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Slide 79 -
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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 (0.301.17) 0.64 (0.530.76) 0.65 (0.540.77) 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
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