Does the Pattern of Blood Pressure Effects During the Day Matter PowerPoint Presentation

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Does the Pattern of Blood Pressure Effects During the Day Matter? Thomas Pickering MD, DPhil Behavioral Cardiovascular Health and Hypertension Program Division of General Medicine Columbia Presbyterian Medical Center New York

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Does the Pattern of Blood Pressure Effects During the Day Matter? Thomas Pickering MD, DPhil Behavioral Cardiovascular Health and Hypertension Program Division of General Medicine Columbia Presbyterian Medical Center New York Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs

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Does the Pattern of Blood Pressure Effects During the Day Matter? Thomas Pickering MD, DPhil Behavioral Cardiovascular Health and Hypertension Program Division of General Medicine Columbia Presbyterian Medical Center New York Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs

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Does the Pattern of Blood Pressure Effects During the Day Matter? Thomas Pickering MD, DPhil Behavioral Cardiovascular Health and Hypertension Program Division of General Medicine Columbia Presbyterian Medical Center New York Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs What is the True Blood Pressure? Clinic BP? Home BP? 24 Hr Average BP? Daytime BP? Nighttime BP? Dipping Pattern? Morning Surge? Variability of BP?

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Does the Pattern of Blood Pressure Effects During the Day Matter? Thomas Pickering MD, DPhil Behavioral Cardiovascular Health and Hypertension Program Division of General Medicine Columbia Presbyterian Medical Center New York Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs What is the True Blood Pressure? Clinic BP? Home BP? 24 Hr Average BP? Daytime BP? Nighttime BP? Dipping Pattern? Morning Surge? Variability of BP? Ambulatory BP Differences for Normotensives, and Mild and Established HTN Patients 120- 110- 100- 90- 80- 70- 60- 0- Diastolic Blood Pressure (mm Hg) Clinic Work Home Sleep Normotensives Mild hypertensives Established hypertensives

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Does the Pattern of Blood Pressure Effects During the Day Matter? Thomas Pickering MD, DPhil Behavioral Cardiovascular Health and Hypertension Program Division of General Medicine Columbia Presbyterian Medical Center New York Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs What is the True Blood Pressure? Clinic BP? Home BP? 24 Hr Average BP? Daytime BP? Nighttime BP? Dipping Pattern? Morning Surge? Variability of BP? Ambulatory BP Differences for Normotensives, and Mild and Established HTN Patients 120- 110- 100- 90- 80- 70- 60- 0- Diastolic Blood Pressure (mm Hg) Clinic Work Home Sleep Normotensives Mild hypertensives Established hypertensives Clinical situations in which the normal diurnal rhythm of BP may be lost Autonomic Dysfunction Syndromes Diabetes Mellitus Renal Failure Secondary forms of hypertension e.g. Cushing’s disease Drugs, e.g. cyclosporine African-American ethnicity

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Does the Pattern of Blood Pressure Effects During the Day Matter? Thomas Pickering MD, DPhil Behavioral Cardiovascular Health and Hypertension Program Division of General Medicine Columbia Presbyterian Medical Center New York Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs What is the True Blood Pressure? Clinic BP? Home BP? 24 Hr Average BP? Daytime BP? Nighttime BP? Dipping Pattern? Morning Surge? Variability of BP? Ambulatory BP Differences for Normotensives, and Mild and Established HTN Patients 120- 110- 100- 90- 80- 70- 60- 0- Diastolic Blood Pressure (mm Hg) Clinic Work Home Sleep Normotensives Mild hypertensives Established hypertensives Clinical situations in which the normal diurnal rhythm of BP may be lost Autonomic Dysfunction Syndromes Diabetes Mellitus Renal Failure Secondary forms of hypertension e.g. Cushing’s disease Drugs, e.g. cyclosporine African-American ethnicity Nocturnal BP Changes and CV Mortality: Ohasama study (Ohkubo et al; AJH 1997; 10: 1201) Extreme dippers Dippers Non-dippers Risers Risk of CV Mortality

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Does the Pattern of Blood Pressure Effects During the Day Matter? Thomas Pickering MD, DPhil Behavioral Cardiovascular Health and Hypertension Program Division of General Medicine Columbia Presbyterian Medical Center New York Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs What is the True Blood Pressure? Clinic BP? Home BP? 24 Hr Average BP? Daytime BP? Nighttime BP? Dipping Pattern? Morning Surge? Variability of BP? Ambulatory BP Differences for Normotensives, and Mild and Established HTN Patients 120- 110- 100- 90- 80- 70- 60- 0- Diastolic Blood Pressure (mm Hg) Clinic Work Home Sleep Normotensives Mild hypertensives Established hypertensives Clinical situations in which the normal diurnal rhythm of BP may be lost Autonomic Dysfunction Syndromes Diabetes Mellitus Renal Failure Secondary forms of hypertension e.g. Cushing’s disease Drugs, e.g. cyclosporine African-American ethnicity Nocturnal BP Changes and CV Mortality: Ohasama study (Ohkubo et al; AJH 1997; 10: 1201) Extreme dippers Dippers Non-dippers Risers Risk of CV Mortality Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs

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Does the Pattern of Blood Pressure Effects During the Day Matter? Thomas Pickering MD, DPhil Behavioral Cardiovascular Health and Hypertension Program Division of General Medicine Columbia Presbyterian Medical Center New York Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs What is the True Blood Pressure? Clinic BP? Home BP? 24 Hr Average BP? Daytime BP? Nighttime BP? Dipping Pattern? Morning Surge? Variability of BP? Ambulatory BP Differences for Normotensives, and Mild and Established HTN Patients 120- 110- 100- 90- 80- 70- 60- 0- Diastolic Blood Pressure (mm Hg) Clinic Work Home Sleep Normotensives Mild hypertensives Established hypertensives Clinical situations in which the normal diurnal rhythm of BP may be lost Autonomic Dysfunction Syndromes Diabetes Mellitus Renal Failure Secondary forms of hypertension e.g. Cushing’s disease Drugs, e.g. cyclosporine African-American ethnicity Nocturnal BP Changes and CV Mortality: Ohasama study (Ohkubo et al; AJH 1997; 10: 1201) Extreme dippers Dippers Non-dippers Risers Risk of CV Mortality Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Morning Peak of VT Detected by Implanted Cardioverter/Defibrillator (Tofler Circ 1995;92: 1203) Episodes of VT

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Does the Pattern of Blood Pressure Effects During the Day Matter? Thomas Pickering MD, DPhil Behavioral Cardiovascular Health and Hypertension Program Division of General Medicine Columbia Presbyterian Medical Center New York Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs What is the True Blood Pressure? Clinic BP? Home BP? 24 Hr Average BP? Daytime BP? Nighttime BP? Dipping Pattern? Morning Surge? Variability of BP? Ambulatory BP Differences for Normotensives, and Mild and Established HTN Patients 120- 110- 100- 90- 80- 70- 60- 0- Diastolic Blood Pressure (mm Hg) Clinic Work Home Sleep Normotensives Mild hypertensives Established hypertensives Clinical situations in which the normal diurnal rhythm of BP may be lost Autonomic Dysfunction Syndromes Diabetes Mellitus Renal Failure Secondary forms of hypertension e.g. Cushing’s disease Drugs, e.g. cyclosporine African-American ethnicity Nocturnal BP Changes and CV Mortality: Ohasama study (Ohkubo et al; AJH 1997; 10: 1201) Extreme dippers Dippers Non-dippers Risers Risk of CV Mortality Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Morning Peak of VT Detected by Implanted Cardioverter/Defibrillator (Tofler Circ 1995;92: 1203) Episodes of VT Circadian Rhythm of Ischemic & Hemorrhagic Strokes Gallerani et al, Acta Neurol Scand 1993; 87: 482) % of strokes 1-6 6 -12 12-18 18-24 Hour of day Ischemic Hemorrhagic

