005; 352: 1179–1189. PCI-CLARITY: Reduction in CV Death, MI, Stroke from PCI to 30 Days Days Post PCI Percentage with Outcome (%) 0 2 0 5 10 15 20 25 30 46%* p=0.008 Clopidogrel Pretreatment (3.6%) No Pretreatment (6.2%) 4 6 8 M Sabatine, et al. JAMA 2005 PCI-CLARITY: MI, Stroke, or CV Death Events pre and post PCI ***MI or Stroke M Sabatine, et al. JAMA 2005, Prehospital Fibrinolysis with Double Antiplatelet Therapy in Acute ST-Elevation Myocardial Infarction: The Clarity Ambulance Substudy Substudy Sites and Patient Numbers France: 172 patients L Soulat: 57 Y Lambert: 48 F Lapostolle: 28 F Thieuleux: 21 C Gully: 10 D Pollet: 5 D Galley: 2 L Olliver: 1 UK: 40 patients J Adgey: 27 J Purvis: 13 Sweden: 5 patients J-E Karlsson: 5 217 patients in total Angiographic & ECG Parameters: Ambulance vs. Non-Ambulance *Complete considered to be >70%; ECG=electrocardiogram p value Event rate (%) Ambulance Non- ambulance Non-ambulance better Ambulance better Odds ratio (95% CI) 0 0.5 1.0 1.5 2.0 Ambulance Non-ambulance Overall Clopidogrel better Placebo better Odds ratio (95% CI) Primary Endpoint of TIMI Flow Grade 0/1, MI or Death 0.60 (0.301.17) 0.64 (0.530.76) 0.65 (0.540.77) ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Clopidogrel 75mg q.d. + ASA 75-325 mg q.d.* (6259 patients) Placebo + ASA 75-325 mg q.d.* (6303 patients) Day 1 6 m. Visit 9 m. Visit 12 m. or Final Visit 3 m. Visit Discharge Visit 1 m. Visit Patients with Acute Coronary Syndrome (unstable angina or non-ST-segment elevation MI) R Placebo loading dose R = Randomization * In combination with other standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Study Design 3 months £ double-blind treatment £ 12 months Clopidogrel 300 mg loading dose CURE Clopidogrel + ASA* 3 6 9 Placebo + ASA* Months of Follow-Up 11.4% 9.3% 20% RRR P < 0.001 N = 12,562 0 12 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Primary End Point - MI/Stroke/CV Death CURE Clopidogrel + ASA* 10 20 30 Placebo + ASA* Days of Follow-Up 0 21% RRR P = 0.003 N = 12,562 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. MI/Stroke/CV Death within 30 Days CURE 1 CV death, nonfatal MI, stroke or refractory or severe ischemia 34% NEJM 2001; 345:495-502 MI/Stroke/CV Death or severe Ischemia at 24 hours CURE 1 % patients requiring thrombolytic therapy 43% % patients requiring GP IIb/IIIa inhibitors 18% NEJM 2001; 345:495-502 Need for Additional Anti-Thrombotic After Randomization P< 0.001 P= 0.003 Thrombolysis GP IIb/IIIa Inhibitor CURE 1 Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? GP IIb/IIIa receptor is the final common pathway in platelet aggregation. GP IIb/IIIa blockade is the most effective antiplatelet aggregation therapy. Bleeding risk is not increased if therapy is stopped 2-4 hours prior to CABG. Bleeding risk is markedly increased unless clopidogrel is stopped 3-5 days prior to CABG. Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? Is there additional benefit to clopidogrel that would justify: Increased CABG bleeding or alternatively Need to postpone CABG for 3-5 days No data in the literature however Adhesion The Role of Platelets in Atherothrombosis Aggregation 3 Reproduced with permission from Cannon CP. Atherothrombosis slide compendium. Available at: www.theheart.org. 1 Activation 2 Conclusions: Early Clopidogrel Therapy Treatment with clopidogrel is indicated as soon as possible in patients with acute coronary syndrome ST elevation and non ST elevation Treatment is effective to reduce ischemic complications Before coronay angiography During and after PCI 1 Conclusions: Early Clopidogrel Therapy Loading dose should be 600mg to achieve early optimal antiplatelet effect ?? 300mg in patients after fibrinolytic therapy It is unclear whether therapy should be added to “upstream” GP IIb/IIIa antagonists Especially in high risk patients in whom the likelihood for CABG is high 1 Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month after PCI / stent improving long-term outcome 1 2 Discharge/Post-Discharge Medications - Guidelines ASA, if not contraindicated Clopidogrel, when ASA contraindicated Aspirin + Clopidogrel for up to 9 months -blocker, if not contraindicated Lipid  agents + diet, if LDL >130 mg/dL ACE Inhibitor: CHF, EF < 40%, DM, or HTN I IIa IIb III 2 Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization PCI PLACEBO + ASA * CLOPIDOGREL + ASA * 30 days post PCI End of follow-up Up to 12 months after randomization Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 2,658 patients undergoing PCI N = 1345 N = 1313 PCI-CURE Overall Study Design: PCI-CURE R Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE Question 1 Question 2 Clopidogrel Arm Placebo Arm PCI* 28 Days Placebo + ASA† (325 mg) Randomization - Pre-treatment Clopidogrel 300 mg + ASA† (325 mg) Clopidogrel 75 mg QD + ASA† 325 mg QD Clopidogrel 75 mg QD + ASA† 325 mg QD R 12 Months Steinhubl S, Berger P, Tift Mann III J et al. JAMA. 2002;Vol 288,No 19:2411-2420. Placebo QD + ASA† (81-325 mg) QD Clopidogrel 75 mg QD + ASA† (81-325 mg) QD Overall Study Design: CREDO Question 1 Question 2 1 2 Open label clopidogrel continuation Methodological Pitfall Can a study with a single randomization provide an answer to two questions? Alternatively Should a second randomization be done in order to answer the second question? PCI PLACEBO + ASA * CLOPIDOGREL + ASA * 30 days post PCI End of follow-up Up to 12 months after randomization Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 1345 N = 1313 PCI-CURE Study Design single randomization R Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE Continuation Continuation PCI PLACEBO + ASA * CLOPIDOGREL + ASA * Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 1345 N = 1313 PCI-CURE Alternative Study Design two randomizations R1 Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE R2 R2 Clop. Placebo Continuation Continuation Question 2 2 Is it just methodology? Can we really expect long term benefit from early antiplatelet therapy? Adjunct antiplatelet therapy for PCI EPISTENT Randomized study designed to determine the effect of treatment with abciximab TARGET Randomized study designed to show that tirofiban is not inferior to abciximab Post-hoc nonrandomized comparison among those who were or were not pre-treated with clopidogrel PCI-CURE Subgroup of CURE patients who underwent PCI Randomized comparison of pre-treatment and continued clopidogrel therapy vs. placebo Absolute reduction of Death or MI at 1 month and 1 year Abciximab Early clopidogrel Early and continued clopidogrel % reduction * * 6 month data in TARGET Early and long term reduction of death or MI from antiplatelet therapy in patients with ACS Long Term Clopidogrel Post PCI Clinical guidelines: 9 months to 1 year in patients with ACS However, current data does not fully support this recommendation What should we do? 2 Comulative event rate in primary prevention stable CAD and ACS ACS Stable Primary Risk of vascular event after ACS Risk of event Time after ACS Stable CAD Commulative risk Risk per time Risk of vascular event after ACS high and low risk Risk of event Time after ACS High risk Low risk Risk of bleeding after initiation of clopidogrel (high and low risk) Risk of event Time after clopidogrel High risk Low risk Fixed, except for the initial few days heparin, catheterization Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? vascular bleeding Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? vascular bleeding > 1 year High vascular risk
Slide 53 - Early And Long Term Treatment With Clopidogrel In Coronary Artery Disease פרופ’ יוסף רוזנמן מכון הלב, בי"ח וולפסון דצמבר 2005 Acute Coronary Syndromes Acute Coronary Syndrome No ST Elevation ST Elevation Unstable Angina Myocardial Infarction Non Q MI Q wave MI Non ST Elevation MI Braunwald E et al. J Am Coll Cardiol 2000;36:970–1062. Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When angiography / PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until angiography / PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month improving long-term outcome 1 2 Goals of therapy Prevent ischemic events until coronary angiography / PCI Before plaque stabilization was achieved Prevent PCI / stent related ischemic complications Clopidogrel before coronary angiography - Patients with ACS 1 Clopidogrel before coronary angiography - Patients with ACS ST Elevation CLARITY Non ST Elevation CURE 1 ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Study Design Fibrinolytic, ASA, Heparin Clopidogrel 300 mg + 75 mg qd Coronary Angiogram (2-8 days) Primary endpoint: Occluded artery (TIMI Flow Grade 0/1) or D/MI by time of angio randomize Placebo Double-blind, randomized, placebo-controlled trial in 3491 patients, age 18-75 yrs with STEMI < 12 hours Study Drug 30-day clinical follow-up Open-label clopidogrel per MD in both groups Primary Endpoint: Occluded Artery (or D/MI by time of angio) Placebo Clopidogrel P=0.00000036 Odds Ratio 0.64 (95% CI 0.53-0.76) 1.0 0.4 0.6 0.8 1.2 1.6 Clopidogrel better Placebo better n=1752 n=1739 36% Odds Reduction Primary & Angiographic Outcomes (median 3.5 days) Need for Urgent or Additional Treatment 21%  P=0.01 21%  P=0.005 16%  P=0.07 Early Angio (w/in 48 hrs) Urgent Revasc (index hosp) GP IIb/IIIa if PCI CV Death, MI, RI  Urg Revasc days Percentage with endpoint (%) 0 5 10 15 0 5 10 15 20 25 30 Placebo Clopidogrel Odds Ratio 0.80 (95% CI 0.65-0.97) P=0.026 20% 1 CLARITY: Patient Management Clopidogrel Placebo Parameter (n=1,752) (n=1,739) Symptom onset to fibrinolytic (hours) 2.7 2.6 Fibrinolytic to study drug (minutes) 10 10 Median doses of study medication 4 4 Angiography performed (%) 94 94 Study drug to angiography (hours) 84 84 Coronary revascularization (%): 63 63 PCI 57.2 56.6 CABG 5.9 6.0 Sabatine M et al. New Engl J Med 2005; 352: 1179–1189. PCI-CLARITY: Reduction in CV Death, MI, Stroke from PCI to 30 Days Days Post PCI Percentage with Outcome (%) 0 2 0 5 10 15 20 25 30 46%* p=0.008 Clopidogrel Pretreatment (3.6%) No Pretreatment (6.2%) 4 6 8 M Sabatine, et al. JAMA 2005 PCI-CLARITY: MI, Stroke, or CV Death Events pre and post PCI ***MI or Stroke M Sabatine, et al. JAMA 2005, Prehospital Fibrinolysis with Double Antiplatelet Therapy in Acute ST-Elevation Myocardial Infarction: The Clarity Ambulance Substudy Substudy Sites and Patient Numbers France: 172 patients L Soulat: 57 Y Lambert: 48 F Lapostolle: 28 F Thieuleux: 21 C Gully: 10 D Pollet: 5 D Galley: 2 L Olliver: 1 UK: 40 patients J Adgey: 27 J Purvis: 13 Sweden: 5 patients J-E Karlsson: 5 217 patients in total Angiographic & ECG Parameters: Ambulance vs. Non-Ambulance *Complete considered to be >70%; ECG=electrocardiogram p value Event rate (%) Ambulance Non- ambulance Non-ambulance better Ambulance better Odds ratio (95% CI) 0 0.5 1.0 1.5 2.0 Ambulance Non-ambulance Overall Clopidogrel better Placebo better Odds ratio (95% CI) Primary Endpoint of TIMI Flow Grade 0/1, MI or Death 0.60 (0.301.17) 0.64 (0.530.76) 0.65 (0.540.77) ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Clopidogrel 75mg q.d. + ASA 75-325 mg q.d.* (6259 patients) Placebo + ASA 75-325 mg q.d.* (6303 patients) Day 1 6 m. Visit 9 m. Visit 12 m. or Final Visit 3 m. Visit Discharge Visit 1 m. Visit Patients with Acute Coronary Syndrome (unstable angina or non-ST-segment elevation MI) R Placebo loading dose R = Randomization * In combination with other standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Study Design 3 months £ double-blind treatment £ 12 months Clopidogrel 300 mg loading dose CURE Clopidogrel + ASA* 3 6 9 Placebo + ASA* Months of Follow-Up 11.4% 9.3% 20% RRR P < 0.001 N = 12,562 0 12 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Primary End Point - MI/Stroke/CV Death CURE Clopidogrel + ASA* 10 20 30 Placebo + ASA* Days of Follow-Up 0 21% RRR P = 0.003 N = 12,562 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. MI/Stroke/CV Death within 30 Days CURE 1 CV death, nonfatal MI, stroke or refractory or severe ischemia 34% NEJM 2001; 345:495-502 MI/Stroke/CV Death or severe Ischemia at 24 hours CURE 1 % patients requiring thrombolytic therapy 43% % patients requiring GP IIb/IIIa inhibitors 18% NEJM 2001; 345:495-502 Need for Additional Anti-Thrombotic After Randomization P< 0.001 P= 0.003 Thrombolysis GP IIb/IIIa Inhibitor CURE 1 Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? GP IIb/IIIa receptor is the final common pathway in platelet aggregation. GP IIb/IIIa blockade is the most effective antiplatelet aggregation therapy. Bleeding risk is not increased if therapy is stopped 2-4 hours prior to CABG. Bleeding risk is markedly increased unless clopidogrel is stopped 3-5 days prior to CABG. Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? Is there additional benefit to clopidogrel that would justify: Increased CABG bleeding or alternatively Need to postpone CABG for 3-5 days No data in the literature however Adhesion The Role of Platelets in Atherothrombosis Aggregation 3 Reproduced with permission from Cannon CP. Atherothrombosis slide compendium. Available at: www.theheart.org. 1 Activation 2 Conclusions: Early Clopidogrel Therapy Treatment with clopidogrel is indicated as soon as possible in patients with acute coronary syndrome ST elevation and non ST elevation Treatment is effective to reduce ischemic complications Before coronay angiography During and after PCI 1 Conclusions: Early Clopidogrel Therapy Loading dose should be 600mg to achieve early optimal antiplatelet effect ?? 300mg in patients after fibrinolytic therapy It is unclear whether therapy should be added to “upstream” GP IIb/IIIa antagonists Especially in high risk patients in whom the likelihood for CABG is high 1 Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month after PCI / stent improving long-term outcome 1 2 Discharge/Post-Discharge Medications - Guidelines ASA, if not contraindicated Clopidogrel, when ASA contraindicated Aspirin + Clopidogrel for up to 9 months -blocker, if not contraindicated Lipid  agents + diet, if LDL >130 mg/dL ACE Inhibitor: CHF, EF < 40%, DM, or HTN I IIa IIb III 2 Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization PCI PLACEBO + ASA * CLOPIDOGREL + ASA * 30 days post PCI End of follow-up Up to 12 months after randomization Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 2,658 patients undergoing PCI N = 1345 N = 1313 PCI-CURE Overall Study Design: PCI-CURE R Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE Question 1 Question 2 Clopidogrel Arm Placebo Arm PCI* 28 Days Placebo + ASA† (325 mg) Randomization - Pre-treatment Clopidogrel 300 mg + ASA† (325 mg) Clopidogrel 75 mg QD + ASA† 325 mg QD Clopidogrel 75 mg QD + ASA† 325 mg QD R 12 Months Steinhubl S, Berger P, Tift Mann III J et al. JAMA. 2002;Vol 288,No 19:2411-2420. Placebo QD + ASA† (81-325 mg) QD Clopidogrel 75 mg QD + ASA† (81-325 mg) QD Overall Study Design: CREDO Question 1 Question 2 1 2 Open label clopidogrel continuation Methodological Pitfall Can a study with a single randomization provide an answer to two questions? Alternatively Should a second randomization be done in order to answer the second question? PCI PLACEBO + ASA * CLOPIDOGREL + ASA * 30 days post PCI End of follow-up Up to 12 months after randomization Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 1345 N = 1313 PCI-CURE Study Design single randomization R Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE Continuation Continuation PCI PLACEBO + ASA * CLOPIDOGREL + ASA * Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 1345 N = 1313 PCI-CURE Alternative Study Design two randomizations R1 Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE R2 R2 Clop. Placebo Continuation Continuation Question 2 2 Is it just methodology? Can we really expect long term benefit from early antiplatelet therapy? Adjunct antiplatelet therapy for PCI EPISTENT Randomized study designed to determine the effect of treatment with abciximab TARGET Randomized study designed to show that tirofiban is not inferior to abciximab Post-hoc nonrandomized comparison among those who were or were not pre-treated with clopidogrel PCI-CURE Subgroup of CURE patients who underwent PCI Randomized comparison of pre-treatment and continued clopidogrel therapy vs. placebo Absolute reduction of Death or MI at 1 month and 1 year Abciximab Early clopidogrel Early and continued clopidogrel % reduction * * 6 month data in TARGET Early and long term reduction of death or MI from antiplatelet therapy in patients with ACS Long Term Clopidogrel Post PCI Clinical guidelines: 9 months to 1 year in patients with ACS However, current data does not fully support this recommendation What should we do? 2 Comulative event rate in primary prevention stable CAD and ACS ACS Stable Primary Risk of vascular event after ACS Risk of event Time after ACS Stable CAD Commulative risk Risk per time Risk of vascular event after ACS high and low risk Risk of event Time after ACS High risk Low risk Risk of bleeding after initiation of clopidogrel (high and low risk) Risk of event Time after clopidogrel High risk Low risk Fixed, except for the initial few days heparin, catheterization Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? vascular bleeding Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? vascular bleeding > 1 year High vascular risk Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? vascular bleeding < 1 months High bleeding risk e.g. coumadin
Slide 54 - Early And Long Term Treatment With Clopidogrel In Coronary Artery Disease פרופ’ יוסף רוזנמן מכון הלב, בי"ח וולפסון דצמבר 2005 Acute Coronary Syndromes Acute Coronary Syndrome No ST Elevation ST Elevation Unstable Angina Myocardial Infarction Non Q MI Q wave MI Non ST Elevation MI Braunwald E et al. J Am Coll Cardiol 2000;36:970–1062. Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When angiography / PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until angiography / PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month improving long-term outcome 1 2 Goals of therapy Prevent ischemic events until coronary angiography / PCI Before plaque stabilization was achieved Prevent PCI / stent related ischemic complications Clopidogrel before coronary angiography - Patients with ACS 1 Clopidogrel before coronary angiography - Patients with ACS ST Elevation CLARITY Non ST Elevation CURE 1 ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Study Design Fibrinolytic, ASA, Heparin Clopidogrel 300 mg + 75 mg qd Coronary Angiogram (2-8 days) Primary endpoint: Occluded artery (TIMI Flow Grade 0/1) or D/MI by time of angio randomize Placebo Double-blind, randomized, placebo-controlled trial in 3491 patients, age 18-75 yrs with STEMI < 12 hours Study Drug 30-day clinical follow-up Open-label clopidogrel per MD in both groups Primary Endpoint: Occluded Artery (or D/MI by time of angio) Placebo Clopidogrel P=0.00000036 Odds Ratio 0.64 (95% CI 0.53-0.76) 1.0 0.4 0.6 0.8 1.2 1.6 Clopidogrel better Placebo better n=1752 n=1739 36% Odds Reduction Primary & Angiographic Outcomes (median 3.5 days) Need for Urgent or Additional Treatment 21%  P=0.01 21%  P=0.005 16%  P=0.07 Early Angio (w/in 48 hrs) Urgent Revasc (index hosp) GP IIb/IIIa if PCI CV Death, MI, RI  Urg Revasc days Percentage with endpoint (%) 0 5 10 15 0 5 10 15 20 25 30 Placebo Clopidogrel Odds Ratio 0.80 (95% CI 0.65-0.97) P=0.026 20% 1 CLARITY: Patient Management Clopidogrel Placebo Parameter (n=1,752) (n=1,739) Symptom onset to fibrinolytic (hours) 2.7 2.6 Fibrinolytic to study drug (minutes) 10 10 Median doses of study medication 4 4 Angiography performed (%) 94 94 Study drug to angiography (hours) 84 84 Coronary revascularization (%): 63 63 PCI 57.2 56.6 CABG 5.9 6.0 Sabatine M et al. New Engl J Med 2005; 352: 1179–1189. PCI-CLARITY: Reduction in CV Death, MI, Stroke from PCI to 30 Days Days Post PCI Percentage with Outcome (%) 0 2 0 5 10 15 20 25 30 46%* p=0.008 Clopidogrel Pretreatment (3.6%) No Pretreatment (6.2%) 4 6 8 M Sabatine, et al. JAMA 2005 PCI-CLARITY: MI, Stroke, or CV Death Events pre and post PCI ***MI or Stroke M Sabatine, et al. JAMA 2005, Prehospital Fibrinolysis with Double Antiplatelet Therapy in Acute ST-Elevation Myocardial Infarction: The Clarity Ambulance Substudy Substudy Sites and Patient Numbers France: 172 patients L Soulat: 57 Y Lambert: 48 F Lapostolle: 28 F Thieuleux: 21 C Gully: 10 D Pollet: 5 D Galley: 2 L Olliver: 1 UK: 40 patients J Adgey: 27 J Purvis: 13 Sweden: 5 patients J-E Karlsson: 5 217 patients in total Angiographic & ECG Parameters: Ambulance vs. Non-Ambulance *Complete considered to be >70%; ECG=electrocardiogram p value Event rate (%) Ambulance Non- ambulance Non-ambulance better Ambulance better Odds ratio (95% CI) 0 0.5 1.0 1.5 2.0 Ambulance Non-ambulance Overall Clopidogrel better Placebo better Odds ratio (95% CI) Primary Endpoint of TIMI Flow Grade 0/1, MI or Death 0.60 (0.301.17) 0.64 (0.530.76) 0.65 (0.540.77) ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Clopidogrel 75mg q.d. + ASA 75-325 mg q.d.* (6259 patients) Placebo + ASA 75-325 mg q.d.* (6303 patients) Day 1 6 m. Visit 9 m. Visit 12 m. or Final Visit 3 m. Visit Discharge Visit 1 m. Visit Patients with Acute Coronary Syndrome (unstable angina or non-ST-segment elevation MI) R Placebo loading dose R = Randomization * In combination with other standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Study Design 3 months £ double-blind treatment £ 12 months Clopidogrel 300 mg loading dose CURE Clopidogrel + ASA* 3 6 9 Placebo + ASA* Months of Follow-Up 11.4% 9.3% 20% RRR P < 0.001 N = 12,562 0 12 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Primary End Point - MI/Stroke/CV Death CURE Clopidogrel + ASA* 10 20 30 Placebo + ASA* Days of Follow-Up 0 21% RRR P = 0.003 N = 12,562 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. MI/Stroke/CV Death within 30 Days CURE 1 CV death, nonfatal MI, stroke or refractory or severe ischemia 34% NEJM 2001; 345:495-502 MI/Stroke/CV Death or severe Ischemia at 24 hours CURE 1 % patients requiring thrombolytic therapy 43% % patients requiring GP IIb/IIIa inhibitors 18% NEJM 2001; 345:495-502 Need for Additional Anti-Thrombotic After Randomization P< 0.001 P= 0.003 Thrombolysis GP IIb/IIIa Inhibitor CURE 1 Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? GP IIb/IIIa receptor is the final common pathway in platelet aggregation. GP IIb/IIIa blockade is the most effective antiplatelet aggregation therapy. Bleeding risk is not increased if therapy is stopped 2-4 hours prior to CABG. Bleeding risk is markedly increased unless clopidogrel is stopped 3-5 days prior to CABG. Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? Is there additional benefit to clopidogrel that would justify: Increased CABG bleeding or alternatively Need to postpone CABG for 3-5 days No data in the literature however Adhesion The Role of Platelets in Atherothrombosis Aggregation 3 Reproduced with permission from Cannon CP. Atherothrombosis slide compendium. Available at: www.theheart.org. 1 Activation 2 Conclusions: Early Clopidogrel Therapy Treatment with clopidogrel is indicated as soon as possible in patients with acute coronary syndrome ST elevation and non ST elevation Treatment is effective to reduce ischemic complications Before coronay angiography During and after PCI 1 Conclusions: Early Clopidogrel Therapy Loading dose should be 600mg to achieve early optimal antiplatelet effect ?? 300mg in patients after fibrinolytic therapy It is unclear whether therapy should be added to “upstream” GP IIb/IIIa antagonists Especially in high risk patients in whom the likelihood for CABG is high 1 Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month after PCI / stent improving long-term outcome 1 2 Discharge/Post-Discharge Medications - Guidelines ASA, if not contraindicated Clopidogrel, when ASA contraindicated Aspirin + Clopidogrel for up to 9 months -blocker, if not contraindicated Lipid  agents + diet, if LDL >130 mg/dL ACE Inhibitor: CHF, EF < 40%, DM, or HTN I IIa IIb III 2 Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization PCI PLACEBO + ASA * CLOPIDOGREL + ASA * 30 days post PCI End of follow-up Up to 12 months after randomization Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 2,658 patients undergoing PCI N = 1345 N = 1313 PCI-CURE Overall Study Design: PCI-CURE R Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE Question 1 Question 2 Clopidogrel Arm Placebo Arm PCI* 28 Days Placebo + ASA† (325 mg) Randomization - Pre-treatment Clopidogrel 300 mg + ASA† (325 mg) Clopidogrel 75 mg QD + ASA† 325 mg QD Clopidogrel 75 mg QD + ASA† 325 mg QD R 12 Months Steinhubl S, Berger P, Tift Mann III J et al. JAMA. 2002;Vol 288,No 19:2411-2420. Placebo QD + ASA† (81-325 mg) QD Clopidogrel 75 mg QD + ASA† (81-325 mg) QD Overall Study Design: CREDO Question 1 Question 2 1 2 Open label clopidogrel continuation Methodological Pitfall Can a study with a single randomization provide an answer to two questions? Alternatively Should a second randomization be done in order to answer the second question? PCI PLACEBO + ASA * CLOPIDOGREL + ASA * 30 days post PCI End of follow-up Up to 12 months after randomization Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 1345 N = 1313 PCI-CURE Study Design single randomization R Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE Continuation Continuation PCI PLACEBO + ASA * CLOPIDOGREL + ASA * Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 1345 N = 1313 PCI-CURE Alternative Study Design two randomizations R1 Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE R2 R2 Clop. Placebo Continuation Continuation Question 2 2 Is it just methodology? Can we really expect long term benefit from early antiplatelet therapy? Adjunct antiplatelet therapy for PCI EPISTENT Randomized study designed to determine the effect of treatment with abciximab TARGET Randomized study designed to show that tirofiban is not inferior to abciximab Post-hoc nonrandomized comparison among those who were or were not pre-treated with clopidogrel PCI-CURE Subgroup of CURE patients who underwent PCI Randomized comparison of pre-treatment and continued clopidogrel therapy vs. placebo Absolute reduction of Death or MI at 1 month and 1 year Abciximab Early clopidogrel Early and continued clopidogrel % reduction * * 6 month data in TARGET Early and long term reduction of death or MI from antiplatelet therapy in patients with ACS Long Term Clopidogrel Post PCI Clinical guidelines: 9 months to 1 year in patients with ACS However, current data does not fully support this recommendation What should we do? 2 Comulative event rate in primary prevention stable CAD and ACS ACS Stable Primary Risk of vascular event after ACS Risk of event Time after ACS Stable CAD Commulative risk Risk per time Risk of vascular event after ACS high and low risk Risk of event Time after ACS High risk Low risk Risk of bleeding after initiation of clopidogrel (high and low risk) Risk of event Time after clopidogrel High risk Low risk Fixed, except for the initial few days heparin, catheterization Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? vascular bleeding Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? vascular bleeding > 1 year High vascular risk Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? vascular bleeding < 1 months High bleeding risk e.g. coumadin Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? Long term clopidogrel for patients with High risk for vascular event Low bleeding risk Short term clopidogrel for patients with Low risk for vascular event High bleeding risk vascular bleeding
Slide 55 - Early And Long Term Treatment With Clopidogrel In Coronary Artery Disease פרופ’ יוסף רוזנמן מכון הלב, בי"ח וולפסון דצמבר 2005 Acute Coronary Syndromes Acute Coronary Syndrome No ST Elevation ST Elevation Unstable Angina Myocardial Infarction Non Q MI Q wave MI Non ST Elevation MI Braunwald E et al. J Am Coll Cardiol 2000;36:970–1062. Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When angiography / PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until angiography / PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month improving long-term outcome 1 2 Goals of therapy Prevent ischemic events until coronary angiography / PCI Before plaque stabilization was achieved Prevent PCI / stent related ischemic complications Clopidogrel before coronary angiography - Patients with ACS 1 Clopidogrel before coronary angiography - Patients with ACS ST Elevation CLARITY Non ST Elevation CURE 1 ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Study Design Fibrinolytic, ASA, Heparin Clopidogrel 300 mg + 75 mg qd Coronary Angiogram (2-8 days) Primary endpoint: Occluded artery (TIMI Flow Grade 0/1) or D/MI by time of angio randomize Placebo Double-blind, randomized, placebo-controlled trial in 3491 patients, age 18-75 yrs with STEMI < 12 hours Study Drug 30-day clinical follow-up Open-label clopidogrel per MD in both groups Primary Endpoint: Occluded Artery (or D/MI by time of angio) Placebo Clopidogrel P=0.00000036 Odds Ratio 0.64 (95% CI 0.53-0.76) 1.0 0.4 0.6 0.8 1.2 1.6 Clopidogrel better Placebo better n=1752 n=1739 36% Odds Reduction Primary & Angiographic Outcomes (median 3.5 days) Need for Urgent or Additional Treatment 21%  P=0.01 21%  P=0.005 16%  P=0.07 Early Angio (w/in 48 hrs) Urgent Revasc (index hosp) GP IIb/IIIa if PCI CV Death, MI, RI  Urg Revasc days Percentage with endpoint (%) 0 5 10 15 0 5 10 15 20 25 30 Placebo Clopidogrel Odds Ratio 0.80 (95% CI 0.65-0.97) P=0.026 20% 1 CLARITY: Patient Management Clopidogrel Placebo Parameter (n=1,752) (n=1,739) Symptom onset to fibrinolytic (hours) 2.7 2.6 Fibrinolytic to study drug (minutes) 10 10 Median doses of study medication 4 4 Angiography performed (%) 94 94 Study drug to angiography (hours) 84 84 Coronary revascularization (%): 63 63 PCI 57.2 56.6 CABG 5.9 6.0 Sabatine M et al. New Engl J Med 2005; 352: 1179–1189. PCI-CLARITY: Reduction in CV Death, MI, Stroke from PCI to 30 Days Days Post PCI Percentage with Outcome (%) 0 2 0 5 10 15 20 25 30 46%* p=0.008 Clopidogrel Pretreatment (3.6%) No Pretreatment (6.2%) 4 6 8 M Sabatine, et al. JAMA 2005 PCI-CLARITY: MI, Stroke, or CV Death Events pre and post PCI ***MI or Stroke M Sabatine, et al. JAMA 2005, Prehospital Fibrinolysis with Double Antiplatelet Therapy in Acute ST-Elevation Myocardial Infarction: The Clarity Ambulance Substudy Substudy Sites and Patient Numbers France: 172 patients L Soulat: 57 Y Lambert: 48 F Lapostolle: 28 F Thieuleux: 21 C Gully: 10 D Pollet: 5 D Galley: 2 L Olliver: 1 UK: 40 patients J Adgey: 27 J Purvis: 13 Sweden: 5 patients J-E Karlsson: 5 217 patients in total Angiographic & ECG Parameters: Ambulance vs. Non-Ambulance *Complete considered to be >70%; ECG=electrocardiogram p value Event rate (%) Ambulance Non- ambulance Non-ambulance better Ambulance better Odds ratio (95% CI) 0 0.5 1.0 1.5 2.0 Ambulance Non-ambulance Overall Clopidogrel better Placebo better Odds ratio (95% CI) Primary Endpoint of TIMI Flow Grade 0/1, MI or Death 0.60 (0.301.17) 0.64 (0.530.76) 0.65 (0.540.77) ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Clopidogrel 75mg q.d. + ASA 75-325 mg q.d.* (6259 patients) Placebo + ASA 75-325 mg q.d.* (6303 patients) Day 1 6 m. Visit 9 m. Visit 12 m. or Final Visit 3 m. Visit Discharge Visit 1 m. Visit Patients with Acute Coronary Syndrome (unstable angina or non-ST-segment elevation MI) R Placebo loading dose R = Randomization * In combination with other standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Study Design 3 months £ double-blind treatment £ 12 months Clopidogrel 300 mg loading dose CURE Clopidogrel + ASA* 3 6 9 Placebo + ASA* Months of Follow-Up 11.4% 9.3% 20% RRR P < 0.001 N = 12,562 0 12 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Primary End Point - MI/Stroke/CV Death CURE Clopidogrel + ASA* 10 20 30 Placebo + ASA* Days of Follow-Up 0 21% RRR P = 0.003 N = 12,562 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. MI/Stroke/CV Death within 30 Days CURE 1 CV death, nonfatal MI, stroke or refractory or severe ischemia 34% NEJM 2001; 345:495-502 MI/Stroke/CV Death or severe Ischemia at 24 hours CURE 1 % patients requiring thrombolytic therapy 43% % patients requiring GP IIb/IIIa inhibitors 18% NEJM 2001; 345:495-502 Need for Additional Anti-Thrombotic After Randomization P< 0.001 P= 0.003 Thrombolysis GP IIb/IIIa Inhibitor CURE 1 Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? GP IIb/IIIa receptor is the final common pathway in platelet aggregation. GP IIb/IIIa blockade is the most effective antiplatelet aggregation therapy. Bleeding risk is not increased if therapy is stopped 2-4 hours prior to CABG. Bleeding risk is markedly increased unless clopidogrel is stopped 3-5 days prior to CABG. Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? Is there additional benefit to clopidogrel that would justify: Increased CABG bleeding or alternatively Need to postpone CABG for 3-5 days No data in the literature however Adhesion The Role of Platelets in Atherothrombosis Aggregation 3 Reproduced with permission from Cannon CP. Atherothrombosis slide compendium. Available at: www.theheart.org. 1 Activation 2 Conclusions: Early Clopidogrel Therapy Treatment with clopidogrel is indicated as soon as possible in patients with acute coronary syndrome ST elevation and non ST elevation Treatment is effective to reduce ischemic complications Before coronay angiography During and after PCI 1 Conclusions: Early Clopidogrel Therapy Loading dose should be 600mg to achieve early optimal antiplatelet effect ?? 300mg in patients after fibrinolytic therapy It is unclear whether therapy should be added to “upstream” GP IIb/IIIa antagonists Especially in high risk patients in whom the likelihood for CABG is high 1 Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month after PCI / stent improving long-term outcome 1 2 Discharge/Post-Discharge Medications - Guidelines ASA, if not contraindicated Clopidogrel, when ASA contraindicated Aspirin + Clopidogrel for up to 9 months -blocker, if not contraindicated Lipid  agents + diet, if LDL >130 mg/dL ACE Inhibitor: CHF, EF < 40%, DM, or HTN I IIa IIb III 2 Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization PCI PLACEBO + ASA * CLOPIDOGREL + ASA * 30 days post PCI End of follow-up Up to 12 months after randomization Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 2,658 patients undergoing PCI N = 1345 N = 1313 PCI-CURE Overall Study Design: PCI-CURE R Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE Question 1 Question 2 Clopidogrel Arm Placebo Arm PCI* 28 Days Placebo + ASA† (325 mg) Randomization - Pre-treatment Clopidogrel 300 mg + ASA† (325 mg) Clopidogrel 75 mg QD + ASA† 325 mg QD Clopidogrel 75 mg QD + ASA† 325 mg QD R 12 Months Steinhubl S, Berger P, Tift Mann III J et al. JAMA. 2002;Vol 288,No 19:2411-2420. Placebo QD + ASA† (81-325 mg) QD Clopidogrel 75 mg QD + ASA† (81-325 mg) QD Overall Study Design: CREDO Question 1 Question 2 1 2 Open label clopidogrel continuation Methodological Pitfall Can a study with a single randomization provide an answer to two questions? Alternatively Should a second randomization be done in order to answer the second question? PCI PLACEBO + ASA * CLOPIDOGREL + ASA * 30 days post PCI End of follow-up Up to 12 months after randomization Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 1345 N = 1313 PCI-CURE Study Design single randomization R Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE Continuation Continuation PCI PLACEBO + ASA * CLOPIDOGREL + ASA * Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 1345 N = 1313 PCI-CURE Alternative Study Design two randomizations R1 Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE R2 R2 Clop. Placebo Continuation Continuation Question 2 2 Is it just methodology? Can we really expect long term benefit from early antiplatelet therapy? Adjunct antiplatelet therapy for PCI EPISTENT Randomized study designed to determine the effect of treatment with abciximab TARGET Randomized study designed to show that tirofiban is not inferior to abciximab Post-hoc nonrandomized comparison among those who were or were not pre-treated with clopidogrel PCI-CURE Subgroup of CURE patients who underwent PCI Randomized comparison of pre-treatment and continued clopidogrel therapy vs. placebo Absolute reduction of Death or MI at 1 month and 1 year Abciximab Early clopidogrel Early and continued clopidogrel % reduction * * 6 month data in TARGET Early and long term reduction of death or MI from antiplatelet therapy in patients with ACS Long Term Clopidogrel Post PCI Clinical guidelines: 9 months to 1 year in patients with ACS However, current data does not fully support this recommendation What should we do? 2 Comulative event rate in primary prevention stable CAD and ACS ACS Stable Primary Risk of vascular event after ACS Risk of event Time after ACS Stable CAD Commulative risk Risk per time Risk of vascular event after ACS high and low risk Risk of event Time after ACS High risk Low risk Risk of bleeding after initiation of clopidogrel (high and low risk) Risk of event Time after clopidogrel High risk Low risk Fixed, except for the initial few days heparin, catheterization Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? vascular bleeding Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? vascular bleeding > 1 year High vascular risk Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? vascular bleeding < 1 months High bleeding risk e.g. coumadin Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? Long term clopidogrel for patients with High risk for vascular event Low bleeding risk Short term clopidogrel for patients with Low risk for vascular event High bleeding risk vascular bleeding Who is ”High Risk” Patients in whom long term clopidogrel should be considered The vulnerable patient TIMI risk score Aspirin Failure Others