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Does the Pattern of Blood Pressure Effects During the Day Matter? Thomas Pickering MD, DPhil Behavioral Cardiovascular Health and Hypertension Program Division of General Medicine Columbia Presbyterian Medical Center New York Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs What is the True Blood Pressure? Clinic BP? Home BP? 24 Hr Average BP? Daytime BP? Nighttime BP? Dipping Pattern? Morning Surge? Variability of BP? Ambulatory BP Differences for Normotensives, and Mild and Established HTN Patients 120- 110- 100- 90- 80- 70- 60- 0- Diastolic Blood Pressure (mm Hg) Clinic Work Home Sleep Normotensives Mild hypertensives Established hypertensives Clinical situations in which the normal diurnal rhythm of BP may be lost Autonomic Dysfunction Syndromes Diabetes Mellitus Renal Failure Secondary forms of hypertension e.g. Cushing’s disease Drugs, e.g. cyclosporine African-American ethnicity Nocturnal BP Changes and CV Mortality: Ohasama study (Ohkubo et al; AJH 1997; 10: 1201) Extreme dippers Dippers Non-dippers Risers Risk of CV Mortality Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Morning Peak of VT Detected by Implanted Cardioverter/Defibrillator (Tofler Circ 1995;92: 1203) Episodes of VT Circadian Rhythm of Ischemic & Hemorrhagic Strokes Gallerani et al, Acta Neurol Scand 1993; 87: 482) % of strokes 1-6 6 -12 12-18 18-24 Hour of day Ischemic Hemorrhagic Analysis of The Influence of the Morning Surge of BP on Stroke Incidence (Kario, Pickering et al, Circ 2003; 107:1401)) Cox regression analysis for clinical stroke events Covariates RR P value Age (10 yrs) 1.80 (1.21-2.69) 0.004 Male gender 1.42 (0.76-2.67) 0.266 BMI 0.98 (0.90-1.07) 0.663 24 hr SBP 1.37 (1.16-1.63 0.003 SCI 4.40 (1.95-10.1) 0.001 Morning BP surge* 1.29 (1.10-1.51) 0.001 Nocturnal BP fall* 0.88 (0.73-1.06) 0.167 Lowest sleep BP 1.05 (0.65-1.71) 0.837 * per 10 mmHg

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Does the Pattern of Blood Pressure Effects During the Day Matter? Thomas Pickering MD, DPhil Behavioral Cardiovascular Health and Hypertension Program Division of General Medicine Columbia Presbyterian Medical Center New York Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs What is the True Blood Pressure? Clinic BP? Home BP? 24 Hr Average BP? Daytime BP? Nighttime BP? Dipping Pattern? Morning Surge? Variability of BP? Ambulatory BP Differences for Normotensives, and Mild and Established HTN Patients 120- 110- 100- 90- 80- 70- 60- 0- Diastolic Blood Pressure (mm Hg) Clinic Work Home Sleep Normotensives Mild hypertensives Established hypertensives Clinical situations in which the normal diurnal rhythm of BP may be lost Autonomic Dysfunction Syndromes Diabetes Mellitus Renal Failure Secondary forms of hypertension e.g. Cushing’s disease Drugs, e.g. cyclosporine African-American ethnicity Nocturnal BP Changes and CV Mortality: Ohasama study (Ohkubo et al; AJH 1997; 10: 1201) Extreme dippers Dippers Non-dippers Risers Risk of CV Mortality Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Morning Peak of VT Detected by Implanted Cardioverter/Defibrillator (Tofler Circ 1995;92: 1203) Episodes of VT Circadian Rhythm of Ischemic & Hemorrhagic Strokes Gallerani et al, Acta Neurol Scand 1993; 87: 482) % of strokes 1-6 6 -12 12-18 18-24 Hour of day Ischemic Hemorrhagic Analysis of The Influence of the Morning Surge of BP on Stroke Incidence (Kario, Pickering et al, Circ 2003; 107:1401)) Cox regression analysis for clinical stroke events Covariates RR P value Age (10 yrs) 1.80 (1.21-2.69) 0.004 Male gender 1.42 (0.76-2.67) 0.266 BMI 0.98 (0.90-1.07) 0.663 24 hr SBP 1.37 (1.16-1.63 0.003 SCI 4.40 (1.95-10.1) 0.001 Morning BP surge* 1.29 (1.10-1.51) 0.001 Nocturnal BP fall* 0.88 (0.73-1.06) 0.167 Lowest sleep BP 1.05 (0.65-1.71) 0.837 * per 10 mmHg Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs

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Does the Pattern of Blood Pressure Effects During the Day Matter? Thomas Pickering MD, DPhil Behavioral Cardiovascular Health and Hypertension Program Division of General Medicine Columbia Presbyterian Medical Center New York Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs What is the True Blood Pressure? Clinic BP? Home BP? 24 Hr Average BP? Daytime BP? Nighttime BP? Dipping Pattern? Morning Surge? Variability of BP? Ambulatory BP Differences for Normotensives, and Mild and Established HTN Patients 120- 110- 100- 90- 80- 70- 60- 0- Diastolic Blood Pressure (mm Hg) Clinic Work Home Sleep Normotensives Mild hypertensives Established hypertensives Clinical situations in which the normal diurnal rhythm of BP may be lost Autonomic Dysfunction Syndromes Diabetes Mellitus Renal Failure Secondary forms of hypertension e.g. Cushing’s disease Drugs, e.g. cyclosporine African-American ethnicity Nocturnal BP Changes and CV Mortality: Ohasama study (Ohkubo et al; AJH 1997; 10: 1201) Extreme dippers Dippers Non-dippers Risers Risk of CV Mortality Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Morning Peak of VT Detected by Implanted Cardioverter/Defibrillator (Tofler Circ 1995;92: 1203) Episodes of VT Circadian Rhythm of Ischemic & Hemorrhagic Strokes Gallerani et al, Acta Neurol Scand 1993; 87: 482) % of strokes 1-6 6 -12 12-18 18-24 Hour of day Ischemic Hemorrhagic Analysis of The Influence of the Morning Surge of BP on Stroke Incidence (Kario, Pickering et al, Circ 2003; 107:1401)) Cox regression analysis for clinical stroke events Covariates RR P value Age (10 yrs) 1.80 (1.21-2.69) 0.004 Male gender 1.42 (0.76-2.67) 0.266 BMI 0.98 (0.90-1.07) 0.663 24 hr SBP 1.37 (1.16-1.63 0.003 SCI 4.40 (1.95-10.1) 0.001 Morning BP surge* 1.29 (1.10-1.51) 0.001 Nocturnal BP fall* 0.88 (0.73-1.06) 0.167 Lowest sleep BP 1.05 (0.65-1.71) 0.837 * per 10 mmHg Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Efficacy: telmisartan vs amlodipine using 24-h ABPM Placebo (n=58) Amlodipine (5-10 mg) (n=65) Telmisartan (40-120 mg) (n=62) 0800 1200 1600 2000 2400 0400 0800 BP (mm Hg) Lacourcière Y et al, in press 160 140 120 100 0 Time Week 12, SBP

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Does the Pattern of Blood Pressure Effects During the Day Matter? Thomas Pickering MD, DPhil Behavioral Cardiovascular Health and Hypertension Program Division of General Medicine Columbia Presbyterian Medical Center New York Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs What is the True Blood Pressure? Clinic BP? Home BP? 24 Hr Average BP? Daytime BP? Nighttime BP? Dipping Pattern? Morning Surge? Variability of BP? Ambulatory BP Differences for Normotensives, and Mild and Established HTN Patients 120- 110- 100- 90- 80- 70- 60- 0- Diastolic Blood Pressure (mm Hg) Clinic Work Home Sleep Normotensives Mild hypertensives Established hypertensives Clinical situations in which the normal diurnal rhythm of BP may be lost Autonomic Dysfunction Syndromes Diabetes Mellitus Renal Failure Secondary forms of hypertension e.g. Cushing’s disease Drugs, e.g. cyclosporine African-American ethnicity Nocturnal BP Changes and CV Mortality: Ohasama study (Ohkubo et al; AJH 1997; 10: 1201) Extreme dippers Dippers Non-dippers Risers Risk of CV Mortality Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Morning Peak of VT Detected by Implanted Cardioverter/Defibrillator (Tofler Circ 1995;92: 1203) Episodes of VT Circadian Rhythm of Ischemic & Hemorrhagic Strokes Gallerani et al, Acta Neurol Scand 1993; 87: 482) % of strokes 1-6 6 -12 12-18 18-24 Hour of day Ischemic Hemorrhagic Analysis of The Influence of the Morning Surge of BP on Stroke Incidence (Kario, Pickering et al, Circ 2003; 107:1401)) Cox regression analysis for clinical stroke events Covariates RR P value Age (10 yrs) 1.80 (1.21-2.69) 0.004 Male gender 1.42 (0.76-2.67) 0.266 BMI 0.98 (0.90-1.07) 0.663 24 hr SBP 1.37 (1.16-1.63 0.003 SCI 4.40 (1.95-10.1) 0.001 Morning BP surge* 1.29 (1.10-1.51) 0.001 Nocturnal BP fall* 0.88 (0.73-1.06) 0.167 Lowest sleep BP 1.05 (0.65-1.71) 0.837 * per 10 mmHg Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Efficacy: telmisartan vs amlodipine using 24-h ABPM Placebo (n=58) Amlodipine (5-10 mg) (n=65) Telmisartan (40-120 mg) (n=62) 0800 1200 1600 2000 2400 0400 0800 BP (mm Hg) Lacourcière Y et al, in press 160 140 120 100 0 Time Week 12, SBP Effects of Two ARBs Approved for Once Daily Dosing on 24 Hour Blood Pressure (Mancia et al AJC 1999: 84; 28S) Missed Dose

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Does the Pattern of Blood Pressure Effects During the Day Matter? Thomas Pickering MD, DPhil Behavioral Cardiovascular Health and Hypertension Program Division of General Medicine Columbia Presbyterian Medical Center New York Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs What is the True Blood Pressure? Clinic BP? Home BP? 24 Hr Average BP? Daytime BP? Nighttime BP? Dipping Pattern? Morning Surge? Variability of BP? Ambulatory BP Differences for Normotensives, and Mild and Established HTN Patients 120- 110- 100- 90- 80- 70- 60- 0- Diastolic Blood Pressure (mm Hg) Clinic Work Home Sleep Normotensives Mild hypertensives Established hypertensives Clinical situations in which the normal diurnal rhythm of BP may be lost Autonomic Dysfunction Syndromes Diabetes Mellitus Renal Failure Secondary forms of hypertension e.g. Cushing’s disease Drugs, e.g. cyclosporine African-American ethnicity Nocturnal BP Changes and CV Mortality: Ohasama study (Ohkubo et al; AJH 1997; 10: 1201) Extreme dippers Dippers Non-dippers Risers Risk of CV Mortality Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Morning Peak of VT Detected by Implanted Cardioverter/Defibrillator (Tofler Circ 1995;92: 1203) Episodes of VT Circadian Rhythm of Ischemic & Hemorrhagic Strokes Gallerani et al, Acta Neurol Scand 1993; 87: 482) % of strokes 1-6 6 -12 12-18 18-24 Hour of day Ischemic Hemorrhagic Analysis of The Influence of the Morning Surge of BP on Stroke Incidence (Kario, Pickering et al, Circ 2003; 107:1401)) Cox regression analysis for clinical stroke events Covariates RR P value Age (10 yrs) 1.80 (1.21-2.69) 0.004 Male gender 1.42 (0.76-2.67) 0.266 BMI 0.98 (0.90-1.07) 0.663 24 hr SBP 1.37 (1.16-1.63 0.003 SCI 4.40 (1.95-10.1) 0.001 Morning BP surge* 1.29 (1.10-1.51) 0.001 Nocturnal BP fall* 0.88 (0.73-1.06) 0.167 Lowest sleep BP 1.05 (0.65-1.71) 0.837 * per 10 mmHg Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Efficacy: telmisartan vs amlodipine using 24-h ABPM Placebo (n=58) Amlodipine (5-10 mg) (n=65) Telmisartan (40-120 mg) (n=62) 0800 1200 1600 2000 2400 0400 0800 BP (mm Hg) Lacourcière Y et al, in press 160 140 120 100 0 Time Week 12, SBP Effects of Two ARBs Approved for Once Daily Dosing on 24 Hour Blood Pressure (Mancia et al AJC 1999: 84; 28S) Missed Dose Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs

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Does the Pattern of Blood Pressure Effects During the Day Matter? Thomas Pickering MD, DPhil Behavioral Cardiovascular Health and Hypertension Program Division of General Medicine Columbia Presbyterian Medical Center New York Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs What is the True Blood Pressure? Clinic BP? Home BP? 24 Hr Average BP? Daytime BP? Nighttime BP? Dipping Pattern? Morning Surge? Variability of BP? Ambulatory BP Differences for Normotensives, and Mild and Established HTN Patients 120- 110- 100- 90- 80- 70- 60- 0- Diastolic Blood Pressure (mm Hg) Clinic Work Home Sleep Normotensives Mild hypertensives Established hypertensives Clinical situations in which the normal diurnal rhythm of BP may be lost Autonomic Dysfunction Syndromes Diabetes Mellitus Renal Failure Secondary forms of hypertension e.g. Cushing’s disease Drugs, e.g. cyclosporine African-American ethnicity Nocturnal BP Changes and CV Mortality: Ohasama study (Ohkubo et al; AJH 1997; 10: 1201) Extreme dippers Dippers Non-dippers Risers Risk of CV Mortality Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Morning Peak of VT Detected by Implanted Cardioverter/Defibrillator (Tofler Circ 1995;92: 1203) Episodes of VT Circadian Rhythm of Ischemic & Hemorrhagic Strokes Gallerani et al, Acta Neurol Scand 1993; 87: 482) % of strokes 1-6 6 -12 12-18 18-24 Hour of day Ischemic Hemorrhagic Analysis of The Influence of the Morning Surge of BP on Stroke Incidence (Kario, Pickering et al, Circ 2003; 107:1401)) Cox regression analysis for clinical stroke events Covariates RR P value Age (10 yrs) 1.80 (1.21-2.69) 0.004 Male gender 1.42 (0.76-2.67) 0.266 BMI 0.98 (0.90-1.07) 0.663 24 hr SBP 1.37 (1.16-1.63 0.003 SCI 4.40 (1.95-10.1) 0.001 Morning BP surge* 1.29 (1.10-1.51) 0.001 Nocturnal BP fall* 0.88 (0.73-1.06) 0.167 Lowest sleep BP 1.05 (0.65-1.71) 0.837 * per 10 mmHg Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Efficacy: telmisartan vs amlodipine using 24-h ABPM Placebo (n=58) Amlodipine (5-10 mg) (n=65) Telmisartan (40-120 mg) (n=62) 0800 1200 1600 2000 2400 0400 0800 BP (mm Hg) Lacourcière Y et al, in press 160 140 120 100 0 Time Week 12, SBP Effects of Two ARBs Approved for Once Daily Dosing on 24 Hour Blood Pressure (Mancia et al AJC 1999: 84; 28S) Missed Dose Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Do different drug classes have different effects on Daytime vs. Nighttime BP?