Slide 56 - Early And Long Term Treatment With Clopidogrel In Coronary Artery Disease פרופ’ יוסף רוזנמן מכון הלב, בי"ח וולפסון דצמבר 2005 Acute Coronary Syndromes Acute Coronary Syndrome No ST Elevation ST Elevation Unstable Angina Myocardial Infarction Non Q MI Q wave MI Non ST Elevation MI Braunwald E et al. J Am Coll Cardiol 2000;36:970–1062. Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When angiography / PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until angiography / PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month improving long-term outcome 1 2 Goals of therapy Prevent ischemic events until coronary angiography / PCI Before plaque stabilization was achieved Prevent PCI / stent related ischemic complications Clopidogrel before coronary angiography - Patients with ACS 1 Clopidogrel before coronary angiography - Patients with ACS ST Elevation CLARITY Non ST Elevation CURE 1 ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Study Design Fibrinolytic, ASA, Heparin Clopidogrel 300 mg + 75 mg qd Coronary Angiogram (2-8 days) Primary endpoint: Occluded artery (TIMI Flow Grade 0/1) or D/MI by time of angio randomize Placebo Double-blind, randomized, placebo-controlled trial in 3491 patients, age 18-75 yrs with STEMI < 12 hours Study Drug 30-day clinical follow-up Open-label clopidogrel per MD in both groups Primary Endpoint: Occluded Artery (or D/MI by time of angio) Placebo Clopidogrel P=0.00000036 Odds Ratio 0.64 (95% CI 0.53-0.76) 1.0 0.4 0.6 0.8 1.2 1.6 Clopidogrel better Placebo better n=1752 n=1739 36% Odds Reduction Primary & Angiographic Outcomes (median 3.5 days) Need for Urgent or Additional Treatment 21%  P=0.01 21%  P=0.005 16%  P=0.07 Early Angio (w/in 48 hrs) Urgent Revasc (index hosp) GP IIb/IIIa if PCI CV Death, MI, RI  Urg Revasc days Percentage with endpoint (%) 0 5 10 15 0 5 10 15 20 25 30 Placebo Clopidogrel Odds Ratio 0.80 (95% CI 0.65-0.97) P=0.026 20% 1 CLARITY: Patient Management Clopidogrel Placebo Parameter (n=1,752) (n=1,739) Symptom onset to fibrinolytic (hours) 2.7 2.6 Fibrinolytic to study drug (minutes) 10 10 Median doses of study medication 4 4 Angiography performed (%) 94 94 Study drug to angiography (hours) 84 84 Coronary revascularization (%): 63 63 PCI 57.2 56.6 CABG 5.9 6.0 Sabatine M et al. New Engl J Med 2005; 352: 1179–1189. PCI-CLARITY: Reduction in CV Death, MI, Stroke from PCI to 30 Days Days Post PCI Percentage with Outcome (%) 0 2 0 5 10 15 20 25 30 46%* p=0.008 Clopidogrel Pretreatment (3.6%) No Pretreatment (6.2%) 4 6 8 M Sabatine, et al. JAMA 2005 PCI-CLARITY: MI, Stroke, or CV Death Events pre and post PCI ***MI or Stroke M Sabatine, et al. JAMA 2005, Prehospital Fibrinolysis with Double Antiplatelet Therapy in Acute ST-Elevation Myocardial Infarction: The Clarity Ambulance Substudy Substudy Sites and Patient Numbers France: 172 patients L Soulat: 57 Y Lambert: 48 F Lapostolle: 28 F Thieuleux: 21 C Gully: 10 D Pollet: 5 D Galley: 2 L Olliver: 1 UK: 40 patients J Adgey: 27 J Purvis: 13 Sweden: 5 patients J-E Karlsson: 5 217 patients in total Angiographic & ECG Parameters: Ambulance vs. Non-Ambulance *Complete considered to be >70%; ECG=electrocardiogram p value Event rate (%) Ambulance Non- ambulance Non-ambulance better Ambulance better Odds ratio (95% CI) 0 0.5 1.0 1.5 2.0 Ambulance Non-ambulance Overall Clopidogrel better Placebo better Odds ratio (95% CI) Primary Endpoint of TIMI Flow Grade 0/1, MI or Death 0.60 (0.301.17) 0.64 (0.530.76) 0.65 (0.540.77) ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Clopidogrel 75mg q.d. + ASA 75-325 mg q.d.* (6259 patients) Placebo + ASA 75-325 mg q.d.* (6303 patients) Day 1 6 m. Visit 9 m. Visit 12 m. or Final Visit 3 m. Visit Discharge Visit 1 m. Visit Patients with Acute Coronary Syndrome (unstable angina or non-ST-segment elevation MI) R Placebo loading dose R = Randomization * In combination with other standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Study Design 3 months £ double-blind treatment £ 12 months Clopidogrel 300 mg loading dose CURE Clopidogrel + ASA* 3 6 9 Placebo + ASA* Months of Follow-Up 11.4% 9.3% 20% RRR P < 0.001 N = 12,562 0 12 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Primary End Point - MI/Stroke/CV Death CURE Clopidogrel + ASA* 10 20 30 Placebo + ASA* Days of Follow-Up 0 21% RRR P = 0.003 N = 12,562 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. MI/Stroke/CV Death within 30 Days CURE 1 CV death, nonfatal MI, stroke or refractory or severe ischemia 34% NEJM 2001; 345:495-502 MI/Stroke/CV Death or severe Ischemia at 24 hours CURE 1 % patients requiring thrombolytic therapy 43% % patients requiring GP IIb/IIIa inhibitors 18% NEJM 2001; 345:495-502 Need for Additional Anti-Thrombotic After Randomization P< 0.001 P= 0.003 Thrombolysis GP IIb/IIIa Inhibitor CURE 1 Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? GP IIb/IIIa receptor is the final common pathway in platelet aggregation. GP IIb/IIIa blockade is the most effective antiplatelet aggregation therapy. Bleeding risk is not increased if therapy is stopped 2-4 hours prior to CABG. Bleeding risk is markedly increased unless clopidogrel is stopped 3-5 days prior to CABG. Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? Is there additional benefit to clopidogrel that would justify: Increased CABG bleeding or alternatively Need to postpone CABG for 3-5 days No data in the literature however Adhesion The Role of Platelets in Atherothrombosis Aggregation 3 Reproduced with permission from Cannon CP. Atherothrombosis slide compendium. Available at: www.theheart.org. 1 Activation 2 Conclusions: Early Clopidogrel Therapy Treatment with clopidogrel is indicated as soon as possible in patients with acute coronary syndrome ST elevation and non ST elevation Treatment is effective to reduce ischemic complications Before coronay angiography During and after PCI 1 Conclusions: Early Clopidogrel Therapy Loading dose should be 600mg to achieve early optimal antiplatelet effect ?? 300mg in patients after fibrinolytic therapy It is unclear whether therapy should be added to “upstream” GP IIb/IIIa antagonists Especially in high risk patients in whom the likelihood for CABG is high 1 Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month after PCI / stent improving long-term outcome 1 2 Discharge/Post-Discharge Medications - Guidelines ASA, if not contraindicated Clopidogrel, when ASA contraindicated Aspirin + Clopidogrel for up to 9 months -blocker, if not contraindicated Lipid  agents + diet, if LDL >130 mg/dL ACE Inhibitor: CHF, EF < 40%, DM, or HTN I IIa IIb III 2 Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization PCI PLACEBO + ASA * CLOPIDOGREL + ASA * 30 days post PCI End of follow-up Up to 12 months after randomization Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 2,658 patients undergoing PCI N = 1345 N = 1313 PCI-CURE Overall Study Design: PCI-CURE R Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE Question 1 Question 2 Clopidogrel Arm Placebo Arm PCI* 28 Days Placebo + ASA† (325 mg) Randomization - Pre-treatment Clopidogrel 300 mg + ASA† (325 mg) Clopidogrel 75 mg QD + ASA† 325 mg QD Clopidogrel 75 mg QD + ASA† 325 mg QD R 12 Months Steinhubl S, Berger P, Tift Mann III J et al. JAMA. 2002;Vol 288,No 19:2411-2420. Placebo QD + ASA† (81-325 mg) QD Clopidogrel 75 mg QD + ASA† (81-325 mg) QD Overall Study Design: CREDO Question 1 Question 2 1 2 Open label clopidogrel continuation Methodological Pitfall Can a study with a single randomization provide an answer to two questions? Alternatively Should a second randomization be done in order to answer the second question? PCI PLACEBO + ASA * CLOPIDOGREL + ASA * 30 days post PCI End of follow-up Up to 12 months after randomization Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 1345 N = 1313 PCI-CURE Study Design single randomization R Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE Continuation Continuation PCI PLACEBO + ASA * CLOPIDOGREL + ASA * Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 1345 N = 1313 PCI-CURE Alternative Study Design two randomizations R1 Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE R2 R2 Clop. Placebo Continuation Continuation Question 2 2 Is it just methodology? Can we really expect long term benefit from early antiplatelet therapy? Adjunct antiplatelet therapy for PCI EPISTENT Randomized study designed to determine the effect of treatment with abciximab TARGET Randomized study designed to show that tirofiban is not inferior to abciximab Post-hoc nonrandomized comparison among those who were or were not pre-treated with clopidogrel PCI-CURE Subgroup of CURE patients who underwent PCI Randomized comparison of pre-treatment and continued clopidogrel therapy vs. placebo Absolute reduction of Death or MI at 1 month and 1 year Abciximab Early clopidogrel Early and continued clopidogrel % reduction * * 6 month data in TARGET Early and long term reduction of death or MI from antiplatelet therapy in patients with ACS Long Term Clopidogrel Post PCI Clinical guidelines: 9 months to 1 year in patients with ACS However, current data does not fully support this recommendation What should we do? 2 Comulative event rate in primary prevention stable CAD and ACS ACS Stable Primary Risk of vascular event after ACS Risk of event Time after ACS Stable CAD Commulative risk Risk per time Risk of vascular event after ACS high and low risk Risk of event Time after ACS High risk Low risk Risk of bleeding after initiation of clopidogrel (high and low risk) Risk of event Time after clopidogrel High risk Low risk Fixed, except for the initial few days heparin, catheterization Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? vascular bleeding Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? vascular bleeding > 1 year High vascular risk Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? vascular bleeding < 1 months High bleeding risk e.g. coumadin Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? Long term clopidogrel for patients with High risk for vascular event Low bleeding risk Short term clopidogrel for patients with Low risk for vascular event High bleeding risk vascular bleeding Who is ”High Risk” Patients in whom long term clopidogrel should be considered The vulnerable patient TIMI risk score Aspirin Failure Others Who is ”High Risk” Patients in whom long term clopidogrel should be considered The vulnerable patient TIMI risk score Aspirin Failure Others
Slide 57 - Early And Long Term Treatment With Clopidogrel In Coronary Artery Disease פרופ’ יוסף רוזנמן מכון הלב, בי"ח וולפסון דצמבר 2005 Acute Coronary Syndromes Acute Coronary Syndrome No ST Elevation ST Elevation Unstable Angina Myocardial Infarction Non Q MI Q wave MI Non ST Elevation MI Braunwald E et al. J Am Coll Cardiol 2000;36:970–1062. Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When angiography / PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until angiography / PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month improving long-term outcome 1 2 Goals of therapy Prevent ischemic events until coronary angiography / PCI Before plaque stabilization was achieved Prevent PCI / stent related ischemic complications Clopidogrel before coronary angiography - Patients with ACS 1 Clopidogrel before coronary angiography - Patients with ACS ST Elevation CLARITY Non ST Elevation CURE 1 ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Study Design Fibrinolytic, ASA, Heparin Clopidogrel 300 mg + 75 mg qd Coronary Angiogram (2-8 days) Primary endpoint: Occluded artery (TIMI Flow Grade 0/1) or D/MI by time of angio randomize Placebo Double-blind, randomized, placebo-controlled trial in 3491 patients, age 18-75 yrs with STEMI < 12 hours Study Drug 30-day clinical follow-up Open-label clopidogrel per MD in both groups Primary Endpoint: Occluded Artery (or D/MI by time of angio) Placebo Clopidogrel P=0.00000036 Odds Ratio 0.64 (95% CI 0.53-0.76) 1.0 0.4 0.6 0.8 1.2 1.6 Clopidogrel better Placebo better n=1752 n=1739 36% Odds Reduction Primary & Angiographic Outcomes (median 3.5 days) Need for Urgent or Additional Treatment 21%  P=0.01 21%  P=0.005 16%  P=0.07 Early Angio (w/in 48 hrs) Urgent Revasc (index hosp) GP IIb/IIIa if PCI CV Death, MI, RI  Urg Revasc days Percentage with endpoint (%) 0 5 10 15 0 5 10 15 20 25 30 Placebo Clopidogrel Odds Ratio 0.80 (95% CI 0.65-0.97) P=0.026 20% 1 CLARITY: Patient Management Clopidogrel Placebo Parameter (n=1,752) (n=1,739) Symptom onset to fibrinolytic (hours) 2.7 2.6 Fibrinolytic to study drug (minutes) 10 10 Median doses of study medication 4 4 Angiography performed (%) 94 94 Study drug to angiography (hours) 84 84 Coronary revascularization (%): 63 63 PCI 57.2 56.6 CABG 5.9 6.0 Sabatine M et al. New Engl J Med 2005; 352: 1179–1189. PCI-CLARITY: Reduction in CV Death, MI, Stroke from PCI to 30 Days Days Post PCI Percentage with Outcome (%) 0 2 0 5 10 15 20 25 30 46%* p=0.008 Clopidogrel Pretreatment (3.6%) No Pretreatment (6.2%) 4 6 8 M Sabatine, et al. JAMA 2005 PCI-CLARITY: MI, Stroke, or CV Death Events pre and post PCI ***MI or Stroke M Sabatine, et al. JAMA 2005, Prehospital Fibrinolysis with Double Antiplatelet Therapy in Acute ST-Elevation Myocardial Infarction: The Clarity Ambulance Substudy Substudy Sites and Patient Numbers France: 172 patients L Soulat: 57 Y Lambert: 48 F Lapostolle: 28 F Thieuleux: 21 C Gully: 10 D Pollet: 5 D Galley: 2 L Olliver: 1 UK: 40 patients J Adgey: 27 J Purvis: 13 Sweden: 5 patients J-E Karlsson: 5 217 patients in total Angiographic & ECG Parameters: Ambulance vs. Non-Ambulance *Complete considered to be >70%; ECG=electrocardiogram p value Event rate (%) Ambulance Non- ambulance Non-ambulance better Ambulance better Odds ratio (95% CI) 0 0.5 1.0 1.5 2.0 Ambulance Non-ambulance Overall Clopidogrel better Placebo better Odds ratio (95% CI) Primary Endpoint of TIMI Flow Grade 0/1, MI or Death 0.60 (0.301.17) 0.64 (0.530.76) 0.65 (0.540.77) ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Clopidogrel 75mg q.d. + ASA 75-325 mg q.d.* (6259 patients) Placebo + ASA 75-325 mg q.d.* (6303 patients) Day 1 6 m. Visit 9 m. Visit 12 m. or Final Visit 3 m. Visit Discharge Visit 1 m. Visit Patients with Acute Coronary Syndrome (unstable angina or non-ST-segment elevation MI) R Placebo loading dose R = Randomization * In combination with other standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Study Design 3 months £ double-blind treatment £ 12 months Clopidogrel 300 mg loading dose CURE Clopidogrel + ASA* 3 6 9 Placebo + ASA* Months of Follow-Up 11.4% 9.3% 20% RRR P < 0.001 N = 12,562 0 12 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Primary End Point - MI/Stroke/CV Death CURE Clopidogrel + ASA* 10 20 30 Placebo + ASA* Days of Follow-Up 0 21% RRR P = 0.003 N = 12,562 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. MI/Stroke/CV Death within 30 Days CURE 1 CV death, nonfatal MI, stroke or refractory or severe ischemia 34% NEJM 2001; 345:495-502 MI/Stroke/CV Death or severe Ischemia at 24 hours CURE 1 % patients requiring thrombolytic therapy 43% % patients requiring GP IIb/IIIa inhibitors 18% NEJM 2001; 345:495-502 Need for Additional Anti-Thrombotic After Randomization P< 0.001 P= 0.003 Thrombolysis GP IIb/IIIa Inhibitor CURE 1 Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? GP IIb/IIIa receptor is the final common pathway in platelet aggregation. GP IIb/IIIa blockade is the most effective antiplatelet aggregation therapy. Bleeding risk is not increased if therapy is stopped 2-4 hours prior to CABG. Bleeding risk is markedly increased unless clopidogrel is stopped 3-5 days prior to CABG. Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? Is there additional benefit to clopidogrel that would justify: Increased CABG bleeding or alternatively Need to postpone CABG for 3-5 days No data in the literature however Adhesion The Role of Platelets in Atherothrombosis Aggregation 3 Reproduced with permission from Cannon CP. Atherothrombosis slide compendium. Available at: www.theheart.org. 1 Activation 2 Conclusions: Early Clopidogrel Therapy Treatment with clopidogrel is indicated as soon as possible in patients with acute coronary syndrome ST elevation and non ST elevation Treatment is effective to reduce ischemic complications Before coronay angiography During and after PCI 1 Conclusions: Early Clopidogrel Therapy Loading dose should be 600mg to achieve early optimal antiplatelet effect ?? 300mg in patients after fibrinolytic therapy It is unclear whether therapy should be added to “upstream” GP IIb/IIIa antagonists Especially in high risk patients in whom the likelihood for CABG is high 1 Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month after PCI / stent improving long-term outcome 1 2 Discharge/Post-Discharge Medications - Guidelines ASA, if not contraindicated Clopidogrel, when ASA contraindicated Aspirin + Clopidogrel for up to 9 months -blocker, if not contraindicated Lipid  agents + diet, if LDL >130 mg/dL ACE Inhibitor: CHF, EF < 40%, DM, or HTN I IIa IIb III 2 Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization PCI PLACEBO + ASA * CLOPIDOGREL + ASA * 30 days post PCI End of follow-up Up to 12 months after randomization Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 2,658 patients undergoing PCI N = 1345 N = 1313 PCI-CURE Overall Study Design: PCI-CURE R Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE Question 1 Question 2 Clopidogrel Arm Placebo Arm PCI* 28 Days Placebo + ASA† (325 mg) Randomization - Pre-treatment Clopidogrel 300 mg + ASA† (325 mg) Clopidogrel 75 mg QD + ASA† 325 mg QD Clopidogrel 75 mg QD + ASA† 325 mg QD R 12 Months Steinhubl S, Berger P, Tift Mann III J et al. JAMA. 2002;Vol 288,No 19:2411-2420. Placebo QD + ASA† (81-325 mg) QD Clopidogrel 75 mg QD + ASA† (81-325 mg) QD Overall Study Design: CREDO Question 1 Question 2 1 2 Open label clopidogrel continuation Methodological Pitfall Can a study with a single randomization provide an answer to two questions? Alternatively Should a second randomization be done in order to answer the second question? PCI PLACEBO + ASA * CLOPIDOGREL + ASA * 30 days post PCI End of follow-up Up to 12 months after randomization Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 1345 N = 1313 PCI-CURE Study Design single randomization R Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE Continuation Continuation PCI PLACEBO + ASA * CLOPIDOGREL + ASA * Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 1345 N = 1313 PCI-CURE Alternative Study Design two randomizations R1 Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE R2 R2 Clop. Placebo Continuation Continuation Question 2 2 Is it just methodology? Can we really expect long term benefit from early antiplatelet therapy? Adjunct antiplatelet therapy for PCI EPISTENT Randomized study designed to determine the effect of treatment with abciximab TARGET Randomized study designed to show that tirofiban is not inferior to abciximab Post-hoc nonrandomized comparison among those who were or were not pre-treated with clopidogrel PCI-CURE Subgroup of CURE patients who underwent PCI Randomized comparison of pre-treatment and continued clopidogrel therapy vs. placebo Absolute reduction of Death or MI at 1 month and 1 year Abciximab Early clopidogrel Early and continued clopidogrel % reduction * * 6 month data in TARGET Early and long term reduction of death or MI from antiplatelet therapy in patients with ACS Long Term Clopidogrel Post PCI Clinical guidelines: 9 months to 1 year in patients with ACS However, current data does not fully support this recommendation What should we do? 2 Comulative event rate in primary prevention stable CAD and ACS ACS Stable Primary Risk of vascular event after ACS Risk of event Time after ACS Stable CAD Commulative risk Risk per time Risk of vascular event after ACS high and low risk Risk of event Time after ACS High risk Low risk Risk of bleeding after initiation of clopidogrel (high and low risk) Risk of event Time after clopidogrel High risk Low risk Fixed, except for the initial few days heparin, catheterization Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? vascular bleeding Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? vascular bleeding > 1 year High vascular risk Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? vascular bleeding < 1 months High bleeding risk e.g. coumadin Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? Long term clopidogrel for patients with High risk for vascular event Low bleeding risk Short term clopidogrel for patients with Low risk for vascular event High bleeding risk vascular bleeding Who is ”High Risk” Patients in whom long term clopidogrel should be considered The vulnerable patient TIMI risk score Aspirin Failure Others Who is ”High Risk” Patients in whom long term clopidogrel should be considered The vulnerable patient TIMI risk score Aspirin Failure Others ACS Pathophysiology Inflammation, Plaque Rupture, Thrombosis, and Microembolization Quiescent plaque Plaque formation Lipids, other risk factors Inflammation LDL, others, Infection? Plaque rupture (erosion) ? Macrophages, metalloproteinases Thrombosis Platelet Activation, Thrombin Vulnerable plaque Macrophages Foam Cells Collagen  platelet activation TF  Clotting Cascade Lipid core Metalloproteinases Inflammation Courtesy of David Kandzari. Plaque rupture Culprit plaque Platelet-thrombin micro-emboli
Slide 58 - Early And Long Term Treatment With Clopidogrel In Coronary Artery Disease פרופ’ יוסף רוזנמן מכון הלב, בי"ח וולפסון דצמבר 2005 Acute Coronary Syndromes Acute Coronary Syndrome No ST Elevation ST Elevation Unstable Angina Myocardial Infarction Non Q MI Q wave MI Non ST Elevation MI Braunwald E et al. J Am Coll Cardiol 2000;36:970–1062. Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When angiography / PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until angiography / PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month improving long-term outcome 1 2 Goals of therapy Prevent ischemic events until coronary angiography / PCI Before plaque stabilization was achieved Prevent PCI / stent related ischemic complications Clopidogrel before coronary angiography - Patients with ACS 1 Clopidogrel before coronary angiography - Patients with ACS ST Elevation CLARITY Non ST Elevation CURE 1 ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Study Design Fibrinolytic, ASA, Heparin Clopidogrel 300 mg + 75 mg qd Coronary Angiogram (2-8 days) Primary endpoint: Occluded artery (TIMI Flow Grade 0/1) or D/MI by time of angio randomize Placebo Double-blind, randomized, placebo-controlled trial in 3491 patients, age 18-75 yrs with STEMI < 12 hours Study Drug 30-day clinical follow-up Open-label clopidogrel per MD in both groups Primary Endpoint: Occluded Artery (or D/MI by time of angio) Placebo Clopidogrel P=0.00000036 Odds Ratio 0.64 (95% CI 0.53-0.76) 1.0 0.4 0.6 0.8 1.2 1.6 Clopidogrel better Placebo better n=1752 n=1739 36% Odds Reduction Primary & Angiographic Outcomes (median 3.5 days) Need for Urgent or Additional Treatment 21%  P=0.01 21%  P=0.005 16%  P=0.07 Early Angio (w/in 48 hrs) Urgent Revasc (index hosp) GP IIb/IIIa if PCI CV Death, MI, RI  Urg Revasc days Percentage with endpoint (%) 0 5 10 15 0 5 10 15 20 25 30 Placebo Clopidogrel Odds Ratio 0.80 (95% CI 0.65-0.97) P=0.026 20% 1 CLARITY: Patient Management Clopidogrel Placebo Parameter (n=1,752) (n=1,739) Symptom onset to fibrinolytic (hours) 2.7 2.6 Fibrinolytic to study drug (minutes) 10 10 Median doses of study medication 4 4 Angiography performed (%) 94 94 Study drug to angiography (hours) 84 84 Coronary revascularization (%): 63 63 PCI 57.2 56.6 CABG 5.9 6.0 Sabatine M et al. New Engl J Med 2005; 352: 1179–1189. PCI-CLARITY: Reduction in CV Death, MI, Stroke from PCI to 30 Days Days Post PCI Percentage with Outcome (%) 0 2 0 5 10 15 20 25 30 46%* p=0.008 Clopidogrel Pretreatment (3.6%) No Pretreatment (6.2%) 4 6 8 M Sabatine, et al. JAMA 2005 PCI-CLARITY: MI, Stroke, or CV Death Events pre and post PCI ***MI or Stroke M Sabatine, et al. JAMA 2005, Prehospital Fibrinolysis with Double Antiplatelet Therapy in Acute ST-Elevation Myocardial Infarction: The Clarity Ambulance Substudy Substudy Sites and Patient Numbers France: 172 patients L Soulat: 57 Y Lambert: 48 F Lapostolle: 28 F Thieuleux: 21 C Gully: 10 D Pollet: 5 D Galley: 2 L Olliver: 1 UK: 40 patients J Adgey: 27 J Purvis: 13 Sweden: 5 patients J-E Karlsson: 5 217 patients in total Angiographic & ECG Parameters: Ambulance vs. Non-Ambulance *Complete considered to be >70%; ECG=electrocardiogram p value Event rate (%) Ambulance Non- ambulance Non-ambulance better Ambulance better Odds ratio (95% CI) 0 0.5 1.0 1.5 2.0 Ambulance Non-ambulance Overall Clopidogrel better Placebo better Odds ratio (95% CI) Primary Endpoint of TIMI Flow Grade 0/1, MI or Death 0.60 (0.301.17) 0.64 (0.530.76) 0.65 (0.540.77) ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Clopidogrel 75mg q.d. + ASA 75-325 mg q.d.* (6259 patients) Placebo + ASA 75-325 mg q.d.* (6303 patients) Day 1 6 m. Visit 9 m. Visit 12 m. or Final Visit 3 m. Visit Discharge Visit 1 m. Visit Patients with Acute Coronary Syndrome (unstable angina or non-ST-segment elevation MI) R Placebo loading dose R = Randomization * In combination with other standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Study Design 3 months £ double-blind treatment £ 12 months Clopidogrel 300 mg loading dose CURE Clopidogrel + ASA* 3 6 9 Placebo + ASA* Months of Follow-Up 11.4% 9.3% 20% RRR P < 0.001 N = 12,562 0 12 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Primary End Point - MI/Stroke/CV Death CURE Clopidogrel + ASA* 10 20 30 Placebo + ASA* Days of Follow-Up 0 21% RRR P = 0.003 N = 12,562 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. MI/Stroke/CV Death within 30 Days CURE 1 CV death, nonfatal MI, stroke or refractory or severe ischemia 34% NEJM 2001; 345:495-502 MI/Stroke/CV Death or severe Ischemia at 24 hours CURE 1 % patients requiring thrombolytic therapy 43% % patients requiring GP IIb/IIIa inhibitors 18% NEJM 2001; 345:495-502 Need for Additional Anti-Thrombotic After Randomization P< 0.001 P= 0.003 Thrombolysis GP IIb/IIIa Inhibitor CURE 1 Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? GP IIb/IIIa receptor is the final common pathway in platelet aggregation. GP IIb/IIIa blockade is the most effective antiplatelet aggregation therapy. Bleeding risk is not increased if therapy is stopped 2-4 hours prior to CABG. Bleeding risk is markedly increased unless clopidogrel is stopped 3-5 days prior to CABG. Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? Is there additional benefit to clopidogrel that would justify: Increased CABG bleeding or alternatively Need to postpone CABG for 3-5 days No data in the literature however Adhesion The Role of Platelets in Atherothrombosis Aggregation 3 Reproduced with permission from Cannon CP. Atherothrombosis slide compendium. Available at: www.theheart.org. 1 Activation 2 Conclusions: Early Clopidogrel Therapy Treatment with clopidogrel is indicated as soon as possible in patients with acute coronary syndrome ST elevation and non ST elevation Treatment is effective to reduce ischemic complications Before coronay angiography During and after PCI 1 Conclusions: Early Clopidogrel Therapy Loading dose should be 600mg to achieve early optimal antiplatelet effect ?? 300mg in patients after fibrinolytic therapy It is unclear whether therapy should be added to “upstream” GP IIb/IIIa antagonists Especially in high risk patients in whom the likelihood for CABG is high 1 Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month after PCI / stent improving long-term outcome 1 2 Discharge/Post-Discharge Medications - Guidelines ASA, if not contraindicated Clopidogrel, when ASA contraindicated Aspirin + Clopidogrel for up to 9 months -blocker, if not contraindicated Lipid  agents + diet, if LDL >130 mg/dL ACE Inhibitor: CHF, EF < 40%, DM, or HTN I IIa IIb III 2 Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization PCI PLACEBO + ASA * CLOPIDOGREL + ASA * 30 days post PCI End of follow-up Up to 12 months after randomization Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 2,658 patients undergoing PCI N = 1345 N = 1313 PCI-CURE Overall Study Design: PCI-CURE R Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE Question 1 Question 2 Clopidogrel Arm Placebo Arm PCI* 28 Days Placebo + ASA† (325 mg) Randomization - Pre-treatment Clopidogrel 300 mg + ASA† (325 mg) Clopidogrel 75 mg QD + ASA† 325 mg QD Clopidogrel 75 mg QD + ASA† 325 mg QD R 12 Months Steinhubl S, Berger P, Tift Mann III J et al. JAMA. 2002;Vol 288,No 19:2411-2420. Placebo QD + ASA† (81-325 mg) QD Clopidogrel 75 mg QD + ASA† (81-325 mg) QD Overall Study Design: CREDO Question 1 Question 2 1 2 Open label clopidogrel continuation Methodological Pitfall Can a study with a single randomization provide an answer to two questions? Alternatively Should a second randomization be done in order to answer the second question? PCI PLACEBO + ASA * CLOPIDOGREL + ASA * 30 days post PCI End of follow-up Up to 12 months after randomization Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 1345 N = 1313 PCI-CURE Study Design single randomization R Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE Continuation Continuation PCI PLACEBO + ASA * CLOPIDOGREL + ASA * Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 1345 N = 1313 PCI-CURE Alternative Study Design two randomizations R1 Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE R2 R2 Clop. Placebo Continuation Continuation Question 2 2 Is it just methodology? Can we really expect long term benefit from early antiplatelet therapy? Adjunct antiplatelet therapy for PCI EPISTENT Randomized study designed to determine the effect of treatment with abciximab TARGET Randomized study designed to show that tirofiban is not inferior to abciximab Post-hoc nonrandomized comparison among those who were or were not pre-treated with clopidogrel PCI-CURE Subgroup of CURE patients who underwent PCI Randomized comparison of pre-treatment and continued clopidogrel therapy vs. placebo Absolute reduction of Death or MI at 1 month and 1 year Abciximab Early clopidogrel Early and continued clopidogrel % reduction * * 6 month data in TARGET Early and long term reduction of death or MI from antiplatelet therapy in patients with ACS Long Term Clopidogrel Post PCI Clinical guidelines: 9 months to 1 year in patients with ACS However, current data does not fully support this recommendation What should we do? 2 Comulative event rate in primary prevention stable CAD and ACS ACS Stable Primary Risk of vascular event after ACS Risk of event Time after ACS Stable CAD Commulative risk Risk per time Risk of vascular event after ACS high and low risk Risk of event Time after ACS High risk Low risk Risk of bleeding after initiation of clopidogrel (high and low risk) Risk of event Time after clopidogrel High risk Low risk Fixed, except for the initial few days heparin, catheterization Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? vascular bleeding Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? vascular bleeding > 1 year High vascular risk Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? vascular bleeding < 1 months High bleeding risk e.g. coumadin Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? Long term clopidogrel for patients with High risk for vascular event Low bleeding risk Short term clopidogrel for patients with Low risk for vascular event High bleeding risk vascular bleeding Who is ”High Risk” Patients in whom long term clopidogrel should be considered The vulnerable patient TIMI risk score Aspirin Failure Others Who is ”High Risk” Patients in whom long term clopidogrel should be considered The vulnerable patient TIMI risk score Aspirin Failure Others ACS Pathophysiology Inflammation, Plaque Rupture, Thrombosis, and Microembolization Quiescent plaque Plaque formation Lipids, other risk factors Inflammation LDL, others, Infection? Plaque rupture (erosion) ? Macrophages, metalloproteinases Thrombosis Platelet Activation, Thrombin Vulnerable plaque Macrophages Foam Cells Collagen  platelet activation TF  Clotting Cascade Lipid core Metalloproteinases Inflammation Courtesy of David Kandzari. Plaque rupture Culprit plaque Platelet-thrombin micro-emboli Atherosclerotic Plaques - Terminology Culprit Responsible for the clinical event Vulnerable High risk to become culprit (cause clinical event) Quiescent (Stable) Primary or healed (vulnerable or culprit)
Slide 59 - Early And Long Term Treatment With Clopidogrel In Coronary Artery Disease פרופ’ יוסף רוזנמן מכון הלב, בי"ח וולפסון דצמבר 2005 Acute Coronary Syndromes Acute Coronary Syndrome No ST Elevation ST Elevation Unstable Angina Myocardial Infarction Non Q MI Q wave MI Non ST Elevation MI Braunwald E et al. J Am Coll Cardiol 2000;36:970–1062. Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When angiography / PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until angiography / PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month improving long-term outcome 1 2 Goals of therapy Prevent ischemic events until coronary angiography / PCI Before plaque stabilization was achieved Prevent PCI / stent related ischemic complications Clopidogrel before coronary angiography - Patients with ACS 1 Clopidogrel before coronary angiography - Patients with ACS ST Elevation CLARITY Non ST Elevation CURE 1 ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Study Design Fibrinolytic, ASA, Heparin Clopidogrel 300 mg + 75 mg qd Coronary Angiogram (2-8 days) Primary endpoint: Occluded artery (TIMI Flow Grade 0/1) or D/MI by time of angio randomize Placebo Double-blind, randomized, placebo-controlled trial in 3491 patients, age 18-75 yrs with STEMI < 12 hours Study Drug 30-day clinical follow-up Open-label clopidogrel per MD in both groups Primary Endpoint: Occluded Artery (or D/MI by time of angio) Placebo Clopidogrel P=0.00000036 Odds Ratio 0.64 (95% CI 0.53-0.76) 1.0 0.4 0.6 0.8 1.2 1.6 Clopidogrel better Placebo better n=1752 n=1739 36% Odds Reduction Primary & Angiographic Outcomes (median 3.5 days) Need for Urgent or Additional Treatment 21%  P=0.01 21%  P=0.005 16%  P=0.07 Early Angio (w/in 48 hrs) Urgent Revasc (index hosp) GP IIb/IIIa if PCI CV Death, MI, RI  Urg Revasc days Percentage with endpoint (%) 0 5 10 15 0 5 10 15 20 25 30 Placebo Clopidogrel Odds Ratio 0.80 (95% CI 0.65-0.97) P=0.026 20% 1 CLARITY: Patient Management Clopidogrel Placebo Parameter (n=1,752) (n=1,739) Symptom onset to fibrinolytic (hours) 2.7 2.6 Fibrinolytic to study drug (minutes) 10 10 Median doses of study medication 4 4 Angiography performed (%) 94 94 Study drug to angiography (hours) 84 84 Coronary revascularization (%): 63 63 PCI 57.2 56.6 CABG 5.9 6.0 Sabatine M et al. New Engl J Med 2005; 352: 1179–1189. PCI-CLARITY: Reduction in CV Death, MI, Stroke from PCI to 30 Days Days Post PCI Percentage with Outcome (%) 0 2 0 5 10 15 20 25 30 46%* p=0.008 Clopidogrel Pretreatment (3.6%) No Pretreatment (6.2%) 4 6 8 M Sabatine, et al. JAMA 2005 PCI-CLARITY: MI, Stroke, or CV Death Events pre and post PCI ***MI or Stroke M Sabatine, et al. JAMA 2005, Prehospital Fibrinolysis with Double Antiplatelet Therapy in Acute ST-Elevation Myocardial Infarction: The Clarity Ambulance Substudy Substudy Sites and Patient Numbers France: 172 patients L Soulat: 57 Y Lambert: 48 F Lapostolle: 28 F Thieuleux: 21 C Gully: 10 D Pollet: 5 D Galley: 2 L Olliver: 1 UK: 40 patients J Adgey: 27 J Purvis: 13 Sweden: 5 patients J-E Karlsson: 5 217 patients in total Angiographic & ECG Parameters: Ambulance vs. Non-Ambulance *Complete considered to be >70%; ECG=electrocardiogram p value Event rate (%) Ambulance Non- ambulance Non-ambulance better Ambulance better Odds ratio (95% CI) 0 0.5 1.0 1.5 2.0 Ambulance Non-ambulance Overall Clopidogrel better Placebo better Odds ratio (95% CI) Primary Endpoint of TIMI Flow Grade 0/1, MI or Death 0.60 (0.301.17) 0.64 (0.530.76) 0.65 (0.540.77) ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Clopidogrel 75mg q.d. + ASA 75-325 mg q.d.* (6259 patients) Placebo + ASA 75-325 mg q.d.* (6303 patients) Day 1 6 m. Visit 9 m. Visit 12 m. or Final Visit 3 m. Visit Discharge Visit 1 m. Visit Patients with Acute Coronary Syndrome (unstable angina or non-ST-segment elevation MI) R Placebo loading dose R = Randomization * In combination with other standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Study Design 3 months £ double-blind treatment £ 12 months Clopidogrel 300 mg loading dose CURE Clopidogrel + ASA* 3 6 9 Placebo + ASA* Months of Follow-Up 11.4% 9.3% 20% RRR P < 0.001 N = 12,562 0 12 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Primary End Point - MI/Stroke/CV Death CURE Clopidogrel + ASA* 10 20 30 Placebo + ASA* Days of Follow-Up 0 21% RRR P = 0.003 N = 12,562 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. MI/Stroke/CV Death within 30 Days CURE 1 CV death, nonfatal MI, stroke or refractory or severe ischemia 34% NEJM 2001; 345:495-502 MI/Stroke/CV Death or severe Ischemia at 24 hours CURE 1 % patients requiring thrombolytic therapy 43% % patients requiring GP IIb/IIIa inhibitors 18% NEJM 2001; 345:495-502 Need for Additional Anti-Thrombotic After Randomization P< 0.001 P= 0.003 Thrombolysis GP IIb/IIIa Inhibitor CURE 1 Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? GP IIb/IIIa receptor is the final common pathway in platelet aggregation. GP IIb/IIIa blockade is the most effective antiplatelet aggregation therapy. Bleeding risk is not increased if therapy is stopped 2-4 hours prior to CABG. Bleeding risk is markedly increased unless clopidogrel is stopped 3-5 days prior to CABG. Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? Is there additional benefit to clopidogrel that would justify: Increased CABG bleeding or alternatively Need to postpone CABG for 3-5 days No data in the literature however Adhesion The Role of Platelets in Atherothrombosis Aggregation 3 Reproduced with permission from Cannon CP. Atherothrombosis slide compendium. Available at: www.theheart.org. 1 Activation 2 Conclusions: Early Clopidogrel Therapy Treatment with clopidogrel is indicated as soon as possible in patients with acute coronary syndrome ST elevation and non ST elevation Treatment is effective to reduce ischemic complications Before coronay angiography During and after PCI 1 Conclusions: Early Clopidogrel Therapy Loading dose should be 600mg to achieve early optimal antiplatelet effect ?? 300mg in patients after fibrinolytic therapy It is unclear whether therapy should be added to “upstream” GP IIb/IIIa antagonists Especially in high risk patients in whom the likelihood for CABG is high 1 Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month after PCI / stent improving long-term outcome 1 2 Discharge/Post-Discharge Medications - Guidelines ASA, if not contraindicated Clopidogrel, when ASA contraindicated Aspirin + Clopidogrel for up to 9 months -blocker, if not contraindicated Lipid  agents + diet, if LDL >130 mg/dL ACE Inhibitor: CHF, EF < 40%, DM, or HTN I IIa IIb III 2 Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization PCI PLACEBO + ASA * CLOPIDOGREL + ASA * 30 days post PCI End of follow-up Up to 12 months after randomization Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 2,658 patients undergoing PCI N = 1345 N = 1313 PCI-CURE Overall Study Design: PCI-CURE R Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE Question 1 Question 2 Clopidogrel Arm Placebo Arm PCI* 28 Days Placebo + ASA† (325 mg) Randomization - Pre-treatment Clopidogrel 300 mg + ASA† (325 mg) Clopidogrel 75 mg QD + ASA† 325 mg QD Clopidogrel 75 mg QD + ASA† 325 mg QD R 12 Months Steinhubl S, Berger P, Tift Mann III J et al. JAMA. 2002;Vol 288,No 19:2411-2420. Placebo QD + ASA† (81-325 mg) QD Clopidogrel 75 mg QD + ASA† (81-325 mg) QD Overall Study Design: CREDO Question 1 Question 2 1 2 Open label clopidogrel continuation Methodological Pitfall Can a study with a single randomization provide an answer to two questions? Alternatively Should a second randomization be done in order to answer the second question? PCI PLACEBO + ASA * CLOPIDOGREL + ASA * 30 days post PCI End of follow-up Up to 12 months after randomization Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 1345 N = 1313 PCI-CURE Study Design single randomization R Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE Continuation Continuation PCI PLACEBO + ASA * CLOPIDOGREL + ASA * Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 1345 N = 1313 PCI-CURE Alternative Study Design two randomizations R1 Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE R2 R2 Clop. Placebo Continuation Continuation Question 2 2 Is it just methodology? Can we really expect long term benefit from early antiplatelet therapy? Adjunct antiplatelet therapy for PCI EPISTENT Randomized study designed to determine the effect of treatment with abciximab TARGET Randomized study designed to show that tirofiban is not inferior to abciximab Post-hoc nonrandomized comparison among those who were or were not pre-treated with clopidogrel PCI-CURE Subgroup of CURE patients who underwent PCI Randomized comparison of pre-treatment and continued clopidogrel therapy vs. placebo Absolute reduction of Death or MI at 1 month and 1 year Abciximab Early clopidogrel Early and continued clopidogrel % reduction * * 6 month data in TARGET Early and long term reduction of death or MI from antiplatelet therapy in patients with ACS Long Term Clopidogrel Post PCI Clinical guidelines: 9 months to 1 year in patients with ACS However, current data does not fully support this recommendation What should we do? 2 Comulative event rate in primary prevention stable CAD and ACS ACS Stable Primary Risk of vascular event after ACS Risk of event Time after ACS Stable CAD Commulative risk Risk per time Risk of vascular event after ACS high and low risk Risk of event Time after ACS High risk Low risk Risk of bleeding after initiation of clopidogrel (high and low risk) Risk of event Time after clopidogrel High risk Low risk Fixed, except for the initial few days heparin, catheterization Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? vascular bleeding Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? vascular bleeding > 1 year High vascular risk Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? vascular bleeding < 1 months High bleeding risk e.g. coumadin Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? Long term clopidogrel for patients with High risk for vascular event Low bleeding risk Short term clopidogrel for patients with Low risk for vascular event High bleeding risk vascular bleeding Who is ”High Risk” Patients in whom long term clopidogrel should be considered The vulnerable patient TIMI risk score Aspirin Failure Others Who is ”High Risk” Patients in whom long term clopidogrel should be considered The vulnerable patient TIMI risk score Aspirin Failure Others ACS Pathophysiology Inflammation, Plaque Rupture, Thrombosis, and Microembolization Quiescent plaque Plaque formation Lipids, other risk factors Inflammation LDL, others, Infection? Plaque rupture (erosion) ? Macrophages, metalloproteinases Thrombosis Platelet Activation, Thrombin Vulnerable plaque Macrophages Foam Cells Collagen  platelet activation TF  Clotting Cascade Lipid core Metalloproteinases Inflammation Courtesy of David Kandzari. Plaque rupture Culprit plaque Platelet-thrombin micro-emboli Atherosclerotic Plaques - Terminology Culprit Responsible for the clinical event Vulnerable High risk to become culprit (cause clinical event) Quiescent (Stable) Primary or healed (vulnerable or culprit) Fuster, V. et al. J Am Coll Cardiol 2005;46:937-954 Coronary Artery Disease: Diffuse disease with a variable mix of stable, vulnerable and culprit plaques Culprit and healed plaques in a coronary bifurcation