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Does the Pattern of Blood Pressure Effects During the Day Matter? Thomas Pickering MD, DPhil Behavioral Cardiovascular Health and Hypertension Program Division of General Medicine Columbia Presbyterian Medical Center New York Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs What is the True Blood Pressure? Clinic BP? Home BP? 24 Hr Average BP? Daytime BP? Nighttime BP? Dipping Pattern? Morning Surge? Variability of BP? Ambulatory BP Differences for Normotensives, and Mild and Established HTN Patients 120- 110- 100- 90- 80- 70- 60- 0- Diastolic Blood Pressure (mm Hg) Clinic Work Home Sleep Normotensives Mild hypertensives Established hypertensives Clinical situations in which the normal diurnal rhythm of BP may be lost Autonomic Dysfunction Syndromes Diabetes Mellitus Renal Failure Secondary forms of hypertension e.g. Cushing’s disease Drugs, e.g. cyclosporine African-American ethnicity Nocturnal BP Changes and CV Mortality: Ohasama study (Ohkubo et al; AJH 1997; 10: 1201) Extreme dippers Dippers Non-dippers Risers Risk of CV Mortality Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Morning Peak of VT Detected by Implanted Cardioverter/Defibrillator (Tofler Circ 1995;92: 1203) Episodes of VT Circadian Rhythm of Ischemic & Hemorrhagic Strokes Gallerani et al, Acta Neurol Scand 1993; 87: 482) % of strokes 1-6 6 -12 12-18 18-24 Hour of day Ischemic Hemorrhagic Analysis of The Influence of the Morning Surge of BP on Stroke Incidence (Kario, Pickering et al, Circ 2003; 107:1401)) Cox regression analysis for clinical stroke events Covariates RR P value Age (10 yrs) 1.80 (1.21-2.69) 0.004 Male gender 1.42 (0.76-2.67) 0.266 BMI 0.98 (0.90-1.07) 0.663 24 hr SBP 1.37 (1.16-1.63 0.003 SCI 4.40 (1.95-10.1) 0.001 Morning BP surge* 1.29 (1.10-1.51) 0.001 Nocturnal BP fall* 0.88 (0.73-1.06) 0.167 Lowest sleep BP 1.05 (0.65-1.71) 0.837 * per 10 mmHg Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Efficacy: telmisartan vs amlodipine using 24-h ABPM Placebo (n=58) Amlodipine (5-10 mg) (n=65) Telmisartan (40-120 mg) (n=62) 0800 1200 1600 2000 2400 0400 0800 BP (mm Hg) Lacourcière Y et al, in press 160 140 120 100 0 Time Week 12, SBP Effects of Two ARBs Approved for Once Daily Dosing on 24 Hour Blood Pressure (Mancia et al AJC 1999: 84; 28S) Missed Dose Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Do different drug classes have different effects on Daytime vs. Nighttime BP? Meta-Analysis of Effects of Antihypertensive Drug Classes on Daytime & Nighttime BP Weiner, Rieckmann, & Pickering, 2005 Medline search of trials in which effects of antihypertensive drugs on daytime, nighttime, and 24 hr BP were described 55 trials satisfied criteria, & were grouped into 3 classes: ACEI, ARBs, Beta blockers (n=10), CCBs & Diuretics (n=35), and combinations (n=10). Across all studies, the absolute change of daytime BP (14/8 mmHg) was significantly greater than the change of nighttime BP (12.5/4.5 mmHg, p<0.01). The magnitude of the difference between the daytime & nighttime changes did not differ between the groups (p>0.7).

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Does the Pattern of Blood Pressure Effects During the Day Matter? Thomas Pickering MD, DPhil Behavioral Cardiovascular Health and Hypertension Program Division of General Medicine Columbia Presbyterian Medical Center New York Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs What is the True Blood Pressure? Clinic BP? Home BP? 24 Hr Average BP? Daytime BP? Nighttime BP? Dipping Pattern? Morning Surge? Variability of BP? Ambulatory BP Differences for Normotensives, and Mild and Established HTN Patients 120- 110- 100- 90- 80- 70- 60- 0- Diastolic Blood Pressure (mm Hg) Clinic Work Home Sleep Normotensives Mild hypertensives Established hypertensives Clinical situations in which the normal diurnal rhythm of BP may be lost Autonomic Dysfunction Syndromes Diabetes Mellitus Renal Failure Secondary forms of hypertension e.g. Cushing’s disease Drugs, e.g. cyclosporine African-American ethnicity Nocturnal BP Changes and CV Mortality: Ohasama study (Ohkubo et al; AJH 1997; 10: 1201) Extreme dippers Dippers Non-dippers Risers Risk of CV Mortality Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Morning Peak of VT Detected by Implanted Cardioverter/Defibrillator (Tofler Circ 1995;92: 1203) Episodes of VT Circadian Rhythm of Ischemic & Hemorrhagic Strokes Gallerani et al, Acta Neurol Scand 1993; 87: 482) % of strokes 1-6 6 -12 12-18 18-24 Hour of day Ischemic Hemorrhagic Analysis of The Influence of the Morning Surge of BP on Stroke Incidence (Kario, Pickering et al, Circ 2003; 107:1401)) Cox regression analysis for clinical stroke events Covariates RR P value Age (10 yrs) 1.80 (1.21-2.69) 0.004 Male gender 1.42 (0.76-2.67) 0.266 BMI 0.98 (0.90-1.07) 0.663 24 hr SBP 1.37 (1.16-1.63 0.003 SCI 4.40 (1.95-10.1) 0.001 Morning BP surge* 1.29 (1.10-1.51) 0.001 Nocturnal BP fall* 0.88 (0.73-1.06) 0.167 Lowest sleep BP 1.05 (0.65-1.71) 0.837 * per 10 mmHg Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Efficacy: telmisartan vs amlodipine using 24-h ABPM Placebo (n=58) Amlodipine (5-10 mg) (n=65) Telmisartan (40-120 mg) (n=62) 0800 1200 1600 2000 2400 0400 0800 BP (mm Hg) Lacourcière Y et al, in press 160 140 120 100 0 Time Week 12, SBP Effects of Two ARBs Approved for Once Daily Dosing on 24 Hour Blood Pressure (Mancia et al AJC 1999: 84; 28S) Missed Dose Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Do different drug classes have different effects on Daytime vs. Nighttime BP? Meta-Analysis of Effects of Antihypertensive Drug Classes on Daytime & Nighttime BP Weiner, Rieckmann, & Pickering, 2005 Medline search of trials in which effects of antihypertensive drugs on daytime, nighttime, and 24 hr BP were described 55 trials satisfied criteria, & were grouped into 3 classes: ACEI, ARBs, Beta blockers (n=10), CCBs & Diuretics (n=35), and combinations (n=10). Across all studies, the absolute change of daytime BP (14/8 mmHg) was significantly greater than the change of nighttime BP (12.5/4.5 mmHg, p<0.01). The magnitude of the difference between the daytime & nighttime changes did not differ between the groups (p>0.7). Meta-Analysis of Effects of Antihypertensive Drug Classes on Daytime & Nighttime BP Weiner, Rieckmann, & Pickering, 2005 Change of SBP with Treatment mmHg

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Does the Pattern of Blood Pressure Effects During the Day Matter? Thomas Pickering MD, DPhil Behavioral Cardiovascular Health and Hypertension Program Division of General Medicine Columbia Presbyterian Medical Center New York Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs What is the True Blood Pressure? Clinic BP? Home BP? 24 Hr Average BP? Daytime BP? Nighttime BP? Dipping Pattern? Morning Surge? Variability of BP? Ambulatory BP Differences for Normotensives, and Mild and Established HTN Patients 120- 110- 100- 90- 80- 70- 60- 0- Diastolic Blood Pressure (mm Hg) Clinic Work Home Sleep Normotensives Mild hypertensives Established hypertensives Clinical situations in which the normal diurnal rhythm of BP may be lost Autonomic Dysfunction Syndromes Diabetes Mellitus Renal Failure Secondary forms of hypertension e.g. Cushing’s disease Drugs, e.g. cyclosporine African-American ethnicity Nocturnal BP Changes and CV Mortality: Ohasama study (Ohkubo et al; AJH 1997; 10: 1201) Extreme dippers Dippers Non-dippers Risers Risk of CV Mortality Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Morning Peak of VT Detected by Implanted Cardioverter/Defibrillator (Tofler Circ 1995;92: 1203) Episodes of VT Circadian Rhythm of Ischemic & Hemorrhagic Strokes Gallerani et al, Acta Neurol Scand 1993; 87: 482) % of strokes 1-6 6 -12 12-18 18-24 Hour of day Ischemic Hemorrhagic Analysis of The Influence of the Morning Surge of BP on Stroke Incidence (Kario, Pickering et al, Circ 2003; 107:1401)) Cox regression analysis for clinical stroke events Covariates RR P value Age (10 yrs) 1.80 (1.21-2.69) 0.004 Male gender 1.42 (0.76-2.67) 0.266 BMI 0.98 (0.90-1.07) 0.663 24 hr SBP 1.37 (1.16-1.63 0.003 SCI 4.40 (1.95-10.1) 0.001 Morning BP surge* 1.29 (1.10-1.51) 0.001 Nocturnal BP fall* 0.88 (0.73-1.06) 0.167 Lowest sleep BP 1.05 (0.65-1.71) 0.837 * per 10 mmHg Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Efficacy: telmisartan vs amlodipine using 24-h ABPM Placebo (n=58) Amlodipine (5-10 mg) (n=65) Telmisartan (40-120 mg) (n=62) 0800 1200 1600 2000 2400 0400 0800 BP (mm Hg) Lacourcière Y et al, in press 160 140 120 100 0 Time Week 12, SBP Effects of Two ARBs Approved for Once Daily Dosing on 24 Hour Blood Pressure (Mancia et al AJC 1999: 84; 28S) Missed Dose Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Do different drug classes have different effects on Daytime vs. Nighttime BP? Meta-Analysis of Effects of Antihypertensive Drug Classes on Daytime & Nighttime BP Weiner, Rieckmann, & Pickering, 2005 Medline search of trials in which effects of antihypertensive drugs on daytime, nighttime, and 24 hr BP were described 55 trials satisfied criteria, & were grouped into 3 classes: ACEI, ARBs, Beta blockers (n=10), CCBs & Diuretics (n=35), and combinations (n=10). Across all studies, the absolute change of daytime BP (14/8 mmHg) was significantly greater than the change of nighttime BP (12.5/4.5 mmHg, p<0.01). The magnitude of the difference between the daytime & nighttime changes did not differ between the groups (p>0.7). Meta-Analysis of Effects of Antihypertensive Drug Classes on Daytime & Nighttime BP Weiner, Rieckmann, & Pickering, 2005 Change of SBP with Treatment mmHg DAY NIGHT Baseline Systolic BP mmHg BP Change mmHg ACEI, ARBs CCBs, Diuretics Meta-Analysis of Effects of Antihypertensive Drug Classes on Daytime & Nighttime BP Weiner, Rieckmann, & Pickering, 2005 Day: B=.07 (p=0.53) Night: B=.04 (p=0.63) Day: B=.55 (p<0.001) Night: B=.55 (p<0.001)

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Does the Pattern of Blood Pressure Effects During the Day Matter? Thomas Pickering MD, DPhil Behavioral Cardiovascular Health and Hypertension Program Division of General Medicine Columbia Presbyterian Medical Center New York Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs What is the True Blood Pressure? Clinic BP? Home BP? 24 Hr Average BP? Daytime BP? Nighttime BP? Dipping Pattern? Morning Surge? Variability of BP? Ambulatory BP Differences for Normotensives, and Mild and Established HTN Patients 120- 110- 100- 90- 80- 70- 60- 0- Diastolic Blood Pressure (mm Hg) Clinic Work Home Sleep Normotensives Mild hypertensives Established hypertensives Clinical situations in which the normal diurnal rhythm of BP may be lost Autonomic Dysfunction Syndromes Diabetes Mellitus Renal Failure Secondary forms of hypertension e.g. Cushing’s disease Drugs, e.g. cyclosporine African-American ethnicity Nocturnal BP Changes and CV Mortality: Ohasama study (Ohkubo et al; AJH 1997; 10: 1201) Extreme dippers Dippers Non-dippers Risers Risk of CV Mortality Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Morning Peak of VT Detected by Implanted Cardioverter/Defibrillator (Tofler Circ 1995;92: 1203) Episodes of VT Circadian Rhythm of Ischemic & Hemorrhagic Strokes Gallerani et al, Acta Neurol Scand 1993; 87: 482) % of strokes 1-6 6 -12 12-18 18-24 Hour of day Ischemic Hemorrhagic Analysis of The Influence of the Morning Surge of BP on Stroke Incidence (Kario, Pickering et al, Circ 2003; 107:1401)) Cox regression analysis for clinical stroke events Covariates RR P value Age (10 yrs) 1.80 (1.21-2.69) 0.004 Male gender 1.42 (0.76-2.67) 0.266 BMI 0.98 (0.90-1.07) 0.663 24 hr SBP 1.37 (1.16-1.63 0.003 SCI 4.40 (1.95-10.1) 0.001 Morning BP surge* 1.29 (1.10-1.51) 0.001 Nocturnal BP fall* 0.88 (0.73-1.06) 0.167 Lowest sleep BP 1.05 (0.65-1.71) 0.837 * per 10 mmHg Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Efficacy: telmisartan vs amlodipine using 24-h ABPM Placebo (n=58) Amlodipine (5-10 mg) (n=65) Telmisartan (40-120 mg) (n=62) 0800 1200 1600 2000 2400 0400 0800 BP (mm Hg) Lacourcière Y et al, in press 160 140 120 100 0 Time Week 12, SBP Effects of Two ARBs Approved for Once Daily Dosing on 24 Hour Blood Pressure (Mancia et al AJC 1999: 84; 28S) Missed Dose Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Do different drug classes have different effects on Daytime vs. Nighttime BP? Meta-Analysis of Effects of Antihypertensive Drug Classes on Daytime & Nighttime BP Weiner, Rieckmann, & Pickering, 2005 Medline search of trials in which effects of antihypertensive drugs on daytime, nighttime, and 24 hr BP were described 55 trials satisfied criteria, & were grouped into 3 classes: ACEI, ARBs, Beta blockers (n=10), CCBs & Diuretics (n=35), and combinations (n=10). Across all studies, the absolute change of daytime BP (14/8 mmHg) was significantly greater than the change of nighttime BP (12.5/4.5 mmHg, p<0.01). The magnitude of the difference between the daytime & nighttime changes did not differ between the groups (p>0.7). Meta-Analysis of Effects of Antihypertensive Drug Classes on Daytime & Nighttime BP Weiner, Rieckmann, & Pickering, 2005 Change of SBP with Treatment mmHg DAY NIGHT Baseline Systolic BP mmHg BP Change mmHg ACEI, ARBs CCBs, Diuretics Meta-Analysis of Effects of Antihypertensive Drug Classes on Daytime & Nighttime BP Weiner, Rieckmann, & Pickering, 2005 Day: B=.07 (p=0.53) Night: B=.04 (p=0.63) Day: B=.55 (p<0.001) Night: B=.55 (p<0.001) Are there class differences in thresholds for lowering BP? (Sekino et al, J Hum Hypertens 1998: 12: 719) Drug Average Effect Threshold BP* on BP Level CBP ABP Daytime Nighttime Nilvadipine -26 -12.5 127 110 Amlodipine -20 -15 127 106 Bisoprolol -19 -12 124 110 Lisinopril -20 -19 97 108 * Estimated from regression line of baseline BP versus change