Slide 60 - Early And Long Term Treatment With Clopidogrel In Coronary Artery Disease פרופ’ יוסף רוזנמן מכון הלב, בי"ח וולפסון דצמבר 2005 Acute Coronary Syndromes Acute Coronary Syndrome No ST Elevation ST Elevation Unstable Angina Myocardial Infarction Non Q MI Q wave MI Non ST Elevation MI Braunwald E et al. J Am Coll Cardiol 2000;36:970–1062. Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When angiography / PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until angiography / PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month improving long-term outcome 1 2 Goals of therapy Prevent ischemic events until coronary angiography / PCI Before plaque stabilization was achieved Prevent PCI / stent related ischemic complications Clopidogrel before coronary angiography - Patients with ACS 1 Clopidogrel before coronary angiography - Patients with ACS ST Elevation CLARITY Non ST Elevation CURE 1 ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Study Design Fibrinolytic, ASA, Heparin Clopidogrel 300 mg + 75 mg qd Coronary Angiogram (2-8 days) Primary endpoint: Occluded artery (TIMI Flow Grade 0/1) or D/MI by time of angio randomize Placebo Double-blind, randomized, placebo-controlled trial in 3491 patients, age 18-75 yrs with STEMI < 12 hours Study Drug 30-day clinical follow-up Open-label clopidogrel per MD in both groups Primary Endpoint: Occluded Artery (or D/MI by time of angio) Placebo Clopidogrel P=0.00000036 Odds Ratio 0.64 (95% CI 0.53-0.76) 1.0 0.4 0.6 0.8 1.2 1.6 Clopidogrel better Placebo better n=1752 n=1739 36% Odds Reduction Primary & Angiographic Outcomes (median 3.5 days) Need for Urgent or Additional Treatment 21%  P=0.01 21%  P=0.005 16%  P=0.07 Early Angio (w/in 48 hrs) Urgent Revasc (index hosp) GP IIb/IIIa if PCI CV Death, MI, RI  Urg Revasc days Percentage with endpoint (%) 0 5 10 15 0 5 10 15 20 25 30 Placebo Clopidogrel Odds Ratio 0.80 (95% CI 0.65-0.97) P=0.026 20% 1 CLARITY: Patient Management Clopidogrel Placebo Parameter (n=1,752) (n=1,739) Symptom onset to fibrinolytic (hours) 2.7 2.6 Fibrinolytic to study drug (minutes) 10 10 Median doses of study medication 4 4 Angiography performed (%) 94 94 Study drug to angiography (hours) 84 84 Coronary revascularization (%): 63 63 PCI 57.2 56.6 CABG 5.9 6.0 Sabatine M et al. New Engl J Med 2005; 352: 1179–1189. PCI-CLARITY: Reduction in CV Death, MI, Stroke from PCI to 30 Days Days Post PCI Percentage with Outcome (%) 0 2 0 5 10 15 20 25 30 46%* p=0.008 Clopidogrel Pretreatment (3.6%) No Pretreatment (6.2%) 4 6 8 M Sabatine, et al. JAMA 2005 PCI-CLARITY: MI, Stroke, or CV Death Events pre and post PCI ***MI or Stroke M Sabatine, et al. JAMA 2005, Prehospital Fibrinolysis with Double Antiplatelet Therapy in Acute ST-Elevation Myocardial Infarction: The Clarity Ambulance Substudy Substudy Sites and Patient Numbers France: 172 patients L Soulat: 57 Y Lambert: 48 F Lapostolle: 28 F Thieuleux: 21 C Gully: 10 D Pollet: 5 D Galley: 2 L Olliver: 1 UK: 40 patients J Adgey: 27 J Purvis: 13 Sweden: 5 patients J-E Karlsson: 5 217 patients in total Angiographic & ECG Parameters: Ambulance vs. Non-Ambulance *Complete considered to be >70%; ECG=electrocardiogram p value Event rate (%) Ambulance Non- ambulance Non-ambulance better Ambulance better Odds ratio (95% CI) 0 0.5 1.0 1.5 2.0 Ambulance Non-ambulance Overall Clopidogrel better Placebo better Odds ratio (95% CI) Primary Endpoint of TIMI Flow Grade 0/1, MI or Death 0.60 (0.301.17) 0.64 (0.530.76) 0.65 (0.540.77) ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Clopidogrel 75mg q.d. + ASA 75-325 mg q.d.* (6259 patients) Placebo + ASA 75-325 mg q.d.* (6303 patients) Day 1 6 m. Visit 9 m. Visit 12 m. or Final Visit 3 m. Visit Discharge Visit 1 m. Visit Patients with Acute Coronary Syndrome (unstable angina or non-ST-segment elevation MI) R Placebo loading dose R = Randomization * In combination with other standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Study Design 3 months £ double-blind treatment £ 12 months Clopidogrel 300 mg loading dose CURE Clopidogrel + ASA* 3 6 9 Placebo + ASA* Months of Follow-Up 11.4% 9.3% 20% RRR P < 0.001 N = 12,562 0 12 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Primary End Point - MI/Stroke/CV Death CURE Clopidogrel + ASA* 10 20 30 Placebo + ASA* Days of Follow-Up 0 21% RRR P = 0.003 N = 12,562 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. MI/Stroke/CV Death within 30 Days CURE 1 CV death, nonfatal MI, stroke or refractory or severe ischemia 34% NEJM 2001; 345:495-502 MI/Stroke/CV Death or severe Ischemia at 24 hours CURE 1 % patients requiring thrombolytic therapy 43% % patients requiring GP IIb/IIIa inhibitors 18% NEJM 2001; 345:495-502 Need for Additional Anti-Thrombotic After Randomization P< 0.001 P= 0.003 Thrombolysis GP IIb/IIIa Inhibitor CURE 1 Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? GP IIb/IIIa receptor is the final common pathway in platelet aggregation. GP IIb/IIIa blockade is the most effective antiplatelet aggregation therapy. Bleeding risk is not increased if therapy is stopped 2-4 hours prior to CABG. Bleeding risk is markedly increased unless clopidogrel is stopped 3-5 days prior to CABG. Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? Is there additional benefit to clopidogrel that would justify: Increased CABG bleeding or alternatively Need to postpone CABG for 3-5 days No data in the literature however Adhesion The Role of Platelets in Atherothrombosis Aggregation 3 Reproduced with permission from Cannon CP. Atherothrombosis slide compendium. Available at: www.theheart.org. 1 Activation 2 Conclusions: Early Clopidogrel Therapy Treatment with clopidogrel is indicated as soon as possible in patients with acute coronary syndrome ST elevation and non ST elevation Treatment is effective to reduce ischemic complications Before coronay angiography During and after PCI 1 Conclusions: Early Clopidogrel Therapy Loading dose should be 600mg to achieve early optimal antiplatelet effect ?? 300mg in patients after fibrinolytic therapy It is unclear whether therapy should be added to “upstream” GP IIb/IIIa antagonists Especially in high risk patients in whom the likelihood for CABG is high 1 Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month after PCI / stent improving long-term outcome 1 2 Discharge/Post-Discharge Medications - Guidelines ASA, if not contraindicated Clopidogrel, when ASA contraindicated Aspirin + Clopidogrel for up to 9 months -blocker, if not contraindicated Lipid  agents + diet, if LDL >130 mg/dL ACE Inhibitor: CHF, EF < 40%, DM, or HTN I IIa IIb III 2 Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization PCI PLACEBO + ASA * CLOPIDOGREL + ASA * 30 days post PCI End of follow-up Up to 12 months after randomization Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 2,658 patients undergoing PCI N = 1345 N = 1313 PCI-CURE Overall Study Design: PCI-CURE R Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE Question 1 Question 2 Clopidogrel Arm Placebo Arm PCI* 28 Days Placebo + ASA† (325 mg) Randomization - Pre-treatment Clopidogrel 300 mg + ASA† (325 mg) Clopidogrel 75 mg QD + ASA† 325 mg QD Clopidogrel 75 mg QD + ASA† 325 mg QD R 12 Months Steinhubl S, Berger P, Tift Mann III J et al. JAMA. 2002;Vol 288,No 19:2411-2420. Placebo QD + ASA† (81-325 mg) QD Clopidogrel 75 mg QD + ASA† (81-325 mg) QD Overall Study Design: CREDO Question 1 Question 2 1 2 Open label clopidogrel continuation Methodological Pitfall Can a study with a single randomization provide an answer to two questions? Alternatively Should a second randomization be done in order to answer the second question? PCI PLACEBO + ASA * CLOPIDOGREL + ASA * 30 days post PCI End of follow-up Up to 12 months after randomization Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 1345 N = 1313 PCI-CURE Study Design single randomization R Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE Continuation Continuation PCI PLACEBO + ASA * CLOPIDOGREL + ASA * Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 1345 N = 1313 PCI-CURE Alternative Study Design two randomizations R1 Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE R2 R2 Clop. Placebo Continuation Continuation Question 2 2 Is it just methodology? Can we really expect long term benefit from early antiplatelet therapy? Adjunct antiplatelet therapy for PCI EPISTENT Randomized study designed to determine the effect of treatment with abciximab TARGET Randomized study designed to show that tirofiban is not inferior to abciximab Post-hoc nonrandomized comparison among those who were or were not pre-treated with clopidogrel PCI-CURE Subgroup of CURE patients who underwent PCI Randomized comparison of pre-treatment and continued clopidogrel therapy vs. placebo Absolute reduction of Death or MI at 1 month and 1 year Abciximab Early clopidogrel Early and continued clopidogrel % reduction * * 6 month data in TARGET Early and long term reduction of death or MI from antiplatelet therapy in patients with ACS Long Term Clopidogrel Post PCI Clinical guidelines: 9 months to 1 year in patients with ACS However, current data does not fully support this recommendation What should we do? 2 Comulative event rate in primary prevention stable CAD and ACS ACS Stable Primary Risk of vascular event after ACS Risk of event Time after ACS Stable CAD Commulative risk Risk per time Risk of vascular event after ACS high and low risk Risk of event Time after ACS High risk Low risk Risk of bleeding after initiation of clopidogrel (high and low risk) Risk of event Time after clopidogrel High risk Low risk Fixed, except for the initial few days heparin, catheterization Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? vascular bleeding Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? vascular bleeding > 1 year High vascular risk Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? vascular bleeding < 1 months High bleeding risk e.g. coumadin Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? Long term clopidogrel for patients with High risk for vascular event Low bleeding risk Short term clopidogrel for patients with Low risk for vascular event High bleeding risk vascular bleeding Who is ”High Risk” Patients in whom long term clopidogrel should be considered The vulnerable patient TIMI risk score Aspirin Failure Others Who is ”High Risk” Patients in whom long term clopidogrel should be considered The vulnerable patient TIMI risk score Aspirin Failure Others ACS Pathophysiology Inflammation, Plaque Rupture, Thrombosis, and Microembolization Quiescent plaque Plaque formation Lipids, other risk factors Inflammation LDL, others, Infection? Plaque rupture (erosion) ? Macrophages, metalloproteinases Thrombosis Platelet Activation, Thrombin Vulnerable plaque Macrophages Foam Cells Collagen  platelet activation TF  Clotting Cascade Lipid core Metalloproteinases Inflammation Courtesy of David Kandzari. Plaque rupture Culprit plaque Platelet-thrombin micro-emboli Atherosclerotic Plaques - Terminology Culprit Responsible for the clinical event Vulnerable High risk to become culprit (cause clinical event) Quiescent (Stable) Primary or healed (vulnerable or culprit) Fuster, V. et al. J Am Coll Cardiol 2005;46:937-954 Coronary Artery Disease: Diffuse disease with a variable mix of stable, vulnerable and culprit plaques Culprit and healed plaques in a coronary bifurcation N Engl J Med 2000;343:915-22 Angiograms of 253 patients with acute MI Complex Plaques: Single: 153 - 60.5% Multiple: 100 – 39.5%
Slide 61 - Early And Long Term Treatment With Clopidogrel In Coronary Artery Disease פרופ’ יוסף רוזנמן מכון הלב, בי"ח וולפסון דצמבר 2005 Acute Coronary Syndromes Acute Coronary Syndrome No ST Elevation ST Elevation Unstable Angina Myocardial Infarction Non Q MI Q wave MI Non ST Elevation MI Braunwald E et al. J Am Coll Cardiol 2000;36:970–1062. Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When angiography / PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until angiography / PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month improving long-term outcome 1 2 Goals of therapy Prevent ischemic events until coronary angiography / PCI Before plaque stabilization was achieved Prevent PCI / stent related ischemic complications Clopidogrel before coronary angiography - Patients with ACS 1 Clopidogrel before coronary angiography - Patients with ACS ST Elevation CLARITY Non ST Elevation CURE 1 ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Study Design Fibrinolytic, ASA, Heparin Clopidogrel 300 mg + 75 mg qd Coronary Angiogram (2-8 days) Primary endpoint: Occluded artery (TIMI Flow Grade 0/1) or D/MI by time of angio randomize Placebo Double-blind, randomized, placebo-controlled trial in 3491 patients, age 18-75 yrs with STEMI < 12 hours Study Drug 30-day clinical follow-up Open-label clopidogrel per MD in both groups Primary Endpoint: Occluded Artery (or D/MI by time of angio) Placebo Clopidogrel P=0.00000036 Odds Ratio 0.64 (95% CI 0.53-0.76) 1.0 0.4 0.6 0.8 1.2 1.6 Clopidogrel better Placebo better n=1752 n=1739 36% Odds Reduction Primary & Angiographic Outcomes (median 3.5 days) Need for Urgent or Additional Treatment 21%  P=0.01 21%  P=0.005 16%  P=0.07 Early Angio (w/in 48 hrs) Urgent Revasc (index hosp) GP IIb/IIIa if PCI CV Death, MI, RI  Urg Revasc days Percentage with endpoint (%) 0 5 10 15 0 5 10 15 20 25 30 Placebo Clopidogrel Odds Ratio 0.80 (95% CI 0.65-0.97) P=0.026 20% 1 CLARITY: Patient Management Clopidogrel Placebo Parameter (n=1,752) (n=1,739) Symptom onset to fibrinolytic (hours) 2.7 2.6 Fibrinolytic to study drug (minutes) 10 10 Median doses of study medication 4 4 Angiography performed (%) 94 94 Study drug to angiography (hours) 84 84 Coronary revascularization (%): 63 63 PCI 57.2 56.6 CABG 5.9 6.0 Sabatine M et al. New Engl J Med 2005; 352: 1179–1189. PCI-CLARITY: Reduction in CV Death, MI, Stroke from PCI to 30 Days Days Post PCI Percentage with Outcome (%) 0 2 0 5 10 15 20 25 30 46%* p=0.008 Clopidogrel Pretreatment (3.6%) No Pretreatment (6.2%) 4 6 8 M Sabatine, et al. JAMA 2005 PCI-CLARITY: MI, Stroke, or CV Death Events pre and post PCI ***MI or Stroke M Sabatine, et al. JAMA 2005, Prehospital Fibrinolysis with Double Antiplatelet Therapy in Acute ST-Elevation Myocardial Infarction: The Clarity Ambulance Substudy Substudy Sites and Patient Numbers France: 172 patients L Soulat: 57 Y Lambert: 48 F Lapostolle: 28 F Thieuleux: 21 C Gully: 10 D Pollet: 5 D Galley: 2 L Olliver: 1 UK: 40 patients J Adgey: 27 J Purvis: 13 Sweden: 5 patients J-E Karlsson: 5 217 patients in total Angiographic & ECG Parameters: Ambulance vs. Non-Ambulance *Complete considered to be >70%; ECG=electrocardiogram p value Event rate (%) Ambulance Non- ambulance Non-ambulance better Ambulance better Odds ratio (95% CI) 0 0.5 1.0 1.5 2.0 Ambulance Non-ambulance Overall Clopidogrel better Placebo better Odds ratio (95% CI) Primary Endpoint of TIMI Flow Grade 0/1, MI or Death 0.60 (0.301.17) 0.64 (0.530.76) 0.65 (0.540.77) ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Clopidogrel 75mg q.d. + ASA 75-325 mg q.d.* (6259 patients) Placebo + ASA 75-325 mg q.d.* (6303 patients) Day 1 6 m. Visit 9 m. Visit 12 m. or Final Visit 3 m. Visit Discharge Visit 1 m. Visit Patients with Acute Coronary Syndrome (unstable angina or non-ST-segment elevation MI) R Placebo loading dose R = Randomization * In combination with other standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Study Design 3 months £ double-blind treatment £ 12 months Clopidogrel 300 mg loading dose CURE Clopidogrel + ASA* 3 6 9 Placebo + ASA* Months of Follow-Up 11.4% 9.3% 20% RRR P < 0.001 N = 12,562 0 12 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Primary End Point - MI/Stroke/CV Death CURE Clopidogrel + ASA* 10 20 30 Placebo + ASA* Days of Follow-Up 0 21% RRR P = 0.003 N = 12,562 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. MI/Stroke/CV Death within 30 Days CURE 1 CV death, nonfatal MI, stroke or refractory or severe ischemia 34% NEJM 2001; 345:495-502 MI/Stroke/CV Death or severe Ischemia at 24 hours CURE 1 % patients requiring thrombolytic therapy 43% % patients requiring GP IIb/IIIa inhibitors 18% NEJM 2001; 345:495-502 Need for Additional Anti-Thrombotic After Randomization P< 0.001 P= 0.003 Thrombolysis GP IIb/IIIa Inhibitor CURE 1 Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? GP IIb/IIIa receptor is the final common pathway in platelet aggregation. GP IIb/IIIa blockade is the most effective antiplatelet aggregation therapy. Bleeding risk is not increased if therapy is stopped 2-4 hours prior to CABG. Bleeding risk is markedly increased unless clopidogrel is stopped 3-5 days prior to CABG. Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? Is there additional benefit to clopidogrel that would justify: Increased CABG bleeding or alternatively Need to postpone CABG for 3-5 days No data in the literature however Adhesion The Role of Platelets in Atherothrombosis Aggregation 3 Reproduced with permission from Cannon CP. Atherothrombosis slide compendium. Available at: www.theheart.org. 1 Activation 2 Conclusions: Early Clopidogrel Therapy Treatment with clopidogrel is indicated as soon as possible in patients with acute coronary syndrome ST elevation and non ST elevation Treatment is effective to reduce ischemic complications Before coronay angiography During and after PCI 1 Conclusions: Early Clopidogrel Therapy Loading dose should be 600mg to achieve early optimal antiplatelet effect ?? 300mg in patients after fibrinolytic therapy It is unclear whether therapy should be added to “upstream” GP IIb/IIIa antagonists Especially in high risk patients in whom the likelihood for CABG is high 1 Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month after PCI / stent improving long-term outcome 1 2 Discharge/Post-Discharge Medications - Guidelines ASA, if not contraindicated Clopidogrel, when ASA contraindicated Aspirin + Clopidogrel for up to 9 months -blocker, if not contraindicated Lipid  agents + diet, if LDL >130 mg/dL ACE Inhibitor: CHF, EF < 40%, DM, or HTN I IIa IIb III 2 Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization PCI PLACEBO + ASA * CLOPIDOGREL + ASA * 30 days post PCI End of follow-up Up to 12 months after randomization Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 2,658 patients undergoing PCI N = 1345 N = 1313 PCI-CURE Overall Study Design: PCI-CURE R Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE Question 1 Question 2 Clopidogrel Arm Placebo Arm PCI* 28 Days Placebo + ASA† (325 mg) Randomization - Pre-treatment Clopidogrel 300 mg + ASA† (325 mg) Clopidogrel 75 mg QD + ASA† 325 mg QD Clopidogrel 75 mg QD + ASA† 325 mg QD R 12 Months Steinhubl S, Berger P, Tift Mann III J et al. JAMA. 2002;Vol 288,No 19:2411-2420. Placebo QD + ASA† (81-325 mg) QD Clopidogrel 75 mg QD + ASA† (81-325 mg) QD Overall Study Design: CREDO Question 1 Question 2 1 2 Open label clopidogrel continuation Methodological Pitfall Can a study with a single randomization provide an answer to two questions? Alternatively Should a second randomization be done in order to answer the second question? PCI PLACEBO + ASA * CLOPIDOGREL + ASA * 30 days post PCI End of follow-up Up to 12 months after randomization Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 1345 N = 1313 PCI-CURE Study Design single randomization R Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE Continuation Continuation PCI PLACEBO + ASA * CLOPIDOGREL + ASA * Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 1345 N = 1313 PCI-CURE Alternative Study Design two randomizations R1 Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE R2 R2 Clop. Placebo Continuation Continuation Question 2 2 Is it just methodology? Can we really expect long term benefit from early antiplatelet therapy? Adjunct antiplatelet therapy for PCI EPISTENT Randomized study designed to determine the effect of treatment with abciximab TARGET Randomized study designed to show that tirofiban is not inferior to abciximab Post-hoc nonrandomized comparison among those who were or were not pre-treated with clopidogrel PCI-CURE Subgroup of CURE patients who underwent PCI Randomized comparison of pre-treatment and continued clopidogrel therapy vs. placebo Absolute reduction of Death or MI at 1 month and 1 year Abciximab Early clopidogrel Early and continued clopidogrel % reduction * * 6 month data in TARGET Early and long term reduction of death or MI from antiplatelet therapy in patients with ACS Long Term Clopidogrel Post PCI Clinical guidelines: 9 months to 1 year in patients with ACS However, current data does not fully support this recommendation What should we do? 2 Comulative event rate in primary prevention stable CAD and ACS ACS Stable Primary Risk of vascular event after ACS Risk of event Time after ACS Stable CAD Commulative risk Risk per time Risk of vascular event after ACS high and low risk Risk of event Time after ACS High risk Low risk Risk of bleeding after initiation of clopidogrel (high and low risk) Risk of event Time after clopidogrel High risk Low risk Fixed, except for the initial few days heparin, catheterization Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? vascular bleeding Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? vascular bleeding > 1 year High vascular risk Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? vascular bleeding < 1 months High bleeding risk e.g. coumadin Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? Long term clopidogrel for patients with High risk for vascular event Low bleeding risk Short term clopidogrel for patients with Low risk for vascular event High bleeding risk vascular bleeding Who is ”High Risk” Patients in whom long term clopidogrel should be considered The vulnerable patient TIMI risk score Aspirin Failure Others Who is ”High Risk” Patients in whom long term clopidogrel should be considered The vulnerable patient TIMI risk score Aspirin Failure Others ACS Pathophysiology Inflammation, Plaque Rupture, Thrombosis, and Microembolization Quiescent plaque Plaque formation Lipids, other risk factors Inflammation LDL, others, Infection? Plaque rupture (erosion) ? Macrophages, metalloproteinases Thrombosis Platelet Activation, Thrombin Vulnerable plaque Macrophages Foam Cells Collagen  platelet activation TF  Clotting Cascade Lipid core Metalloproteinases Inflammation Courtesy of David Kandzari. Plaque rupture Culprit plaque Platelet-thrombin micro-emboli Atherosclerotic Plaques - Terminology Culprit Responsible for the clinical event Vulnerable High risk to become culprit (cause clinical event) Quiescent (Stable) Primary or healed (vulnerable or culprit) Fuster, V. et al. J Am Coll Cardiol 2005;46:937-954 Coronary Artery Disease: Diffuse disease with a variable mix of stable, vulnerable and culprit plaques Culprit and healed plaques in a coronary bifurcation N Engl J Med 2000;343:915-22 Angiograms of 253 patients with acute MI Complex Plaques: Single: 153 - 60.5% Multiple: 100 – 39.5% Clinical Outcome at 1 Year – Single vs. Multiple Complex Plaques Similar results when analysis was restricted to patients with multivessel coronary disease: 74.5% of single 91.0% of multiple
Slide 62 - Early And Long Term Treatment With Clopidogrel In Coronary Artery Disease פרופ’ יוסף רוזנמן מכון הלב, בי"ח וולפסון דצמבר 2005 Acute Coronary Syndromes Acute Coronary Syndrome No ST Elevation ST Elevation Unstable Angina Myocardial Infarction Non Q MI Q wave MI Non ST Elevation MI Braunwald E et al. J Am Coll Cardiol 2000;36:970–1062. Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When angiography / PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until angiography / PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month improving long-term outcome 1 2 Goals of therapy Prevent ischemic events until coronary angiography / PCI Before plaque stabilization was achieved Prevent PCI / stent related ischemic complications Clopidogrel before coronary angiography - Patients with ACS 1 Clopidogrel before coronary angiography - Patients with ACS ST Elevation CLARITY Non ST Elevation CURE 1 ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Study Design Fibrinolytic, ASA, Heparin Clopidogrel 300 mg + 75 mg qd Coronary Angiogram (2-8 days) Primary endpoint: Occluded artery (TIMI Flow Grade 0/1) or D/MI by time of angio randomize Placebo Double-blind, randomized, placebo-controlled trial in 3491 patients, age 18-75 yrs with STEMI < 12 hours Study Drug 30-day clinical follow-up Open-label clopidogrel per MD in both groups Primary Endpoint: Occluded Artery (or D/MI by time of angio) Placebo Clopidogrel P=0.00000036 Odds Ratio 0.64 (95% CI 0.53-0.76) 1.0 0.4 0.6 0.8 1.2 1.6 Clopidogrel better Placebo better n=1752 n=1739 36% Odds Reduction Primary & Angiographic Outcomes (median 3.5 days) Need for Urgent or Additional Treatment 21%  P=0.01 21%  P=0.005 16%  P=0.07 Early Angio (w/in 48 hrs) Urgent Revasc (index hosp) GP IIb/IIIa if PCI CV Death, MI, RI  Urg Revasc days Percentage with endpoint (%) 0 5 10 15 0 5 10 15 20 25 30 Placebo Clopidogrel Odds Ratio 0.80 (95% CI 0.65-0.97) P=0.026 20% 1 CLARITY: Patient Management Clopidogrel Placebo Parameter (n=1,752) (n=1,739) Symptom onset to fibrinolytic (hours) 2.7 2.6 Fibrinolytic to study drug (minutes) 10 10 Median doses of study medication 4 4 Angiography performed (%) 94 94 Study drug to angiography (hours) 84 84 Coronary revascularization (%): 63 63 PCI 57.2 56.6 CABG 5.9 6.0 Sabatine M et al. New Engl J Med 2005; 352: 1179–1189. PCI-CLARITY: Reduction in CV Death, MI, Stroke from PCI to 30 Days Days Post PCI Percentage with Outcome (%) 0 2 0 5 10 15 20 25 30 46%* p=0.008 Clopidogrel Pretreatment (3.6%) No Pretreatment (6.2%) 4 6 8 M Sabatine, et al. JAMA 2005 PCI-CLARITY: MI, Stroke, or CV Death Events pre and post PCI ***MI or Stroke M Sabatine, et al. JAMA 2005, Prehospital Fibrinolysis with Double Antiplatelet Therapy in Acute ST-Elevation Myocardial Infarction: The Clarity Ambulance Substudy Substudy Sites and Patient Numbers France: 172 patients L Soulat: 57 Y Lambert: 48 F Lapostolle: 28 F Thieuleux: 21 C Gully: 10 D Pollet: 5 D Galley: 2 L Olliver: 1 UK: 40 patients J Adgey: 27 J Purvis: 13 Sweden: 5 patients J-E Karlsson: 5 217 patients in total Angiographic & ECG Parameters: Ambulance vs. Non-Ambulance *Complete considered to be >70%; ECG=electrocardiogram p value Event rate (%) Ambulance Non- ambulance Non-ambulance better Ambulance better Odds ratio (95% CI) 0 0.5 1.0 1.5 2.0 Ambulance Non-ambulance Overall Clopidogrel better Placebo better Odds ratio (95% CI) Primary Endpoint of TIMI Flow Grade 0/1, MI or Death 0.60 (0.301.17) 0.64 (0.530.76) 0.65 (0.540.77) ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Clopidogrel 75mg q.d. + ASA 75-325 mg q.d.* (6259 patients) Placebo + ASA 75-325 mg q.d.* (6303 patients) Day 1 6 m. Visit 9 m. Visit 12 m. or Final Visit 3 m. Visit Discharge Visit 1 m. Visit Patients with Acute Coronary Syndrome (unstable angina or non-ST-segment elevation MI) R Placebo loading dose R = Randomization * In combination with other standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Study Design 3 months £ double-blind treatment £ 12 months Clopidogrel 300 mg loading dose CURE Clopidogrel + ASA* 3 6 9 Placebo + ASA* Months of Follow-Up 11.4% 9.3% 20% RRR P < 0.001 N = 12,562 0 12 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Primary End Point - MI/Stroke/CV Death CURE Clopidogrel + ASA* 10 20 30 Placebo + ASA* Days of Follow-Up 0 21% RRR P = 0.003 N = 12,562 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. MI/Stroke/CV Death within 30 Days CURE 1 CV death, nonfatal MI, stroke or refractory or severe ischemia 34% NEJM 2001; 345:495-502 MI/Stroke/CV Death or severe Ischemia at 24 hours CURE 1 % patients requiring thrombolytic therapy 43% % patients requiring GP IIb/IIIa inhibitors 18% NEJM 2001; 345:495-502 Need for Additional Anti-Thrombotic After Randomization P< 0.001 P= 0.003 Thrombolysis GP IIb/IIIa Inhibitor CURE 1 Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? GP IIb/IIIa receptor is the final common pathway in platelet aggregation. GP IIb/IIIa blockade is the most effective antiplatelet aggregation therapy. Bleeding risk is not increased if therapy is stopped 2-4 hours prior to CABG. Bleeding risk is markedly increased unless clopidogrel is stopped 3-5 days prior to CABG. Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? Is there additional benefit to clopidogrel that would justify: Increased CABG bleeding or alternatively Need to postpone CABG for 3-5 days No data in the literature however Adhesion The Role of Platelets in Atherothrombosis Aggregation 3 Reproduced with permission from Cannon CP. Atherothrombosis slide compendium. Available at: www.theheart.org. 1 Activation 2 Conclusions: Early Clopidogrel Therapy Treatment with clopidogrel is indicated as soon as possible in patients with acute coronary syndrome ST elevation and non ST elevation Treatment is effective to reduce ischemic complications Before coronay angiography During and after PCI 1 Conclusions: Early Clopidogrel Therapy Loading dose should be 600mg to achieve early optimal antiplatelet effect ?? 300mg in patients after fibrinolytic therapy It is unclear whether therapy should be added to “upstream” GP IIb/IIIa antagonists Especially in high risk patients in whom the likelihood for CABG is high 1 Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month after PCI / stent improving long-term outcome 1 2 Discharge/Post-Discharge Medications - Guidelines ASA, if not contraindicated Clopidogrel, when ASA contraindicated Aspirin + Clopidogrel for up to 9 months -blocker, if not contraindicated Lipid  agents + diet, if LDL >130 mg/dL ACE Inhibitor: CHF, EF < 40%, DM, or HTN I IIa IIb III 2 Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization PCI PLACEBO + ASA * CLOPIDOGREL + ASA * 30 days post PCI End of follow-up Up to 12 months after randomization Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 2,658 patients undergoing PCI N = 1345 N = 1313 PCI-CURE Overall Study Design: PCI-CURE R Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE Question 1 Question 2 Clopidogrel Arm Placebo Arm PCI* 28 Days Placebo + ASA† (325 mg) Randomization - Pre-treatment Clopidogrel 300 mg + ASA† (325 mg) Clopidogrel 75 mg QD + ASA† 325 mg QD Clopidogrel 75 mg QD + ASA† 325 mg QD R 12 Months Steinhubl S, Berger P, Tift Mann III J et al. JAMA. 2002;Vol 288,No 19:2411-2420. Placebo QD + ASA† (81-325 mg) QD Clopidogrel 75 mg QD + ASA† (81-325 mg) QD Overall Study Design: CREDO Question 1 Question 2 1 2 Open label clopidogrel continuation Methodological Pitfall Can a study with a single randomization provide an answer to two questions? Alternatively Should a second randomization be done in order to answer the second question? PCI PLACEBO + ASA * CLOPIDOGREL + ASA * 30 days post PCI End of follow-up Up to 12 months after randomization Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 1345 N = 1313 PCI-CURE Study Design single randomization R Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE Continuation Continuation PCI PLACEBO + ASA * CLOPIDOGREL + ASA * Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 1345 N = 1313 PCI-CURE Alternative Study Design two randomizations R1 Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE R2 R2 Clop. Placebo Continuation Continuation Question 2 2 Is it just methodology? Can we really expect long term benefit from early antiplatelet therapy? Adjunct antiplatelet therapy for PCI EPISTENT Randomized study designed to determine the effect of treatment with abciximab TARGET Randomized study designed to show that tirofiban is not inferior to abciximab Post-hoc nonrandomized comparison among those who were or were not pre-treated with clopidogrel PCI-CURE Subgroup of CURE patients who underwent PCI Randomized comparison of pre-treatment and continued clopidogrel therapy vs. placebo Absolute reduction of Death or MI at 1 month and 1 year Abciximab Early clopidogrel Early and continued clopidogrel % reduction * * 6 month data in TARGET Early and long term reduction of death or MI from antiplatelet therapy in patients with ACS Long Term Clopidogrel Post PCI Clinical guidelines: 9 months to 1 year in patients with ACS However, current data does not fully support this recommendation What should we do? 2 Comulative event rate in primary prevention stable CAD and ACS ACS Stable Primary Risk of vascular event after ACS Risk of event Time after ACS Stable CAD Commulative risk Risk per time Risk of vascular event after ACS high and low risk Risk of event Time after ACS High risk Low risk Risk of bleeding after initiation of clopidogrel (high and low risk) Risk of event Time after clopidogrel High risk Low risk Fixed, except for the initial few days heparin, catheterization Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? vascular bleeding Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? vascular bleeding > 1 year High vascular risk Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? vascular bleeding < 1 months High bleeding risk e.g. coumadin Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? Long term clopidogrel for patients with High risk for vascular event Low bleeding risk Short term clopidogrel for patients with Low risk for vascular event High bleeding risk vascular bleeding Who is ”High Risk” Patients in whom long term clopidogrel should be considered The vulnerable patient TIMI risk score Aspirin Failure Others Who is ”High Risk” Patients in whom long term clopidogrel should be considered The vulnerable patient TIMI risk score Aspirin Failure Others ACS Pathophysiology Inflammation, Plaque Rupture, Thrombosis, and Microembolization Quiescent plaque Plaque formation Lipids, other risk factors Inflammation LDL, others, Infection? Plaque rupture (erosion) ? Macrophages, metalloproteinases Thrombosis Platelet Activation, Thrombin Vulnerable plaque Macrophages Foam Cells Collagen  platelet activation TF  Clotting Cascade Lipid core Metalloproteinases Inflammation Courtesy of David Kandzari. Plaque rupture Culprit plaque Platelet-thrombin micro-emboli Atherosclerotic Plaques - Terminology Culprit Responsible for the clinical event Vulnerable High risk to become culprit (cause clinical event) Quiescent (Stable) Primary or healed (vulnerable or culprit) Fuster, V. et al. J Am Coll Cardiol 2005;46:937-954 Coronary Artery Disease: Diffuse disease with a variable mix of stable, vulnerable and culprit plaques Culprit and healed plaques in a coronary bifurcation N Engl J Med 2000;343:915-22 Angiograms of 253 patients with acute MI Complex Plaques: Single: 153 - 60.5% Multiple: 100 – 39.5% Clinical Outcome at 1 Year – Single vs. Multiple Complex Plaques Similar results when analysis was restricted to patients with multivessel coronary disease: 74.5% of single 91.0% of multiple Characteristics of Carotid Plaques: Patients with Unstable versus Stable Angina Multivariate analysis: UA and CRP >3 mg/l were independently and strongly associated with complex carotid plaques
Slide 63 - Early And Long Term Treatment With Clopidogrel In Coronary Artery Disease פרופ’ יוסף רוזנמן מכון הלב, בי"ח וולפסון דצמבר 2005 Acute Coronary Syndromes Acute Coronary Syndrome No ST Elevation ST Elevation Unstable Angina Myocardial Infarction Non Q MI Q wave MI Non ST Elevation MI Braunwald E et al. J Am Coll Cardiol 2000;36:970–1062. Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When angiography / PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until angiography / PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month improving long-term outcome 1 2 Goals of therapy Prevent ischemic events until coronary angiography / PCI Before plaque stabilization was achieved Prevent PCI / stent related ischemic complications Clopidogrel before coronary angiography - Patients with ACS 1 Clopidogrel before coronary angiography - Patients with ACS ST Elevation CLARITY Non ST Elevation CURE 1 ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Study Design Fibrinolytic, ASA, Heparin Clopidogrel 300 mg + 75 mg qd Coronary Angiogram (2-8 days) Primary endpoint: Occluded artery (TIMI Flow Grade 0/1) or D/MI by time of angio randomize Placebo Double-blind, randomized, placebo-controlled trial in 3491 patients, age 18-75 yrs with STEMI < 12 hours Study Drug 30-day clinical follow-up Open-label clopidogrel per MD in both groups Primary Endpoint: Occluded Artery (or D/MI by time of angio) Placebo Clopidogrel P=0.00000036 Odds Ratio 0.64 (95% CI 0.53-0.76) 1.0 0.4 0.6 0.8 1.2 1.6 Clopidogrel better Placebo better n=1752 n=1739 36% Odds Reduction Primary & Angiographic Outcomes (median 3.5 days) Need for Urgent or Additional Treatment 21%  P=0.01 21%  P=0.005 16%  P=0.07 Early Angio (w/in 48 hrs) Urgent Revasc (index hosp) GP IIb/IIIa if PCI CV Death, MI, RI  Urg Revasc days Percentage with endpoint (%) 0 5 10 15 0 5 10 15 20 25 30 Placebo Clopidogrel Odds Ratio 0.80 (95% CI 0.65-0.97) P=0.026 20% 1 CLARITY: Patient Management Clopidogrel Placebo Parameter (n=1,752) (n=1,739) Symptom onset to fibrinolytic (hours) 2.7 2.6 Fibrinolytic to study drug (minutes) 10 10 Median doses of study medication 4 4 Angiography performed (%) 94 94 Study drug to angiography (hours) 84 84 Coronary revascularization (%): 63 63 PCI 57.2 56.6 CABG 5.9 6.0 Sabatine M et al. New Engl J Med 2005; 352: 1179–1189. PCI-CLARITY: Reduction in CV Death, MI, Stroke from PCI to 30 Days Days Post PCI Percentage with Outcome (%) 0 2 0 5 10 15 20 25 30 46%* p=0.008 Clopidogrel Pretreatment (3.6%) No Pretreatment (6.2%) 4 6 8 M Sabatine, et al. JAMA 2005 PCI-CLARITY: MI, Stroke, or CV Death Events pre and post PCI ***MI or Stroke M Sabatine, et al. JAMA 2005, Prehospital Fibrinolysis with Double Antiplatelet Therapy in Acute ST-Elevation Myocardial Infarction: The Clarity Ambulance Substudy Substudy Sites and Patient Numbers France: 172 patients L Soulat: 57 Y Lambert: 48 F Lapostolle: 28 F Thieuleux: 21 C Gully: 10 D Pollet: 5 D Galley: 2 L Olliver: 1 UK: 40 patients J Adgey: 27 J Purvis: 13 Sweden: 5 patients J-E Karlsson: 5 217 patients in total Angiographic & ECG Parameters: Ambulance vs. Non-Ambulance *Complete considered to be >70%; ECG=electrocardiogram p value Event rate (%) Ambulance Non- ambulance Non-ambulance better Ambulance better Odds ratio (95% CI) 0 0.5 1.0 1.5 2.0 Ambulance Non-ambulance Overall Clopidogrel better Placebo better Odds ratio (95% CI) Primary Endpoint of TIMI Flow Grade 0/1, MI or Death 0.60 (0.301.17) 0.64 (0.530.76) 0.65 (0.540.77) ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Clopidogrel 75mg q.d. + ASA 75-325 mg q.d.* (6259 patients) Placebo + ASA 75-325 mg q.d.* (6303 patients) Day 1 6 m. Visit 9 m. Visit 12 m. or Final Visit 3 m. Visit Discharge Visit 1 m. Visit Patients with Acute Coronary Syndrome (unstable angina or non-ST-segment elevation MI) R Placebo loading dose R = Randomization * In combination with other standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Study Design 3 months £ double-blind treatment £ 12 months Clopidogrel 300 mg loading dose CURE Clopidogrel + ASA* 3 6 9 Placebo + ASA* Months of Follow-Up 11.4% 9.3% 20% RRR P < 0.001 N = 12,562 0 12 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Primary End Point - MI/Stroke/CV Death CURE Clopidogrel + ASA* 10 20 30 Placebo + ASA* Days of Follow-Up 0 21% RRR P = 0.003 N = 12,562 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. MI/Stroke/CV Death within 30 Days CURE 1 CV death, nonfatal MI, stroke or refractory or severe ischemia 34% NEJM 2001; 345:495-502 MI/Stroke/CV Death or severe Ischemia at 24 hours CURE 1 % patients requiring thrombolytic therapy 43% % patients requiring GP IIb/IIIa inhibitors 18% NEJM 2001; 345:495-502 Need for Additional Anti-Thrombotic After Randomization P< 0.001 P= 0.003 Thrombolysis GP IIb/IIIa Inhibitor CURE 1 Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? GP IIb/IIIa receptor is the final common pathway in platelet aggregation. GP IIb/IIIa blockade is the most effective antiplatelet aggregation therapy. Bleeding risk is not increased if therapy is stopped 2-4 hours prior to CABG. Bleeding risk is markedly increased unless clopidogrel is stopped 3-5 days prior to CABG. Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? Is there additional benefit to clopidogrel that would justify: Increased CABG bleeding or alternatively Need to postpone CABG for 3-5 days No data in the literature however Adhesion The Role of Platelets in Atherothrombosis Aggregation 3 Reproduced with permission from Cannon CP. Atherothrombosis slide compendium. Available at: www.theheart.org. 1 Activation 2 Conclusions: Early Clopidogrel Therapy Treatment with clopidogrel is indicated as soon as possible in patients with acute coronary syndrome ST elevation and non ST elevation Treatment is effective to reduce ischemic complications Before coronay angiography During and after PCI 1 Conclusions: Early Clopidogrel Therapy Loading dose should be 600mg to achieve early optimal antiplatelet effect ?? 300mg in patients after fibrinolytic therapy It is unclear whether therapy should be added to “upstream” GP IIb/IIIa antagonists Especially in high risk patients in whom the likelihood for CABG is high 1 Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month after PCI / stent improving long-term outcome 1 2 Discharge/Post-Discharge Medications - Guidelines ASA, if not contraindicated Clopidogrel, when ASA contraindicated Aspirin + Clopidogrel for up to 9 months -blocker, if not contraindicated Lipid  agents + diet, if LDL >130 mg/dL ACE Inhibitor: CHF, EF < 40%, DM, or HTN I IIa IIb III 2 Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization PCI PLACEBO + ASA * CLOPIDOGREL + ASA * 30 days post PCI End of follow-up Up to 12 months after randomization Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 2,658 patients undergoing PCI N = 1345 N = 1313 PCI-CURE Overall Study Design: PCI-CURE R Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE Question 1 Question 2 Clopidogrel Arm Placebo Arm PCI* 28 Days Placebo + ASA† (325 mg) Randomization - Pre-treatment Clopidogrel 300 mg + ASA† (325 mg) Clopidogrel 75 mg QD + ASA† 325 mg QD Clopidogrel 75 mg QD + ASA† 325 mg QD R 12 Months Steinhubl S, Berger P, Tift Mann III J et al. JAMA. 2002;Vol 288,No 19:2411-2420. Placebo QD + ASA† (81-325 mg) QD Clopidogrel 75 mg QD + ASA† (81-325 mg) QD Overall Study Design: CREDO Question 1 Question 2 1 2 Open label clopidogrel continuation Methodological Pitfall Can a study with a single randomization provide an answer to two questions? Alternatively Should a second randomization be done in order to answer the second question? PCI PLACEBO + ASA * CLOPIDOGREL + ASA * 30 days post PCI End of follow-up Up to 12 months after randomization Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 1345 N = 1313 PCI-CURE Study Design single randomization R Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE Continuation Continuation PCI PLACEBO + ASA * CLOPIDOGREL + ASA * Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 1345 N = 1313 PCI-CURE Alternative Study Design two randomizations R1 Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE R2 R2 Clop. Placebo Continuation Continuation Question 2 2 Is it just methodology? Can we really expect long term benefit from early antiplatelet therapy? Adjunct antiplatelet therapy for PCI EPISTENT Randomized study designed to determine the effect of treatment with abciximab TARGET Randomized study designed to show that tirofiban is not inferior to abciximab Post-hoc nonrandomized comparison among those who were or were not pre-treated with clopidogrel PCI-CURE Subgroup of CURE patients who underwent PCI Randomized comparison of pre-treatment and continued clopidogrel therapy vs. placebo Absolute reduction of Death or MI at 1 month and 1 year Abciximab Early clopidogrel Early and continued clopidogrel % reduction * * 6 month data in TARGET Early and long term reduction of death or MI from antiplatelet therapy in patients with ACS Long Term Clopidogrel Post PCI Clinical guidelines: 9 months to 1 year in patients with ACS However, current data does not fully support this recommendation What should we do? 2 Comulative event rate in primary prevention stable CAD and ACS ACS Stable Primary Risk of vascular event after ACS Risk of event Time after ACS Stable CAD Commulative risk Risk per time Risk of vascular event after ACS high and low risk Risk of event Time after ACS High risk Low risk Risk of bleeding after initiation of clopidogrel (high and low risk) Risk of event Time after clopidogrel High risk Low risk Fixed, except for the initial few days heparin, catheterization Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? vascular bleeding Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? vascular bleeding > 1 year High vascular risk Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? vascular bleeding < 1 months High bleeding risk e.g. coumadin Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? Long term clopidogrel for patients with High risk for vascular event Low bleeding risk Short term clopidogrel for patients with Low risk for vascular event High bleeding risk vascular bleeding Who is ”High Risk” Patients in whom long term clopidogrel should be considered The vulnerable patient TIMI risk score Aspirin Failure Others Who is ”High Risk” Patients in whom long term clopidogrel should be considered The vulnerable patient TIMI risk score Aspirin Failure Others ACS Pathophysiology Inflammation, Plaque Rupture, Thrombosis, and Microembolization Quiescent plaque Plaque formation Lipids, other risk factors Inflammation LDL, others, Infection? Plaque rupture (erosion) ? Macrophages, metalloproteinases Thrombosis Platelet Activation, Thrombin Vulnerable plaque Macrophages Foam Cells Collagen  platelet activation TF  Clotting Cascade Lipid core Metalloproteinases Inflammation Courtesy of David Kandzari. Plaque rupture Culprit plaque Platelet-thrombin micro-emboli Atherosclerotic Plaques - Terminology Culprit Responsible for the clinical event Vulnerable High risk to become culprit (cause clinical event) Quiescent (Stable) Primary or healed (vulnerable or culprit) Fuster, V. et al. J Am Coll Cardiol 2005;46:937-954 Coronary Artery Disease: Diffuse disease with a variable mix of stable, vulnerable and culprit plaques Culprit and healed plaques in a coronary bifurcation N Engl J Med 2000;343:915-22 Angiograms of 253 patients with acute MI Complex Plaques: Single: 153 - 60.5% Multiple: 100 – 39.5% Clinical Outcome at 1 Year – Single vs. Multiple Complex Plaques Similar results when analysis was restricted to patients with multivessel coronary disease: 74.5% of single 91.0% of multiple Characteristics of Carotid Plaques: Patients with Unstable versus Stable Angina Multivariate analysis: UA and CRP >3 mg/l were independently and strongly associated with complex carotid plaques Vulnerable Patient – at high risk for vascular event coronary elsewhere
Slide 64 - Early And Long Term Treatment With Clopidogrel In Coronary Artery Disease פרופ’ יוסף רוזנמן מכון הלב, בי"ח וולפסון דצמבר 2005 Acute Coronary Syndromes Acute Coronary Syndrome No ST Elevation ST Elevation Unstable Angina Myocardial Infarction Non Q MI Q wave MI Non ST Elevation MI Braunwald E et al. J Am Coll Cardiol 2000;36:970–1062. Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When angiography / PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until angiography / PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month improving long-term outcome 1 2 Goals of therapy Prevent ischemic events until coronary angiography / PCI Before plaque stabilization was achieved Prevent PCI / stent related ischemic complications Clopidogrel before coronary angiography - Patients with ACS 1 Clopidogrel before coronary angiography - Patients with ACS ST Elevation CLARITY Non ST Elevation CURE 1 ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Study Design Fibrinolytic, ASA, Heparin Clopidogrel 300 mg + 75 mg qd Coronary Angiogram (2-8 days) Primary endpoint: Occluded artery (TIMI Flow Grade 0/1) or D/MI by time of angio randomize Placebo Double-blind, randomized, placebo-controlled trial in 3491 patients, age 18-75 yrs with STEMI < 12 hours Study Drug 30-day clinical follow-up Open-label clopidogrel per MD in both groups Primary Endpoint: Occluded Artery (or D/MI by time of angio) Placebo Clopidogrel P=0.00000036 Odds Ratio 0.64 (95% CI 0.53-0.76) 1.0 0.4 0.6 0.8 1.2 1.6 Clopidogrel better Placebo better n=1752 n=1739 36% Odds Reduction Primary & Angiographic Outcomes (median 3.5 days) Need for Urgent or Additional Treatment 21%  P=0.01 21%  P=0.005 16%  P=0.07 Early Angio (w/in 48 hrs) Urgent Revasc (index hosp) GP IIb/IIIa if PCI CV Death, MI, RI  Urg Revasc days Percentage with endpoint (%) 0 5 10 15 0 5 10 15 20 25 30 Placebo Clopidogrel Odds Ratio 0.80 (95% CI 0.65-0.97) P=0.026 20% 1 CLARITY: Patient Management Clopidogrel Placebo Parameter (n=1,752) (n=1,739) Symptom onset to fibrinolytic (hours) 2.7 2.6 Fibrinolytic to study drug (minutes) 10 10 Median doses of study medication 4 4 Angiography performed (%) 94 94 Study drug to angiography (hours) 84 84 Coronary revascularization (%): 63 63 PCI 57.2 56.6 CABG 5.9 6.0 Sabatine M et al. New Engl J Med 2005; 352: 1179–1189. PCI-CLARITY: Reduction in CV Death, MI, Stroke from PCI to 30 Days Days Post PCI Percentage with Outcome (%) 0 2 0 5 10 15 20 25 30 46%* p=0.008 Clopidogrel Pretreatment (3.6%) No Pretreatment (6.2%) 4 6 8 M Sabatine, et al. JAMA 2005 PCI-CLARITY: MI, Stroke, or CV Death Events pre and post PCI ***MI or Stroke M Sabatine, et al. JAMA 2005, Prehospital Fibrinolysis with Double Antiplatelet Therapy in Acute ST-Elevation Myocardial Infarction: The Clarity Ambulance Substudy Substudy Sites and Patient Numbers France: 172 patients L Soulat: 57 Y Lambert: 48 F Lapostolle: 28 F Thieuleux: 21 C Gully: 10 D Pollet: 5 D Galley: 2 L Olliver: 1 UK: 40 patients J Adgey: 27 J Purvis: 13 Sweden: 5 patients J-E Karlsson: 5 217 patients in total Angiographic & ECG Parameters: Ambulance vs. Non-Ambulance *Complete considered to be >70%; ECG=electrocardiogram p value Event rate (%) Ambulance Non- ambulance Non-ambulance better Ambulance better Odds ratio (95% CI) 0 0.5 1.0 1.5 2.0 Ambulance Non-ambulance Overall Clopidogrel better Placebo better Odds ratio (95% CI) Primary Endpoint of TIMI Flow Grade 0/1, MI or Death 0.60 (0.301.17) 0.64 (0.530.76) 0.65 (0.540.77) ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Clopidogrel 75mg q.d. + ASA 75-325 mg q.d.* (6259 patients) Placebo + ASA 75-325 mg q.d.* (6303 patients) Day 1 6 m. Visit 9 m. Visit 12 m. or Final Visit 3 m. Visit Discharge Visit 1 m. Visit Patients with Acute Coronary Syndrome (unstable angina or non-ST-segment elevation MI) R Placebo loading dose R = Randomization * In combination with other standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Study Design 3 months £ double-blind treatment £ 12 months Clopidogrel 300 mg loading dose CURE Clopidogrel + ASA* 3 6 9 Placebo + ASA* Months of Follow-Up 11.4% 9.3% 20% RRR P < 0.001 N = 12,562 0 12 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Primary End Point - MI/Stroke/CV Death CURE Clopidogrel + ASA* 10 20 30 Placebo + ASA* Days of Follow-Up 0 21% RRR P = 0.003 N = 12,562 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. MI/Stroke/CV Death within 30 Days CURE 1 CV death, nonfatal MI, stroke or refractory or severe ischemia 34% NEJM 2001; 345:495-502 MI/Stroke/CV Death or severe Ischemia at 24 hours CURE 1 % patients requiring thrombolytic therapy 43% % patients requiring GP IIb/IIIa inhibitors 18% NEJM 2001; 345:495-502 Need for Additional Anti-Thrombotic After Randomization P< 0.001 P= 0.003 Thrombolysis GP IIb/IIIa Inhibitor CURE 1 Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? GP IIb/IIIa receptor is the final common pathway in platelet aggregation. GP IIb/IIIa blockade is the most effective antiplatelet aggregation therapy. Bleeding risk is not increased if therapy is stopped 2-4 hours prior to CABG. Bleeding risk is markedly increased unless clopidogrel is stopped 3-5 days prior to CABG. Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? Is there additional benefit to clopidogrel that would justify: Increased CABG bleeding or alternatively Need to postpone CABG for 3-5 days No data in the literature however Adhesion The Role of Platelets in Atherothrombosis Aggregation 3 Reproduced with permission from Cannon CP. Atherothrombosis slide compendium. Available at: www.theheart.org. 1 Activation 2 Conclusions: Early Clopidogrel Therapy Treatment with clopidogrel is indicated as soon as possible in patients with acute coronary syndrome ST elevation and non ST elevation Treatment is effective to reduce ischemic complications Before coronay angiography During and after PCI 1 Conclusions: Early Clopidogrel Therapy Loading dose should be 600mg to achieve early optimal antiplatelet effect ?? 300mg in patients after fibrinolytic therapy It is unclear whether therapy should be added to “upstream” GP IIb/IIIa antagonists Especially in high risk patients in whom the likelihood for CABG is high 1 Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month after PCI / stent improving long-term outcome 1 2 Discharge/Post-Discharge Medications - Guidelines ASA, if not contraindicated Clopidogrel, when ASA contraindicated Aspirin + Clopidogrel for up to 9 months -blocker, if not contraindicated Lipid  agents + diet, if LDL >130 mg/dL ACE Inhibitor: CHF, EF < 40%, DM, or HTN I IIa IIb III 2 Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization PCI PLACEBO + ASA * CLOPIDOGREL + ASA * 30 days post PCI End of follow-up Up to 12 months after randomization Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 2,658 patients undergoing PCI N = 1345 N = 1313 PCI-CURE Overall Study Design: PCI-CURE R Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE Question 1 Question 2 Clopidogrel Arm Placebo Arm PCI* 28 Days Placebo + ASA† (325 mg) Randomization - Pre-treatment Clopidogrel 300 mg + ASA† (325 mg) Clopidogrel 75 mg QD + ASA† 325 mg QD Clopidogrel 75 mg QD + ASA† 325 mg QD R 12 Months Steinhubl S, Berger P, Tift Mann III J et al. JAMA. 2002;Vol 288,No 19:2411-2420. Placebo QD + ASA† (81-325 mg) QD Clopidogrel 75 mg QD + ASA† (81-325 mg) QD Overall Study Design: CREDO Question 1 Question 2 1 2 Open label clopidogrel continuation Methodological Pitfall Can a study with a single randomization provide an answer to two questions? Alternatively Should a second randomization be done in order to answer the second question? PCI PLACEBO + ASA * CLOPIDOGREL + ASA * 30 days post PCI End of follow-up Up to 12 months after randomization Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 1345 N = 1313 PCI-CURE Study Design single randomization R Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE Continuation Continuation PCI PLACEBO + ASA * CLOPIDOGREL + ASA * Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 1345 N = 1313 PCI-CURE Alternative Study Design two randomizations R1 Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE R2 R2 Clop. Placebo Continuation Continuation Question 2 2 Is it just methodology? Can we really expect long term benefit from early antiplatelet therapy? Adjunct antiplatelet therapy for PCI EPISTENT Randomized study designed to determine the effect of treatment with abciximab TARGET Randomized study designed to show that tirofiban is not inferior to abciximab Post-hoc nonrandomized comparison among those who were or were not pre-treated with clopidogrel PCI-CURE Subgroup of CURE patients who underwent PCI Randomized comparison of pre-treatment and continued clopidogrel therapy vs. placebo Absolute reduction of Death or MI at 1 month and 1 year Abciximab Early clopidogrel Early and continued clopidogrel % reduction * * 6 month data in TARGET Early and long term reduction of death or MI from antiplatelet therapy in patients with ACS Long Term Clopidogrel Post PCI Clinical guidelines: 9 months to 1 year in patients with ACS However, current data does not fully support this recommendation What should we do? 2 Comulative event rate in primary prevention stable CAD and ACS ACS Stable Primary Risk of vascular event after ACS Risk of event Time after ACS Stable CAD Commulative risk Risk per time Risk of vascular event after ACS high and low risk Risk of event Time after ACS High risk Low risk Risk of bleeding after initiation of clopidogrel (high and low risk) Risk of event Time after clopidogrel High risk Low risk Fixed, except for the initial few days heparin, catheterization Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? vascular bleeding Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? vascular bleeding > 1 year High vascular risk Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? vascular bleeding < 1 months High bleeding risk e.g. coumadin Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? Long term clopidogrel for patients with High risk for vascular event Low bleeding risk Short term clopidogrel for patients with Low risk for vascular event High bleeding risk vascular bleeding Who is ”High Risk” Patients in whom long term clopidogrel should be considered The vulnerable patient TIMI risk score Aspirin Failure Others Who is ”High Risk” Patients in whom long term clopidogrel should be considered The vulnerable patient TIMI risk score Aspirin Failure Others ACS Pathophysiology Inflammation, Plaque Rupture, Thrombosis, and Microembolization Quiescent plaque Plaque formation Lipids, other risk factors Inflammation LDL, others, Infection? Plaque rupture (erosion) ? Macrophages, metalloproteinases Thrombosis Platelet Activation, Thrombin Vulnerable plaque Macrophages Foam Cells Collagen  platelet activation TF  Clotting Cascade Lipid core Metalloproteinases Inflammation Courtesy of David Kandzari. Plaque rupture Culprit plaque Platelet-thrombin micro-emboli Atherosclerotic Plaques - Terminology Culprit Responsible for the clinical event Vulnerable High risk to become culprit (cause clinical event) Quiescent (Stable) Primary or healed (vulnerable or culprit) Fuster, V. et al. J Am Coll Cardiol 2005;46:937-954 Coronary Artery Disease: Diffuse disease with a variable mix of stable, vulnerable and culprit plaques Culprit and healed plaques in a coronary bifurcation N Engl J Med 2000;343:915-22 Angiograms of 253 patients with acute MI Complex Plaques: Single: 153 - 60.5% Multiple: 100 – 39.5% Clinical Outcome at 1 Year – Single vs. Multiple Complex Plaques Similar results when analysis was restricted to patients with multivessel coronary disease: 74.5% of single 91.0% of multiple Characteristics of Carotid Plaques: Patients with Unstable versus Stable Angina Multivariate analysis: UA and CRP >3 mg/l were independently and strongly associated with complex carotid plaques Vulnerable Patient – at high risk for vascular event coronary elsewhere Who is the vulnerable patient? Patient with current multiple complex plaques Coronary, carotid etc Patient with multiple uncontrolled risk factors At risk to develop new complex plaques
Slide 65 - Early And Long Term Treatment With Clopidogrel In Coronary Artery Disease פרופ’ יוסף רוזנמן מכון הלב, בי"ח וולפסון דצמבר 2005 Acute Coronary Syndromes Acute Coronary Syndrome No ST Elevation ST Elevation Unstable Angina Myocardial Infarction Non Q MI Q wave MI Non ST Elevation MI Braunwald E et al. J Am Coll Cardiol 2000;36:970–1062. Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When angiography / PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until angiography / PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month improving long-term outcome 1 2 Goals of therapy Prevent ischemic events until coronary angiography / PCI Before plaque stabilization was achieved Prevent PCI / stent related ischemic complications Clopidogrel before coronary angiography - Patients with ACS 1 Clopidogrel before coronary angiography - Patients with ACS ST Elevation CLARITY Non ST Elevation CURE 1 ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Study Design Fibrinolytic, ASA, Heparin Clopidogrel 300 mg + 75 mg qd Coronary Angiogram (2-8 days) Primary endpoint: Occluded artery (TIMI Flow Grade 0/1) or D/MI by time of angio randomize Placebo Double-blind, randomized, placebo-controlled trial in 3491 patients, age 18-75 yrs with STEMI < 12 hours Study Drug 30-day clinical follow-up Open-label clopidogrel per MD in both groups Primary Endpoint: Occluded Artery (or D/MI by time of angio) Placebo Clopidogrel P=0.00000036 Odds Ratio 0.64 (95% CI 0.53-0.76) 1.0 0.4 0.6 0.8 1.2 1.6 Clopidogrel better Placebo better n=1752 n=1739 36% Odds Reduction Primary & Angiographic Outcomes (median 3.5 days) Need for Urgent or Additional Treatment 21%  P=0.01 21%  P=0.005 16%  P=0.07 Early Angio (w/in 48 hrs) Urgent Revasc (index hosp) GP IIb/IIIa if PCI CV Death, MI, RI  Urg Revasc days Percentage with endpoint (%) 0 5 10 15 0 5 10 15 20 25 30 Placebo Clopidogrel Odds Ratio 0.80 (95% CI 0.65-0.97) P=0.026 20% 1 CLARITY: Patient Management Clopidogrel Placebo Parameter (n=1,752) (n=1,739) Symptom onset to fibrinolytic (hours) 2.7 2.6 Fibrinolytic to study drug (minutes) 10 10 Median doses of study medication 4 4 Angiography performed (%) 94 94 Study drug to angiography (hours) 84 84 Coronary revascularization (%): 63 63 PCI 57.2 56.6 CABG 5.9 6.0 Sabatine M et al. New Engl J Med 2005; 352: 1179–1189. PCI-CLARITY: Reduction in CV Death, MI, Stroke from PCI to 30 Days Days Post PCI Percentage with Outcome (%) 0 2 0 5 10 15 20 25 30 46%* p=0.008 Clopidogrel Pretreatment (3.6%) No Pretreatment (6.2%) 4 6 8 M Sabatine, et al. JAMA 2005 PCI-CLARITY: MI, Stroke, or CV Death Events pre and post PCI ***MI or Stroke M Sabatine, et al. JAMA 2005, Prehospital Fibrinolysis with Double Antiplatelet Therapy in Acute ST-Elevation Myocardial Infarction: The Clarity Ambulance Substudy Substudy Sites and Patient Numbers France: 172 patients L Soulat: 57 Y Lambert: 48 F Lapostolle: 28 F Thieuleux: 21 C Gully: 10 D Pollet: 5 D Galley: 2 L Olliver: 1 UK: 40 patients J Adgey: 27 J Purvis: 13 Sweden: 5 patients J-E Karlsson: 5 217 patients in total Angiographic & ECG Parameters: Ambulance vs. Non-Ambulance *Complete considered to be >70%; ECG=electrocardiogram p value Event rate (%) Ambulance Non- ambulance Non-ambulance better Ambulance better Odds ratio (95% CI) 0 0.5 1.0 1.5 2.0 Ambulance Non-ambulance Overall Clopidogrel better Placebo better Odds ratio (95% CI) Primary Endpoint of TIMI Flow Grade 0/1, MI or Death 0.60 (0.301.17) 0.64 (0.530.76) 0.65 (0.540.77) ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Clopidogrel 75mg q.d. + ASA 75-325 mg q.d.* (6259 patients) Placebo + ASA 75-325 mg q.d.* (6303 patients) Day 1 6 m. Visit 9 m. Visit 12 m. or Final Visit 3 m. Visit Discharge Visit 1 m. Visit Patients with Acute Coronary Syndrome (unstable angina or non-ST-segment elevation MI) R Placebo loading dose R = Randomization * In combination with other standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Study Design 3 months £ double-blind treatment £ 12 months Clopidogrel 300 mg loading dose CURE Clopidogrel + ASA* 3 6 9 Placebo + ASA* Months of Follow-Up 11.4% 9.3% 20% RRR P < 0.001 N = 12,562 0 12 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Primary End Point - MI/Stroke/CV Death CURE Clopidogrel + ASA* 10 20 30 Placebo + ASA* Days of Follow-Up 0 21% RRR P = 0.003 N = 12,562 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. MI/Stroke/CV Death within 30 Days CURE 1 CV death, nonfatal MI, stroke or refractory or severe ischemia 34% NEJM 2001; 345:495-502 MI/Stroke/CV Death or severe Ischemia at 24 hours CURE 1 % patients requiring thrombolytic therapy 43% % patients requiring GP IIb/IIIa inhibitors 18% NEJM 2001; 345:495-502 Need for Additional Anti-Thrombotic After Randomization P< 0.001 P= 0.003 Thrombolysis GP IIb/IIIa Inhibitor CURE 1 Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? GP IIb/IIIa receptor is the final common pathway in platelet aggregation. GP IIb/IIIa blockade is the most effective antiplatelet aggregation therapy. Bleeding risk is not increased if therapy is stopped 2-4 hours prior to CABG. Bleeding risk is markedly increased unless clopidogrel is stopped 3-5 days prior to CABG. Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? Is there additional benefit to clopidogrel that would justify: Increased CABG bleeding or alternatively Need to postpone CABG for 3-5 days No data in the literature however Adhesion The Role of Platelets in Atherothrombosis Aggregation 3 Reproduced with permission from Cannon CP. Atherothrombosis slide compendium. Available at: www.theheart.org. 1 Activation 2 Conclusions: Early Clopidogrel Therapy Treatment with clopidogrel is indicated as soon as possible in patients with acute coronary syndrome ST elevation and non ST elevation Treatment is effective to reduce ischemic complications Before coronay angiography During and after PCI 1 Conclusions: Early Clopidogrel Therapy Loading dose should be 600mg to achieve early optimal antiplatelet effect ?? 300mg in patients after fibrinolytic therapy It is unclear whether therapy should be added to “upstream” GP IIb/IIIa antagonists Especially in high risk patients in whom the likelihood for CABG is high 1 Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month after PCI / stent improving long-term outcome 1 2 Discharge/Post-Discharge Medications - Guidelines ASA, if not contraindicated Clopidogrel, when ASA contraindicated Aspirin + Clopidogrel for up to 9 months -blocker, if not contraindicated Lipid  agents + diet, if LDL >130 mg/dL ACE Inhibitor: CHF, EF < 40%, DM, or HTN I IIa IIb III 2 Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization PCI PLACEBO + ASA * CLOPIDOGREL + ASA * 30 days post PCI End of follow-up Up to 12 months after randomization Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 2,658 patients undergoing PCI N = 1345 N = 1313 PCI-CURE Overall Study Design: PCI-CURE R Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE Question 1 Question 2 Clopidogrel Arm Placebo Arm PCI* 28 Days Placebo + ASA† (325 mg) Randomization - Pre-treatment Clopidogrel 300 mg + ASA† (325 mg) Clopidogrel 75 mg QD + ASA† 325 mg QD Clopidogrel 75 mg QD + ASA† 325 mg QD R 12 Months Steinhubl S, Berger P, Tift Mann III J et al. JAMA. 2002;Vol 288,No 19:2411-2420. Placebo QD + ASA† (81-325 mg) QD Clopidogrel 75 mg QD + ASA† (81-325 mg) QD Overall Study Design: CREDO Question 1 Question 2 1 2 Open label clopidogrel continuation Methodological Pitfall Can a study with a single randomization provide an answer to two questions? Alternatively Should a second randomization be done in order to answer the second question? PCI PLACEBO + ASA * CLOPIDOGREL + ASA * 30 days post PCI End of follow-up Up to 12 months after randomization Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 1345 N = 1313 PCI-CURE Study Design single randomization R Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE Continuation Continuation PCI PLACEBO + ASA * CLOPIDOGREL + ASA * Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 1345 N = 1313 PCI-CURE Alternative Study Design two randomizations R1 Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE R2 R2 Clop. Placebo Continuation Continuation Question 2 2 Is it just methodology? Can we really expect long term benefit from early antiplatelet therapy? Adjunct antiplatelet therapy for PCI EPISTENT Randomized study designed to determine the effect of treatment with abciximab TARGET Randomized study designed to show that tirofiban is not inferior to abciximab Post-hoc nonrandomized comparison among those who were or were not pre-treated with clopidogrel PCI-CURE Subgroup of CURE patients who underwent PCI Randomized comparison of pre-treatment and continued clopidogrel therapy vs. placebo Absolute reduction of Death or MI at 1 month and 1 year Abciximab Early clopidogrel Early and continued clopidogrel % reduction * * 6 month data in TARGET Early and long term reduction of death or MI from antiplatelet therapy in patients with ACS Long Term Clopidogrel Post PCI Clinical guidelines: 9 months to 1 year in patients with ACS However, current data does not fully support this recommendation What should we do? 2 Comulative event rate in primary prevention stable CAD and ACS ACS Stable Primary Risk of vascular event after ACS Risk of event Time after ACS Stable CAD Commulative risk Risk per time Risk of vascular event after ACS high and low risk Risk of event Time after ACS High risk Low risk Risk of bleeding after initiation of clopidogrel (high and low risk) Risk of event Time after clopidogrel High risk Low risk Fixed, except for the initial few days heparin, catheterization Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? vascular bleeding Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? vascular bleeding > 1 year High vascular risk Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? vascular bleeding < 1 months High bleeding risk e.g. coumadin Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? Long term clopidogrel for patients with High risk for vascular event Low bleeding risk Short term clopidogrel for patients with Low risk for vascular event High bleeding risk vascular bleeding Who is ”High Risk” Patients in whom long term clopidogrel should be considered The vulnerable patient TIMI risk score Aspirin Failure Others Who is ”High Risk” Patients in whom long term clopidogrel should be considered The vulnerable patient TIMI risk score Aspirin Failure Others ACS Pathophysiology Inflammation, Plaque Rupture, Thrombosis, and Microembolization Quiescent plaque Plaque formation Lipids, other risk factors Inflammation LDL, others, Infection? Plaque rupture (erosion) ? Macrophages, metalloproteinases Thrombosis Platelet Activation, Thrombin Vulnerable plaque Macrophages Foam Cells Collagen  platelet activation TF  Clotting Cascade Lipid core Metalloproteinases Inflammation Courtesy of David Kandzari. Plaque rupture Culprit plaque Platelet-thrombin micro-emboli Atherosclerotic Plaques - Terminology Culprit Responsible for the clinical event Vulnerable High risk to become culprit (cause clinical event) Quiescent (Stable) Primary or healed (vulnerable or culprit) Fuster, V. et al. J Am Coll Cardiol 2005;46:937-954 Coronary Artery Disease: Diffuse disease with a variable mix of stable, vulnerable and culprit plaques Culprit and healed plaques in a coronary bifurcation N Engl J Med 2000;343:915-22 Angiograms of 253 patients with acute MI Complex Plaques: Single: 153 - 60.5% Multiple: 100 – 39.5% Clinical Outcome at 1 Year – Single vs. Multiple Complex Plaques Similar results when analysis was restricted to patients with multivessel coronary disease: 74.5% of single 91.0% of multiple Characteristics of Carotid Plaques: Patients with Unstable versus Stable Angina Multivariate analysis: UA and CRP >3 mg/l were independently and strongly associated with complex carotid plaques Vulnerable Patient – at high risk for vascular event coronary elsewhere Who is the vulnerable patient? Patient with current multiple complex plaques Coronary, carotid etc Patient with multiple uncontrolled risk factors At risk to develop new complex plaques Vulnerability cutoff value ?
Slide 66 - Early And Long Term Treatment With Clopidogrel In Coronary Artery Disease פרופ’ יוסף רוזנמן מכון הלב, בי"ח וולפסון דצמבר 2005 Acute Coronary Syndromes Acute Coronary Syndrome No ST Elevation ST Elevation Unstable Angina Myocardial Infarction Non Q MI Q wave MI Non ST Elevation MI Braunwald E et al. J Am Coll Cardiol 2000;36:970–1062. Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When angiography / PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until angiography / PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month improving long-term outcome 1 2 Goals of therapy Prevent ischemic events until coronary angiography / PCI Before plaque stabilization was achieved Prevent PCI / stent related ischemic complications Clopidogrel before coronary angiography - Patients with ACS 1 Clopidogrel before coronary angiography - Patients with ACS ST Elevation CLARITY Non ST Elevation CURE 1 ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Study Design Fibrinolytic, ASA, Heparin Clopidogrel 300 mg + 75 mg qd Coronary Angiogram (2-8 days) Primary endpoint: Occluded artery (TIMI Flow Grade 0/1) or D/MI by time of angio randomize Placebo Double-blind, randomized, placebo-controlled trial in 3491 patients, age 18-75 yrs with STEMI < 12 hours Study Drug 30-day clinical follow-up Open-label clopidogrel per MD in both groups Primary Endpoint: Occluded Artery (or D/MI by time of angio) Placebo Clopidogrel P=0.00000036 Odds Ratio 0.64 (95% CI 0.53-0.76) 1.0 0.4 0.6 0.8 1.2 1.6 Clopidogrel better Placebo better n=1752 n=1739 36% Odds Reduction Primary & Angiographic Outcomes (median 3.5 days) Need for Urgent or Additional Treatment 21%  P=0.01 21%  P=0.005 16%  P=0.07 Early Angio (w/in 48 hrs) Urgent Revasc (index hosp) GP IIb/IIIa if PCI CV Death, MI, RI  Urg Revasc days Percentage with endpoint (%) 0 5 10 15 0 5 10 15 20 25 30 Placebo Clopidogrel Odds Ratio 0.80 (95% CI 0.65-0.97) P=0.026 20% 1 CLARITY: Patient Management Clopidogrel Placebo Parameter (n=1,752) (n=1,739) Symptom onset to fibrinolytic (hours) 2.7 2.6 Fibrinolytic to study drug (minutes) 10 10 Median doses of study medication 4 4 Angiography performed (%) 94 94 Study drug to angiography (hours) 84 84 Coronary revascularization (%): 63 63 PCI 57.2 56.6 CABG 5.9 6.0 Sabatine M et al. New Engl J Med 2005; 352: 1179–1189. PCI-CLARITY: Reduction in CV Death, MI, Stroke from PCI to 30 Days Days Post PCI Percentage with Outcome (%) 0 2 0 5 10 15 20 25 30 46%* p=0.008 Clopidogrel Pretreatment (3.6%) No Pretreatment (6.2%) 4 6 8 M Sabatine, et al. JAMA 2005 PCI-CLARITY: MI, Stroke, or CV Death Events pre and post PCI ***MI or Stroke M Sabatine, et al. JAMA 2005, Prehospital Fibrinolysis with Double Antiplatelet Therapy in Acute ST-Elevation Myocardial Infarction: The Clarity Ambulance Substudy Substudy Sites and Patient Numbers France: 172 patients L Soulat: 57 Y Lambert: 48 F Lapostolle: 28 F Thieuleux: 21 C Gully: 10 D Pollet: 5 D Galley: 2 L Olliver: 1 UK: 40 patients J Adgey: 27 J Purvis: 13 Sweden: 5 patients J-E Karlsson: 5 217 patients in total Angiographic & ECG Parameters: Ambulance vs. Non-Ambulance *Complete considered to be >70%; ECG=electrocardiogram p value Event rate (%) Ambulance Non- ambulance Non-ambulance better Ambulance better Odds ratio (95% CI) 0 0.5 1.0 1.5 2.0 Ambulance Non-ambulance Overall Clopidogrel better Placebo better Odds ratio (95% CI) Primary Endpoint of TIMI Flow Grade 0/1, MI or Death 0.60 (0.301.17) 0.64 (0.530.76) 0.65 (0.540.77) ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Clopidogrel 75mg q.d. + ASA 75-325 mg q.d.* (6259 patients) Placebo + ASA 75-325 mg q.d.* (6303 patients) Day 1 6 m. Visit 9 m. Visit 12 m. or Final Visit 3 m. Visit Discharge Visit 1 m. Visit Patients with Acute Coronary Syndrome (unstable angina or non-ST-segment elevation MI) R Placebo loading dose R = Randomization * In combination with other standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Study Design 3 months £ double-blind treatment £ 12 months Clopidogrel 300 mg loading dose CURE Clopidogrel + ASA* 3 6 9 Placebo + ASA* Months of Follow-Up 11.4% 9.3% 20% RRR P < 0.001 N = 12,562 0 12 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Primary End Point - MI/Stroke/CV Death CURE Clopidogrel + ASA* 10 20 30 Placebo + ASA* Days of Follow-Up 0 21% RRR P = 0.003 N = 12,562 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. MI/Stroke/CV Death within 30 Days CURE 1 CV death, nonfatal MI, stroke or refractory or severe ischemia 34% NEJM 2001; 345:495-502 MI/Stroke/CV Death or severe Ischemia at 24 hours CURE 1 % patients requiring thrombolytic therapy 43% % patients requiring GP IIb/IIIa inhibitors 18% NEJM 2001; 345:495-502 Need for Additional Anti-Thrombotic After Randomization P< 0.001 P= 0.003 Thrombolysis GP IIb/IIIa Inhibitor CURE 1 Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? GP IIb/IIIa receptor is the final common pathway in platelet aggregation. GP IIb/IIIa blockade is the most effective antiplatelet aggregation therapy. Bleeding risk is not increased if therapy is stopped 2-4 hours prior to CABG. Bleeding risk is markedly increased unless clopidogrel is stopped 3-5 days prior to CABG. Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? Is there additional benefit to clopidogrel that would justify: Increased CABG bleeding or alternatively Need to postpone CABG for 3-5 days No data in the literature however Adhesion The Role of Platelets in Atherothrombosis Aggregation 3 Reproduced with permission from Cannon CP. Atherothrombosis slide compendium. Available at: www.theheart.org. 1 Activation 2 Conclusions: Early Clopidogrel Therapy Treatment with clopidogrel is indicated as soon as possible in patients with acute coronary syndrome ST elevation and non ST elevation Treatment is effective to reduce ischemic complications Before coronay angiography During and after PCI 1 Conclusions: Early Clopidogrel Therapy Loading dose should be 600mg to achieve early optimal antiplatelet effect ?? 300mg in patients after fibrinolytic therapy It is unclear whether therapy should be added to “upstream” GP IIb/IIIa antagonists Especially in high risk patients in whom the likelihood for CABG is high 1 Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month after PCI / stent improving long-term outcome 1 2 Discharge/Post-Discharge Medications - Guidelines ASA, if not contraindicated Clopidogrel, when ASA contraindicated Aspirin + Clopidogrel for up to 9 months -blocker, if not contraindicated Lipid  agents + diet, if LDL >130 mg/dL ACE Inhibitor: CHF, EF < 40%, DM, or HTN I IIa IIb III 2 Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization PCI PLACEBO + ASA * CLOPIDOGREL + ASA * 30 days post PCI End of follow-up Up to 12 months after randomization Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 2,658 patients undergoing PCI N = 1345 N = 1313 PCI-CURE Overall Study Design: PCI-CURE R Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE Question 1 Question 2 Clopidogrel Arm Placebo Arm PCI* 28 Days Placebo + ASA† (325 mg) Randomization - Pre-treatment Clopidogrel 300 mg + ASA† (325 mg) Clopidogrel 75 mg QD + ASA† 325 mg QD Clopidogrel 75 mg QD + ASA† 325 mg QD R 12 Months Steinhubl S, Berger P, Tift Mann III J et al. JAMA. 2002;Vol 288,No 19:2411-2420. Placebo QD + ASA† (81-325 mg) QD Clopidogrel 75 mg QD + ASA† (81-325 mg) QD Overall Study Design: CREDO Question 1 Question 2 1 2 Open label clopidogrel continuation Methodological Pitfall Can a study with a single randomization provide an answer to two questions? Alternatively Should a second randomization be done in order to answer the second question? PCI PLACEBO + ASA * CLOPIDOGREL + ASA * 30 days post PCI End of follow-up Up to 12 months after randomization Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 1345 N = 1313 PCI-CURE Study Design single randomization R Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE Continuation Continuation PCI PLACEBO + ASA * CLOPIDOGREL + ASA * Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 1345 N = 1313 PCI-CURE Alternative Study Design two randomizations R1 Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE R2 R2 Clop. Placebo Continuation Continuation Question 2 2 Is it just methodology? Can we really expect long term benefit from early antiplatelet therapy? Adjunct antiplatelet therapy for PCI EPISTENT Randomized study designed to determine the effect of treatment with abciximab TARGET Randomized study designed to show that tirofiban is not inferior to abciximab Post-hoc nonrandomized comparison among those who were or were not pre-treated with clopidogrel PCI-CURE Subgroup of CURE patients who underwent PCI Randomized comparison of pre-treatment and continued clopidogrel therapy vs. placebo Absolute reduction of Death or MI at 1 month and 1 year Abciximab Early clopidogrel Early and continued clopidogrel % reduction * * 6 month data in TARGET Early and long term reduction of death or MI from antiplatelet therapy in patients with ACS Long Term Clopidogrel Post PCI Clinical guidelines: 9 months to 1 year in patients with ACS However, current data does not fully support this recommendation What should we do? 2 Comulative event rate in primary prevention stable CAD and ACS ACS Stable Primary Risk of vascular event after ACS Risk of event Time after ACS Stable CAD Commulative risk Risk per time Risk of vascular event after ACS high and low risk Risk of event Time after ACS High risk Low risk Risk of bleeding after initiation of clopidogrel (high and low risk) Risk of event Time after clopidogrel High risk Low risk Fixed, except for the initial few days heparin, catheterization Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? vascular bleeding Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? vascular bleeding > 1 year High vascular risk Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? vascular bleeding < 1 months High bleeding risk e.g. coumadin Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? Long term clopidogrel for patients with High risk for vascular event Low bleeding risk Short term clopidogrel for patients with Low risk for vascular event High bleeding risk vascular bleeding Who is ”High Risk” Patients in whom long term clopidogrel should be considered The vulnerable patient TIMI risk score Aspirin Failure Others Who is ”High Risk” Patients in whom long term clopidogrel should be considered The vulnerable patient TIMI risk score Aspirin Failure Others ACS Pathophysiology Inflammation, Plaque Rupture, Thrombosis, and Microembolization Quiescent plaque Plaque formation Lipids, other risk factors Inflammation LDL, others, Infection? Plaque rupture (erosion) ? Macrophages, metalloproteinases Thrombosis Platelet Activation, Thrombin Vulnerable plaque Macrophages Foam Cells Collagen  platelet activation TF  Clotting Cascade Lipid core Metalloproteinases Inflammation Courtesy of David Kandzari. Plaque rupture Culprit plaque Platelet-thrombin micro-emboli Atherosclerotic Plaques - Terminology Culprit Responsible for the clinical event Vulnerable High risk to become culprit (cause clinical event) Quiescent (Stable) Primary or healed (vulnerable or culprit) Fuster, V. et al. J Am Coll Cardiol 2005;46:937-954 Coronary Artery Disease: Diffuse disease with a variable mix of stable, vulnerable and culprit plaques Culprit and healed plaques in a coronary bifurcation N Engl J Med 2000;343:915-22 Angiograms of 253 patients with acute MI Complex Plaques: Single: 153 - 60.5% Multiple: 100 – 39.5% Clinical Outcome at 1 Year – Single vs. Multiple Complex Plaques Similar results when analysis was restricted to patients with multivessel coronary disease: 74.5% of single 91.0% of multiple Characteristics of Carotid Plaques: Patients with Unstable versus Stable Angina Multivariate analysis: UA and CRP >3 mg/l were independently and strongly associated with complex carotid plaques Vulnerable Patient – at high risk for vascular event coronary elsewhere Who is the vulnerable patient? Patient with current multiple complex plaques Coronary, carotid etc Patient with multiple uncontrolled risk factors At risk to develop new complex plaques Vulnerability cutoff value ?