Slide 21 -

Does the Pattern of Blood Pressure Effects During the Day Matter? Thomas Pickering MD, DPhil Behavioral Cardiovascular Health and Hypertension Program Division of General Medicine Columbia Presbyterian Medical Center New York Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs What is the True Blood Pressure? Clinic BP? Home BP? 24 Hr Average BP? Daytime BP? Nighttime BP? Dipping Pattern? Morning Surge? Variability of BP? Ambulatory BP Differences for Normotensives, and Mild and Established HTN Patients 120- 110- 100- 90- 80- 70- 60- 0- Diastolic Blood Pressure (mm Hg) Clinic Work Home Sleep Normotensives Mild hypertensives Established hypertensives Clinical situations in which the normal diurnal rhythm of BP may be lost Autonomic Dysfunction Syndromes Diabetes Mellitus Renal Failure Secondary forms of hypertension e.g. Cushing’s disease Drugs, e.g. cyclosporine African-American ethnicity Nocturnal BP Changes and CV Mortality: Ohasama study (Ohkubo et al; AJH 1997; 10: 1201) Extreme dippers Dippers Non-dippers Risers Risk of CV Mortality Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Morning Peak of VT Detected by Implanted Cardioverter/Defibrillator (Tofler Circ 1995;92: 1203) Episodes of VT Circadian Rhythm of Ischemic & Hemorrhagic Strokes Gallerani et al, Acta Neurol Scand 1993; 87: 482) % of strokes 1-6 6 -12 12-18 18-24 Hour of day Ischemic Hemorrhagic Analysis of The Influence of the Morning Surge of BP on Stroke Incidence (Kario, Pickering et al, Circ 2003; 107:1401)) Cox regression analysis for clinical stroke events Covariates RR P value Age (10 yrs) 1.80 (1.21-2.69) 0.004 Male gender 1.42 (0.76-2.67) 0.266 BMI 0.98 (0.90-1.07) 0.663 24 hr SBP 1.37 (1.16-1.63 0.003 SCI 4.40 (1.95-10.1) 0.001 Morning BP surge* 1.29 (1.10-1.51) 0.001 Nocturnal BP fall* 0.88 (0.73-1.06) 0.167 Lowest sleep BP 1.05 (0.65-1.71) 0.837 * per 10 mmHg Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Efficacy: telmisartan vs amlodipine using 24-h ABPM Placebo (n=58) Amlodipine (5-10 mg) (n=65) Telmisartan (40-120 mg) (n=62) 0800 1200 1600 2000 2400 0400 0800 BP (mm Hg) Lacourcière Y et al, in press 160 140 120 100 0 Time Week 12, SBP Effects of Two ARBs Approved for Once Daily Dosing on 24 Hour Blood Pressure (Mancia et al AJC 1999: 84; 28S) Missed Dose Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Do different drug classes have different effects on Daytime vs. Nighttime BP? Meta-Analysis of Effects of Antihypertensive Drug Classes on Daytime & Nighttime BP Weiner, Rieckmann, & Pickering, 2005 Medline search of trials in which effects of antihypertensive drugs on daytime, nighttime, and 24 hr BP were described 55 trials satisfied criteria, & were grouped into 3 classes: ACEI, ARBs, Beta blockers (n=10), CCBs & Diuretics (n=35), and combinations (n=10). Across all studies, the absolute change of daytime BP (14/8 mmHg) was significantly greater than the change of nighttime BP (12.5/4.5 mmHg, p<0.01). The magnitude of the difference between the daytime & nighttime changes did not differ between the groups (p>0.7). Meta-Analysis of Effects of Antihypertensive Drug Classes on Daytime & Nighttime BP Weiner, Rieckmann, & Pickering, 2005 Change of SBP with Treatment mmHg DAY NIGHT Baseline Systolic BP mmHg BP Change mmHg ACEI, ARBs CCBs, Diuretics Meta-Analysis of Effects of Antihypertensive Drug Classes on Daytime & Nighttime BP Weiner, Rieckmann, & Pickering, 2005 Day: B=.07 (p=0.53) Night: B=.04 (p=0.63) Day: B=.55 (p<0.001) Night: B=.55 (p<0.001) Are there class differences in thresholds for lowering BP? (Sekino et al, J Hum Hypertens 1998: 12: 719) Drug Average Effect Threshold BP* on BP Level CBP ABP Daytime Nighttime Nilvadipine -26 -12.5 127 110 Amlodipine -20 -15 127 106 Bisoprolol -19 -12 124 110 Lisinopril -20 -19 97 108 * Estimated from regression line of baseline BP versus change Are there class differences in thresholds for lowering BP? (Sekino et al, J Hum Hypertens 1998: 12: 719) Drug Average Effect Threshold BP* on BP Level CBP ABP Daytime Nighttime Nilvadipine -26 -12.5 127 110 Amlodipine -20 -15 127 106 Bisoprolol -19 -12 124 110 Lisinopril -20 -19 97 108 Combination1 -20 -14 128 106 * Estimated from regression line of baseline BP versus change 1- ACEI + CCB- Fagard et al Am J Hypertens 1993: 6: 648

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Does the Pattern of Blood Pressure Effects During the Day Matter? Thomas Pickering MD, DPhil Behavioral Cardiovascular Health and Hypertension Program Division of General Medicine Columbia Presbyterian Medical Center New York Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs What is the True Blood Pressure? Clinic BP? Home BP? 24 Hr Average BP? Daytime BP? Nighttime BP? Dipping Pattern? Morning Surge? Variability of BP? Ambulatory BP Differences for Normotensives, and Mild and Established HTN Patients 120- 110- 100- 90- 80- 70- 60- 0- Diastolic Blood Pressure (mm Hg) Clinic Work Home Sleep Normotensives Mild hypertensives Established hypertensives Clinical situations in which the normal diurnal rhythm of BP may be lost Autonomic Dysfunction Syndromes Diabetes Mellitus Renal Failure Secondary forms of hypertension e.g. Cushing’s disease Drugs, e.g. cyclosporine African-American ethnicity Nocturnal BP Changes and CV Mortality: Ohasama study (Ohkubo et al; AJH 1997; 10: 1201) Extreme dippers Dippers Non-dippers Risers Risk of CV Mortality Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Morning Peak of VT Detected by Implanted Cardioverter/Defibrillator (Tofler Circ 1995;92: 1203) Episodes of VT Circadian Rhythm of Ischemic & Hemorrhagic Strokes Gallerani et al, Acta Neurol Scand 1993; 87: 482) % of strokes 1-6 6 -12 12-18 18-24 Hour of day Ischemic Hemorrhagic Analysis of The Influence of the Morning Surge of BP on Stroke Incidence (Kario, Pickering et al, Circ 2003; 107:1401)) Cox regression analysis for clinical stroke events Covariates RR P value Age (10 yrs) 1.80 (1.21-2.69) 0.004 Male gender 1.42 (0.76-2.67) 0.266 BMI 0.98 (0.90-1.07) 0.663 24 hr SBP 1.37 (1.16-1.63 0.003 SCI 4.40 (1.95-10.1) 0.001 Morning BP surge* 1.29 (1.10-1.51) 0.001 Nocturnal BP fall* 0.88 (0.73-1.06) 0.167 Lowest sleep BP 1.05 (0.65-1.71) 0.837 * per 10 mmHg Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Efficacy: telmisartan vs amlodipine using 24-h ABPM Placebo (n=58) Amlodipine (5-10 mg) (n=65) Telmisartan (40-120 mg) (n=62) 0800 1200 1600 2000 2400 0400 0800 BP (mm Hg) Lacourcière Y et al, in press 160 140 120 100 0 Time Week 12, SBP Effects of Two ARBs Approved for Once Daily Dosing on 24 Hour Blood Pressure (Mancia et al AJC 1999: 84; 28S) Missed Dose Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Do different drug classes have different effects on Daytime vs. Nighttime BP? Meta-Analysis of Effects of Antihypertensive Drug Classes on Daytime & Nighttime BP Weiner, Rieckmann, & Pickering, 2005 Medline search of trials in which effects of antihypertensive drugs on daytime, nighttime, and 24 hr BP were described 55 trials satisfied criteria, & were grouped into 3 classes: ACEI, ARBs, Beta blockers (n=10), CCBs & Diuretics (n=35), and combinations (n=10). Across all studies, the absolute change of daytime BP (14/8 mmHg) was significantly greater than the change of nighttime BP (12.5/4.5 mmHg, p<0.01). The magnitude of the difference between the daytime & nighttime changes did not differ between the groups (p>0.7). Meta-Analysis of Effects of Antihypertensive Drug Classes on Daytime & Nighttime BP Weiner, Rieckmann, & Pickering, 2005 Change of SBP with Treatment mmHg DAY NIGHT Baseline Systolic BP mmHg BP Change mmHg ACEI, ARBs CCBs, Diuretics Meta-Analysis of Effects of Antihypertensive Drug Classes on Daytime & Nighttime BP Weiner, Rieckmann, & Pickering, 2005 Day: B=.07 (p=0.53) Night: B=.04 (p=0.63) Day: B=.55 (p<0.001) Night: B=.55 (p<0.001) Are there class differences in thresholds for lowering BP? (Sekino et al, J Hum Hypertens 1998: 12: 719) Drug Average Effect Threshold BP* on BP Level CBP ABP Daytime Nighttime Nilvadipine -26 -12.5 127 110 Amlodipine -20 -15 127 106 Bisoprolol -19 -12 124 110 Lisinopril -20 -19 97 108 * Estimated from regression line of baseline BP versus change Are there class differences in thresholds for lowering BP? (Sekino et al, J Hum Hypertens 1998: 12: 719) Drug Average Effect Threshold BP* on BP Level CBP ABP Daytime Nighttime Nilvadipine -26 -12.5 127 110 Amlodipine -20 -15 127 106 Bisoprolol -19 -12 124 110 Lisinopril -20 -19 97 108 Combination1 -20 -14 128 106 * Estimated from regression line of baseline BP versus change 1- ACEI + CCB- Fagard et al Am J Hypertens 1993: 6: 648 Diuretics Convert Non-Dippers to Dippers (Uzu & Kimura Circ 1999; 100:1635) Systolic pressure mmHg Day Night No Rx HCTZ No Rx HCTZ Dippers Non-Dippers