Slide 67 - Early And Long Term Treatment With Clopidogrel In Coronary Artery Disease פרופ’ יוסף רוזנמן מכון הלב, בי"ח וולפסון דצמבר 2005 Acute Coronary Syndromes Acute Coronary Syndrome No ST Elevation ST Elevation Unstable Angina Myocardial Infarction Non Q MI Q wave MI Non ST Elevation MI Braunwald E et al. J Am Coll Cardiol 2000;36:970–1062. Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When angiography / PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until angiography / PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month improving long-term outcome 1 2 Goals of therapy Prevent ischemic events until coronary angiography / PCI Before plaque stabilization was achieved Prevent PCI / stent related ischemic complications Clopidogrel before coronary angiography - Patients with ACS 1 Clopidogrel before coronary angiography - Patients with ACS ST Elevation CLARITY Non ST Elevation CURE 1 ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Study Design Fibrinolytic, ASA, Heparin Clopidogrel 300 mg + 75 mg qd Coronary Angiogram (2-8 days) Primary endpoint: Occluded artery (TIMI Flow Grade 0/1) or D/MI by time of angio randomize Placebo Double-blind, randomized, placebo-controlled trial in 3491 patients, age 18-75 yrs with STEMI < 12 hours Study Drug 30-day clinical follow-up Open-label clopidogrel per MD in both groups Primary Endpoint: Occluded Artery (or D/MI by time of angio) Placebo Clopidogrel P=0.00000036 Odds Ratio 0.64 (95% CI 0.53-0.76) 1.0 0.4 0.6 0.8 1.2 1.6 Clopidogrel better Placebo better n=1752 n=1739 36% Odds Reduction Primary & Angiographic Outcomes (median 3.5 days) Need for Urgent or Additional Treatment 21%  P=0.01 21%  P=0.005 16%  P=0.07 Early Angio (w/in 48 hrs) Urgent Revasc (index hosp) GP IIb/IIIa if PCI CV Death, MI, RI  Urg Revasc days Percentage with endpoint (%) 0 5 10 15 0 5 10 15 20 25 30 Placebo Clopidogrel Odds Ratio 0.80 (95% CI 0.65-0.97) P=0.026 20% 1 CLARITY: Patient Management Clopidogrel Placebo Parameter (n=1,752) (n=1,739) Symptom onset to fibrinolytic (hours) 2.7 2.6 Fibrinolytic to study drug (minutes) 10 10 Median doses of study medication 4 4 Angiography performed (%) 94 94 Study drug to angiography (hours) 84 84 Coronary revascularization (%): 63 63 PCI 57.2 56.6 CABG 5.9 6.0 Sabatine M et al. New Engl J Med 2005; 352: 1179–1189. PCI-CLARITY: Reduction in CV Death, MI, Stroke from PCI to 30 Days Days Post PCI Percentage with Outcome (%) 0 2 0 5 10 15 20 25 30 46%* p=0.008 Clopidogrel Pretreatment (3.6%) No Pretreatment (6.2%) 4 6 8 M Sabatine, et al. JAMA 2005 PCI-CLARITY: MI, Stroke, or CV Death Events pre and post PCI ***MI or Stroke M Sabatine, et al. JAMA 2005, Prehospital Fibrinolysis with Double Antiplatelet Therapy in Acute ST-Elevation Myocardial Infarction: The Clarity Ambulance Substudy Substudy Sites and Patient Numbers France: 172 patients L Soulat: 57 Y Lambert: 48 F Lapostolle: 28 F Thieuleux: 21 C Gully: 10 D Pollet: 5 D Galley: 2 L Olliver: 1 UK: 40 patients J Adgey: 27 J Purvis: 13 Sweden: 5 patients J-E Karlsson: 5 217 patients in total Angiographic & ECG Parameters: Ambulance vs. Non-Ambulance *Complete considered to be >70%; ECG=electrocardiogram p value Event rate (%) Ambulance Non- ambulance Non-ambulance better Ambulance better Odds ratio (95% CI) 0 0.5 1.0 1.5 2.0 Ambulance Non-ambulance Overall Clopidogrel better Placebo better Odds ratio (95% CI) Primary Endpoint of TIMI Flow Grade 0/1, MI or Death 0.60 (0.301.17) 0.64 (0.530.76) 0.65 (0.540.77) ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Clopidogrel 75mg q.d. + ASA 75-325 mg q.d.* (6259 patients) Placebo + ASA 75-325 mg q.d.* (6303 patients) Day 1 6 m. Visit 9 m. Visit 12 m. or Final Visit 3 m. Visit Discharge Visit 1 m. Visit Patients with Acute Coronary Syndrome (unstable angina or non-ST-segment elevation MI) R Placebo loading dose R = Randomization * In combination with other standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Study Design 3 months £ double-blind treatment £ 12 months Clopidogrel 300 mg loading dose CURE Clopidogrel + ASA* 3 6 9 Placebo + ASA* Months of Follow-Up 11.4% 9.3% 20% RRR P < 0.001 N = 12,562 0 12 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Primary End Point - MI/Stroke/CV Death CURE Clopidogrel + ASA* 10 20 30 Placebo + ASA* Days of Follow-Up 0 21% RRR P = 0.003 N = 12,562 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. MI/Stroke/CV Death within 30 Days CURE 1 CV death, nonfatal MI, stroke or refractory or severe ischemia 34% NEJM 2001; 345:495-502 MI/Stroke/CV Death or severe Ischemia at 24 hours CURE 1 % patients requiring thrombolytic therapy 43% % patients requiring GP IIb/IIIa inhibitors 18% NEJM 2001; 345:495-502 Need for Additional Anti-Thrombotic After Randomization P< 0.001 P= 0.003 Thrombolysis GP IIb/IIIa Inhibitor CURE 1 Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? GP IIb/IIIa receptor is the final common pathway in platelet aggregation. GP IIb/IIIa blockade is the most effective antiplatelet aggregation therapy. Bleeding risk is not increased if therapy is stopped 2-4 hours prior to CABG. Bleeding risk is markedly increased unless clopidogrel is stopped 3-5 days prior to CABG. Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? Is there additional benefit to clopidogrel that would justify: Increased CABG bleeding or alternatively Need to postpone CABG for 3-5 days No data in the literature however Adhesion The Role of Platelets in Atherothrombosis Aggregation 3 Reproduced with permission from Cannon CP. Atherothrombosis slide compendium. Available at: www.theheart.org. 1 Activation 2 Conclusions: Early Clopidogrel Therapy Treatment with clopidogrel is indicated as soon as possible in patients with acute coronary syndrome ST elevation and non ST elevation Treatment is effective to reduce ischemic complications Before coronay angiography During and after PCI 1 Conclusions: Early Clopidogrel Therapy Loading dose should be 600mg to achieve early optimal antiplatelet effect ?? 300mg in patients after fibrinolytic therapy It is unclear whether therapy should be added to “upstream” GP IIb/IIIa antagonists Especially in high risk patients in whom the likelihood for CABG is high 1 Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month after PCI / stent improving long-term outcome 1 2 Discharge/Post-Discharge Medications - Guidelines ASA, if not contraindicated Clopidogrel, when ASA contraindicated Aspirin + Clopidogrel for up to 9 months -blocker, if not contraindicated Lipid  agents + diet, if LDL >130 mg/dL ACE Inhibitor: CHF, EF < 40%, DM, or HTN I IIa IIb III 2 Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization PCI PLACEBO + ASA * CLOPIDOGREL + ASA * 30 days post PCI End of follow-up Up to 12 months after randomization Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 2,658 patients undergoing PCI N = 1345 N = 1313 PCI-CURE Overall Study Design: PCI-CURE R Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE Question 1 Question 2 Clopidogrel Arm Placebo Arm PCI* 28 Days Placebo + ASA† (325 mg) Randomization - Pre-treatment Clopidogrel 300 mg + ASA† (325 mg) Clopidogrel 75 mg QD + ASA† 325 mg QD Clopidogrel 75 mg QD + ASA† 325 mg QD R 12 Months Steinhubl S, Berger P, Tift Mann III J et al. JAMA. 2002;Vol 288,No 19:2411-2420. Placebo QD + ASA† (81-325 mg) QD Clopidogrel 75 mg QD + ASA† (81-325 mg) QD Overall Study Design: CREDO Question 1 Question 2 1 2 Open label clopidogrel continuation Methodological Pitfall Can a study with a single randomization provide an answer to two questions? Alternatively Should a second randomization be done in order to answer the second question? PCI PLACEBO + ASA * CLOPIDOGREL + ASA * 30 days post PCI End of follow-up Up to 12 months after randomization Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 1345 N = 1313 PCI-CURE Study Design single randomization R Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE Continuation Continuation PCI PLACEBO + ASA * CLOPIDOGREL + ASA * Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 1345 N = 1313 PCI-CURE Alternative Study Design two randomizations R1 Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE R2 R2 Clop. Placebo Continuation Continuation Question 2 2 Is it just methodology? Can we really expect long term benefit from early antiplatelet therapy? Adjunct antiplatelet therapy for PCI EPISTENT Randomized study designed to determine the effect of treatment with abciximab TARGET Randomized study designed to show that tirofiban is not inferior to abciximab Post-hoc nonrandomized comparison among those who were or were not pre-treated with clopidogrel PCI-CURE Subgroup of CURE patients who underwent PCI Randomized comparison of pre-treatment and continued clopidogrel therapy vs. placebo Absolute reduction of Death or MI at 1 month and 1 year Abciximab Early clopidogrel Early and continued clopidogrel % reduction * * 6 month data in TARGET Early and long term reduction of death or MI from antiplatelet therapy in patients with ACS Long Term Clopidogrel Post PCI Clinical guidelines: 9 months to 1 year in patients with ACS However, current data does not fully support this recommendation What should we do? 2 Comulative event rate in primary prevention stable CAD and ACS ACS Stable Primary Risk of vascular event after ACS Risk of event Time after ACS Stable CAD Commulative risk Risk per time Risk of vascular event after ACS high and low risk Risk of event Time after ACS High risk Low risk Risk of bleeding after initiation of clopidogrel (high and low risk) Risk of event Time after clopidogrel High risk Low risk Fixed, except for the initial few days heparin, catheterization Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? vascular bleeding Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? vascular bleeding > 1 year High vascular risk Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? vascular bleeding < 1 months High bleeding risk e.g. coumadin Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? Long term clopidogrel for patients with High risk for vascular event Low bleeding risk Short term clopidogrel for patients with Low risk for vascular event High bleeding risk vascular bleeding Who is ”High Risk” Patients in whom long term clopidogrel should be considered The vulnerable patient TIMI risk score Aspirin Failure Others Who is ”High Risk” Patients in whom long term clopidogrel should be considered The vulnerable patient TIMI risk score Aspirin Failure Others ACS Pathophysiology Inflammation, Plaque Rupture, Thrombosis, and Microembolization Quiescent plaque Plaque formation Lipids, other risk factors Inflammation LDL, others, Infection? Plaque rupture (erosion) ? Macrophages, metalloproteinases Thrombosis Platelet Activation, Thrombin Vulnerable plaque Macrophages Foam Cells Collagen  platelet activation TF  Clotting Cascade Lipid core Metalloproteinases Inflammation Courtesy of David Kandzari. Plaque rupture Culprit plaque Platelet-thrombin micro-emboli Atherosclerotic Plaques - Terminology Culprit Responsible for the clinical event Vulnerable High risk to become culprit (cause clinical event) Quiescent (Stable) Primary or healed (vulnerable or culprit) Fuster, V. et al. J Am Coll Cardiol 2005;46:937-954 Coronary Artery Disease: Diffuse disease with a variable mix of stable, vulnerable and culprit plaques Culprit and healed plaques in a coronary bifurcation N Engl J Med 2000;343:915-22 Angiograms of 253 patients with acute MI Complex Plaques: Single: 153 - 60.5% Multiple: 100 – 39.5% Clinical Outcome at 1 Year – Single vs. Multiple Complex Plaques Similar results when analysis was restricted to patients with multivessel coronary disease: 74.5% of single 91.0% of multiple Characteristics of Carotid Plaques: Patients with Unstable versus Stable Angina Multivariate analysis: UA and CRP >3 mg/l were independently and strongly associated with complex carotid plaques Vulnerable Patient – at high risk for vascular event coronary elsewhere Who is the vulnerable patient? Patient with current multiple complex plaques Coronary, carotid etc Patient with multiple uncontrolled risk factors At risk to develop new complex plaques Vulnerability cutoff value ? Who is ”High Risk” Patients in whom long term clopidogrel should be considered The vulnerable patient TIMI risk score Aspirin Failure Others
Slide 68 - Early And Long Term Treatment With Clopidogrel In Coronary Artery Disease פרופ’ יוסף רוזנמן מכון הלב, בי"ח וולפסון דצמבר 2005 Acute Coronary Syndromes Acute Coronary Syndrome No ST Elevation ST Elevation Unstable Angina Myocardial Infarction Non Q MI Q wave MI Non ST Elevation MI Braunwald E et al. J Am Coll Cardiol 2000;36:970–1062. Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When angiography / PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until angiography / PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month improving long-term outcome 1 2 Goals of therapy Prevent ischemic events until coronary angiography / PCI Before plaque stabilization was achieved Prevent PCI / stent related ischemic complications Clopidogrel before coronary angiography - Patients with ACS 1 Clopidogrel before coronary angiography - Patients with ACS ST Elevation CLARITY Non ST Elevation CURE 1 ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Study Design Fibrinolytic, ASA, Heparin Clopidogrel 300 mg + 75 mg qd Coronary Angiogram (2-8 days) Primary endpoint: Occluded artery (TIMI Flow Grade 0/1) or D/MI by time of angio randomize Placebo Double-blind, randomized, placebo-controlled trial in 3491 patients, age 18-75 yrs with STEMI < 12 hours Study Drug 30-day clinical follow-up Open-label clopidogrel per MD in both groups Primary Endpoint: Occluded Artery (or D/MI by time of angio) Placebo Clopidogrel P=0.00000036 Odds Ratio 0.64 (95% CI 0.53-0.76) 1.0 0.4 0.6 0.8 1.2 1.6 Clopidogrel better Placebo better n=1752 n=1739 36% Odds Reduction Primary & Angiographic Outcomes (median 3.5 days) Need for Urgent or Additional Treatment 21%  P=0.01 21%  P=0.005 16%  P=0.07 Early Angio (w/in 48 hrs) Urgent Revasc (index hosp) GP IIb/IIIa if PCI CV Death, MI, RI  Urg Revasc days Percentage with endpoint (%) 0 5 10 15 0 5 10 15 20 25 30 Placebo Clopidogrel Odds Ratio 0.80 (95% CI 0.65-0.97) P=0.026 20% 1 CLARITY: Patient Management Clopidogrel Placebo Parameter (n=1,752) (n=1,739) Symptom onset to fibrinolytic (hours) 2.7 2.6 Fibrinolytic to study drug (minutes) 10 10 Median doses of study medication 4 4 Angiography performed (%) 94 94 Study drug to angiography (hours) 84 84 Coronary revascularization (%): 63 63 PCI 57.2 56.6 CABG 5.9 6.0 Sabatine M et al. New Engl J Med 2005; 352: 1179–1189. PCI-CLARITY: Reduction in CV Death, MI, Stroke from PCI to 30 Days Days Post PCI Percentage with Outcome (%) 0 2 0 5 10 15 20 25 30 46%* p=0.008 Clopidogrel Pretreatment (3.6%) No Pretreatment (6.2%) 4 6 8 M Sabatine, et al. JAMA 2005 PCI-CLARITY: MI, Stroke, or CV Death Events pre and post PCI ***MI or Stroke M Sabatine, et al. JAMA 2005, Prehospital Fibrinolysis with Double Antiplatelet Therapy in Acute ST-Elevation Myocardial Infarction: The Clarity Ambulance Substudy Substudy Sites and Patient Numbers France: 172 patients L Soulat: 57 Y Lambert: 48 F Lapostolle: 28 F Thieuleux: 21 C Gully: 10 D Pollet: 5 D Galley: 2 L Olliver: 1 UK: 40 patients J Adgey: 27 J Purvis: 13 Sweden: 5 patients J-E Karlsson: 5 217 patients in total Angiographic & ECG Parameters: Ambulance vs. Non-Ambulance *Complete considered to be >70%; ECG=electrocardiogram p value Event rate (%) Ambulance Non- ambulance Non-ambulance better Ambulance better Odds ratio (95% CI) 0 0.5 1.0 1.5 2.0 Ambulance Non-ambulance Overall Clopidogrel better Placebo better Odds ratio (95% CI) Primary Endpoint of TIMI Flow Grade 0/1, MI or Death 0.60 (0.301.17) 0.64 (0.530.76) 0.65 (0.540.77) ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Clopidogrel 75mg q.d. + ASA 75-325 mg q.d.* (6259 patients) Placebo + ASA 75-325 mg q.d.* (6303 patients) Day 1 6 m. Visit 9 m. Visit 12 m. or Final Visit 3 m. Visit Discharge Visit 1 m. Visit Patients with Acute Coronary Syndrome (unstable angina or non-ST-segment elevation MI) R Placebo loading dose R = Randomization * In combination with other standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Study Design 3 months £ double-blind treatment £ 12 months Clopidogrel 300 mg loading dose CURE Clopidogrel + ASA* 3 6 9 Placebo + ASA* Months of Follow-Up 11.4% 9.3% 20% RRR P < 0.001 N = 12,562 0 12 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Primary End Point - MI/Stroke/CV Death CURE Clopidogrel + ASA* 10 20 30 Placebo + ASA* Days of Follow-Up 0 21% RRR P = 0.003 N = 12,562 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. MI/Stroke/CV Death within 30 Days CURE 1 CV death, nonfatal MI, stroke or refractory or severe ischemia 34% NEJM 2001; 345:495-502 MI/Stroke/CV Death or severe Ischemia at 24 hours CURE 1 % patients requiring thrombolytic therapy 43% % patients requiring GP IIb/IIIa inhibitors 18% NEJM 2001; 345:495-502 Need for Additional Anti-Thrombotic After Randomization P< 0.001 P= 0.003 Thrombolysis GP IIb/IIIa Inhibitor CURE 1 Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? GP IIb/IIIa receptor is the final common pathway in platelet aggregation. GP IIb/IIIa blockade is the most effective antiplatelet aggregation therapy. Bleeding risk is not increased if therapy is stopped 2-4 hours prior to CABG. Bleeding risk is markedly increased unless clopidogrel is stopped 3-5 days prior to CABG. Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? Is there additional benefit to clopidogrel that would justify: Increased CABG bleeding or alternatively Need to postpone CABG for 3-5 days No data in the literature however Adhesion The Role of Platelets in Atherothrombosis Aggregation 3 Reproduced with permission from Cannon CP. Atherothrombosis slide compendium. Available at: www.theheart.org. 1 Activation 2 Conclusions: Early Clopidogrel Therapy Treatment with clopidogrel is indicated as soon as possible in patients with acute coronary syndrome ST elevation and non ST elevation Treatment is effective to reduce ischemic complications Before coronay angiography During and after PCI 1 Conclusions: Early Clopidogrel Therapy Loading dose should be 600mg to achieve early optimal antiplatelet effect ?? 300mg in patients after fibrinolytic therapy It is unclear whether therapy should be added to “upstream” GP IIb/IIIa antagonists Especially in high risk patients in whom the likelihood for CABG is high 1 Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month after PCI / stent improving long-term outcome 1 2 Discharge/Post-Discharge Medications - Guidelines ASA, if not contraindicated Clopidogrel, when ASA contraindicated Aspirin + Clopidogrel for up to 9 months -blocker, if not contraindicated Lipid  agents + diet, if LDL >130 mg/dL ACE Inhibitor: CHF, EF < 40%, DM, or HTN I IIa IIb III 2 Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization PCI PLACEBO + ASA * CLOPIDOGREL + ASA * 30 days post PCI End of follow-up Up to 12 months after randomization Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 2,658 patients undergoing PCI N = 1345 N = 1313 PCI-CURE Overall Study Design: PCI-CURE R Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE Question 1 Question 2 Clopidogrel Arm Placebo Arm PCI* 28 Days Placebo + ASA† (325 mg) Randomization - Pre-treatment Clopidogrel 300 mg + ASA† (325 mg) Clopidogrel 75 mg QD + ASA† 325 mg QD Clopidogrel 75 mg QD + ASA† 325 mg QD R 12 Months Steinhubl S, Berger P, Tift Mann III J et al. JAMA. 2002;Vol 288,No 19:2411-2420. Placebo QD + ASA† (81-325 mg) QD Clopidogrel 75 mg QD + ASA† (81-325 mg) QD Overall Study Design: CREDO Question 1 Question 2 1 2 Open label clopidogrel continuation Methodological Pitfall Can a study with a single randomization provide an answer to two questions? Alternatively Should a second randomization be done in order to answer the second question? PCI PLACEBO + ASA * CLOPIDOGREL + ASA * 30 days post PCI End of follow-up Up to 12 months after randomization Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 1345 N = 1313 PCI-CURE Study Design single randomization R Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE Continuation Continuation PCI PLACEBO + ASA * CLOPIDOGREL + ASA * Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 1345 N = 1313 PCI-CURE Alternative Study Design two randomizations R1 Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE R2 R2 Clop. Placebo Continuation Continuation Question 2 2 Is it just methodology? Can we really expect long term benefit from early antiplatelet therapy? Adjunct antiplatelet therapy for PCI EPISTENT Randomized study designed to determine the effect of treatment with abciximab TARGET Randomized study designed to show that tirofiban is not inferior to abciximab Post-hoc nonrandomized comparison among those who were or were not pre-treated with clopidogrel PCI-CURE Subgroup of CURE patients who underwent PCI Randomized comparison of pre-treatment and continued clopidogrel therapy vs. placebo Absolute reduction of Death or MI at 1 month and 1 year Abciximab Early clopidogrel Early and continued clopidogrel % reduction * * 6 month data in TARGET Early and long term reduction of death or MI from antiplatelet therapy in patients with ACS Long Term Clopidogrel Post PCI Clinical guidelines: 9 months to 1 year in patients with ACS However, current data does not fully support this recommendation What should we do? 2 Comulative event rate in primary prevention stable CAD and ACS ACS Stable Primary Risk of vascular event after ACS Risk of event Time after ACS Stable CAD Commulative risk Risk per time Risk of vascular event after ACS high and low risk Risk of event Time after ACS High risk Low risk Risk of bleeding after initiation of clopidogrel (high and low risk) Risk of event Time after clopidogrel High risk Low risk Fixed, except for the initial few days heparin, catheterization Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? vascular bleeding Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? vascular bleeding > 1 year High vascular risk Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? vascular bleeding < 1 months High bleeding risk e.g. coumadin Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? Long term clopidogrel for patients with High risk for vascular event Low bleeding risk Short term clopidogrel for patients with Low risk for vascular event High bleeding risk vascular bleeding Who is ”High Risk” Patients in whom long term clopidogrel should be considered The vulnerable patient TIMI risk score Aspirin Failure Others Who is ”High Risk” Patients in whom long term clopidogrel should be considered The vulnerable patient TIMI risk score Aspirin Failure Others ACS Pathophysiology Inflammation, Plaque Rupture, Thrombosis, and Microembolization Quiescent plaque Plaque formation Lipids, other risk factors Inflammation LDL, others, Infection? Plaque rupture (erosion) ? Macrophages, metalloproteinases Thrombosis Platelet Activation, Thrombin Vulnerable plaque Macrophages Foam Cells Collagen  platelet activation TF  Clotting Cascade Lipid core Metalloproteinases Inflammation Courtesy of David Kandzari. Plaque rupture Culprit plaque Platelet-thrombin micro-emboli Atherosclerotic Plaques - Terminology Culprit Responsible for the clinical event Vulnerable High risk to become culprit (cause clinical event) Quiescent (Stable) Primary or healed (vulnerable or culprit) Fuster, V. et al. J Am Coll Cardiol 2005;46:937-954 Coronary Artery Disease: Diffuse disease with a variable mix of stable, vulnerable and culprit plaques Culprit and healed plaques in a coronary bifurcation N Engl J Med 2000;343:915-22 Angiograms of 253 patients with acute MI Complex Plaques: Single: 153 - 60.5% Multiple: 100 – 39.5% Clinical Outcome at 1 Year – Single vs. Multiple Complex Plaques Similar results when analysis was restricted to patients with multivessel coronary disease: 74.5% of single 91.0% of multiple Characteristics of Carotid Plaques: Patients with Unstable versus Stable Angina Multivariate analysis: UA and CRP >3 mg/l were independently and strongly associated with complex carotid plaques Vulnerable Patient – at high risk for vascular event coronary elsewhere Who is the vulnerable patient? Patient with current multiple complex plaques Coronary, carotid etc Patient with multiple uncontrolled risk factors At risk to develop new complex plaques Vulnerability cutoff value ? Who is ”High Risk” Patients in whom long term clopidogrel should be considered The vulnerable patient TIMI risk score Aspirin Failure Others TIMI Risk Score and Outcome Budaj et al. circulation 2002 Excess major bleeding risk with clopidogrel is independent of the TIMI risk – it is 1%
Slide 69 - Early And Long Term Treatment With Clopidogrel In Coronary Artery Disease פרופ’ יוסף רוזנמן מכון הלב, בי"ח וולפסון דצמבר 2005 Acute Coronary Syndromes Acute Coronary Syndrome No ST Elevation ST Elevation Unstable Angina Myocardial Infarction Non Q MI Q wave MI Non ST Elevation MI Braunwald E et al. J Am Coll Cardiol 2000;36:970–1062. Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When angiography / PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until angiography / PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month improving long-term outcome 1 2 Goals of therapy Prevent ischemic events until coronary angiography / PCI Before plaque stabilization was achieved Prevent PCI / stent related ischemic complications Clopidogrel before coronary angiography - Patients with ACS 1 Clopidogrel before coronary angiography - Patients with ACS ST Elevation CLARITY Non ST Elevation CURE 1 ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Study Design Fibrinolytic, ASA, Heparin Clopidogrel 300 mg + 75 mg qd Coronary Angiogram (2-8 days) Primary endpoint: Occluded artery (TIMI Flow Grade 0/1) or D/MI by time of angio randomize Placebo Double-blind, randomized, placebo-controlled trial in 3491 patients, age 18-75 yrs with STEMI < 12 hours Study Drug 30-day clinical follow-up Open-label clopidogrel per MD in both groups Primary Endpoint: Occluded Artery (or D/MI by time of angio) Placebo Clopidogrel P=0.00000036 Odds Ratio 0.64 (95% CI 0.53-0.76) 1.0 0.4 0.6 0.8 1.2 1.6 Clopidogrel better Placebo better n=1752 n=1739 36% Odds Reduction Primary & Angiographic Outcomes (median 3.5 days) Need for Urgent or Additional Treatment 21%  P=0.01 21%  P=0.005 16%  P=0.07 Early Angio (w/in 48 hrs) Urgent Revasc (index hosp) GP IIb/IIIa if PCI CV Death, MI, RI  Urg Revasc days Percentage with endpoint (%) 0 5 10 15 0 5 10 15 20 25 30 Placebo Clopidogrel Odds Ratio 0.80 (95% CI 0.65-0.97) P=0.026 20% 1 CLARITY: Patient Management Clopidogrel Placebo Parameter (n=1,752) (n=1,739) Symptom onset to fibrinolytic (hours) 2.7 2.6 Fibrinolytic to study drug (minutes) 10 10 Median doses of study medication 4 4 Angiography performed (%) 94 94 Study drug to angiography (hours) 84 84 Coronary revascularization (%): 63 63 PCI 57.2 56.6 CABG 5.9 6.0 Sabatine M et al. New Engl J Med 2005; 352: 1179–1189. PCI-CLARITY: Reduction in CV Death, MI, Stroke from PCI to 30 Days Days Post PCI Percentage with Outcome (%) 0 2 0 5 10 15 20 25 30 46%* p=0.008 Clopidogrel Pretreatment (3.6%) No Pretreatment (6.2%) 4 6 8 M Sabatine, et al. JAMA 2005 PCI-CLARITY: MI, Stroke, or CV Death Events pre and post PCI ***MI or Stroke M Sabatine, et al. JAMA 2005, Prehospital Fibrinolysis with Double Antiplatelet Therapy in Acute ST-Elevation Myocardial Infarction: The Clarity Ambulance Substudy Substudy Sites and Patient Numbers France: 172 patients L Soulat: 57 Y Lambert: 48 F Lapostolle: 28 F Thieuleux: 21 C Gully: 10 D Pollet: 5 D Galley: 2 L Olliver: 1 UK: 40 patients J Adgey: 27 J Purvis: 13 Sweden: 5 patients J-E Karlsson: 5 217 patients in total Angiographic & ECG Parameters: Ambulance vs. Non-Ambulance *Complete considered to be >70%; ECG=electrocardiogram p value Event rate (%) Ambulance Non- ambulance Non-ambulance better Ambulance better Odds ratio (95% CI) 0 0.5 1.0 1.5 2.0 Ambulance Non-ambulance Overall Clopidogrel better Placebo better Odds ratio (95% CI) Primary Endpoint of TIMI Flow Grade 0/1, MI or Death 0.60 (0.301.17) 0.64 (0.530.76) 0.65 (0.540.77) ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Clopidogrel 75mg q.d. + ASA 75-325 mg q.d.* (6259 patients) Placebo + ASA 75-325 mg q.d.* (6303 patients) Day 1 6 m. Visit 9 m. Visit 12 m. or Final Visit 3 m. Visit Discharge Visit 1 m. Visit Patients with Acute Coronary Syndrome (unstable angina or non-ST-segment elevation MI) R Placebo loading dose R = Randomization * In combination with other standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Study Design 3 months £ double-blind treatment £ 12 months Clopidogrel 300 mg loading dose CURE Clopidogrel + ASA* 3 6 9 Placebo + ASA* Months of Follow-Up 11.4% 9.3% 20% RRR P < 0.001 N = 12,562 0 12 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Primary End Point - MI/Stroke/CV Death CURE Clopidogrel + ASA* 10 20 30 Placebo + ASA* Days of Follow-Up 0 21% RRR P = 0.003 N = 12,562 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. MI/Stroke/CV Death within 30 Days CURE 1 CV death, nonfatal MI, stroke or refractory or severe ischemia 34% NEJM 2001; 345:495-502 MI/Stroke/CV Death or severe Ischemia at 24 hours CURE 1 % patients requiring thrombolytic therapy 43% % patients requiring GP IIb/IIIa inhibitors 18% NEJM 2001; 345:495-502 Need for Additional Anti-Thrombotic After Randomization P< 0.001 P= 0.003 Thrombolysis GP IIb/IIIa Inhibitor CURE 1 Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? GP IIb/IIIa receptor is the final common pathway in platelet aggregation. GP IIb/IIIa blockade is the most effective antiplatelet aggregation therapy. Bleeding risk is not increased if therapy is stopped 2-4 hours prior to CABG. Bleeding risk is markedly increased unless clopidogrel is stopped 3-5 days prior to CABG. Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? Is there additional benefit to clopidogrel that would justify: Increased CABG bleeding or alternatively Need to postpone CABG for 3-5 days No data in the literature however Adhesion The Role of Platelets in Atherothrombosis Aggregation 3 Reproduced with permission from Cannon CP. Atherothrombosis slide compendium. Available at: www.theheart.org. 1 Activation 2 Conclusions: Early Clopidogrel Therapy Treatment with clopidogrel is indicated as soon as possible in patients with acute coronary syndrome ST elevation and non ST elevation Treatment is effective to reduce ischemic complications Before coronay angiography During and after PCI 1 Conclusions: Early Clopidogrel Therapy Loading dose should be 600mg to achieve early optimal antiplatelet effect ?? 300mg in patients after fibrinolytic therapy It is unclear whether therapy should be added to “upstream” GP IIb/IIIa antagonists Especially in high risk patients in whom the likelihood for CABG is high 1 Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month after PCI / stent improving long-term outcome 1 2 Discharge/Post-Discharge Medications - Guidelines ASA, if not contraindicated Clopidogrel, when ASA contraindicated Aspirin + Clopidogrel for up to 9 months -blocker, if not contraindicated Lipid  agents + diet, if LDL >130 mg/dL ACE Inhibitor: CHF, EF < 40%, DM, or HTN I IIa IIb III 2 Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization PCI PLACEBO + ASA * CLOPIDOGREL + ASA * 30 days post PCI End of follow-up Up to 12 months after randomization Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 2,658 patients undergoing PCI N = 1345 N = 1313 PCI-CURE Overall Study Design: PCI-CURE R Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE Question 1 Question 2 Clopidogrel Arm Placebo Arm PCI* 28 Days Placebo + ASA† (325 mg) Randomization - Pre-treatment Clopidogrel 300 mg + ASA† (325 mg) Clopidogrel 75 mg QD + ASA† 325 mg QD Clopidogrel 75 mg QD + ASA† 325 mg QD R 12 Months Steinhubl S, Berger P, Tift Mann III J et al. JAMA. 2002;Vol 288,No 19:2411-2420. Placebo QD + ASA† (81-325 mg) QD Clopidogrel 75 mg QD + ASA† (81-325 mg) QD Overall Study Design: CREDO Question 1 Question 2 1 2 Open label clopidogrel continuation Methodological Pitfall Can a study with a single randomization provide an answer to two questions? Alternatively Should a second randomization be done in order to answer the second question? PCI PLACEBO + ASA * CLOPIDOGREL + ASA * 30 days post PCI End of follow-up Up to 12 months after randomization Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 1345 N = 1313 PCI-CURE Study Design single randomization R Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE Continuation Continuation PCI PLACEBO + ASA * CLOPIDOGREL + ASA * Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 1345 N = 1313 PCI-CURE Alternative Study Design two randomizations R1 Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE R2 R2 Clop. Placebo Continuation Continuation Question 2 2 Is it just methodology? Can we really expect long term benefit from early antiplatelet therapy? Adjunct antiplatelet therapy for PCI EPISTENT Randomized study designed to determine the effect of treatment with abciximab TARGET Randomized study designed to show that tirofiban is not inferior to abciximab Post-hoc nonrandomized comparison among those who were or were not pre-treated with clopidogrel PCI-CURE Subgroup of CURE patients who underwent PCI Randomized comparison of pre-treatment and continued clopidogrel therapy vs. placebo Absolute reduction of Death or MI at 1 month and 1 year Abciximab Early clopidogrel Early and continued clopidogrel % reduction * * 6 month data in TARGET Early and long term reduction of death or MI from antiplatelet therapy in patients with ACS Long Term Clopidogrel Post PCI Clinical guidelines: 9 months to 1 year in patients with ACS However, current data does not fully support this recommendation What should we do? 2 Comulative event rate in primary prevention stable CAD and ACS ACS Stable Primary Risk of vascular event after ACS Risk of event Time after ACS Stable CAD Commulative risk Risk per time Risk of vascular event after ACS high and low risk Risk of event Time after ACS High risk Low risk Risk of bleeding after initiation of clopidogrel (high and low risk) Risk of event Time after clopidogrel High risk Low risk Fixed, except for the initial few days heparin, catheterization Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? vascular bleeding Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? vascular bleeding > 1 year High vascular risk Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? vascular bleeding < 1 months High bleeding risk e.g. coumadin Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? Long term clopidogrel for patients with High risk for vascular event Low bleeding risk Short term clopidogrel for patients with Low risk for vascular event High bleeding risk vascular bleeding Who is ”High Risk” Patients in whom long term clopidogrel should be considered The vulnerable patient TIMI risk score Aspirin Failure Others Who is ”High Risk” Patients in whom long term clopidogrel should be considered The vulnerable patient TIMI risk score Aspirin Failure Others ACS Pathophysiology Inflammation, Plaque Rupture, Thrombosis, and Microembolization Quiescent plaque Plaque formation Lipids, other risk factors Inflammation LDL, others, Infection? Plaque rupture (erosion) ? Macrophages, metalloproteinases Thrombosis Platelet Activation, Thrombin Vulnerable plaque Macrophages Foam Cells Collagen  platelet activation TF  Clotting Cascade Lipid core Metalloproteinases Inflammation Courtesy of David Kandzari. Plaque rupture Culprit plaque Platelet-thrombin micro-emboli Atherosclerotic Plaques - Terminology Culprit Responsible for the clinical event Vulnerable High risk to become culprit (cause clinical event) Quiescent (Stable) Primary or healed (vulnerable or culprit) Fuster, V. et al. J Am Coll Cardiol 2005;46:937-954 Coronary Artery Disease: Diffuse disease with a variable mix of stable, vulnerable and culprit plaques Culprit and healed plaques in a coronary bifurcation N Engl J Med 2000;343:915-22 Angiograms of 253 patients with acute MI Complex Plaques: Single: 153 - 60.5% Multiple: 100 – 39.5% Clinical Outcome at 1 Year – Single vs. Multiple Complex Plaques Similar results when analysis was restricted to patients with multivessel coronary disease: 74.5% of single 91.0% of multiple Characteristics of Carotid Plaques: Patients with Unstable versus Stable Angina Multivariate analysis: UA and CRP >3 mg/l were independently and strongly associated with complex carotid plaques Vulnerable Patient – at high risk for vascular event coronary elsewhere Who is the vulnerable patient? Patient with current multiple complex plaques Coronary, carotid etc Patient with multiple uncontrolled risk factors At risk to develop new complex plaques Vulnerability cutoff value ? Who is ”High Risk” Patients in whom long term clopidogrel should be considered The vulnerable patient TIMI risk score Aspirin Failure Others TIMI Risk Score and Outcome Budaj et al. circulation 2002 Excess major bleeding risk with clopidogrel is independent of the TIMI risk – it is 1% TIMI Risk Score and Absolute Reduction of death/MI/Stroke with Clopidogrel TIMI Risk Score N= 752 2524 3730 3567 1593 396 Percent reduction Major bleeding – 1% Majority of patients
Slide 70 - Early And Long Term Treatment With Clopidogrel In Coronary Artery Disease פרופ’ יוסף רוזנמן מכון הלב, בי"ח וולפסון דצמבר 2005 Acute Coronary Syndromes Acute Coronary Syndrome No ST Elevation ST Elevation Unstable Angina Myocardial Infarction Non Q MI Q wave MI Non ST Elevation MI Braunwald E et al. J Am Coll Cardiol 2000;36:970–1062. Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When angiography / PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until angiography / PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month improving long-term outcome 1 2 Goals of therapy Prevent ischemic events until coronary angiography / PCI Before plaque stabilization was achieved Prevent PCI / stent related ischemic complications Clopidogrel before coronary angiography - Patients with ACS 1 Clopidogrel before coronary angiography - Patients with ACS ST Elevation CLARITY Non ST Elevation CURE 1 ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Study Design Fibrinolytic, ASA, Heparin Clopidogrel 300 mg + 75 mg qd Coronary Angiogram (2-8 days) Primary endpoint: Occluded artery (TIMI Flow Grade 0/1) or D/MI by time of angio randomize Placebo Double-blind, randomized, placebo-controlled trial in 3491 patients, age 18-75 yrs with STEMI < 12 hours Study Drug 30-day clinical follow-up Open-label clopidogrel per MD in both groups Primary Endpoint: Occluded Artery (or D/MI by time of angio) Placebo Clopidogrel P=0.00000036 Odds Ratio 0.64 (95% CI 0.53-0.76) 1.0 0.4 0.6 0.8 1.2 1.6 Clopidogrel better Placebo better n=1752 n=1739 36% Odds Reduction Primary & Angiographic Outcomes (median 3.5 days) Need for Urgent or Additional Treatment 21%  P=0.01 21%  P=0.005 16%  P=0.07 Early Angio (w/in 48 hrs) Urgent Revasc (index hosp) GP IIb/IIIa if PCI CV Death, MI, RI  Urg Revasc days Percentage with endpoint (%) 0 5 10 15 0 5 10 15 20 25 30 Placebo Clopidogrel Odds Ratio 0.80 (95% CI 0.65-0.97) P=0.026 20% 1 CLARITY: Patient Management Clopidogrel Placebo Parameter (n=1,752) (n=1,739) Symptom onset to fibrinolytic (hours) 2.7 2.6 Fibrinolytic to study drug (minutes) 10 10 Median doses of study medication 4 4 Angiography performed (%) 94 94 Study drug to angiography (hours) 84 84 Coronary revascularization (%): 63 63 PCI 57.2 56.6 CABG 5.9 6.0 Sabatine M et al. New Engl J Med 2005; 352: 1179–1189. PCI-CLARITY: Reduction in CV Death, MI, Stroke from PCI to 30 Days Days Post PCI Percentage with Outcome (%) 0 2 0 5 10 15 20 25 30 46%* p=0.008 Clopidogrel Pretreatment (3.6%) No Pretreatment (6.2%) 4 6 8 M Sabatine, et al. JAMA 2005 PCI-CLARITY: MI, Stroke, or CV Death Events pre and post PCI ***MI or Stroke M Sabatine, et al. JAMA 2005, Prehospital Fibrinolysis with Double Antiplatelet Therapy in Acute ST-Elevation Myocardial Infarction: The Clarity Ambulance Substudy Substudy Sites and Patient Numbers France: 172 patients L Soulat: 57 Y Lambert: 48 F Lapostolle: 28 F Thieuleux: 21 C Gully: 10 D Pollet: 5 D Galley: 2 L Olliver: 1 UK: 40 patients J Adgey: 27 J Purvis: 13 Sweden: 5 patients J-E Karlsson: 5 217 patients in total Angiographic & ECG Parameters: Ambulance vs. Non-Ambulance *Complete considered to be >70%; ECG=electrocardiogram p value Event rate (%) Ambulance Non- ambulance Non-ambulance better Ambulance better Odds ratio (95% CI) 0 0.5 1.0 1.5 2.0 Ambulance Non-ambulance Overall Clopidogrel better Placebo better Odds ratio (95% CI) Primary Endpoint of TIMI Flow Grade 0/1, MI or Death 0.60 (0.301.17) 0.64 (0.530.76) 0.65 (0.540.77) ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Clopidogrel 75mg q.d. + ASA 75-325 mg q.d.* (6259 patients) Placebo + ASA 75-325 mg q.d.* (6303 patients) Day 1 6 m. Visit 9 m. Visit 12 m. or Final Visit 3 m. Visit Discharge Visit 1 m. Visit Patients with Acute Coronary Syndrome (unstable angina or non-ST-segment elevation MI) R Placebo loading dose R = Randomization * In combination with other standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Study Design 3 months £ double-blind treatment £ 12 months Clopidogrel 300 mg loading dose CURE Clopidogrel + ASA* 3 6 9 Placebo + ASA* Months of Follow-Up 11.4% 9.3% 20% RRR P < 0.001 N = 12,562 0 12 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Primary End Point - MI/Stroke/CV Death CURE Clopidogrel + ASA* 10 20 30 Placebo + ASA* Days of Follow-Up 0 21% RRR P = 0.003 N = 12,562 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. MI/Stroke/CV Death within 30 Days CURE 1 CV death, nonfatal MI, stroke or refractory or severe ischemia 34% NEJM 2001; 345:495-502 MI/Stroke/CV Death or severe Ischemia at 24 hours CURE 1 % patients requiring thrombolytic therapy 43% % patients requiring GP IIb/IIIa inhibitors 18% NEJM 2001; 345:495-502 Need for Additional Anti-Thrombotic After Randomization P< 0.001 P= 0.003 Thrombolysis GP IIb/IIIa Inhibitor CURE 1 Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? GP IIb/IIIa receptor is the final common pathway in platelet aggregation. GP IIb/IIIa blockade is the most effective antiplatelet aggregation therapy. Bleeding risk is not increased if therapy is stopped 2-4 hours prior to CABG. Bleeding risk is markedly increased unless clopidogrel is stopped 3-5 days prior to CABG. Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? Is there additional benefit to clopidogrel that would justify: Increased CABG bleeding or alternatively Need to postpone CABG for 3-5 days No data in the literature however Adhesion The Role of Platelets in Atherothrombosis Aggregation 3 Reproduced with permission from Cannon CP. Atherothrombosis slide compendium. Available at: www.theheart.org. 1 Activation 2 Conclusions: Early Clopidogrel Therapy Treatment with clopidogrel is indicated as soon as possible in patients with acute coronary syndrome ST elevation and non ST elevation Treatment is effective to reduce ischemic complications Before coronay angiography During and after PCI 1 Conclusions: Early Clopidogrel Therapy Loading dose should be 600mg to achieve early optimal antiplatelet effect ?? 300mg in patients after fibrinolytic therapy It is unclear whether therapy should be added to “upstream” GP IIb/IIIa antagonists Especially in high risk patients in whom the likelihood for CABG is high 1 Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month after PCI / stent improving long-term outcome 1 2 Discharge/Post-Discharge Medications - Guidelines ASA, if not contraindicated Clopidogrel, when ASA contraindicated Aspirin + Clopidogrel for up to 9 months -blocker, if not contraindicated Lipid  agents + diet, if LDL >130 mg/dL ACE Inhibitor: CHF, EF < 40%, DM, or HTN I IIa IIb III 2 Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization PCI PLACEBO + ASA * CLOPIDOGREL + ASA * 30 days post PCI End of follow-up Up to 12 months after randomization Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 2,658 patients undergoing PCI N = 1345 N = 1313 PCI-CURE Overall Study Design: PCI-CURE R Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE Question 1 Question 2 Clopidogrel Arm Placebo Arm PCI* 28 Days Placebo + ASA† (325 mg) Randomization - Pre-treatment Clopidogrel 300 mg + ASA† (325 mg) Clopidogrel 75 mg QD + ASA† 325 mg QD Clopidogrel 75 mg QD + ASA† 325 mg QD R 12 Months Steinhubl S, Berger P, Tift Mann III J et al. JAMA. 2002;Vol 288,No 19:2411-2420. Placebo QD + ASA† (81-325 mg) QD Clopidogrel 75 mg QD + ASA† (81-325 mg) QD Overall Study Design: CREDO Question 1 Question 2 1 2 Open label clopidogrel continuation Methodological Pitfall Can a study with a single randomization provide an answer to two questions? Alternatively Should a second randomization be done in order to answer the second question? PCI PLACEBO + ASA * CLOPIDOGREL + ASA * 30 days post PCI End of follow-up Up to 12 months after randomization Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 1345 N = 1313 PCI-CURE Study Design single randomization R Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE Continuation Continuation PCI PLACEBO + ASA * CLOPIDOGREL + ASA * Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 1345 N = 1313 PCI-CURE Alternative Study Design two randomizations R1 Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE R2 R2 Clop. Placebo Continuation Continuation Question 2 2 Is it just methodology? Can we really expect long term benefit from early antiplatelet therapy? Adjunct antiplatelet therapy for PCI EPISTENT Randomized study designed to determine the effect of treatment with abciximab TARGET Randomized study designed to show that tirofiban is not inferior to abciximab Post-hoc nonrandomized comparison among those who were or were not pre-treated with clopidogrel PCI-CURE Subgroup of CURE patients who underwent PCI Randomized comparison of pre-treatment and continued clopidogrel therapy vs. placebo Absolute reduction of Death or MI at 1 month and 1 year Abciximab Early clopidogrel Early and continued clopidogrel % reduction * * 6 month data in TARGET Early and long term reduction of death or MI from antiplatelet therapy in patients with ACS Long Term Clopidogrel Post PCI Clinical guidelines: 9 months to 1 year in patients with ACS However, current data does not fully support this recommendation What should we do? 2 Comulative event rate in primary prevention stable CAD and ACS ACS Stable Primary Risk of vascular event after ACS Risk of event Time after ACS Stable CAD Commulative risk Risk per time Risk of vascular event after ACS high and low risk Risk of event Time after ACS High risk Low risk Risk of bleeding after initiation of clopidogrel (high and low risk) Risk of event Time after clopidogrel High risk Low risk Fixed, except for the initial few days heparin, catheterization Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? vascular bleeding Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? vascular bleeding > 1 year High vascular risk Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? vascular bleeding < 1 months High bleeding risk e.g. coumadin Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? Long term clopidogrel for patients with High risk for vascular event Low bleeding risk Short term clopidogrel for patients with Low risk for vascular event High bleeding risk vascular bleeding Who is ”High Risk” Patients in whom long term clopidogrel should be considered The vulnerable patient TIMI risk score Aspirin Failure Others Who is ”High Risk” Patients in whom long term clopidogrel should be considered The vulnerable patient TIMI risk score Aspirin Failure Others ACS Pathophysiology Inflammation, Plaque Rupture, Thrombosis, and Microembolization Quiescent plaque Plaque formation Lipids, other risk factors Inflammation LDL, others, Infection? Plaque rupture (erosion) ? Macrophages, metalloproteinases Thrombosis Platelet Activation, Thrombin Vulnerable plaque Macrophages Foam Cells Collagen  platelet activation TF  Clotting Cascade Lipid core Metalloproteinases Inflammation Courtesy of David Kandzari. Plaque rupture Culprit plaque Platelet-thrombin micro-emboli Atherosclerotic Plaques - Terminology Culprit Responsible for the clinical event Vulnerable High risk to become culprit (cause clinical event) Quiescent (Stable) Primary or healed (vulnerable or culprit) Fuster, V. et al. J Am Coll Cardiol 2005;46:937-954 Coronary Artery Disease: Diffuse disease with a variable mix of stable, vulnerable and culprit plaques Culprit and healed plaques in a coronary bifurcation N Engl J Med 2000;343:915-22 Angiograms of 253 patients with acute MI Complex Plaques: Single: 153 - 60.5% Multiple: 100 – 39.5% Clinical Outcome at 1 Year – Single vs. Multiple Complex Plaques Similar results when analysis was restricted to patients with multivessel coronary disease: 74.5% of single 91.0% of multiple Characteristics of Carotid Plaques: Patients with Unstable versus Stable Angina Multivariate analysis: UA and CRP >3 mg/l were independently and strongly associated with complex carotid plaques Vulnerable Patient – at high risk for vascular event coronary elsewhere Who is the vulnerable patient? Patient with current multiple complex plaques Coronary, carotid etc Patient with multiple uncontrolled risk factors At risk to develop new complex plaques Vulnerability cutoff value ? Who is ”High Risk” Patients in whom long term clopidogrel should be considered The vulnerable patient TIMI risk score Aspirin Failure Others TIMI Risk Score and Outcome Budaj et al. circulation 2002 Excess major bleeding risk with clopidogrel is independent of the TIMI risk – it is 1% TIMI Risk Score and Absolute Reduction of death/MI/Stroke with Clopidogrel TIMI Risk Score N= 752 2524 3730 3567 1593 396 Percent reduction Major bleeding – 1% Majority of patients Who is ”High Risk” Patients in whom long term clopidogrel should be considered The vulnerable patient TIMI risk score Aspirin Failure Others