Slide 23 -

Does the Pattern of Blood Pressure Effects During the Day Matter? Thomas Pickering MD, DPhil Behavioral Cardiovascular Health and Hypertension Program Division of General Medicine Columbia Presbyterian Medical Center New York Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs What is the True Blood Pressure? Clinic BP? Home BP? 24 Hr Average BP? Daytime BP? Nighttime BP? Dipping Pattern? Morning Surge? Variability of BP? Ambulatory BP Differences for Normotensives, and Mild and Established HTN Patients 120- 110- 100- 90- 80- 70- 60- 0- Diastolic Blood Pressure (mm Hg) Clinic Work Home Sleep Normotensives Mild hypertensives Established hypertensives Clinical situations in which the normal diurnal rhythm of BP may be lost Autonomic Dysfunction Syndromes Diabetes Mellitus Renal Failure Secondary forms of hypertension e.g. Cushing’s disease Drugs, e.g. cyclosporine African-American ethnicity Nocturnal BP Changes and CV Mortality: Ohasama study (Ohkubo et al; AJH 1997; 10: 1201) Extreme dippers Dippers Non-dippers Risers Risk of CV Mortality Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Morning Peak of VT Detected by Implanted Cardioverter/Defibrillator (Tofler Circ 1995;92: 1203) Episodes of VT Circadian Rhythm of Ischemic & Hemorrhagic Strokes Gallerani et al, Acta Neurol Scand 1993; 87: 482) % of strokes 1-6 6 -12 12-18 18-24 Hour of day Ischemic Hemorrhagic Analysis of The Influence of the Morning Surge of BP on Stroke Incidence (Kario, Pickering et al, Circ 2003; 107:1401)) Cox regression analysis for clinical stroke events Covariates RR P value Age (10 yrs) 1.80 (1.21-2.69) 0.004 Male gender 1.42 (0.76-2.67) 0.266 BMI 0.98 (0.90-1.07) 0.663 24 hr SBP 1.37 (1.16-1.63 0.003 SCI 4.40 (1.95-10.1) 0.001 Morning BP surge* 1.29 (1.10-1.51) 0.001 Nocturnal BP fall* 0.88 (0.73-1.06) 0.167 Lowest sleep BP 1.05 (0.65-1.71) 0.837 * per 10 mmHg Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Efficacy: telmisartan vs amlodipine using 24-h ABPM Placebo (n=58) Amlodipine (5-10 mg) (n=65) Telmisartan (40-120 mg) (n=62) 0800 1200 1600 2000 2400 0400 0800 BP (mm Hg) Lacourcière Y et al, in press 160 140 120 100 0 Time Week 12, SBP Effects of Two ARBs Approved for Once Daily Dosing on 24 Hour Blood Pressure (Mancia et al AJC 1999: 84; 28S) Missed Dose Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Do different drug classes have different effects on Daytime vs. Nighttime BP? Meta-Analysis of Effects of Antihypertensive Drug Classes on Daytime & Nighttime BP Weiner, Rieckmann, & Pickering, 2005 Medline search of trials in which effects of antihypertensive drugs on daytime, nighttime, and 24 hr BP were described 55 trials satisfied criteria, & were grouped into 3 classes: ACEI, ARBs, Beta blockers (n=10), CCBs & Diuretics (n=35), and combinations (n=10). Across all studies, the absolute change of daytime BP (14/8 mmHg) was significantly greater than the change of nighttime BP (12.5/4.5 mmHg, p<0.01). The magnitude of the difference between the daytime & nighttime changes did not differ between the groups (p>0.7). Meta-Analysis of Effects of Antihypertensive Drug Classes on Daytime & Nighttime BP Weiner, Rieckmann, & Pickering, 2005 Change of SBP with Treatment mmHg DAY NIGHT Baseline Systolic BP mmHg BP Change mmHg ACEI, ARBs CCBs, Diuretics Meta-Analysis of Effects of Antihypertensive Drug Classes on Daytime & Nighttime BP Weiner, Rieckmann, & Pickering, 2005 Day: B=.07 (p=0.53) Night: B=.04 (p=0.63) Day: B=.55 (p<0.001) Night: B=.55 (p<0.001) Are there class differences in thresholds for lowering BP? (Sekino et al, J Hum Hypertens 1998: 12: 719) Drug Average Effect Threshold BP* on BP Level CBP ABP Daytime Nighttime Nilvadipine -26 -12.5 127 110 Amlodipine -20 -15 127 106 Bisoprolol -19 -12 124 110 Lisinopril -20 -19 97 108 * Estimated from regression line of baseline BP versus change Are there class differences in thresholds for lowering BP? (Sekino et al, J Hum Hypertens 1998: 12: 719) Drug Average Effect Threshold BP* on BP Level CBP ABP Daytime Nighttime Nilvadipine -26 -12.5 127 110 Amlodipine -20 -15 127 106 Bisoprolol -19 -12 124 110 Lisinopril -20 -19 97 108 Combination1 -20 -14 128 106 * Estimated from regression line of baseline BP versus change 1- ACEI + CCB- Fagard et al Am J Hypertens 1993: 6: 648 Diuretics Convert Non-Dippers to Dippers (Uzu & Kimura Circ 1999; 100:1635) Systolic pressure mmHg Day Night No Rx HCTZ No Rx HCTZ Dippers Non-Dippers Diuretics Convert Non-Dippers to Dippers (Uzu & Kimura Circ 1999; 100:1635) Systolic pressure mmHg Day Night No Rx HCTZ No Rx HCTZ Dippers Non-Dippers