Slide 71 - Early And Long Term Treatment With Clopidogrel In Coronary Artery Disease פרופ’ יוסף רוזנמן מכון הלב, בי"ח וולפסון דצמבר 2005 Acute Coronary Syndromes Acute Coronary Syndrome No ST Elevation ST Elevation Unstable Angina Myocardial Infarction Non Q MI Q wave MI Non ST Elevation MI Braunwald E et al. J Am Coll Cardiol 2000;36:970–1062. Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When angiography / PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until angiography / PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month improving long-term outcome 1 2 Goals of therapy Prevent ischemic events until coronary angiography / PCI Before plaque stabilization was achieved Prevent PCI / stent related ischemic complications Clopidogrel before coronary angiography - Patients with ACS 1 Clopidogrel before coronary angiography - Patients with ACS ST Elevation CLARITY Non ST Elevation CURE 1 ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Study Design Fibrinolytic, ASA, Heparin Clopidogrel 300 mg + 75 mg qd Coronary Angiogram (2-8 days) Primary endpoint: Occluded artery (TIMI Flow Grade 0/1) or D/MI by time of angio randomize Placebo Double-blind, randomized, placebo-controlled trial in 3491 patients, age 18-75 yrs with STEMI < 12 hours Study Drug 30-day clinical follow-up Open-label clopidogrel per MD in both groups Primary Endpoint: Occluded Artery (or D/MI by time of angio) Placebo Clopidogrel P=0.00000036 Odds Ratio 0.64 (95% CI 0.53-0.76) 1.0 0.4 0.6 0.8 1.2 1.6 Clopidogrel better Placebo better n=1752 n=1739 36% Odds Reduction Primary & Angiographic Outcomes (median 3.5 days) Need for Urgent or Additional Treatment 21%  P=0.01 21%  P=0.005 16%  P=0.07 Early Angio (w/in 48 hrs) Urgent Revasc (index hosp) GP IIb/IIIa if PCI CV Death, MI, RI  Urg Revasc days Percentage with endpoint (%) 0 5 10 15 0 5 10 15 20 25 30 Placebo Clopidogrel Odds Ratio 0.80 (95% CI 0.65-0.97) P=0.026 20% 1 CLARITY: Patient Management Clopidogrel Placebo Parameter (n=1,752) (n=1,739) Symptom onset to fibrinolytic (hours) 2.7 2.6 Fibrinolytic to study drug (minutes) 10 10 Median doses of study medication 4 4 Angiography performed (%) 94 94 Study drug to angiography (hours) 84 84 Coronary revascularization (%): 63 63 PCI 57.2 56.6 CABG 5.9 6.0 Sabatine M et al. New Engl J Med 2005; 352: 1179–1189. PCI-CLARITY: Reduction in CV Death, MI, Stroke from PCI to 30 Days Days Post PCI Percentage with Outcome (%) 0 2 0 5 10 15 20 25 30 46%* p=0.008 Clopidogrel Pretreatment (3.6%) No Pretreatment (6.2%) 4 6 8 M Sabatine, et al. JAMA 2005 PCI-CLARITY: MI, Stroke, or CV Death Events pre and post PCI ***MI or Stroke M Sabatine, et al. JAMA 2005, Prehospital Fibrinolysis with Double Antiplatelet Therapy in Acute ST-Elevation Myocardial Infarction: The Clarity Ambulance Substudy Substudy Sites and Patient Numbers France: 172 patients L Soulat: 57 Y Lambert: 48 F Lapostolle: 28 F Thieuleux: 21 C Gully: 10 D Pollet: 5 D Galley: 2 L Olliver: 1 UK: 40 patients J Adgey: 27 J Purvis: 13 Sweden: 5 patients J-E Karlsson: 5 217 patients in total Angiographic & ECG Parameters: Ambulance vs. Non-Ambulance *Complete considered to be >70%; ECG=electrocardiogram p value Event rate (%) Ambulance Non- ambulance Non-ambulance better Ambulance better Odds ratio (95% CI) 0 0.5 1.0 1.5 2.0 Ambulance Non-ambulance Overall Clopidogrel better Placebo better Odds ratio (95% CI) Primary Endpoint of TIMI Flow Grade 0/1, MI or Death 0.60 (0.301.17) 0.64 (0.530.76) 0.65 (0.540.77) ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Clopidogrel 75mg q.d. + ASA 75-325 mg q.d.* (6259 patients) Placebo + ASA 75-325 mg q.d.* (6303 patients) Day 1 6 m. Visit 9 m. Visit 12 m. or Final Visit 3 m. Visit Discharge Visit 1 m. Visit Patients with Acute Coronary Syndrome (unstable angina or non-ST-segment elevation MI) R Placebo loading dose R = Randomization * In combination with other standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Study Design 3 months £ double-blind treatment £ 12 months Clopidogrel 300 mg loading dose CURE Clopidogrel + ASA* 3 6 9 Placebo + ASA* Months of Follow-Up 11.4% 9.3% 20% RRR P < 0.001 N = 12,562 0 12 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Primary End Point - MI/Stroke/CV Death CURE Clopidogrel + ASA* 10 20 30 Placebo + ASA* Days of Follow-Up 0 21% RRR P = 0.003 N = 12,562 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. MI/Stroke/CV Death within 30 Days CURE 1 CV death, nonfatal MI, stroke or refractory or severe ischemia 34% NEJM 2001; 345:495-502 MI/Stroke/CV Death or severe Ischemia at 24 hours CURE 1 % patients requiring thrombolytic therapy 43% % patients requiring GP IIb/IIIa inhibitors 18% NEJM 2001; 345:495-502 Need for Additional Anti-Thrombotic After Randomization P< 0.001 P= 0.003 Thrombolysis GP IIb/IIIa Inhibitor CURE 1 Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? GP IIb/IIIa receptor is the final common pathway in platelet aggregation. GP IIb/IIIa blockade is the most effective antiplatelet aggregation therapy. Bleeding risk is not increased if therapy is stopped 2-4 hours prior to CABG. Bleeding risk is markedly increased unless clopidogrel is stopped 3-5 days prior to CABG. Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? Is there additional benefit to clopidogrel that would justify: Increased CABG bleeding or alternatively Need to postpone CABG for 3-5 days No data in the literature however Adhesion The Role of Platelets in Atherothrombosis Aggregation 3 Reproduced with permission from Cannon CP. Atherothrombosis slide compendium. Available at: www.theheart.org. 1 Activation 2 Conclusions: Early Clopidogrel Therapy Treatment with clopidogrel is indicated as soon as possible in patients with acute coronary syndrome ST elevation and non ST elevation Treatment is effective to reduce ischemic complications Before coronay angiography During and after PCI 1 Conclusions: Early Clopidogrel Therapy Loading dose should be 600mg to achieve early optimal antiplatelet effect ?? 300mg in patients after fibrinolytic therapy It is unclear whether therapy should be added to “upstream” GP IIb/IIIa antagonists Especially in high risk patients in whom the likelihood for CABG is high 1 Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month after PCI / stent improving long-term outcome 1 2 Discharge/Post-Discharge Medications - Guidelines ASA, if not contraindicated Clopidogrel, when ASA contraindicated Aspirin + Clopidogrel for up to 9 months -blocker, if not contraindicated Lipid  agents + diet, if LDL >130 mg/dL ACE Inhibitor: CHF, EF < 40%, DM, or HTN I IIa IIb III 2 Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization PCI PLACEBO + ASA * CLOPIDOGREL + ASA * 30 days post PCI End of follow-up Up to 12 months after randomization Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 2,658 patients undergoing PCI N = 1345 N = 1313 PCI-CURE Overall Study Design: PCI-CURE R Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE Question 1 Question 2 Clopidogrel Arm Placebo Arm PCI* 28 Days Placebo + ASA† (325 mg) Randomization - Pre-treatment Clopidogrel 300 mg + ASA† (325 mg) Clopidogrel 75 mg QD + ASA† 325 mg QD Clopidogrel 75 mg QD + ASA† 325 mg QD R 12 Months Steinhubl S, Berger P, Tift Mann III J et al. JAMA. 2002;Vol 288,No 19:2411-2420. Placebo QD + ASA† (81-325 mg) QD Clopidogrel 75 mg QD + ASA† (81-325 mg) QD Overall Study Design: CREDO Question 1 Question 2 1 2 Open label clopidogrel continuation Methodological Pitfall Can a study with a single randomization provide an answer to two questions? Alternatively Should a second randomization be done in order to answer the second question? PCI PLACEBO + ASA * CLOPIDOGREL + ASA * 30 days post PCI End of follow-up Up to 12 months after randomization Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 1345 N = 1313 PCI-CURE Study Design single randomization R Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE Continuation Continuation PCI PLACEBO + ASA * CLOPIDOGREL + ASA * Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 1345 N = 1313 PCI-CURE Alternative Study Design two randomizations R1 Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE R2 R2 Clop. Placebo Continuation Continuation Question 2 2 Is it just methodology? Can we really expect long term benefit from early antiplatelet therapy? Adjunct antiplatelet therapy for PCI EPISTENT Randomized study designed to determine the effect of treatment with abciximab TARGET Randomized study designed to show that tirofiban is not inferior to abciximab Post-hoc nonrandomized comparison among those who were or were not pre-treated with clopidogrel PCI-CURE Subgroup of CURE patients who underwent PCI Randomized comparison of pre-treatment and continued clopidogrel therapy vs. placebo Absolute reduction of Death or MI at 1 month and 1 year Abciximab Early clopidogrel Early and continued clopidogrel % reduction * * 6 month data in TARGET Early and long term reduction of death or MI from antiplatelet therapy in patients with ACS Long Term Clopidogrel Post PCI Clinical guidelines: 9 months to 1 year in patients with ACS However, current data does not fully support this recommendation What should we do? 2 Comulative event rate in primary prevention stable CAD and ACS ACS Stable Primary Risk of vascular event after ACS Risk of event Time after ACS Stable CAD Commulative risk Risk per time Risk of vascular event after ACS high and low risk Risk of event Time after ACS High risk Low risk Risk of bleeding after initiation of clopidogrel (high and low risk) Risk of event Time after clopidogrel High risk Low risk Fixed, except for the initial few days heparin, catheterization Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? vascular bleeding Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? vascular bleeding > 1 year High vascular risk Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? vascular bleeding < 1 months High bleeding risk e.g. coumadin Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? Long term clopidogrel for patients with High risk for vascular event Low bleeding risk Short term clopidogrel for patients with Low risk for vascular event High bleeding risk vascular bleeding Who is ”High Risk” Patients in whom long term clopidogrel should be considered The vulnerable patient TIMI risk score Aspirin Failure Others Who is ”High Risk” Patients in whom long term clopidogrel should be considered The vulnerable patient TIMI risk score Aspirin Failure Others ACS Pathophysiology Inflammation, Plaque Rupture, Thrombosis, and Microembolization Quiescent plaque Plaque formation Lipids, other risk factors Inflammation LDL, others, Infection? Plaque rupture (erosion) ? Macrophages, metalloproteinases Thrombosis Platelet Activation, Thrombin Vulnerable plaque Macrophages Foam Cells Collagen  platelet activation TF  Clotting Cascade Lipid core Metalloproteinases Inflammation Courtesy of David Kandzari. Plaque rupture Culprit plaque Platelet-thrombin micro-emboli Atherosclerotic Plaques - Terminology Culprit Responsible for the clinical event Vulnerable High risk to become culprit (cause clinical event) Quiescent (Stable) Primary or healed (vulnerable or culprit) Fuster, V. et al. J Am Coll Cardiol 2005;46:937-954 Coronary Artery Disease: Diffuse disease with a variable mix of stable, vulnerable and culprit plaques Culprit and healed plaques in a coronary bifurcation N Engl J Med 2000;343:915-22 Angiograms of 253 patients with acute MI Complex Plaques: Single: 153 - 60.5% Multiple: 100 – 39.5% Clinical Outcome at 1 Year – Single vs. Multiple Complex Plaques Similar results when analysis was restricted to patients with multivessel coronary disease: 74.5% of single 91.0% of multiple Characteristics of Carotid Plaques: Patients with Unstable versus Stable Angina Multivariate analysis: UA and CRP >3 mg/l were independently and strongly associated with complex carotid plaques Vulnerable Patient – at high risk for vascular event coronary elsewhere Who is the vulnerable patient? Patient with current multiple complex plaques Coronary, carotid etc Patient with multiple uncontrolled risk factors At risk to develop new complex plaques Vulnerability cutoff value ? Who is ”High Risk” Patients in whom long term clopidogrel should be considered The vulnerable patient TIMI risk score Aspirin Failure Others TIMI Risk Score and Outcome Budaj et al. circulation 2002 Excess major bleeding risk with clopidogrel is independent of the TIMI risk – it is 1% TIMI Risk Score and Absolute Reduction of death/MI/Stroke with Clopidogrel TIMI Risk Score N= 752 2524 3730 3567 1593 396 Percent reduction Major bleeding – 1% Majority of patients Who is ”High Risk” Patients in whom long term clopidogrel should be considered The vulnerable patient TIMI risk score Aspirin Failure Others Aspirin Failure – Patient with acute vascular event (coronary, cerebral) while being treated with aspirin Aspirin was not enough to prevent the event Aspirin is ineffective as an antiplatelet agent – resistance? Aspirin is effective as an antiplatelet agent but the disease risk is high and there is a need for more aggressive antiplatelet therapy
Slide 72 - Early And Long Term Treatment With Clopidogrel In Coronary Artery Disease פרופ’ יוסף רוזנמן מכון הלב, בי"ח וולפסון דצמבר 2005 Acute Coronary Syndromes Acute Coronary Syndrome No ST Elevation ST Elevation Unstable Angina Myocardial Infarction Non Q MI Q wave MI Non ST Elevation MI Braunwald E et al. J Am Coll Cardiol 2000;36:970–1062. Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When angiography / PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until angiography / PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month improving long-term outcome 1 2 Goals of therapy Prevent ischemic events until coronary angiography / PCI Before plaque stabilization was achieved Prevent PCI / stent related ischemic complications Clopidogrel before coronary angiography - Patients with ACS 1 Clopidogrel before coronary angiography - Patients with ACS ST Elevation CLARITY Non ST Elevation CURE 1 ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Study Design Fibrinolytic, ASA, Heparin Clopidogrel 300 mg + 75 mg qd Coronary Angiogram (2-8 days) Primary endpoint: Occluded artery (TIMI Flow Grade 0/1) or D/MI by time of angio randomize Placebo Double-blind, randomized, placebo-controlled trial in 3491 patients, age 18-75 yrs with STEMI < 12 hours Study Drug 30-day clinical follow-up Open-label clopidogrel per MD in both groups Primary Endpoint: Occluded Artery (or D/MI by time of angio) Placebo Clopidogrel P=0.00000036 Odds Ratio 0.64 (95% CI 0.53-0.76) 1.0 0.4 0.6 0.8 1.2 1.6 Clopidogrel better Placebo better n=1752 n=1739 36% Odds Reduction Primary & Angiographic Outcomes (median 3.5 days) Need for Urgent or Additional Treatment 21%  P=0.01 21%  P=0.005 16%  P=0.07 Early Angio (w/in 48 hrs) Urgent Revasc (index hosp) GP IIb/IIIa if PCI CV Death, MI, RI  Urg Revasc days Percentage with endpoint (%) 0 5 10 15 0 5 10 15 20 25 30 Placebo Clopidogrel Odds Ratio 0.80 (95% CI 0.65-0.97) P=0.026 20% 1 CLARITY: Patient Management Clopidogrel Placebo Parameter (n=1,752) (n=1,739) Symptom onset to fibrinolytic (hours) 2.7 2.6 Fibrinolytic to study drug (minutes) 10 10 Median doses of study medication 4 4 Angiography performed (%) 94 94 Study drug to angiography (hours) 84 84 Coronary revascularization (%): 63 63 PCI 57.2 56.6 CABG 5.9 6.0 Sabatine M et al. New Engl J Med 2005; 352: 1179–1189. PCI-CLARITY: Reduction in CV Death, MI, Stroke from PCI to 30 Days Days Post PCI Percentage with Outcome (%) 0 2 0 5 10 15 20 25 30 46%* p=0.008 Clopidogrel Pretreatment (3.6%) No Pretreatment (6.2%) 4 6 8 M Sabatine, et al. JAMA 2005 PCI-CLARITY: MI, Stroke, or CV Death Events pre and post PCI ***MI or Stroke M Sabatine, et al. JAMA 2005, Prehospital Fibrinolysis with Double Antiplatelet Therapy in Acute ST-Elevation Myocardial Infarction: The Clarity Ambulance Substudy Substudy Sites and Patient Numbers France: 172 patients L Soulat: 57 Y Lambert: 48 F Lapostolle: 28 F Thieuleux: 21 C Gully: 10 D Pollet: 5 D Galley: 2 L Olliver: 1 UK: 40 patients J Adgey: 27 J Purvis: 13 Sweden: 5 patients J-E Karlsson: 5 217 patients in total Angiographic & ECG Parameters: Ambulance vs. Non-Ambulance *Complete considered to be >70%; ECG=electrocardiogram p value Event rate (%) Ambulance Non- ambulance Non-ambulance better Ambulance better Odds ratio (95% CI) 0 0.5 1.0 1.5 2.0 Ambulance Non-ambulance Overall Clopidogrel better Placebo better Odds ratio (95% CI) Primary Endpoint of TIMI Flow Grade 0/1, MI or Death 0.60 (0.301.17) 0.64 (0.530.76) 0.65 (0.540.77) ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Clopidogrel 75mg q.d. + ASA 75-325 mg q.d.* (6259 patients) Placebo + ASA 75-325 mg q.d.* (6303 patients) Day 1 6 m. Visit 9 m. Visit 12 m. or Final Visit 3 m. Visit Discharge Visit 1 m. Visit Patients with Acute Coronary Syndrome (unstable angina or non-ST-segment elevation MI) R Placebo loading dose R = Randomization * In combination with other standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Study Design 3 months £ double-blind treatment £ 12 months Clopidogrel 300 mg loading dose CURE Clopidogrel + ASA* 3 6 9 Placebo + ASA* Months of Follow-Up 11.4% 9.3% 20% RRR P < 0.001 N = 12,562 0 12 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Primary End Point - MI/Stroke/CV Death CURE Clopidogrel + ASA* 10 20 30 Placebo + ASA* Days of Follow-Up 0 21% RRR P = 0.003 N = 12,562 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. MI/Stroke/CV Death within 30 Days CURE 1 CV death, nonfatal MI, stroke or refractory or severe ischemia 34% NEJM 2001; 345:495-502 MI/Stroke/CV Death or severe Ischemia at 24 hours CURE 1 % patients requiring thrombolytic therapy 43% % patients requiring GP IIb/IIIa inhibitors 18% NEJM 2001; 345:495-502 Need for Additional Anti-Thrombotic After Randomization P< 0.001 P= 0.003 Thrombolysis GP IIb/IIIa Inhibitor CURE 1 Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? GP IIb/IIIa receptor is the final common pathway in platelet aggregation. GP IIb/IIIa blockade is the most effective antiplatelet aggregation therapy. Bleeding risk is not increased if therapy is stopped 2-4 hours prior to CABG. Bleeding risk is markedly increased unless clopidogrel is stopped 3-5 days prior to CABG. Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? Is there additional benefit to clopidogrel that would justify: Increased CABG bleeding or alternatively Need to postpone CABG for 3-5 days No data in the literature however Adhesion The Role of Platelets in Atherothrombosis Aggregation 3 Reproduced with permission from Cannon CP. Atherothrombosis slide compendium. Available at: www.theheart.org. 1 Activation 2 Conclusions: Early Clopidogrel Therapy Treatment with clopidogrel is indicated as soon as possible in patients with acute coronary syndrome ST elevation and non ST elevation Treatment is effective to reduce ischemic complications Before coronay angiography During and after PCI 1 Conclusions: Early Clopidogrel Therapy Loading dose should be 600mg to achieve early optimal antiplatelet effect ?? 300mg in patients after fibrinolytic therapy It is unclear whether therapy should be added to “upstream” GP IIb/IIIa antagonists Especially in high risk patients in whom the likelihood for CABG is high 1 Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month after PCI / stent improving long-term outcome 1 2 Discharge/Post-Discharge Medications - Guidelines ASA, if not contraindicated Clopidogrel, when ASA contraindicated Aspirin + Clopidogrel for up to 9 months -blocker, if not contraindicated Lipid  agents + diet, if LDL >130 mg/dL ACE Inhibitor: CHF, EF < 40%, DM, or HTN I IIa IIb III 2 Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization PCI PLACEBO + ASA * CLOPIDOGREL + ASA * 30 days post PCI End of follow-up Up to 12 months after randomization Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 2,658 patients undergoing PCI N = 1345 N = 1313 PCI-CURE Overall Study Design: PCI-CURE R Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE Question 1 Question 2 Clopidogrel Arm Placebo Arm PCI* 28 Days Placebo + ASA† (325 mg) Randomization - Pre-treatment Clopidogrel 300 mg + ASA† (325 mg) Clopidogrel 75 mg QD + ASA† 325 mg QD Clopidogrel 75 mg QD + ASA† 325 mg QD R 12 Months Steinhubl S, Berger P, Tift Mann III J et al. JAMA. 2002;Vol 288,No 19:2411-2420. Placebo QD + ASA† (81-325 mg) QD Clopidogrel 75 mg QD + ASA† (81-325 mg) QD Overall Study Design: CREDO Question 1 Question 2 1 2 Open label clopidogrel continuation Methodological Pitfall Can a study with a single randomization provide an answer to two questions? Alternatively Should a second randomization be done in order to answer the second question? PCI PLACEBO + ASA * CLOPIDOGREL + ASA * 30 days post PCI End of follow-up Up to 12 months after randomization Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 1345 N = 1313 PCI-CURE Study Design single randomization R Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE Continuation Continuation PCI PLACEBO + ASA * CLOPIDOGREL + ASA * Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 1345 N = 1313 PCI-CURE Alternative Study Design two randomizations R1 Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE R2 R2 Clop. Placebo Continuation Continuation Question 2 2 Is it just methodology? Can we really expect long term benefit from early antiplatelet therapy? Adjunct antiplatelet therapy for PCI EPISTENT Randomized study designed to determine the effect of treatment with abciximab TARGET Randomized study designed to show that tirofiban is not inferior to abciximab Post-hoc nonrandomized comparison among those who were or were not pre-treated with clopidogrel PCI-CURE Subgroup of CURE patients who underwent PCI Randomized comparison of pre-treatment and continued clopidogrel therapy vs. placebo Absolute reduction of Death or MI at 1 month and 1 year Abciximab Early clopidogrel Early and continued clopidogrel % reduction * * 6 month data in TARGET Early and long term reduction of death or MI from antiplatelet therapy in patients with ACS Long Term Clopidogrel Post PCI Clinical guidelines: 9 months to 1 year in patients with ACS However, current data does not fully support this recommendation What should we do? 2 Comulative event rate in primary prevention stable CAD and ACS ACS Stable Primary Risk of vascular event after ACS Risk of event Time after ACS Stable CAD Commulative risk Risk per time Risk of vascular event after ACS high and low risk Risk of event Time after ACS High risk Low risk Risk of bleeding after initiation of clopidogrel (high and low risk) Risk of event Time after clopidogrel High risk Low risk Fixed, except for the initial few days heparin, catheterization Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? vascular bleeding Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? vascular bleeding > 1 year High vascular risk Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? vascular bleeding < 1 months High bleeding risk e.g. coumadin Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? Long term clopidogrel for patients with High risk for vascular event Low bleeding risk Short term clopidogrel for patients with Low risk for vascular event High bleeding risk vascular bleeding Who is ”High Risk” Patients in whom long term clopidogrel should be considered The vulnerable patient TIMI risk score Aspirin Failure Others Who is ”High Risk” Patients in whom long term clopidogrel should be considered The vulnerable patient TIMI risk score Aspirin Failure Others ACS Pathophysiology Inflammation, Plaque Rupture, Thrombosis, and Microembolization Quiescent plaque Plaque formation Lipids, other risk factors Inflammation LDL, others, Infection? Plaque rupture (erosion) ? Macrophages, metalloproteinases Thrombosis Platelet Activation, Thrombin Vulnerable plaque Macrophages Foam Cells Collagen  platelet activation TF  Clotting Cascade Lipid core Metalloproteinases Inflammation Courtesy of David Kandzari. Plaque rupture Culprit plaque Platelet-thrombin micro-emboli Atherosclerotic Plaques - Terminology Culprit Responsible for the clinical event Vulnerable High risk to become culprit (cause clinical event) Quiescent (Stable) Primary or healed (vulnerable or culprit) Fuster, V. et al. J Am Coll Cardiol 2005;46:937-954 Coronary Artery Disease: Diffuse disease with a variable mix of stable, vulnerable and culprit plaques Culprit and healed plaques in a coronary bifurcation N Engl J Med 2000;343:915-22 Angiograms of 253 patients with acute MI Complex Plaques: Single: 153 - 60.5% Multiple: 100 – 39.5% Clinical Outcome at 1 Year – Single vs. Multiple Complex Plaques Similar results when analysis was restricted to patients with multivessel coronary disease: 74.5% of single 91.0% of multiple Characteristics of Carotid Plaques: Patients with Unstable versus Stable Angina Multivariate analysis: UA and CRP >3 mg/l were independently and strongly associated with complex carotid plaques Vulnerable Patient – at high risk for vascular event coronary elsewhere Who is the vulnerable patient? Patient with current multiple complex plaques Coronary, carotid etc Patient with multiple uncontrolled risk factors At risk to develop new complex plaques Vulnerability cutoff value ? Who is ”High Risk” Patients in whom long term clopidogrel should be considered The vulnerable patient TIMI risk score Aspirin Failure Others TIMI Risk Score and Outcome Budaj et al. circulation 2002 Excess major bleeding risk with clopidogrel is independent of the TIMI risk – it is 1% TIMI Risk Score and Absolute Reduction of death/MI/Stroke with Clopidogrel TIMI Risk Score N= 752 2524 3730 3567 1593 396 Percent reduction Major bleeding – 1% Majority of patients Who is ”High Risk” Patients in whom long term clopidogrel should be considered The vulnerable patient TIMI risk score Aspirin Failure Others Aspirin Failure – Patient with acute vascular event (coronary, cerebral) while being treated with aspirin Aspirin was not enough to prevent the event Aspirin is ineffective as an antiplatelet agent – resistance? Aspirin is effective as an antiplatelet agent but the disease risk is high and there is a need for more aggressive antiplatelet therapy Aspirin Resistance Cellular Factors Insufficient suppression of COX-1 Overexpression of COX-2 mRNA Erythrocyte-induced platelet activation Increased norepinephrine Generation of 8-iso-PGF2 Adapted with permission from Bhatt DL. J Am Coll Cardiol. 2004;43:1127-1129. Aspirin Resistance Genetic Polymorphisms COX-1 GP IIIa receptor Collagen receptor vWF receptor Clinical Factors Failure to prescribe Noncompliance Nonabsorption Interaction with ibuprofen Can be intermittent
Slide 73 - Early And Long Term Treatment With Clopidogrel In Coronary Artery Disease פרופ’ יוסף רוזנמן מכון הלב, בי"ח וולפסון דצמבר 2005 Acute Coronary Syndromes Acute Coronary Syndrome No ST Elevation ST Elevation Unstable Angina Myocardial Infarction Non Q MI Q wave MI Non ST Elevation MI Braunwald E et al. J Am Coll Cardiol 2000;36:970–1062. Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When angiography / PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until angiography / PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month improving long-term outcome 1 2 Goals of therapy Prevent ischemic events until coronary angiography / PCI Before plaque stabilization was achieved Prevent PCI / stent related ischemic complications Clopidogrel before coronary angiography - Patients with ACS 1 Clopidogrel before coronary angiography - Patients with ACS ST Elevation CLARITY Non ST Elevation CURE 1 ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Study Design Fibrinolytic, ASA, Heparin Clopidogrel 300 mg + 75 mg qd Coronary Angiogram (2-8 days) Primary endpoint: Occluded artery (TIMI Flow Grade 0/1) or D/MI by time of angio randomize Placebo Double-blind, randomized, placebo-controlled trial in 3491 patients, age 18-75 yrs with STEMI < 12 hours Study Drug 30-day clinical follow-up Open-label clopidogrel per MD in both groups Primary Endpoint: Occluded Artery (or D/MI by time of angio) Placebo Clopidogrel P=0.00000036 Odds Ratio 0.64 (95% CI 0.53-0.76) 1.0 0.4 0.6 0.8 1.2 1.6 Clopidogrel better Placebo better n=1752 n=1739 36% Odds Reduction Primary & Angiographic Outcomes (median 3.5 days) Need for Urgent or Additional Treatment 21%  P=0.01 21%  P=0.005 16%  P=0.07 Early Angio (w/in 48 hrs) Urgent Revasc (index hosp) GP IIb/IIIa if PCI CV Death, MI, RI  Urg Revasc days Percentage with endpoint (%) 0 5 10 15 0 5 10 15 20 25 30 Placebo Clopidogrel Odds Ratio 0.80 (95% CI 0.65-0.97) P=0.026 20% 1 CLARITY: Patient Management Clopidogrel Placebo Parameter (n=1,752) (n=1,739) Symptom onset to fibrinolytic (hours) 2.7 2.6 Fibrinolytic to study drug (minutes) 10 10 Median doses of study medication 4 4 Angiography performed (%) 94 94 Study drug to angiography (hours) 84 84 Coronary revascularization (%): 63 63 PCI 57.2 56.6 CABG 5.9 6.0 Sabatine M et al. New Engl J Med 2005; 352: 1179–1189. PCI-CLARITY: Reduction in CV Death, MI, Stroke from PCI to 30 Days Days Post PCI Percentage with Outcome (%) 0 2 0 5 10 15 20 25 30 46%* p=0.008 Clopidogrel Pretreatment (3.6%) No Pretreatment (6.2%) 4 6 8 M Sabatine, et al. JAMA 2005 PCI-CLARITY: MI, Stroke, or CV Death Events pre and post PCI ***MI or Stroke M Sabatine, et al. JAMA 2005, Prehospital Fibrinolysis with Double Antiplatelet Therapy in Acute ST-Elevation Myocardial Infarction: The Clarity Ambulance Substudy Substudy Sites and Patient Numbers France: 172 patients L Soulat: 57 Y Lambert: 48 F Lapostolle: 28 F Thieuleux: 21 C Gully: 10 D Pollet: 5 D Galley: 2 L Olliver: 1 UK: 40 patients J Adgey: 27 J Purvis: 13 Sweden: 5 patients J-E Karlsson: 5 217 patients in total Angiographic & ECG Parameters: Ambulance vs. Non-Ambulance *Complete considered to be >70%; ECG=electrocardiogram p value Event rate (%) Ambulance Non- ambulance Non-ambulance better Ambulance better Odds ratio (95% CI) 0 0.5 1.0 1.5 2.0 Ambulance Non-ambulance Overall Clopidogrel better Placebo better Odds ratio (95% CI) Primary Endpoint of TIMI Flow Grade 0/1, MI or Death 0.60 (0.301.17) 0.64 (0.530.76) 0.65 (0.540.77) ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Clopidogrel 75mg q.d. + ASA 75-325 mg q.d.* (6259 patients) Placebo + ASA 75-325 mg q.d.* (6303 patients) Day 1 6 m. Visit 9 m. Visit 12 m. or Final Visit 3 m. Visit Discharge Visit 1 m. Visit Patients with Acute Coronary Syndrome (unstable angina or non-ST-segment elevation MI) R Placebo loading dose R = Randomization * In combination with other standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Study Design 3 months £ double-blind treatment £ 12 months Clopidogrel 300 mg loading dose CURE Clopidogrel + ASA* 3 6 9 Placebo + ASA* Months of Follow-Up 11.4% 9.3% 20% RRR P < 0.001 N = 12,562 0 12 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Primary End Point - MI/Stroke/CV Death CURE Clopidogrel + ASA* 10 20 30 Placebo + ASA* Days of Follow-Up 0 21% RRR P = 0.003 N = 12,562 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. MI/Stroke/CV Death within 30 Days CURE 1 CV death, nonfatal MI, stroke or refractory or severe ischemia 34% NEJM 2001; 345:495-502 MI/Stroke/CV Death or severe Ischemia at 24 hours CURE 1 % patients requiring thrombolytic therapy 43% % patients requiring GP IIb/IIIa inhibitors 18% NEJM 2001; 345:495-502 Need for Additional Anti-Thrombotic After Randomization P< 0.001 P= 0.003 Thrombolysis GP IIb/IIIa Inhibitor CURE 1 Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? GP IIb/IIIa receptor is the final common pathway in platelet aggregation. GP IIb/IIIa blockade is the most effective antiplatelet aggregation therapy. Bleeding risk is not increased if therapy is stopped 2-4 hours prior to CABG. Bleeding risk is markedly increased unless clopidogrel is stopped 3-5 days prior to CABG. Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? Is there additional benefit to clopidogrel that would justify: Increased CABG bleeding or alternatively Need to postpone CABG for 3-5 days No data in the literature however Adhesion The Role of Platelets in Atherothrombosis Aggregation 3 Reproduced with permission from Cannon CP. Atherothrombosis slide compendium. Available at: www.theheart.org. 1 Activation 2 Conclusions: Early Clopidogrel Therapy Treatment with clopidogrel is indicated as soon as possible in patients with acute coronary syndrome ST elevation and non ST elevation Treatment is effective to reduce ischemic complications Before coronay angiography During and after PCI 1 Conclusions: Early Clopidogrel Therapy Loading dose should be 600mg to achieve early optimal antiplatelet effect ?? 300mg in patients after fibrinolytic therapy It is unclear whether therapy should be added to “upstream” GP IIb/IIIa antagonists Especially in high risk patients in whom the likelihood for CABG is high 1 Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month after PCI / stent improving long-term outcome 1 2 Discharge/Post-Discharge Medications - Guidelines ASA, if not contraindicated Clopidogrel, when ASA contraindicated Aspirin + Clopidogrel for up to 9 months -blocker, if not contraindicated Lipid  agents + diet, if LDL >130 mg/dL ACE Inhibitor: CHF, EF < 40%, DM, or HTN I IIa IIb III 2 Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization PCI PLACEBO + ASA * CLOPIDOGREL + ASA * 30 days post PCI End of follow-up Up to 12 months after randomization Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 2,658 patients undergoing PCI N = 1345 N = 1313 PCI-CURE Overall Study Design: PCI-CURE R Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE Question 1 Question 2 Clopidogrel Arm Placebo Arm PCI* 28 Days Placebo + ASA† (325 mg) Randomization - Pre-treatment Clopidogrel 300 mg + ASA† (325 mg) Clopidogrel 75 mg QD + ASA† 325 mg QD Clopidogrel 75 mg QD + ASA† 325 mg QD R 12 Months Steinhubl S, Berger P, Tift Mann III J et al. JAMA. 2002;Vol 288,No 19:2411-2420. Placebo QD + ASA† (81-325 mg) QD Clopidogrel 75 mg QD + ASA† (81-325 mg) QD Overall Study Design: CREDO Question 1 Question 2 1 2 Open label clopidogrel continuation Methodological Pitfall Can a study with a single randomization provide an answer to two questions? Alternatively Should a second randomization be done in order to answer the second question? PCI PLACEBO + ASA * CLOPIDOGREL + ASA * 30 days post PCI End of follow-up Up to 12 months after randomization Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 1345 N = 1313 PCI-CURE Study Design single randomization R Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE Continuation Continuation PCI PLACEBO + ASA * CLOPIDOGREL + ASA * Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 1345 N = 1313 PCI-CURE Alternative Study Design two randomizations R1 Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE R2 R2 Clop. Placebo Continuation Continuation Question 2 2 Is it just methodology? Can we really expect long term benefit from early antiplatelet therapy? Adjunct antiplatelet therapy for PCI EPISTENT Randomized study designed to determine the effect of treatment with abciximab TARGET Randomized study designed to show that tirofiban is not inferior to abciximab Post-hoc nonrandomized comparison among those who were or were not pre-treated with clopidogrel PCI-CURE Subgroup of CURE patients who underwent PCI Randomized comparison of pre-treatment and continued clopidogrel therapy vs. placebo Absolute reduction of Death or MI at 1 month and 1 year Abciximab Early clopidogrel Early and continued clopidogrel % reduction * * 6 month data in TARGET Early and long term reduction of death or MI from antiplatelet therapy in patients with ACS Long Term Clopidogrel Post PCI Clinical guidelines: 9 months to 1 year in patients with ACS However, current data does not fully support this recommendation What should we do? 2 Comulative event rate in primary prevention stable CAD and ACS ACS Stable Primary Risk of vascular event after ACS Risk of event Time after ACS Stable CAD Commulative risk Risk per time Risk of vascular event after ACS high and low risk Risk of event Time after ACS High risk Low risk Risk of bleeding after initiation of clopidogrel (high and low risk) Risk of event Time after clopidogrel High risk Low risk Fixed, except for the initial few days heparin, catheterization Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? vascular bleeding Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? vascular bleeding > 1 year High vascular risk Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? vascular bleeding < 1 months High bleeding risk e.g. coumadin Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? Long term clopidogrel for patients with High risk for vascular event Low bleeding risk Short term clopidogrel for patients with Low risk for vascular event High bleeding risk vascular bleeding Who is ”High Risk” Patients in whom long term clopidogrel should be considered The vulnerable patient TIMI risk score Aspirin Failure Others Who is ”High Risk” Patients in whom long term clopidogrel should be considered The vulnerable patient TIMI risk score Aspirin Failure Others ACS Pathophysiology Inflammation, Plaque Rupture, Thrombosis, and Microembolization Quiescent plaque Plaque formation Lipids, other risk factors Inflammation LDL, others, Infection? Plaque rupture (erosion) ? Macrophages, metalloproteinases Thrombosis Platelet Activation, Thrombin Vulnerable plaque Macrophages Foam Cells Collagen  platelet activation TF  Clotting Cascade Lipid core Metalloproteinases Inflammation Courtesy of David Kandzari. Plaque rupture Culprit plaque Platelet-thrombin micro-emboli Atherosclerotic Plaques - Terminology Culprit Responsible for the clinical event Vulnerable High risk to become culprit (cause clinical event) Quiescent (Stable) Primary or healed (vulnerable or culprit) Fuster, V. et al. J Am Coll Cardiol 2005;46:937-954 Coronary Artery Disease: Diffuse disease with a variable mix of stable, vulnerable and culprit plaques Culprit and healed plaques in a coronary bifurcation N Engl J Med 2000;343:915-22 Angiograms of 253 patients with acute MI Complex Plaques: Single: 153 - 60.5% Multiple: 100 – 39.5% Clinical Outcome at 1 Year – Single vs. Multiple Complex Plaques Similar results when analysis was restricted to patients with multivessel coronary disease: 74.5% of single 91.0% of multiple Characteristics of Carotid Plaques: Patients with Unstable versus Stable Angina Multivariate analysis: UA and CRP >3 mg/l were independently and strongly associated with complex carotid plaques Vulnerable Patient – at high risk for vascular event coronary elsewhere Who is the vulnerable patient? Patient with current multiple complex plaques Coronary, carotid etc Patient with multiple uncontrolled risk factors At risk to develop new complex plaques Vulnerability cutoff value ? Who is ”High Risk” Patients in whom long term clopidogrel should be considered The vulnerable patient TIMI risk score Aspirin Failure Others TIMI Risk Score and Outcome Budaj et al. circulation 2002 Excess major bleeding risk with clopidogrel is independent of the TIMI risk – it is 1% TIMI Risk Score and Absolute Reduction of death/MI/Stroke with Clopidogrel TIMI Risk Score N= 752 2524 3730 3567 1593 396 Percent reduction Major bleeding – 1% Majority of patients Who is ”High Risk” Patients in whom long term clopidogrel should be considered The vulnerable patient TIMI risk score Aspirin Failure Others Aspirin Failure – Patient with acute vascular event (coronary, cerebral) while being treated with aspirin Aspirin was not enough to prevent the event Aspirin is ineffective as an antiplatelet agent – resistance? Aspirin is effective as an antiplatelet agent but the disease risk is high and there is a need for more aggressive antiplatelet therapy Aspirin Resistance Cellular Factors Insufficient suppression of COX-1 Overexpression of COX-2 mRNA Erythrocyte-induced platelet activation Increased norepinephrine Generation of 8-iso-PGF2 Adapted with permission from Bhatt DL. J Am Coll Cardiol. 2004;43:1127-1129. Aspirin Resistance Genetic Polymorphisms COX-1 GP IIIa receptor Collagen receptor vWF receptor Clinical Factors Failure to prescribe Noncompliance Nonabsorption Interaction with ibuprofen Can be intermittent Unfortunately (surprisingly) there is no subgroup analysis of CAPRIE or CURE for patients who were on prior aspirin However There are other subgroup analyses
Slide 74 - Early And Long Term Treatment With Clopidogrel In Coronary Artery Disease פרופ’ יוסף רוזנמן מכון הלב, בי"ח וולפסון דצמבר 2005 Acute Coronary Syndromes Acute Coronary Syndrome No ST Elevation ST Elevation Unstable Angina Myocardial Infarction Non Q MI Q wave MI Non ST Elevation MI Braunwald E et al. J Am Coll Cardiol 2000;36:970–1062. Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When angiography / PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until angiography / PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month improving long-term outcome 1 2 Goals of therapy Prevent ischemic events until coronary angiography / PCI Before plaque stabilization was achieved Prevent PCI / stent related ischemic complications Clopidogrel before coronary angiography - Patients with ACS 1 Clopidogrel before coronary angiography - Patients with ACS ST Elevation CLARITY Non ST Elevation CURE 1 ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Study Design Fibrinolytic, ASA, Heparin Clopidogrel 300 mg + 75 mg qd Coronary Angiogram (2-8 days) Primary endpoint: Occluded artery (TIMI Flow Grade 0/1) or D/MI by time of angio randomize Placebo Double-blind, randomized, placebo-controlled trial in 3491 patients, age 18-75 yrs with STEMI < 12 hours Study Drug 30-day clinical follow-up Open-label clopidogrel per MD in both groups Primary Endpoint: Occluded Artery (or D/MI by time of angio) Placebo Clopidogrel P=0.00000036 Odds Ratio 0.64 (95% CI 0.53-0.76) 1.0 0.4 0.6 0.8 1.2 1.6 Clopidogrel better Placebo better n=1752 n=1739 36% Odds Reduction Primary & Angiographic Outcomes (median 3.5 days) Need for Urgent or Additional Treatment 21%  P=0.01 21%  P=0.005 16%  P=0.07 Early Angio (w/in 48 hrs) Urgent Revasc (index hosp) GP IIb/IIIa if PCI CV Death, MI, RI  Urg Revasc days Percentage with endpoint (%) 0 5 10 15 0 5 10 15 20 25 30 Placebo Clopidogrel Odds Ratio 0.80 (95% CI 0.65-0.97) P=0.026 20% 1 CLARITY: Patient Management Clopidogrel Placebo Parameter (n=1,752) (n=1,739) Symptom onset to fibrinolytic (hours) 2.7 2.6 Fibrinolytic to study drug (minutes) 10 10 Median doses of study medication 4 4 Angiography performed (%) 94 94 Study drug to angiography (hours) 84 84 Coronary revascularization (%): 63 63 PCI 57.2 56.6 CABG 5.9 6.0 Sabatine M et al. New Engl J Med 2005; 352: 1179–1189. PCI-CLARITY: Reduction in CV Death, MI, Stroke from PCI to 30 Days Days Post PCI Percentage with Outcome (%) 0 2 0 5 10 15 20 25 30 46%* p=0.008 Clopidogrel Pretreatment (3.6%) No Pretreatment (6.2%) 4 6 8 M Sabatine, et al. JAMA 2005 PCI-CLARITY: MI, Stroke, or CV Death Events pre and post PCI ***MI or Stroke M Sabatine, et al. JAMA 2005, Prehospital Fibrinolysis with Double Antiplatelet Therapy in Acute ST-Elevation Myocardial Infarction: The Clarity Ambulance Substudy Substudy Sites and Patient Numbers France: 172 patients L Soulat: 57 Y Lambert: 48 F Lapostolle: 28 F Thieuleux: 21 C Gully: 10 D Pollet: 5 D Galley: 2 L Olliver: 1 UK: 40 patients J Adgey: 27 J Purvis: 13 Sweden: 5 patients J-E Karlsson: 5 217 patients in total Angiographic & ECG Parameters: Ambulance vs. Non-Ambulance *Complete considered to be >70%; ECG=electrocardiogram p value Event rate (%) Ambulance Non- ambulance Non-ambulance better Ambulance better Odds ratio (95% CI) 0 0.5 1.0 1.5 2.0 Ambulance Non-ambulance Overall Clopidogrel better Placebo better Odds ratio (95% CI) Primary Endpoint of TIMI Flow Grade 0/1, MI or Death 0.60 (0.301.17) 0.64 (0.530.76) 0.65 (0.540.77) ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Clopidogrel 75mg q.d. + ASA 75-325 mg q.d.* (6259 patients) Placebo + ASA 75-325 mg q.d.* (6303 patients) Day 1 6 m. Visit 9 m. Visit 12 m. or Final Visit 3 m. Visit Discharge Visit 1 m. Visit Patients with Acute Coronary Syndrome (unstable angina or non-ST-segment elevation MI) R Placebo loading dose R = Randomization * In combination with other standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Study Design 3 months £ double-blind treatment £ 12 months Clopidogrel 300 mg loading dose CURE Clopidogrel + ASA* 3 6 9 Placebo + ASA* Months of Follow-Up 11.4% 9.3% 20% RRR P < 0.001 N = 12,562 0 12 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Primary End Point - MI/Stroke/CV Death CURE Clopidogrel + ASA* 10 20 30 Placebo + ASA* Days of Follow-Up 0 21% RRR P = 0.003 N = 12,562 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. MI/Stroke/CV Death within 30 Days CURE 1 CV death, nonfatal MI, stroke or refractory or severe ischemia 34% NEJM 2001; 345:495-502 MI/Stroke/CV Death or severe Ischemia at 24 hours CURE 1 % patients requiring thrombolytic therapy 43% % patients requiring GP IIb/IIIa inhibitors 18% NEJM 2001; 345:495-502 Need for Additional Anti-Thrombotic After Randomization P< 0.001 P= 0.003 Thrombolysis GP IIb/IIIa Inhibitor CURE 1 Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? GP IIb/IIIa receptor is the final common pathway in platelet aggregation. GP IIb/IIIa blockade is the most effective antiplatelet aggregation therapy. Bleeding risk is not increased if therapy is stopped 2-4 hours prior to CABG. Bleeding risk is markedly increased unless clopidogrel is stopped 3-5 days prior to CABG. Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? Is there additional benefit to clopidogrel that would justify: Increased CABG bleeding or alternatively Need to postpone CABG for 3-5 days No data in the literature however Adhesion The Role of Platelets in Atherothrombosis Aggregation 3 Reproduced with permission from Cannon CP. Atherothrombosis slide compendium. Available at: www.theheart.org. 1 Activation 2 Conclusions: Early Clopidogrel Therapy Treatment with clopidogrel is indicated as soon as possible in patients with acute coronary syndrome ST elevation and non ST elevation Treatment is effective to reduce ischemic complications Before coronay angiography During and after PCI 1 Conclusions: Early Clopidogrel Therapy Loading dose should be 600mg to achieve early optimal antiplatelet effect ?? 300mg in patients after fibrinolytic therapy It is unclear whether therapy should be added to “upstream” GP IIb/IIIa antagonists Especially in high risk patients in whom the likelihood for CABG is high 1 Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month after PCI / stent improving long-term outcome 1 2 Discharge/Post-Discharge Medications - Guidelines ASA, if not contraindicated Clopidogrel, when ASA contraindicated Aspirin + Clopidogrel for up to 9 months -blocker, if not contraindicated Lipid  agents + diet, if LDL >130 mg/dL ACE Inhibitor: CHF, EF < 40%, DM, or HTN I IIa IIb III 2 Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization PCI PLACEBO + ASA * CLOPIDOGREL + ASA * 30 days post PCI End of follow-up Up to 12 months after randomization Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 2,658 patients undergoing PCI N = 1345 N = 1313 PCI-CURE Overall Study Design: PCI-CURE R Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE Question 1 Question 2 Clopidogrel Arm Placebo Arm PCI* 28 Days Placebo + ASA† (325 mg) Randomization - Pre-treatment Clopidogrel 300 mg + ASA† (325 mg) Clopidogrel 75 mg QD + ASA† 325 mg QD Clopidogrel 75 mg QD + ASA† 325 mg QD R 12 Months Steinhubl S, Berger P, Tift Mann III J et al. JAMA. 2002;Vol 288,No 19:2411-2420. Placebo QD + ASA† (81-325 mg) QD Clopidogrel 75 mg QD + ASA† (81-325 mg) QD Overall Study Design: CREDO Question 1 Question 2 1 2 Open label clopidogrel continuation Methodological Pitfall Can a study with a single randomization provide an answer to two questions? Alternatively Should a second randomization be done in order to answer the second question? PCI PLACEBO + ASA * CLOPIDOGREL + ASA * 30 days post PCI End of follow-up Up to 12 months after randomization Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 1345 N = 1313 PCI-CURE Study Design single randomization R Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE Continuation Continuation PCI PLACEBO + ASA * CLOPIDOGREL + ASA * Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 1345 N = 1313 PCI-CURE Alternative Study Design two randomizations R1 Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE R2 R2 Clop. Placebo Continuation Continuation Question 2 2 Is it just methodology? Can we really expect long term benefit from early antiplatelet therapy? Adjunct antiplatelet therapy for PCI EPISTENT Randomized study designed to determine the effect of treatment with abciximab TARGET Randomized study designed to show that tirofiban is not inferior to abciximab Post-hoc nonrandomized comparison among those who were or were not pre-treated with clopidogrel PCI-CURE Subgroup of CURE patients who underwent PCI Randomized comparison of pre-treatment and continued clopidogrel therapy vs. placebo Absolute reduction of Death or MI at 1 month and 1 year Abciximab Early clopidogrel Early and continued clopidogrel % reduction * * 6 month data in TARGET Early and long term reduction of death or MI from antiplatelet therapy in patients with ACS Long Term Clopidogrel Post PCI Clinical guidelines: 9 months to 1 year in patients with ACS However, current data does not fully support this recommendation What should we do? 2 Comulative event rate in primary prevention stable CAD and ACS ACS Stable Primary Risk of vascular event after ACS Risk of event Time after ACS Stable CAD Commulative risk Risk per time Risk of vascular event after ACS high and low risk Risk of event Time after ACS High risk Low risk Risk of bleeding after initiation of clopidogrel (high and low risk) Risk of event Time after clopidogrel High risk Low risk Fixed, except for the initial few days heparin, catheterization Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? vascular bleeding Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? vascular bleeding > 1 year High vascular risk Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? vascular bleeding < 1 months High bleeding risk e.g. coumadin Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? Long term clopidogrel for patients with High risk for vascular event Low bleeding risk Short term clopidogrel for patients with Low risk for vascular event High bleeding risk vascular bleeding Who is ”High Risk” Patients in whom long term clopidogrel should be considered The vulnerable patient TIMI risk score Aspirin Failure Others Who is ”High Risk” Patients in whom long term clopidogrel should be considered The vulnerable patient TIMI risk score Aspirin Failure Others ACS Pathophysiology Inflammation, Plaque Rupture, Thrombosis, and Microembolization Quiescent plaque Plaque formation Lipids, other risk factors Inflammation LDL, others, Infection? Plaque rupture (erosion) ? Macrophages, metalloproteinases Thrombosis Platelet Activation, Thrombin Vulnerable plaque Macrophages Foam Cells Collagen  platelet activation TF  Clotting Cascade Lipid core Metalloproteinases Inflammation Courtesy of David Kandzari. Plaque rupture Culprit plaque Platelet-thrombin micro-emboli Atherosclerotic Plaques - Terminology Culprit Responsible for the clinical event Vulnerable High risk to become culprit (cause clinical event) Quiescent (Stable) Primary or healed (vulnerable or culprit) Fuster, V. et al. J Am Coll Cardiol 2005;46:937-954 Coronary Artery Disease: Diffuse disease with a variable mix of stable, vulnerable and culprit plaques Culprit and healed plaques in a coronary bifurcation N Engl J Med 2000;343:915-22 Angiograms of 253 patients with acute MI Complex Plaques: Single: 153 - 60.5% Multiple: 100 – 39.5% Clinical Outcome at 1 Year – Single vs. Multiple Complex Plaques Similar results when analysis was restricted to patients with multivessel coronary disease: 74.5% of single 91.0% of multiple Characteristics of Carotid Plaques: Patients with Unstable versus Stable Angina Multivariate analysis: UA and CRP >3 mg/l were independently and strongly associated with complex carotid plaques Vulnerable Patient – at high risk for vascular event coronary elsewhere Who is the vulnerable patient? Patient with current multiple complex plaques Coronary, carotid etc Patient with multiple uncontrolled risk factors At risk to develop new complex plaques Vulnerability cutoff value ? Who is ”High Risk” Patients in whom long term clopidogrel should be considered The vulnerable patient TIMI risk score Aspirin Failure Others TIMI Risk Score and Outcome Budaj et al. circulation 2002 Excess major bleeding risk with clopidogrel is independent of the TIMI risk – it is 1% TIMI Risk Score and Absolute Reduction of death/MI/Stroke with Clopidogrel TIMI Risk Score N= 752 2524 3730 3567 1593 396 Percent reduction Major bleeding – 1% Majority of patients Who is ”High Risk” Patients in whom long term clopidogrel should be considered The vulnerable patient TIMI risk score Aspirin Failure Others Aspirin Failure – Patient with acute vascular event (coronary, cerebral) while being treated with aspirin Aspirin was not enough to prevent the event Aspirin is ineffective as an antiplatelet agent – resistance? Aspirin is effective as an antiplatelet agent but the disease risk is high and there is a need for more aggressive antiplatelet therapy Aspirin Resistance Cellular Factors Insufficient suppression of COX-1 Overexpression of COX-2 mRNA Erythrocyte-induced platelet activation Increased norepinephrine Generation of 8-iso-PGF2 Adapted with permission from Bhatt DL. J Am Coll Cardiol. 2004;43:1127-1129. Aspirin Resistance Genetic Polymorphisms COX-1 GP IIIa receptor Collagen receptor vWF receptor Clinical Factors Failure to prescribe Noncompliance Nonabsorption Interaction with ibuprofen Can be intermittent Unfortunately (surprisingly) there is no subgroup analysis of CAPRIE or CURE for patients who were on prior aspirin However There are other subgroup analyses Clopidogrel in patients with prior CABG CAPRIE substudy (N=1480) Vascular death Combined endpoint: Vascular death, MI, stroke or hospitalization for ischemia or bleeding Circulation 2001; 103: 363-368
Slide 75 - Early And Long Term Treatment With Clopidogrel In Coronary Artery Disease פרופ’ יוסף רוזנמן מכון הלב, בי"ח וולפסון דצמבר 2005 Acute Coronary Syndromes Acute Coronary Syndrome No ST Elevation ST Elevation Unstable Angina Myocardial Infarction Non Q MI Q wave MI Non ST Elevation MI Braunwald E et al. J Am Coll Cardiol 2000;36:970–1062. Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When angiography / PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until angiography / PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month improving long-term outcome 1 2 Goals of therapy Prevent ischemic events until coronary angiography / PCI Before plaque stabilization was achieved Prevent PCI / stent related ischemic complications Clopidogrel before coronary angiography - Patients with ACS 1 Clopidogrel before coronary angiography - Patients with ACS ST Elevation CLARITY Non ST Elevation CURE 1 ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Study Design Fibrinolytic, ASA, Heparin Clopidogrel 300 mg + 75 mg qd Coronary Angiogram (2-8 days) Primary endpoint: Occluded artery (TIMI Flow Grade 0/1) or D/MI by time of angio randomize Placebo Double-blind, randomized, placebo-controlled trial in 3491 patients, age 18-75 yrs with STEMI < 12 hours Study Drug 30-day clinical follow-up Open-label clopidogrel per MD in both groups Primary Endpoint: Occluded Artery (or D/MI by time of angio) Placebo Clopidogrel P=0.00000036 Odds Ratio 0.64 (95% CI 0.53-0.76) 1.0 0.4 0.6 0.8 1.2 1.6 Clopidogrel better Placebo better n=1752 n=1739 36% Odds Reduction Primary & Angiographic Outcomes (median 3.5 days) Need for Urgent or Additional Treatment 21%  P=0.01 21%  P=0.005 16%  P=0.07 Early Angio (w/in 48 hrs) Urgent Revasc (index hosp) GP IIb/IIIa if PCI CV Death, MI, RI  Urg Revasc days Percentage with endpoint (%) 0 5 10 15 0 5 10 15 20 25 30 Placebo Clopidogrel Odds Ratio 0.80 (95% CI 0.65-0.97) P=0.026 20% 1 CLARITY: Patient Management Clopidogrel Placebo Parameter (n=1,752) (n=1,739) Symptom onset to fibrinolytic (hours) 2.7 2.6 Fibrinolytic to study drug (minutes) 10 10 Median doses of study medication 4 4 Angiography performed (%) 94 94 Study drug to angiography (hours) 84 84 Coronary revascularization (%): 63 63 PCI 57.2 56.6 CABG 5.9 6.0 Sabatine M et al. New Engl J Med 2005; 352: 1179–1189. PCI-CLARITY: Reduction in CV Death, MI, Stroke from PCI to 30 Days Days Post PCI Percentage with Outcome (%) 0 2 0 5 10 15 20 25 30 46%* p=0.008 Clopidogrel Pretreatment (3.6%) No Pretreatment (6.2%) 4 6 8 M Sabatine, et al. JAMA 2005 PCI-CLARITY: MI, Stroke, or CV Death Events pre and post PCI ***MI or Stroke M Sabatine, et al. JAMA 2005, Prehospital Fibrinolysis with Double Antiplatelet Therapy in Acute ST-Elevation Myocardial Infarction: The Clarity Ambulance Substudy Substudy Sites and Patient Numbers France: 172 patients L Soulat: 57 Y Lambert: 48 F Lapostolle: 28 F Thieuleux: 21 C Gully: 10 D Pollet: 5 D Galley: 2 L Olliver: 1 UK: 40 patients J Adgey: 27 J Purvis: 13 Sweden: 5 patients J-E Karlsson: 5 217 patients in total Angiographic & ECG Parameters: Ambulance vs. Non-Ambulance *Complete considered to be >70%; ECG=electrocardiogram p value Event rate (%) Ambulance Non- ambulance Non-ambulance better Ambulance better Odds ratio (95% CI) 0 0.5 1.0 1.5 2.0 Ambulance Non-ambulance Overall Clopidogrel better Placebo better Odds ratio (95% CI) Primary Endpoint of TIMI Flow Grade 0/1, MI or Death 0.60 (0.301.17) 0.64 (0.530.76) 0.65 (0.540.77) ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Clopidogrel 75mg q.d. + ASA 75-325 mg q.d.* (6259 patients) Placebo + ASA 75-325 mg q.d.* (6303 patients) Day 1 6 m. Visit 9 m. Visit 12 m. or Final Visit 3 m. Visit Discharge Visit 1 m. Visit Patients with Acute Coronary Syndrome (unstable angina or non-ST-segment elevation MI) R Placebo loading dose R = Randomization * In combination with other standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Study Design 3 months £ double-blind treatment £ 12 months Clopidogrel 300 mg loading dose CURE Clopidogrel + ASA* 3 6 9 Placebo + ASA* Months of Follow-Up 11.4% 9.3% 20% RRR P < 0.001 N = 12,562 0 12 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Primary End Point - MI/Stroke/CV Death CURE Clopidogrel + ASA* 10 20 30 Placebo + ASA* Days of Follow-Up 0 21% RRR P = 0.003 N = 12,562 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. MI/Stroke/CV Death within 30 Days CURE 1 CV death, nonfatal MI, stroke or refractory or severe ischemia 34% NEJM 2001; 345:495-502 MI/Stroke/CV Death or severe Ischemia at 24 hours CURE 1 % patients requiring thrombolytic therapy 43% % patients requiring GP IIb/IIIa inhibitors 18% NEJM 2001; 345:495-502 Need for Additional Anti-Thrombotic After Randomization P< 0.001 P= 0.003 Thrombolysis GP IIb/IIIa Inhibitor CURE 1 Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? GP IIb/IIIa receptor is the final common pathway in platelet aggregation. GP IIb/IIIa blockade is the most effective antiplatelet aggregation therapy. Bleeding risk is not increased if therapy is stopped 2-4 hours prior to CABG. Bleeding risk is markedly increased unless clopidogrel is stopped 3-5 days prior to CABG. Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? Is there additional benefit to clopidogrel that would justify: Increased CABG bleeding or alternatively Need to postpone CABG for 3-5 days No data in the literature however Adhesion The Role of Platelets in Atherothrombosis Aggregation 3 Reproduced with permission from Cannon CP. Atherothrombosis slide compendium. Available at: www.theheart.org. 1 Activation 2 Conclusions: Early Clopidogrel Therapy Treatment with clopidogrel is indicated as soon as possible in patients with acute coronary syndrome ST elevation and non ST elevation Treatment is effective to reduce ischemic complications Before coronay angiography During and after PCI 1 Conclusions: Early Clopidogrel Therapy Loading dose should be 600mg to achieve early optimal antiplatelet effect ?? 300mg in patients after fibrinolytic therapy It is unclear whether therapy should be added to “upstream” GP IIb/IIIa antagonists Especially in high risk patients in whom the likelihood for CABG is high 1 Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month after PCI / stent improving long-term outcome 1 2 Discharge/Post-Discharge Medications - Guidelines ASA, if not contraindicated Clopidogrel, when ASA contraindicated Aspirin + Clopidogrel for up to 9 months -blocker, if not contraindicated Lipid  agents + diet, if LDL >130 mg/dL ACE Inhibitor: CHF, EF < 40%, DM, or HTN I IIa IIb III 2 Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization PCI PLACEBO + ASA * CLOPIDOGREL + ASA * 30 days post PCI End of follow-up Up to 12 months after randomization Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 2,658 patients undergoing PCI N = 1345 N = 1313 PCI-CURE Overall Study Design: PCI-CURE R Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE Question 1 Question 2 Clopidogrel Arm Placebo Arm PCI* 28 Days Placebo + ASA† (325 mg) Randomization - Pre-treatment Clopidogrel 300 mg + ASA† (325 mg) Clopidogrel 75 mg QD + ASA† 325 mg QD Clopidogrel 75 mg QD + ASA† 325 mg QD R 12 Months Steinhubl S, Berger P, Tift Mann III J et al. JAMA. 2002;Vol 288,No 19:2411-2420. Placebo QD + ASA† (81-325 mg) QD Clopidogrel 75 mg QD + ASA† (81-325 mg) QD Overall Study Design: CREDO Question 1 Question 2 1 2 Open label clopidogrel continuation Methodological Pitfall Can a study with a single randomization provide an answer to two questions? Alternatively Should a second randomization be done in order to answer the second question? PCI PLACEBO + ASA * CLOPIDOGREL + ASA * 30 days post PCI End of follow-up Up to 12 months after randomization Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 1345 N = 1313 PCI-CURE Study Design single randomization R Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE Continuation Continuation PCI PLACEBO + ASA * CLOPIDOGREL + ASA * Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 1345 N = 1313 PCI-CURE Alternative Study Design two randomizations R1 Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE R2 R2 Clop. Placebo Continuation Continuation Question 2 2 Is it just methodology? Can we really expect long term benefit from early antiplatelet therapy? Adjunct antiplatelet therapy for PCI EPISTENT Randomized study designed to determine the effect of treatment with abciximab TARGET Randomized study designed to show that tirofiban is not inferior to abciximab Post-hoc nonrandomized comparison among those who were or were not pre-treated with clopidogrel PCI-CURE Subgroup of CURE patients who underwent PCI Randomized comparison of pre-treatment and continued clopidogrel therapy vs. placebo Absolute reduction of Death or MI at 1 month and 1 year Abciximab Early clopidogrel Early and continued clopidogrel % reduction * * 6 month data in TARGET Early and long term reduction of death or MI from antiplatelet therapy in patients with ACS Long Term Clopidogrel Post PCI Clinical guidelines: 9 months to 1 year in patients with ACS However, current data does not fully support this recommendation What should we do? 2 Comulative event rate in primary prevention stable CAD and ACS ACS Stable Primary Risk of vascular event after ACS Risk of event Time after ACS Stable CAD Commulative risk Risk per time Risk of vascular event after ACS high and low risk Risk of event Time after ACS High risk Low risk Risk of bleeding after initiation of clopidogrel (high and low risk) Risk of event Time after clopidogrel High risk Low risk Fixed, except for the initial few days heparin, catheterization Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? vascular bleeding Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? vascular bleeding > 1 year High vascular risk Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? vascular bleeding < 1 months High bleeding risk e.g. coumadin Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? Long term clopidogrel for patients with High risk for vascular event Low bleeding risk Short term clopidogrel for patients with Low risk for vascular event High bleeding risk vascular bleeding Who is ”High Risk” Patients in whom long term clopidogrel should be considered The vulnerable patient TIMI risk score Aspirin Failure Others Who is ”High Risk” Patients in whom long term clopidogrel should be considered The vulnerable patient TIMI risk score Aspirin Failure Others ACS Pathophysiology Inflammation, Plaque Rupture, Thrombosis, and Microembolization Quiescent plaque Plaque formation Lipids, other risk factors Inflammation LDL, others, Infection? Plaque rupture (erosion) ? Macrophages, metalloproteinases Thrombosis Platelet Activation, Thrombin Vulnerable plaque Macrophages Foam Cells Collagen  platelet activation TF  Clotting Cascade Lipid core Metalloproteinases Inflammation Courtesy of David Kandzari. Plaque rupture Culprit plaque Platelet-thrombin micro-emboli Atherosclerotic Plaques - Terminology Culprit Responsible for the clinical event Vulnerable High risk to become culprit (cause clinical event) Quiescent (Stable) Primary or healed (vulnerable or culprit) Fuster, V. et al. J Am Coll Cardiol 2005;46:937-954 Coronary Artery Disease: Diffuse disease with a variable mix of stable, vulnerable and culprit plaques Culprit and healed plaques in a coronary bifurcation N Engl J Med 2000;343:915-22 Angiograms of 253 patients with acute MI Complex Plaques: Single: 153 - 60.5% Multiple: 100 – 39.5% Clinical Outcome at 1 Year – Single vs. Multiple Complex Plaques Similar results when analysis was restricted to patients with multivessel coronary disease: 74.5% of single 91.0% of multiple Characteristics of Carotid Plaques: Patients with Unstable versus Stable Angina Multivariate analysis: UA and CRP >3 mg/l were independently and strongly associated with complex carotid plaques Vulnerable Patient – at high risk for vascular event coronary elsewhere Who is the vulnerable patient? Patient with current multiple complex plaques Coronary, carotid etc Patient with multiple uncontrolled risk factors At risk to develop new complex plaques Vulnerability cutoff value ? Who is ”High Risk” Patients in whom long term clopidogrel should be considered The vulnerable patient TIMI risk score Aspirin Failure Others TIMI Risk Score and Outcome Budaj et al. circulation 2002 Excess major bleeding risk with clopidogrel is independent of the TIMI risk – it is 1% TIMI Risk Score and Absolute Reduction of death/MI/Stroke with Clopidogrel TIMI Risk Score N= 752 2524 3730 3567 1593 396 Percent reduction Major bleeding – 1% Majority of patients Who is ”High Risk” Patients in whom long term clopidogrel should be considered The vulnerable patient TIMI risk score Aspirin Failure Others Aspirin Failure – Patient with acute vascular event (coronary, cerebral) while being treated with aspirin Aspirin was not enough to prevent the event Aspirin is ineffective as an antiplatelet agent – resistance? Aspirin is effective as an antiplatelet agent but the disease risk is high and there is a need for more aggressive antiplatelet therapy Aspirin Resistance Cellular Factors Insufficient suppression of COX-1 Overexpression of COX-2 mRNA Erythrocyte-induced platelet activation Increased norepinephrine Generation of 8-iso-PGF2 Adapted with permission from Bhatt DL. J Am Coll Cardiol. 2004;43:1127-1129. Aspirin Resistance Genetic Polymorphisms COX-1 GP IIIa receptor Collagen receptor vWF receptor Clinical Factors Failure to prescribe Noncompliance Nonabsorption Interaction with ibuprofen Can be intermittent Unfortunately (surprisingly) there is no subgroup analysis of CAPRIE or CURE for patients who were on prior aspirin However There are other subgroup analyses Clopidogrel in patients with prior CABG CAPRIE substudy (N=1480) Vascular death Combined endpoint: Vascular death, MI, stroke or hospitalization for ischemia or bleeding Circulation 2001; 103: 363-368 Ringleb, P. A. et al. Stroke 2004;35:528-532 Clopidogrel in patients with history of prior ischemic event - CAPRIE substudy (N=4496)
Slide 76 - Early And Long Term Treatment With Clopidogrel In Coronary Artery Disease פרופ’ יוסף רוזנמן מכון הלב, בי"ח וולפסון דצמבר 2005 Acute Coronary Syndromes Acute Coronary Syndrome No ST Elevation ST Elevation Unstable Angina Myocardial Infarction Non Q MI Q wave MI Non ST Elevation MI Braunwald E et al. J Am Coll Cardiol 2000;36:970–1062. Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When angiography / PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until angiography / PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month improving long-term outcome 1 2 Goals of therapy Prevent ischemic events until coronary angiography / PCI Before plaque stabilization was achieved Prevent PCI / stent related ischemic complications Clopidogrel before coronary angiography - Patients with ACS 1 Clopidogrel before coronary angiography - Patients with ACS ST Elevation CLARITY Non ST Elevation CURE 1 ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Study Design Fibrinolytic, ASA, Heparin Clopidogrel 300 mg + 75 mg qd Coronary Angiogram (2-8 days) Primary endpoint: Occluded artery (TIMI Flow Grade 0/1) or D/MI by time of angio randomize Placebo Double-blind, randomized, placebo-controlled trial in 3491 patients, age 18-75 yrs with STEMI < 12 hours Study Drug 30-day clinical follow-up Open-label clopidogrel per MD in both groups Primary Endpoint: Occluded Artery (or D/MI by time of angio) Placebo Clopidogrel P=0.00000036 Odds Ratio 0.64 (95% CI 0.53-0.76) 1.0 0.4 0.6 0.8 1.2 1.6 Clopidogrel better Placebo better n=1752 n=1739 36% Odds Reduction Primary & Angiographic Outcomes (median 3.5 days) Need for Urgent or Additional Treatment 21%  P=0.01 21%  P=0.005 16%  P=0.07 Early Angio (w/in 48 hrs) Urgent Revasc (index hosp) GP IIb/IIIa if PCI CV Death, MI, RI  Urg Revasc days Percentage with endpoint (%) 0 5 10 15 0 5 10 15 20 25 30 Placebo Clopidogrel Odds Ratio 0.80 (95% CI 0.65-0.97) P=0.026 20% 1 CLARITY: Patient Management Clopidogrel Placebo Parameter (n=1,752) (n=1,739) Symptom onset to fibrinolytic (hours) 2.7 2.6 Fibrinolytic to study drug (minutes) 10 10 Median doses of study medication 4 4 Angiography performed (%) 94 94 Study drug to angiography (hours) 84 84 Coronary revascularization (%): 63 63 PCI 57.2 56.6 CABG 5.9 6.0 Sabatine M et al. New Engl J Med 2005; 352: 1179–1189. PCI-CLARITY: Reduction in CV Death, MI, Stroke from PCI to 30 Days Days Post PCI Percentage with Outcome (%) 0 2 0 5 10 15 20 25 30 46%* p=0.008 Clopidogrel Pretreatment (3.6%) No Pretreatment (6.2%) 4 6 8 M Sabatine, et al. JAMA 2005 PCI-CLARITY: MI, Stroke, or CV Death Events pre and post PCI ***MI or Stroke M Sabatine, et al. JAMA 2005, Prehospital Fibrinolysis with Double Antiplatelet Therapy in Acute ST-Elevation Myocardial Infarction: The Clarity Ambulance Substudy Substudy Sites and Patient Numbers France: 172 patients L Soulat: 57 Y Lambert: 48 F Lapostolle: 28 F Thieuleux: 21 C Gully: 10 D Pollet: 5 D Galley: 2 L Olliver: 1 UK: 40 patients J Adgey: 27 J Purvis: 13 Sweden: 5 patients J-E Karlsson: 5 217 patients in total Angiographic & ECG Parameters: Ambulance vs. Non-Ambulance *Complete considered to be >70%; ECG=electrocardiogram p value Event rate (%) Ambulance Non- ambulance Non-ambulance better Ambulance better Odds ratio (95% CI) 0 0.5 1.0 1.5 2.0 Ambulance Non-ambulance Overall Clopidogrel better Placebo better Odds ratio (95% CI) Primary Endpoint of TIMI Flow Grade 0/1, MI or Death 0.60 (0.301.17) 0.64 (0.530.76) 0.65 (0.540.77) ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Clopidogrel 75mg q.d. + ASA 75-325 mg q.d.* (6259 patients) Placebo + ASA 75-325 mg q.d.* (6303 patients) Day 1 6 m. Visit 9 m. Visit 12 m. or Final Visit 3 m. Visit Discharge Visit 1 m. Visit Patients with Acute Coronary Syndrome (unstable angina or non-ST-segment elevation MI) R Placebo loading dose R = Randomization * In combination with other standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Study Design 3 months £ double-blind treatment £ 12 months Clopidogrel 300 mg loading dose CURE Clopidogrel + ASA* 3 6 9 Placebo + ASA* Months of Follow-Up 11.4% 9.3% 20% RRR P < 0.001 N = 12,562 0 12 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Primary End Point - MI/Stroke/CV Death CURE Clopidogrel + ASA* 10 20 30 Placebo + ASA* Days of Follow-Up 0 21% RRR P = 0.003 N = 12,562 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. MI/Stroke/CV Death within 30 Days CURE 1 CV death, nonfatal MI, stroke or refractory or severe ischemia 34% NEJM 2001; 345:495-502 MI/Stroke/CV Death or severe Ischemia at 24 hours CURE 1 % patients requiring thrombolytic therapy 43% % patients requiring GP IIb/IIIa inhibitors 18% NEJM 2001; 345:495-502 Need for Additional Anti-Thrombotic After Randomization P< 0.001 P= 0.003 Thrombolysis GP IIb/IIIa Inhibitor CURE 1 Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? GP IIb/IIIa receptor is the final common pathway in platelet aggregation. GP IIb/IIIa blockade is the most effective antiplatelet aggregation therapy. Bleeding risk is not increased if therapy is stopped 2-4 hours prior to CABG. Bleeding risk is markedly increased unless clopidogrel is stopped 3-5 days prior to CABG. Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? Is there additional benefit to clopidogrel that would justify: Increased CABG bleeding or alternatively Need to postpone CABG for 3-5 days No data in the literature however Adhesion The Role of Platelets in Atherothrombosis Aggregation 3 Reproduced with permission from Cannon CP. Atherothrombosis slide compendium. Available at: www.theheart.org. 1 Activation 2 Conclusions: Early Clopidogrel Therapy Treatment with clopidogrel is indicated as soon as possible in patients with acute coronary syndrome ST elevation and non ST elevation Treatment is effective to reduce ischemic complications Before coronay angiography During and after PCI 1 Conclusions: Early Clopidogrel Therapy Loading dose should be 600mg to achieve early optimal antiplatelet effect ?? 300mg in patients after fibrinolytic therapy It is unclear whether therapy should be added to “upstream” GP IIb/IIIa antagonists Especially in high risk patients in whom the likelihood for CABG is high 1 Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month after PCI / stent improving long-term outcome 1 2 Discharge/Post-Discharge Medications - Guidelines ASA, if not contraindicated Clopidogrel, when ASA contraindicated Aspirin + Clopidogrel for up to 9 months -blocker, if not contraindicated Lipid  agents + diet, if LDL >130 mg/dL ACE Inhibitor: CHF, EF < 40%, DM, or HTN I IIa IIb III 2 Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization PCI PLACEBO + ASA * CLOPIDOGREL + ASA * 30 days post PCI End of follow-up Up to 12 months after randomization Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 2,658 patients undergoing PCI N = 1345 N = 1313 PCI-CURE Overall Study Design: PCI-CURE R Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE Question 1 Question 2 Clopidogrel Arm Placebo Arm PCI* 28 Days Placebo + ASA† (325 mg) Randomization - Pre-treatment Clopidogrel 300 mg + ASA† (325 mg) Clopidogrel 75 mg QD + ASA† 325 mg QD Clopidogrel 75 mg QD + ASA† 325 mg QD R 12 Months Steinhubl S, Berger P, Tift Mann III J et al. JAMA. 2002;Vol 288,No 19:2411-2420. Placebo QD + ASA† (81-325 mg) QD Clopidogrel 75 mg QD + ASA† (81-325 mg) QD Overall Study Design: CREDO Question 1 Question 2 1 2 Open label clopidogrel continuation Methodological Pitfall Can a study with a single randomization provide an answer to two questions? Alternatively Should a second randomization be done in order to answer the second question? PCI PLACEBO + ASA * CLOPIDOGREL + ASA * 30 days post PCI End of follow-up Up to 12 months after randomization Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 1345 N = 1313 PCI-CURE Study Design single randomization R Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE Continuation Continuation PCI PLACEBO + ASA * CLOPIDOGREL + ASA * Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 1345 N = 1313 PCI-CURE Alternative Study Design two randomizations R1 Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE R2 R2 Clop. Placebo Continuation Continuation Question 2 2 Is it just methodology? Can we really expect long term benefit from early antiplatelet therapy? Adjunct antiplatelet therapy for PCI EPISTENT Randomized study designed to determine the effect of treatment with abciximab TARGET Randomized study designed to show that tirofiban is not inferior to abciximab Post-hoc nonrandomized comparison among those who were or were not pre-treated with clopidogrel PCI-CURE Subgroup of CURE patients who underwent PCI Randomized comparison of pre-treatment and continued clopidogrel therapy vs. placebo Absolute reduction of Death or MI at 1 month and 1 year Abciximab Early clopidogrel Early and continued clopidogrel % reduction * * 6 month data in TARGET Early and long term reduction of death or MI from antiplatelet therapy in patients with ACS Long Term Clopidogrel Post PCI Clinical guidelines: 9 months to 1 year in patients with ACS However, current data does not fully support this recommendation What should we do? 2 Comulative event rate in primary prevention stable CAD and ACS ACS Stable Primary Risk of vascular event after ACS Risk of event Time after ACS Stable CAD Commulative risk Risk per time Risk of vascular event after ACS high and low risk Risk of event Time after ACS High risk Low risk Risk of bleeding after initiation of clopidogrel (high and low risk) Risk of event Time after clopidogrel High risk Low risk Fixed, except for the initial few days heparin, catheterization Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? vascular bleeding Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? vascular bleeding > 1 year High vascular risk Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? vascular bleeding < 1 months High bleeding risk e.g. coumadin Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? Long term clopidogrel for patients with High risk for vascular event Low bleeding risk Short term clopidogrel for patients with Low risk for vascular event High bleeding risk vascular bleeding Who is ”High Risk” Patients in whom long term clopidogrel should be considered The vulnerable patient TIMI risk score Aspirin Failure Others Who is ”High Risk” Patients in whom long term clopidogrel should be considered The vulnerable patient TIMI risk score Aspirin Failure Others ACS Pathophysiology Inflammation, Plaque Rupture, Thrombosis, and Microembolization Quiescent plaque Plaque formation Lipids, other risk factors Inflammation LDL, others, Infection? Plaque rupture (erosion) ? Macrophages, metalloproteinases Thrombosis Platelet Activation, Thrombin Vulnerable plaque Macrophages Foam Cells Collagen  platelet activation TF  Clotting Cascade Lipid core Metalloproteinases Inflammation Courtesy of David Kandzari. Plaque rupture Culprit plaque Platelet-thrombin micro-emboli Atherosclerotic Plaques - Terminology Culprit Responsible for the clinical event Vulnerable High risk to become culprit (cause clinical event) Quiescent (Stable) Primary or healed (vulnerable or culprit) Fuster, V. et al. J Am Coll Cardiol 2005;46:937-954 Coronary Artery Disease: Diffuse disease with a variable mix of stable, vulnerable and culprit plaques Culprit and healed plaques in a coronary bifurcation N Engl J Med 2000;343:915-22 Angiograms of 253 patients with acute MI Complex Plaques: Single: 153 - 60.5% Multiple: 100 – 39.5% Clinical Outcome at 1 Year – Single vs. Multiple Complex Plaques Similar results when analysis was restricted to patients with multivessel coronary disease: 74.5% of single 91.0% of multiple Characteristics of Carotid Plaques: Patients with Unstable versus Stable Angina Multivariate analysis: UA and CRP >3 mg/l were independently and strongly associated with complex carotid plaques Vulnerable Patient – at high risk for vascular event coronary elsewhere Who is the vulnerable patient? Patient with current multiple complex plaques Coronary, carotid etc Patient with multiple uncontrolled risk factors At risk to develop new complex plaques Vulnerability cutoff value ? Who is ”High Risk” Patients in whom long term clopidogrel should be considered The vulnerable patient TIMI risk score Aspirin Failure Others TIMI Risk Score and Outcome Budaj et al. circulation 2002 Excess major bleeding risk with clopidogrel is independent of the TIMI risk – it is 1% TIMI Risk Score and Absolute Reduction of death/MI/Stroke with Clopidogrel TIMI Risk Score N= 752 2524 3730 3567 1593 396 Percent reduction Major bleeding – 1% Majority of patients Who is ”High Risk” Patients in whom long term clopidogrel should be considered The vulnerable patient TIMI risk score Aspirin Failure Others Aspirin Failure – Patient with acute vascular event (coronary, cerebral) while being treated with aspirin Aspirin was not enough to prevent the event Aspirin is ineffective as an antiplatelet agent – resistance? Aspirin is effective as an antiplatelet agent but the disease risk is high and there is a need for more aggressive antiplatelet therapy Aspirin Resistance Cellular Factors Insufficient suppression of COX-1 Overexpression of COX-2 mRNA Erythrocyte-induced platelet activation Increased norepinephrine Generation of 8-iso-PGF2 Adapted with permission from Bhatt DL. J Am Coll Cardiol. 2004;43:1127-1129. Aspirin Resistance Genetic Polymorphisms COX-1 GP IIIa receptor Collagen receptor vWF receptor Clinical Factors Failure to prescribe Noncompliance Nonabsorption Interaction with ibuprofen Can be intermittent Unfortunately (surprisingly) there is no subgroup analysis of CAPRIE or CURE for patients who were on prior aspirin However There are other subgroup analyses Clopidogrel in patients with prior CABG CAPRIE substudy (N=1480) Vascular death Combined endpoint: Vascular death, MI, stroke or hospitalization for ischemia or bleeding Circulation 2001; 103: 363-368 Ringleb, P. A. et al. Stroke 2004;35:528-532 Clopidogrel in patients with history of prior ischemic event - CAPRIE substudy (N=4496) Overall 12562 9.3 11.4 Associated MI 3283 11.3 13.7 No associated MI 9279 8.6 10.6 Male sex 7726 9.1 11.9 Female sex 4836 9.5 10.7 £65 yr old 6354 5.4 7.6 > 65 yr old 6208 13.3 15.3 ST-segment deviation 6275 11.5 14.3 No ST-segment deviation 6287 7.0 8.6 Enzymes elevated at entry 3176 10.7 13.0 Enzymes not elevated at entry 9386 8.8 10.9 Diabetes 2840 14.2 16.7 No diabetes 9722 7.9 9.9 Low risk 4187 5.1 6.7 Intermediate risk 4185 6.5 9.4 High risk 4184 16.3 18.0 History of revascularization 2246 8.4 14.4 No history of revascularization 10316 9.5 10.7 Revascularization after randomization 4577 11.5 13.9 No revascularization after randomization 7985 8.1 10.0 Placebo + ASA* Characteristic No. of Patients Clopidogrel + ASA* Percentage of Patients with Event Placebo Better Clopidogrel Better Relative Risk (95% CI) 1.2 1.0 0.8 0.6 0.4 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Beneficial Outcomes with Clopidogrel in Various Subgroups CURE
Slide 77 - Early And Long Term Treatment With Clopidogrel In Coronary Artery Disease פרופ’ יוסף רוזנמן מכון הלב, בי"ח וולפסון דצמבר 2005 Acute Coronary Syndromes Acute Coronary Syndrome No ST Elevation ST Elevation Unstable Angina Myocardial Infarction Non Q MI Q wave MI Non ST Elevation MI Braunwald E et al. J Am Coll Cardiol 2000;36:970–1062. Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When angiography / PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until angiography / PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month improving long-term outcome 1 2 Goals of therapy Prevent ischemic events until coronary angiography / PCI Before plaque stabilization was achieved Prevent PCI / stent related ischemic complications Clopidogrel before coronary angiography - Patients with ACS 1 Clopidogrel before coronary angiography - Patients with ACS ST Elevation CLARITY Non ST Elevation CURE 1 ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Study Design Fibrinolytic, ASA, Heparin Clopidogrel 300 mg + 75 mg qd Coronary Angiogram (2-8 days) Primary endpoint: Occluded artery (TIMI Flow Grade 0/1) or D/MI by time of angio randomize Placebo Double-blind, randomized, placebo-controlled trial in 3491 patients, age 18-75 yrs with STEMI < 12 hours Study Drug 30-day clinical follow-up Open-label clopidogrel per MD in both groups Primary Endpoint: Occluded Artery (or D/MI by time of angio) Placebo Clopidogrel P=0.00000036 Odds Ratio 0.64 (95% CI 0.53-0.76) 1.0 0.4 0.6 0.8 1.2 1.6 Clopidogrel better Placebo better n=1752 n=1739 36% Odds Reduction Primary & Angiographic Outcomes (median 3.5 days) Need for Urgent or Additional Treatment 21%  P=0.01 21%  P=0.005 16%  P=0.07 Early Angio (w/in 48 hrs) Urgent Revasc (index hosp) GP IIb/IIIa if PCI CV Death, MI, RI  Urg Revasc days Percentage with endpoint (%) 0 5 10 15 0 5 10 15 20 25 30 Placebo Clopidogrel Odds Ratio 0.80 (95% CI 0.65-0.97) P=0.026 20% 1 CLARITY: Patient Management Clopidogrel Placebo Parameter (n=1,752) (n=1,739) Symptom onset to fibrinolytic (hours) 2.7 2.6 Fibrinolytic to study drug (minutes) 10 10 Median doses of study medication 4 4 Angiography performed (%) 94 94 Study drug to angiography (hours) 84 84 Coronary revascularization (%): 63 63 PCI 57.2 56.6 CABG 5.9 6.0 Sabatine M et al. New Engl J Med 2005; 352: 1179–1189. PCI-CLARITY: Reduction in CV Death, MI, Stroke from PCI to 30 Days Days Post PCI Percentage with Outcome (%) 0 2 0 5 10 15 20 25 30 46%* p=0.008 Clopidogrel Pretreatment (3.6%) No Pretreatment (6.2%) 4 6 8 M Sabatine, et al. JAMA 2005 PCI-CLARITY: MI, Stroke, or CV Death Events pre and post PCI ***MI or Stroke M Sabatine, et al. JAMA 2005, Prehospital Fibrinolysis with Double Antiplatelet Therapy in Acute ST-Elevation Myocardial Infarction: The Clarity Ambulance Substudy Substudy Sites and Patient Numbers France: 172 patients L Soulat: 57 Y Lambert: 48 F Lapostolle: 28 F Thieuleux: 21 C Gully: 10 D Pollet: 5 D Galley: 2 L Olliver: 1 UK: 40 patients J Adgey: 27 J Purvis: 13 Sweden: 5 patients J-E Karlsson: 5 217 patients in total Angiographic & ECG Parameters: Ambulance vs. Non-Ambulance *Complete considered to be >70%; ECG=electrocardiogram p value Event rate (%) Ambulance Non- ambulance Non-ambulance better Ambulance better Odds ratio (95% CI) 0 0.5 1.0 1.5 2.0 Ambulance Non-ambulance Overall Clopidogrel better Placebo better Odds ratio (95% CI) Primary Endpoint of TIMI Flow Grade 0/1, MI or Death 0.60 (0.301.17) 0.64 (0.530.76) 0.65 (0.540.77) ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Clopidogrel 75mg q.d. + ASA 75-325 mg q.d.* (6259 patients) Placebo + ASA 75-325 mg q.d.* (6303 patients) Day 1 6 m. Visit 9 m. Visit 12 m. or Final Visit 3 m. Visit Discharge Visit 1 m. Visit Patients with Acute Coronary Syndrome (unstable angina or non-ST-segment elevation MI) R Placebo loading dose R = Randomization * In combination with other standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Study Design 3 months £ double-blind treatment £ 12 months Clopidogrel 300 mg loading dose CURE Clopidogrel + ASA* 3 6 9 Placebo + ASA* Months of Follow-Up 11.4% 9.3% 20% RRR P < 0.001 N = 12,562 0 12 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Primary End Point - MI/Stroke/CV Death CURE Clopidogrel + ASA* 10 20 30 Placebo + ASA* Days of Follow-Up 0 21% RRR P = 0.003 N = 12,562 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. MI/Stroke/CV Death within 30 Days CURE 1 CV death, nonfatal MI, stroke or refractory or severe ischemia 34% NEJM 2001; 345:495-502 MI/Stroke/CV Death or severe Ischemia at 24 hours CURE 1 % patients requiring thrombolytic therapy 43% % patients requiring GP IIb/IIIa inhibitors 18% NEJM 2001; 345:495-502 Need for Additional Anti-Thrombotic After Randomization P< 0.001 P= 0.003 Thrombolysis GP IIb/IIIa Inhibitor CURE 1 Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? GP IIb/IIIa receptor is the final common pathway in platelet aggregation. GP IIb/IIIa blockade is the most effective antiplatelet aggregation therapy. Bleeding risk is not increased if therapy is stopped 2-4 hours prior to CABG. Bleeding risk is markedly increased unless clopidogrel is stopped 3-5 days prior to CABG. Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? Is there additional benefit to clopidogrel that would justify: Increased CABG bleeding or alternatively Need to postpone CABG for 3-5 days No data in the literature however Adhesion The Role of Platelets in Atherothrombosis Aggregation 3 Reproduced with permission from Cannon CP. Atherothrombosis slide compendium. Available at: www.theheart.org. 1 Activation 2 Conclusions: Early Clopidogrel Therapy Treatment with clopidogrel is indicated as soon as possible in patients with acute coronary syndrome ST elevation and non ST elevation Treatment is effective to reduce ischemic complications Before coronay angiography During and after PCI 1 Conclusions: Early Clopidogrel Therapy Loading dose should be 600mg to achieve early optimal antiplatelet effect ?? 300mg in patients after fibrinolytic therapy It is unclear whether therapy should be added to “upstream” GP IIb/IIIa antagonists Especially in high risk patients in whom the likelihood for CABG is high 1 Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month after PCI / stent improving long-term outcome 1 2 Discharge/Post-Discharge Medications - Guidelines ASA, if not contraindicated Clopidogrel, when ASA contraindicated Aspirin + Clopidogrel for up to 9 months -blocker, if not contraindicated Lipid  agents + diet, if LDL >130 mg/dL ACE Inhibitor: CHF, EF < 40%, DM, or HTN I IIa IIb III 2 Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization PCI PLACEBO + ASA * CLOPIDOGREL + ASA * 30 days post PCI End of follow-up Up to 12 months after randomization Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 2,658 patients undergoing PCI N = 1345 N = 1313 PCI-CURE Overall Study Design: PCI-CURE R Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE Question 1 Question 2 Clopidogrel Arm Placebo Arm PCI* 28 Days Placebo + ASA† (325 mg) Randomization - Pre-treatment Clopidogrel 300 mg + ASA† (325 mg) Clopidogrel 75 mg QD + ASA† 325 mg QD Clopidogrel 75 mg QD + ASA† 325 mg QD R 12 Months Steinhubl S, Berger P, Tift Mann III J et al. JAMA. 2002;Vol 288,No 19:2411-2420. Placebo QD + ASA† (81-325 mg) QD Clopidogrel 75 mg QD + ASA† (81-325 mg) QD Overall Study Design: CREDO Question 1 Question 2 1 2 Open label clopidogrel continuation Methodological Pitfall Can a study with a single randomization provide an answer to two questions? Alternatively Should a second randomization be done in order to answer the second question? PCI PLACEBO + ASA * CLOPIDOGREL + ASA * 30 days post PCI End of follow-up Up to 12 months after randomization Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 1345 N = 1313 PCI-CURE Study Design single randomization R Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE Continuation Continuation PCI PLACEBO + ASA * CLOPIDOGREL + ASA * Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 1345 N = 1313 PCI-CURE Alternative Study Design two randomizations R1 Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE R2 R2 Clop. Placebo Continuation Continuation Question 2 2 Is it just methodology? Can we really expect long term benefit from early antiplatelet therapy? Adjunct antiplatelet therapy for PCI EPISTENT Randomized study designed to determine the effect of treatment with abciximab TARGET Randomized study designed to show that tirofiban is not inferior to abciximab Post-hoc nonrandomized comparison among those who were or were not pre-treated with clopidogrel PCI-CURE Subgroup of CURE patients who underwent PCI Randomized comparison of pre-treatment and continued clopidogrel therapy vs. placebo Absolute reduction of Death or MI at 1 month and 1 year Abciximab Early clopidogrel Early and continued clopidogrel % reduction * * 6 month data in TARGET Early and long term reduction of death or MI from antiplatelet therapy in patients with ACS Long Term Clopidogrel Post PCI Clinical guidelines: 9 months to 1 year in patients with ACS However, current data does not fully support this recommendation What should we do? 2 Comulative event rate in primary prevention stable CAD and ACS ACS Stable Primary Risk of vascular event after ACS Risk of event Time after ACS Stable CAD Commulative risk Risk per time Risk of vascular event after ACS high and low risk Risk of event Time after ACS High risk Low risk Risk of bleeding after initiation of clopidogrel (high and low risk) Risk of event Time after clopidogrel High risk Low risk Fixed, except for the initial few days heparin, catheterization Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? vascular bleeding Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? vascular bleeding > 1 year High vascular risk Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? vascular bleeding < 1 months High bleeding risk e.g. coumadin Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? Long term clopidogrel for patients with High risk for vascular event Low bleeding risk Short term clopidogrel for patients with Low risk for vascular event High bleeding risk vascular bleeding Who is ”High Risk” Patients in whom long term clopidogrel should be considered The vulnerable patient TIMI risk score Aspirin Failure Others Who is ”High Risk” Patients in whom long term clopidogrel should be considered The vulnerable patient TIMI risk score Aspirin Failure Others ACS Pathophysiology Inflammation, Plaque Rupture, Thrombosis, and Microembolization Quiescent plaque Plaque formation Lipids, other risk factors Inflammation LDL, others, Infection? Plaque rupture (erosion) ? Macrophages, metalloproteinases Thrombosis Platelet Activation, Thrombin Vulnerable plaque Macrophages Foam Cells Collagen  platelet activation TF  Clotting Cascade Lipid core Metalloproteinases Inflammation Courtesy of David Kandzari. Plaque rupture Culprit plaque Platelet-thrombin micro-emboli Atherosclerotic Plaques - Terminology Culprit Responsible for the clinical event Vulnerable High risk to become culprit (cause clinical event) Quiescent (Stable) Primary or healed (vulnerable or culprit) Fuster, V. et al. J Am Coll Cardiol 2005;46:937-954 Coronary Artery Disease: Diffuse disease with a variable mix of stable, vulnerable and culprit plaques Culprit and healed plaques in a coronary bifurcation N Engl J Med 2000;343:915-22 Angiograms of 253 patients with acute MI Complex Plaques: Single: 153 - 60.5% Multiple: 100 – 39.5% Clinical Outcome at 1 Year – Single vs. Multiple Complex Plaques Similar results when analysis was restricted to patients with multivessel coronary disease: 74.5% of single 91.0% of multiple Characteristics of Carotid Plaques: Patients with Unstable versus Stable Angina Multivariate analysis: UA and CRP >3 mg/l were independently and strongly associated with complex carotid plaques Vulnerable Patient – at high risk for vascular event coronary elsewhere Who is the vulnerable patient? Patient with current multiple complex plaques Coronary, carotid etc Patient with multiple uncontrolled risk factors At risk to develop new complex plaques Vulnerability cutoff value ? Who is ”High Risk” Patients in whom long term clopidogrel should be considered The vulnerable patient TIMI risk score Aspirin Failure Others TIMI Risk Score and Outcome Budaj et al. circulation 2002 Excess major bleeding risk with clopidogrel is independent of the TIMI risk – it is 1% TIMI Risk Score and Absolute Reduction of death/MI/Stroke with Clopidogrel TIMI Risk Score N= 752 2524 3730 3567 1593 396 Percent reduction Major bleeding – 1% Majority of patients Who is ”High Risk” Patients in whom long term clopidogrel should be considered The vulnerable patient TIMI risk score Aspirin Failure Others Aspirin Failure – Patient with acute vascular event (coronary, cerebral) while being treated with aspirin Aspirin was not enough to prevent the event Aspirin is ineffective as an antiplatelet agent – resistance? Aspirin is effective as an antiplatelet agent but the disease risk is high and there is a need for more aggressive antiplatelet therapy Aspirin Resistance Cellular Factors Insufficient suppression of COX-1 Overexpression of COX-2 mRNA Erythrocyte-induced platelet activation Increased norepinephrine Generation of 8-iso-PGF2 Adapted with permission from Bhatt DL. J Am Coll Cardiol. 2004;43:1127-1129. Aspirin Resistance Genetic Polymorphisms COX-1 GP IIIa receptor Collagen receptor vWF receptor Clinical Factors Failure to prescribe Noncompliance Nonabsorption Interaction with ibuprofen Can be intermittent Unfortunately (surprisingly) there is no subgroup analysis of CAPRIE or CURE for patients who were on prior aspirin However There are other subgroup analyses Clopidogrel in patients with prior CABG CAPRIE substudy (N=1480) Vascular death Combined endpoint: Vascular death, MI, stroke or hospitalization for ischemia or bleeding Circulation 2001; 103: 363-368 Ringleb, P. A. et al. Stroke 2004;35:528-532 Clopidogrel in patients with history of prior ischemic event - CAPRIE substudy (N=4496) Overall 12562 9.3 11.4 Associated MI 3283 11.3 13.7 No associated MI 9279 8.6 10.6 Male sex 7726 9.1 11.9 Female sex 4836 9.5 10.7 £65 yr old 6354 5.4 7.6 > 65 yr old 6208 13.3 15.3 ST-segment deviation 6275 11.5 14.3 No ST-segment deviation 6287 7.0 8.6 Enzymes elevated at entry 3176 10.7 13.0 Enzymes not elevated at entry 9386 8.8 10.9 Diabetes 2840 14.2 16.7 No diabetes 9722 7.9 9.9 Low risk 4187 5.1 6.7 Intermediate risk 4185 6.5 9.4 High risk 4184 16.3 18.0 History of revascularization 2246 8.4 14.4 No history of revascularization 10316 9.5 10.7 Revascularization after randomization 4577 11.5 13.9 No revascularization after randomization 7985 8.1 10.0 Placebo + ASA* Characteristic No. of Patients Clopidogrel + ASA* Percentage of Patients with Event Placebo Better Clopidogrel Better Relative Risk (95% CI) 1.2 1.0 0.8 0.6 0.4 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Beneficial Outcomes with Clopidogrel in Various Subgroups CURE 6.0% 1.2% CURE: Impact of History of Revascularization Percent of Patients with an Event History of Revascularization (N=2246) (N=10316)
Slide 78 - Early And Long Term Treatment With Clopidogrel In Coronary Artery Disease פרופ’ יוסף רוזנמן מכון הלב, בי"ח וולפסון דצמבר 2005 Acute Coronary Syndromes Acute Coronary Syndrome No ST Elevation ST Elevation Unstable Angina Myocardial Infarction Non Q MI Q wave MI Non ST Elevation MI Braunwald E et al. J Am Coll Cardiol 2000;36:970–1062. Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When angiography / PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until angiography / PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month improving long-term outcome 1 2 Goals of therapy Prevent ischemic events until coronary angiography / PCI Before plaque stabilization was achieved Prevent PCI / stent related ischemic complications Clopidogrel before coronary angiography - Patients with ACS 1 Clopidogrel before coronary angiography - Patients with ACS ST Elevation CLARITY Non ST Elevation CURE 1 ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Study Design Fibrinolytic, ASA, Heparin Clopidogrel 300 mg + 75 mg qd Coronary Angiogram (2-8 days) Primary endpoint: Occluded artery (TIMI Flow Grade 0/1) or D/MI by time of angio randomize Placebo Double-blind, randomized, placebo-controlled trial in 3491 patients, age 18-75 yrs with STEMI < 12 hours Study Drug 30-day clinical follow-up Open-label clopidogrel per MD in both groups Primary Endpoint: Occluded Artery (or D/MI by time of angio) Placebo Clopidogrel P=0.00000036 Odds Ratio 0.64 (95% CI 0.53-0.76) 1.0 0.4 0.6 0.8 1.2 1.6 Clopidogrel better Placebo better n=1752 n=1739 36% Odds Reduction Primary & Angiographic Outcomes (median 3.5 days) Need for Urgent or Additional Treatment 21%  P=0.01 21%  P=0.005 16%  P=0.07 Early Angio (w/in 48 hrs) Urgent Revasc (index hosp) GP IIb/IIIa if PCI CV Death, MI, RI  Urg Revasc days Percentage with endpoint (%) 0 5 10 15 0 5 10 15 20 25 30 Placebo Clopidogrel Odds Ratio 0.80 (95% CI 0.65-0.97) P=0.026 20% 1 CLARITY: Patient Management Clopidogrel Placebo Parameter (n=1,752) (n=1,739) Symptom onset to fibrinolytic (hours) 2.7 2.6 Fibrinolytic to study drug (minutes) 10 10 Median doses of study medication 4 4 Angiography performed (%) 94 94 Study drug to angiography (hours) 84 84 Coronary revascularization (%): 63 63 PCI 57.2 56.6 CABG 5.9 6.0 Sabatine M et al. New Engl J Med 2005; 352: 1179–1189. PCI-CLARITY: Reduction in CV Death, MI, Stroke from PCI to 30 Days Days Post PCI Percentage with Outcome (%) 0 2 0 5 10 15 20 25 30 46%* p=0.008 Clopidogrel Pretreatment (3.6%) No Pretreatment (6.2%) 4 6 8 M Sabatine, et al. JAMA 2005 PCI-CLARITY: MI, Stroke, or CV Death Events pre and post PCI ***MI or Stroke M Sabatine, et al. JAMA 2005, Prehospital Fibrinolysis with Double Antiplatelet Therapy in Acute ST-Elevation Myocardial Infarction: The Clarity Ambulance Substudy Substudy Sites and Patient Numbers France: 172 patients L Soulat: 57 Y Lambert: 48 F Lapostolle: 28 F Thieuleux: 21 C Gully: 10 D Pollet: 5 D Galley: 2 L Olliver: 1 UK: 40 patients J Adgey: 27 J Purvis: 13 Sweden: 5 patients J-E Karlsson: 5 217 patients in total Angiographic & ECG Parameters: Ambulance vs. Non-Ambulance *Complete considered to be >70%; ECG=electrocardiogram p value Event rate (%) Ambulance Non- ambulance Non-ambulance better Ambulance better Odds ratio (95% CI) 0 0.5 1.0 1.5 2.0 Ambulance Non-ambulance Overall Clopidogrel better Placebo better Odds ratio (95% CI) Primary Endpoint of TIMI Flow Grade 0/1, MI or Death 0.60 (0.301.17) 0.64 (0.530.76) 0.65 (0.540.77) ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Clopidogrel 75mg q.d. + ASA 75-325 mg q.d.* (6259 patients) Placebo + ASA 75-325 mg q.d.* (6303 patients) Day 1 6 m. Visit 9 m. Visit 12 m. or Final Visit 3 m. Visit Discharge Visit 1 m. Visit Patients with Acute Coronary Syndrome (unstable angina or non-ST-segment elevation MI) R Placebo loading dose R = Randomization * In combination with other standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Study Design 3 months £ double-blind treatment £ 12 months Clopidogrel 300 mg loading dose CURE Clopidogrel + ASA* 3 6 9 Placebo + ASA* Months of Follow-Up 11.4% 9.3% 20% RRR P < 0.001 N = 12,562 0 12 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Primary End Point - MI/Stroke/CV Death CURE Clopidogrel + ASA* 10 20 30 Placebo + ASA* Days of Follow-Up 0 21% RRR P = 0.003 N = 12,562 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. MI/Stroke/CV Death within 30 Days CURE 1 CV death, nonfatal MI, stroke or refractory or severe ischemia 34% NEJM 2001; 345:495-502 MI/Stroke/CV Death or severe Ischemia at 24 hours CURE 1 % patients requiring thrombolytic therapy 43% % patients requiring GP IIb/IIIa inhibitors 18% NEJM 2001; 345:495-502 Need for Additional Anti-Thrombotic After Randomization P< 0.001 P= 0.003 Thrombolysis GP IIb/IIIa Inhibitor CURE 1 Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? GP IIb/IIIa receptor is the final common pathway in platelet aggregation. GP IIb/IIIa blockade is the most effective antiplatelet aggregation therapy. Bleeding risk is not increased if therapy is stopped 2-4 hours prior to CABG. Bleeding risk is markedly increased unless clopidogrel is stopped 3-5 days prior to CABG. Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? Is there additional benefit to clopidogrel that would justify: Increased CABG bleeding or alternatively Need to postpone CABG for 3-5 days No data in the literature however Adhesion The Role of Platelets in Atherothrombosis Aggregation 3 Reproduced with permission from Cannon CP. Atherothrombosis slide compendium. Available at: www.theheart.org. 1 Activation 2 Conclusions: Early Clopidogrel Therapy Treatment with clopidogrel is indicated as soon as possible in patients with acute coronary syndrome ST elevation and non ST elevation Treatment is effective to reduce ischemic complications Before coronay angiography During and after PCI 1 Conclusions: Early Clopidogrel Therapy Loading dose should be 600mg to achieve early optimal antiplatelet effect ?? 300mg in patients after fibrinolytic therapy It is unclear whether therapy should be added to “upstream” GP IIb/IIIa antagonists Especially in high risk patients in whom the likelihood for CABG is high 1 Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month after PCI / stent improving long-term outcome 1 2 Discharge/Post-Discharge Medications - Guidelines ASA, if not contraindicated Clopidogrel, when ASA contraindicated Aspirin + Clopidogrel for up to 9 months -blocker, if not contraindicated Lipid  agents + diet, if LDL >130 mg/dL ACE Inhibitor: CHF, EF < 40%, DM, or HTN I IIa IIb III 2 Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization PCI PLACEBO + ASA * CLOPIDOGREL + ASA * 30 days post PCI End of follow-up Up to 12 months after randomization Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 2,658 patients undergoing PCI N = 1345 N = 1313 PCI-CURE Overall Study Design: PCI-CURE R Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE Question 1 Question 2 Clopidogrel Arm Placebo Arm PCI* 28 Days Placebo + ASA† (325 mg) Randomization - Pre-treatment Clopidogrel 300 mg + ASA† (325 mg) Clopidogrel 75 mg QD + ASA† 325 mg QD Clopidogrel 75 mg QD + ASA† 325 mg QD R 12 Months Steinhubl S, Berger P, Tift Mann III J et al. JAMA. 2002;Vol 288,No 19:2411-2420. Placebo QD + ASA† (81-325 mg) QD Clopidogrel 75 mg QD + ASA† (81-325 mg) QD Overall Study Design: CREDO Question 1 Question 2 1 2 Open label clopidogrel continuation Methodological Pitfall Can a study with a single randomization provide an answer to two questions? Alternatively Should a second randomization be done in order to answer the second question? PCI PLACEBO + ASA * CLOPIDOGREL + ASA * 30 days post PCI End of follow-up Up to 12 months after randomization Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 1345 N = 1313 PCI-CURE Study Design single randomization R Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE Continuation Continuation PCI PLACEBO + ASA * CLOPIDOGREL + ASA * Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 1345 N = 1313 PCI-CURE Alternative Study Design two randomizations R1 Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE R2 R2 Clop. Placebo Continuation Continuation Question 2 2 Is it just methodology? Can we really expect long term benefit from early antiplatelet therapy? Adjunct antiplatelet therapy for PCI EPISTENT Randomized study designed to determine the effect of treatment with abciximab TARGET Randomized study designed to show that tirofiban is not inferior to abciximab Post-hoc nonrandomized comparison among those who were or were not pre-treated with clopidogrel PCI-CURE Subgroup of CURE patients who underwent PCI Randomized comparison of pre-treatment and continued clopidogrel therapy vs. placebo Absolute reduction of Death or MI at 1 month and 1 year Abciximab Early clopidogrel Early and continued clopidogrel % reduction * * 6 month data in TARGET Early and long term reduction of death or MI from antiplatelet therapy in patients with ACS Long Term Clopidogrel Post PCI Clinical guidelines: 9 months to 1 year in patients with ACS However, current data does not fully support this recommendation What should we do? 2 Comulative event rate in primary prevention stable CAD and ACS ACS Stable Primary Risk of vascular event after ACS Risk of event Time after ACS Stable CAD Commulative risk Risk per time Risk of vascular event after ACS high and low risk Risk of event Time after ACS High risk Low risk Risk of bleeding after initiation of clopidogrel (high and low risk) Risk of event Time after clopidogrel High risk Low risk Fixed, except for the initial few days heparin, catheterization Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? vascular bleeding Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? vascular bleeding > 1 year High vascular risk Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? vascular bleeding < 1 months High bleeding risk e.g. coumadin Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? Long term clopidogrel for patients with High risk for vascular event Low bleeding risk Short term clopidogrel for patients with Low risk for vascular event High bleeding risk vascular bleeding Who is ”High Risk” Patients in whom long term clopidogrel should be considered The vulnerable patient TIMI risk score Aspirin Failure Others Who is ”High Risk” Patients in whom long term clopidogrel should be considered The vulnerable patient TIMI risk score Aspirin Failure Others ACS Pathophysiology Inflammation, Plaque Rupture, Thrombosis, and Microembolization Quiescent plaque Plaque formation Lipids, other risk factors Inflammation LDL, others, Infection? Plaque rupture (erosion) ? Macrophages, metalloproteinases Thrombosis Platelet Activation, Thrombin Vulnerable plaque Macrophages Foam Cells Collagen  platelet activation TF  Clotting Cascade Lipid core Metalloproteinases Inflammation Courtesy of David Kandzari. Plaque rupture Culprit plaque Platelet-thrombin micro-emboli Atherosclerotic Plaques - Terminology Culprit Responsible for the clinical event Vulnerable High risk to become culprit (cause clinical event) Quiescent (Stable) Primary or healed (vulnerable or culprit) Fuster, V. et al. J Am Coll Cardiol 2005;46:937-954 Coronary Artery Disease: Diffuse disease with a variable mix of stable, vulnerable and culprit plaques Culprit and healed plaques in a coronary bifurcation N Engl J Med 2000;343:915-22 Angiograms of 253 patients with acute MI Complex Plaques: Single: 153 - 60.5% Multiple: 100 – 39.5% Clinical Outcome at 1 Year – Single vs. Multiple Complex Plaques Similar results when analysis was restricted to patients with multivessel coronary disease: 74.5% of single 91.0% of multiple Characteristics of Carotid Plaques: Patients with Unstable versus Stable Angina Multivariate analysis: UA and CRP >3 mg/l were independently and strongly associated with complex carotid plaques Vulnerable Patient – at high risk for vascular event coronary elsewhere Who is the vulnerable patient? Patient with current multiple complex plaques Coronary, carotid etc Patient with multiple uncontrolled risk factors At risk to develop new complex plaques Vulnerability cutoff value ? Who is ”High Risk” Patients in whom long term clopidogrel should be considered The vulnerable patient TIMI risk score Aspirin Failure Others TIMI Risk Score and Outcome Budaj et al. circulation 2002 Excess major bleeding risk with clopidogrel is independent of the TIMI risk – it is 1% TIMI Risk Score and Absolute Reduction of death/MI/Stroke with Clopidogrel TIMI Risk Score N= 752 2524 3730 3567 1593 396 Percent reduction Major bleeding – 1% Majority of patients Who is ”High Risk” Patients in whom long term clopidogrel should be considered The vulnerable patient TIMI risk score Aspirin Failure Others Aspirin Failure – Patient with acute vascular event (coronary, cerebral) while being treated with aspirin Aspirin was not enough to prevent the event Aspirin is ineffective as an antiplatelet agent – resistance? Aspirin is effective as an antiplatelet agent but the disease risk is high and there is a need for more aggressive antiplatelet therapy Aspirin Resistance Cellular Factors Insufficient suppression of COX-1 Overexpression of COX-2 mRNA Erythrocyte-induced platelet activation Increased norepinephrine Generation of 8-iso-PGF2 Adapted with permission from Bhatt DL. J Am Coll Cardiol. 2004;43:1127-1129. Aspirin Resistance Genetic Polymorphisms COX-1 GP IIIa receptor Collagen receptor vWF receptor Clinical Factors Failure to prescribe Noncompliance Nonabsorption Interaction with ibuprofen Can be intermittent Unfortunately (surprisingly) there is no subgroup analysis of CAPRIE or CURE for patients who were on prior aspirin However There are other subgroup analyses Clopidogrel in patients with prior CABG CAPRIE substudy (N=1480) Vascular death Combined endpoint: Vascular death, MI, stroke or hospitalization for ischemia or bleeding Circulation 2001; 103: 363-368 Ringleb, P. A. et al. Stroke 2004;35:528-532 Clopidogrel in patients with history of prior ischemic event - CAPRIE substudy (N=4496) Overall 12562 9.3 11.4 Associated MI 3283 11.3 13.7 No associated MI 9279 8.6 10.6 Male sex 7726 9.1 11.9 Female sex 4836 9.5 10.7 £65 yr old 6354 5.4 7.6 > 65 yr old 6208 13.3 15.3 ST-segment deviation 6275 11.5 14.3 No ST-segment deviation 6287 7.0 8.6 Enzymes elevated at entry 3176 10.7 13.0 Enzymes not elevated at entry 9386 8.8 10.9 Diabetes 2840 14.2 16.7 No diabetes 9722 7.9 9.9 Low risk 4187 5.1 6.7 Intermediate risk 4185 6.5 9.4 High risk 4184 16.3 18.0 History of revascularization 2246 8.4 14.4 No history of revascularization 10316 9.5 10.7 Revascularization after randomization 4577 11.5 13.9 No revascularization after randomization 7985 8.1 10.0 Placebo + ASA* Characteristic No. of Patients Clopidogrel + ASA* Percentage of Patients with Event Placebo Better Clopidogrel Better Relative Risk (95% CI) 1.2 1.0 0.8 0.6 0.4 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Beneficial Outcomes with Clopidogrel in Various Subgroups CURE 6.0% 1.2% CURE: Impact of History of Revascularization Percent of Patients with an Event History of Revascularization (N=2246) (N=10316) Conclusions – early treatment Clopidogrel loading should be given to patients with ACS (both STE and Non-STE) as soon as possible regardless* of the timing of the planned coronary angiography * It is still unclear whether treatment can be postponed when “upstream” GP IIb/IIIa is being used (especially when the likelihood of CABG is high). will be clarified by ongoing trial – “early ACS”
Slide 79 - Early And Long Term Treatment With Clopidogrel In Coronary Artery Disease פרופ’ יוסף רוזנמן מכון הלב, בי"ח וולפסון דצמבר 2005 Acute Coronary Syndromes Acute Coronary Syndrome No ST Elevation ST Elevation Unstable Angina Myocardial Infarction Non Q MI Q wave MI Non ST Elevation MI Braunwald E et al. J Am Coll Cardiol 2000;36:970–1062. Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When angiography / PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until angiography / PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month improving long-term outcome 1 2 Goals of therapy Prevent ischemic events until coronary angiography / PCI Before plaque stabilization was achieved Prevent PCI / stent related ischemic complications Clopidogrel before coronary angiography - Patients with ACS 1 Clopidogrel before coronary angiography - Patients with ACS ST Elevation CLARITY Non ST Elevation CURE 1 ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Study Design Fibrinolytic, ASA, Heparin Clopidogrel 300 mg + 75 mg qd Coronary Angiogram (2-8 days) Primary endpoint: Occluded artery (TIMI Flow Grade 0/1) or D/MI by time of angio randomize Placebo Double-blind, randomized, placebo-controlled trial in 3491 patients, age 18-75 yrs with STEMI < 12 hours Study Drug 30-day clinical follow-up Open-label clopidogrel per MD in both groups Primary Endpoint: Occluded Artery (or D/MI by time of angio) Placebo Clopidogrel P=0.00000036 Odds Ratio 0.64 (95% CI 0.53-0.76) 1.0 0.4 0.6 0.8 1.2 1.6 Clopidogrel better Placebo better n=1752 n=1739 36% Odds Reduction Primary & Angiographic Outcomes (median 3.5 days) Need for Urgent or Additional Treatment 21%  P=0.01 21%  P=0.005 16%  P=0.07 Early Angio (w/in 48 hrs) Urgent Revasc (index hosp) GP IIb/IIIa if PCI CV Death, MI, RI  Urg Revasc days Percentage with endpoint (%) 0 5 10 15 0 5 10 15 20 25 30 Placebo Clopidogrel Odds Ratio 0.80 (95% CI 0.65-0.97) P=0.026 20% 1 CLARITY: Patient Management Clopidogrel Placebo Parameter (n=1,752) (n=1,739) Symptom onset to fibrinolytic (hours) 2.7 2.6 Fibrinolytic to study drug (minutes) 10 10 Median doses of study medication 4 4 Angiography performed (%) 94 94 Study drug to angiography (hours) 84 84 Coronary revascularization (%): 63 63 PCI 57.2 56.6 CABG 5.9 6.0 Sabatine M et al. New Engl J Med 2005; 352: 1179–1189. PCI-CLARITY: Reduction in CV Death, MI, Stroke from PCI to 30 Days Days Post PCI Percentage with Outcome (%) 0 2 0 5 10 15 20 25 30 46%* p=0.008 Clopidogrel Pretreatment (3.6%) No Pretreatment (6.2%) 4 6 8 M Sabatine, et al. JAMA 2005 PCI-CLARITY: MI, Stroke, or CV Death Events pre and post PCI ***MI or Stroke M Sabatine, et al. JAMA 2005, Prehospital Fibrinolysis with Double Antiplatelet Therapy in Acute ST-Elevation Myocardial Infarction: The Clarity Ambulance Substudy Substudy Sites and Patient Numbers France: 172 patients L Soulat: 57 Y Lambert: 48 F Lapostolle: 28 F Thieuleux: 21 C Gully: 10 D Pollet: 5 D Galley: 2 L Olliver: 1 UK: 40 patients J Adgey: 27 J Purvis: 13 Sweden: 5 patients J-E Karlsson: 5 217 patients in total Angiographic & ECG Parameters: Ambulance vs. Non-Ambulance *Complete considered to be >70%; ECG=electrocardiogram p value Event rate (%) Ambulance Non- ambulance Non-ambulance better Ambulance better Odds ratio (95% CI) 0 0.5 1.0 1.5 2.0 Ambulance Non-ambulance Overall Clopidogrel better Placebo better Odds ratio (95% CI) Primary Endpoint of TIMI Flow Grade 0/1, MI or Death 0.60 (0.301.17) 0.64 (0.530.76) 0.65 (0.540.77) ST Elevation CLARITY Non ST Elevation CURE 1 Clopidogrel before coronary angiography - Patients with ACS Clopidogrel 75mg q.d. + ASA 75-325 mg q.d.* (6259 patients) Placebo + ASA 75-325 mg q.d.* (6303 patients) Day 1 6 m. Visit 9 m. Visit 12 m. or Final Visit 3 m. Visit Discharge Visit 1 m. Visit Patients with Acute Coronary Syndrome (unstable angina or non-ST-segment elevation MI) R Placebo loading dose R = Randomization * In combination with other standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Study Design 3 months £ double-blind treatment £ 12 months Clopidogrel 300 mg loading dose CURE Clopidogrel + ASA* 3 6 9 Placebo + ASA* Months of Follow-Up 11.4% 9.3% 20% RRR P < 0.001 N = 12,562 0 12 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Primary End Point - MI/Stroke/CV Death CURE Clopidogrel + ASA* 10 20 30 Placebo + ASA* Days of Follow-Up 0 21% RRR P = 0.003 N = 12,562 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. MI/Stroke/CV Death within 30 Days CURE 1 CV death, nonfatal MI, stroke or refractory or severe ischemia 34% NEJM 2001; 345:495-502 MI/Stroke/CV Death or severe Ischemia at 24 hours CURE 1 % patients requiring thrombolytic therapy 43% % patients requiring GP IIb/IIIa inhibitors 18% NEJM 2001; 345:495-502 Need for Additional Anti-Thrombotic After Randomization P< 0.001 P= 0.003 Thrombolysis GP IIb/IIIa Inhibitor CURE 1 Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? GP IIb/IIIa receptor is the final common pathway in platelet aggregation. GP IIb/IIIa blockade is the most effective antiplatelet aggregation therapy. Bleeding risk is not increased if therapy is stopped 2-4 hours prior to CABG. Bleeding risk is markedly increased unless clopidogrel is stopped 3-5 days prior to CABG. Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? Is there additional benefit to clopidogrel that would justify: Increased CABG bleeding or alternatively Need to postpone CABG for 3-5 days No data in the literature however Adhesion The Role of Platelets in Atherothrombosis Aggregation 3 Reproduced with permission from Cannon CP. Atherothrombosis slide compendium. Available at: www.theheart.org. 1 Activation 2 Conclusions: Early Clopidogrel Therapy Treatment with clopidogrel is indicated as soon as possible in patients with acute coronary syndrome ST elevation and non ST elevation Treatment is effective to reduce ischemic complications Before coronay angiography During and after PCI 1 Conclusions: Early Clopidogrel Therapy Loading dose should be 600mg to achieve early optimal antiplatelet effect ?? 300mg in patients after fibrinolytic therapy It is unclear whether therapy should be added to “upstream” GP IIb/IIIa antagonists Especially in high risk patients in whom the likelihood for CABG is high 1 Minimize peri-procedural complications (related to the treated plaque) Thrombosis etc Stabilize the rest of the non-occlusive narrowings Prevent progression Prevent atherothrombosis 1 2 Goals of Peri – PCI Medical Treatment (short and long term) The Clinical Questions Combination Rx. (ASA + Clopidogrel) When PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month after PCI / stent improving long-term outcome 1 2 Discharge/Post-Discharge Medications - Guidelines ASA, if not contraindicated Clopidogrel, when ASA contraindicated Aspirin + Clopidogrel for up to 9 months -blocker, if not contraindicated Lipid  agents + diet, if LDL >130 mg/dL ACE Inhibitor: CHF, EF < 40%, DM, or HTN I IIa IIb III 2 Initial Treatment Strategy ACS ST Elevation Non ST Elevation Anti-thrombotic Rx (+ Fibrinolysis) 2. Early / Primary PCI Anti-thrombotic Rx Early PCI Reperfusion and culprit plaque stabilization The best way to stabilize a culprit plaque is with a stent Culprit plaque stabilization PCI PLACEBO + ASA * CLOPIDOGREL + ASA * 30 days post PCI End of follow-up Up to 12 months after randomization Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 2,658 patients undergoing PCI N = 1345 N = 1313 PCI-CURE Overall Study Design: PCI-CURE R Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE Question 1 Question 2 Clopidogrel Arm Placebo Arm PCI* 28 Days Placebo + ASA† (325 mg) Randomization - Pre-treatment Clopidogrel 300 mg + ASA† (325 mg) Clopidogrel 75 mg QD + ASA† 325 mg QD Clopidogrel 75 mg QD + ASA† 325 mg QD R 12 Months Steinhubl S, Berger P, Tift Mann III J et al. JAMA. 2002;Vol 288,No 19:2411-2420. Placebo QD + ASA† (81-325 mg) QD Clopidogrel 75 mg QD + ASA† (81-325 mg) QD Overall Study Design: CREDO Question 1 Question 2 1 2 Open label clopidogrel continuation Methodological Pitfall Can a study with a single randomization provide an answer to two questions? Alternatively Should a second randomization be done in order to answer the second question? PCI PLACEBO + ASA * CLOPIDOGREL + ASA * 30 days post PCI End of follow-up Up to 12 months after randomization Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 1345 N = 1313 PCI-CURE Study Design single randomization R Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE Continuation Continuation PCI PLACEBO + ASA * CLOPIDOGREL + ASA * Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 1345 N = 1313 PCI-CURE Alternative Study Design two randomizations R1 Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502. PCI-CURE R2 R2 Clop. Placebo Continuation Continuation Question 2 2 Is it just methodology? Can we really expect long term benefit from early antiplatelet therapy? Adjunct antiplatelet therapy for PCI EPISTENT Randomized study designed to determine the effect of treatment with abciximab TARGET Randomized study designed to show that tirofiban is not inferior to abciximab Post-hoc nonrandomized comparison among those who were or were not pre-treated with clopidogrel PCI-CURE Subgroup of CURE patients who underwent PCI Randomized comparison of pre-treatment and continued clopidogrel therapy vs. placebo Absolute reduction of Death or MI at 1 month and 1 year Abciximab Early clopidogrel Early and continued clopidogrel % reduction * * 6 month data in TARGET Early and long term reduction of death or MI from antiplatelet therapy in patients with ACS Long Term Clopidogrel Post PCI Clinical guidelines: 9 months to 1 year in patients with ACS However, current data does not fully support this recommendation What should we do? 2 Comulative event rate in primary prevention stable CAD and ACS ACS Stable Primary Risk of vascular event after ACS Risk of event Time after ACS Stable CAD Commulative risk Risk per time Risk of vascular event after ACS high and low risk Risk of event Time after ACS High risk Low risk Risk of bleeding after initiation of clopidogrel (high and low risk) Risk of event Time after clopidogrel High risk Low risk Fixed, except for the initial few days heparin, catheterization Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? vascular bleeding Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? vascular bleeding > 1 year High vascular risk Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? vascular bleeding < 1 months High bleeding risk e.g. coumadin Risk of event (vascular/bleeding) after ACS and clopidogrel Risk of event Time after ACS 3 months ?? Long term clopidogrel for patients with High risk for vascular event Low bleeding risk Short term clopidogrel for patients with Low risk for vascular event High bleeding risk vascular bleeding Who is ”High Risk” Patients in whom long term clopidogrel should be considered The vulnerable patient TIMI risk score Aspirin Failure Others Who is ”High Risk” Patients in whom long term clopidogrel should be considered The vulnerable patient TIMI risk score Aspirin Failure Others ACS Pathophysiology Inflammation, Plaque Rupture, Thrombosis, and Microembolization Quiescent plaque Plaque formation Lipids, other risk factors Inflammation LDL, others, Infection? Plaque rupture (erosion) ? Macrophages, metalloproteinases Thrombosis Platelet Activation, Thrombin Vulnerable plaque Macrophages Foam Cells Collagen  platelet activation TF  Clotting Cascade Lipid core Metalloproteinases Inflammation Courtesy of David Kandzari. Plaque rupture Culprit plaque Platelet-thrombin micro-emboli Atherosclerotic Plaques - Terminology Culprit Responsible for the clinical event Vulnerable High risk to become culprit (cause clinical event) Quiescent (Stable) Primary or healed (vulnerable or culprit) Fuster, V. et al. J Am Coll Cardiol 2005;46:937-954 Coronary Artery Disease: Diffuse disease with a variable mix of stable, vulnerable and culprit plaques Culprit and healed plaques in a coronary bifurcation N Engl J Med 2000;343:915-22 Angiograms of 253 patients with acute MI Complex Plaques: Single: 153 - 60.5% Multiple: 100 – 39.5% Clinical Outcome at 1 Year – Single vs. Multiple Complex Plaques Similar results when analysis was restricted to patients with multivessel coronary disease: 74.5% of single 91.0% of multiple Characteristics of Carotid Plaques: Patients with Unstable versus Stable Angina Multivariate analysis: UA and CRP >3 mg/l were independently and strongly associated with complex carotid plaques Vulnerable Patient – at high risk for vascular event coronary elsewhere Who is the vulnerable patient? Patient with current multiple complex plaques Coronary, carotid etc Patient with multiple uncontrolled risk factors At risk to develop new complex plaques Vulnerability cutoff value ? Who is ”High Risk” Patients in whom long term clopidogrel should be considered The vulnerable patient TIMI risk score Aspirin Failure Others TIMI Risk Score and Outcome Budaj et al. circulation 2002 Excess major bleeding risk with clopidogrel is independent of the TIMI risk – it is 1% TIMI Risk Score and Absolute Reduction of death/MI/Stroke with Clopidogrel TIMI Risk Score N= 752 2524 3730 3567 1593 396 Percent reduction Major bleeding – 1% Majority of patients Who is ”High Risk” Patients in whom long term clopidogrel should be considered The vulnerable patient TIMI risk score Aspirin Failure Others Aspirin Failure – Patient with acute vascular event (coronary, cerebral) while being treated with aspirin Aspirin was not enough to prevent the event Aspirin is ineffective as an antiplatelet agent – resistance? Aspirin is effective as an antiplatelet agent but the disease risk is high and there is a need for more aggressive antiplatelet therapy Aspirin Resistance Cellular Factors Insufficient suppression of COX-1 Overexpression of COX-2 mRNA Erythrocyte-induced platelet activation Increased norepinephrine Generation of 8-iso-PGF2 Adapted with permission from Bhatt DL. J Am Coll Cardiol. 2004;43:1127-1129. Aspirin Resistance Genetic Polymorphisms COX-1 GP IIIa receptor Collagen receptor vWF receptor Clinical Factors Failure to prescribe Noncompliance Nonabsorption Interaction with ibuprofen Can be intermittent Unfortunately (surprisingly) there is no subgroup analysis of CAPRIE or CURE for patients who were on prior aspirin However There are other subgroup analyses Clopidogrel in patients with prior CABG CAPRIE substudy (N=1480) Vascular death Combined endpoint: Vascular death, MI, stroke or hospitalization for ischemia or bleeding Circulation 2001; 103: 363-368 Ringleb, P. A. et al. Stroke 2004;35:528-532 Clopidogrel in patients with history of prior ischemic event - CAPRIE substudy (N=4496) Overall 12562 9.3 11.4 Associated MI 3283 11.3 13.7 No associated MI 9279 8.6 10.6 Male sex 7726 9.1 11.9 Female sex 4836 9.5 10.7 £65 yr old 6354 5.4 7.6 > 65 yr old 6208 13.3 15.3 ST-segment deviation 6275 11.5 14.3 No ST-segment deviation 6287 7.0 8.6 Enzymes elevated at entry 3176 10.7 13.0 Enzymes not elevated at entry 9386 8.8 10.9 Diabetes 2840 14.2 16.7 No diabetes 9722 7.9 9.9 Low risk 4187 5.1 6.7 Intermediate risk 4185 6.5 9.4 High risk 4184 16.3 18.0 History of revascularization 2246 8.4 14.4 No history of revascularization 10316 9.5 10.7 Revascularization after randomization 4577 11.5 13.9 No revascularization after randomization 7985 8.1 10.0 Placebo + ASA* Characteristic No. of Patients Clopidogrel + ASA* Percentage of Patients with Event Placebo Better Clopidogrel Better Relative Risk (95% CI) 1.2 1.0 0.8 0.6 0.4 * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Beneficial Outcomes with Clopidogrel in Various Subgroups CURE 6.0% 1.2% CURE: Impact of History of Revascularization Percent of Patients with an Event History of Revascularization (N=2246) (N=10316) Conclusions – early treatment Clopidogrel loading should be given to patients with ACS (both STE and Non-STE) as soon as possible regardless* of the timing of the planned coronary angiography * It is still unclear whether treatment can be postponed when “upstream” GP IIb/IIIa is being used (especially when the likelihood of CABG is high). will be clarified by ongoing trial – “early ACS” Clinical guidelines recommend 9-12 months clopidogrel to all patients with non-STE ACS Treatment should be definitely continued as long as there is a risk for stent thrombosis Longer duration high risk subset (multiple complex plaques, TIMI risk score >5, continuously elevated CRP?) Aspirin failure ? Shorter duration High bleeding risk (e.g. coumadin etc) Conclusions – long term treatment