Slide 24 -

Does the Pattern of Blood Pressure Effects During the Day Matter? Thomas Pickering MD, DPhil Behavioral Cardiovascular Health and Hypertension Program Division of General Medicine Columbia Presbyterian Medical Center New York Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs What is the True Blood Pressure? Clinic BP? Home BP? 24 Hr Average BP? Daytime BP? Nighttime BP? Dipping Pattern? Morning Surge? Variability of BP? Ambulatory BP Differences for Normotensives, and Mild and Established HTN Patients 120- 110- 100- 90- 80- 70- 60- 0- Diastolic Blood Pressure (mm Hg) Clinic Work Home Sleep Normotensives Mild hypertensives Established hypertensives Clinical situations in which the normal diurnal rhythm of BP may be lost Autonomic Dysfunction Syndromes Diabetes Mellitus Renal Failure Secondary forms of hypertension e.g. Cushing’s disease Drugs, e.g. cyclosporine African-American ethnicity Nocturnal BP Changes and CV Mortality: Ohasama study (Ohkubo et al; AJH 1997; 10: 1201) Extreme dippers Dippers Non-dippers Risers Risk of CV Mortality Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Morning Peak of VT Detected by Implanted Cardioverter/Defibrillator (Tofler Circ 1995;92: 1203) Episodes of VT Circadian Rhythm of Ischemic & Hemorrhagic Strokes Gallerani et al, Acta Neurol Scand 1993; 87: 482) % of strokes 1-6 6 -12 12-18 18-24 Hour of day Ischemic Hemorrhagic Analysis of The Influence of the Morning Surge of BP on Stroke Incidence (Kario, Pickering et al, Circ 2003; 107:1401)) Cox regression analysis for clinical stroke events Covariates RR P value Age (10 yrs) 1.80 (1.21-2.69) 0.004 Male gender 1.42 (0.76-2.67) 0.266 BMI 0.98 (0.90-1.07) 0.663 24 hr SBP 1.37 (1.16-1.63 0.003 SCI 4.40 (1.95-10.1) 0.001 Morning BP surge* 1.29 (1.10-1.51) 0.001 Nocturnal BP fall* 0.88 (0.73-1.06) 0.167 Lowest sleep BP 1.05 (0.65-1.71) 0.837 * per 10 mmHg Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Efficacy: telmisartan vs amlodipine using 24-h ABPM Placebo (n=58) Amlodipine (5-10 mg) (n=65) Telmisartan (40-120 mg) (n=62) 0800 1200 1600 2000 2400 0400 0800 BP (mm Hg) Lacourcière Y et al, in press 160 140 120 100 0 Time Week 12, SBP Effects of Two ARBs Approved for Once Daily Dosing on 24 Hour Blood Pressure (Mancia et al AJC 1999: 84; 28S) Missed Dose Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Do different drug classes have different effects on Daytime vs. Nighttime BP? Meta-Analysis of Effects of Antihypertensive Drug Classes on Daytime & Nighttime BP Weiner, Rieckmann, & Pickering, 2005 Medline search of trials in which effects of antihypertensive drugs on daytime, nighttime, and 24 hr BP were described 55 trials satisfied criteria, & were grouped into 3 classes: ACEI, ARBs, Beta blockers (n=10), CCBs & Diuretics (n=35), and combinations (n=10). Across all studies, the absolute change of daytime BP (14/8 mmHg) was significantly greater than the change of nighttime BP (12.5/4.5 mmHg, p<0.01). The magnitude of the difference between the daytime & nighttime changes did not differ between the groups (p>0.7). Meta-Analysis of Effects of Antihypertensive Drug Classes on Daytime & Nighttime BP Weiner, Rieckmann, & Pickering, 2005 Change of SBP with Treatment mmHg DAY NIGHT Baseline Systolic BP mmHg BP Change mmHg ACEI, ARBs CCBs, Diuretics Meta-Analysis of Effects of Antihypertensive Drug Classes on Daytime & Nighttime BP Weiner, Rieckmann, & Pickering, 2005 Day: B=.07 (p=0.53) Night: B=.04 (p=0.63) Day: B=.55 (p<0.001) Night: B=.55 (p<0.001) Are there class differences in thresholds for lowering BP? (Sekino et al, J Hum Hypertens 1998: 12: 719) Drug Average Effect Threshold BP* on BP Level CBP ABP Daytime Nighttime Nilvadipine -26 -12.5 127 110 Amlodipine -20 -15 127 106 Bisoprolol -19 -12 124 110 Lisinopril -20 -19 97 108 * Estimated from regression line of baseline BP versus change Are there class differences in thresholds for lowering BP? (Sekino et al, J Hum Hypertens 1998: 12: 719) Drug Average Effect Threshold BP* on BP Level CBP ABP Daytime Nighttime Nilvadipine -26 -12.5 127 110 Amlodipine -20 -15 127 106 Bisoprolol -19 -12 124 110 Lisinopril -20 -19 97 108 Combination1 -20 -14 128 106 * Estimated from regression line of baseline BP versus change 1- ACEI + CCB- Fagard et al Am J Hypertens 1993: 6: 648 Diuretics Convert Non-Dippers to Dippers (Uzu & Kimura Circ 1999; 100:1635) Systolic pressure mmHg Day Night No Rx HCTZ No Rx HCTZ Dippers Non-Dippers Diuretics Convert Non-Dippers to Dippers (Uzu & Kimura Circ 1999; 100:1635) Systolic pressure mmHg Day Night No Rx HCTZ No Rx HCTZ Dippers Non-Dippers Regression of Carotid Atherosclerosis by Controlling Morning BP (Marfella et al, Am J Hypertens 2005: 18: 308) Clinic Day Night Morning Carotid IMT 0 -0.02 -0.04 NS NS NS <0.001 <0.02 SBP mmHg IMT mm

Slide 25 -

Does the Pattern of Blood Pressure Effects During the Day Matter? Thomas Pickering MD, DPhil Behavioral Cardiovascular Health and Hypertension Program Division of General Medicine Columbia Presbyterian Medical Center New York Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs What is the True Blood Pressure? Clinic BP? Home BP? 24 Hr Average BP? Daytime BP? Nighttime BP? Dipping Pattern? Morning Surge? Variability of BP? Ambulatory BP Differences for Normotensives, and Mild and Established HTN Patients 120- 110- 100- 90- 80- 70- 60- 0- Diastolic Blood Pressure (mm Hg) Clinic Work Home Sleep Normotensives Mild hypertensives Established hypertensives Clinical situations in which the normal diurnal rhythm of BP may be lost Autonomic Dysfunction Syndromes Diabetes Mellitus Renal Failure Secondary forms of hypertension e.g. Cushing’s disease Drugs, e.g. cyclosporine African-American ethnicity Nocturnal BP Changes and CV Mortality: Ohasama study (Ohkubo et al; AJH 1997; 10: 1201) Extreme dippers Dippers Non-dippers Risers Risk of CV Mortality Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Morning Peak of VT Detected by Implanted Cardioverter/Defibrillator (Tofler Circ 1995;92: 1203) Episodes of VT Circadian Rhythm of Ischemic & Hemorrhagic Strokes Gallerani et al, Acta Neurol Scand 1993; 87: 482) % of strokes 1-6 6 -12 12-18 18-24 Hour of day Ischemic Hemorrhagic Analysis of The Influence of the Morning Surge of BP on Stroke Incidence (Kario, Pickering et al, Circ 2003; 107:1401)) Cox regression analysis for clinical stroke events Covariates RR P value Age (10 yrs) 1.80 (1.21-2.69) 0.004 Male gender 1.42 (0.76-2.67) 0.266 BMI 0.98 (0.90-1.07) 0.663 24 hr SBP 1.37 (1.16-1.63 0.003 SCI 4.40 (1.95-10.1) 0.001 Morning BP surge* 1.29 (1.10-1.51) 0.001 Nocturnal BP fall* 0.88 (0.73-1.06) 0.167 Lowest sleep BP 1.05 (0.65-1.71) 0.837 * per 10 mmHg Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Efficacy: telmisartan vs amlodipine using 24-h ABPM Placebo (n=58) Amlodipine (5-10 mg) (n=65) Telmisartan (40-120 mg) (n=62) 0800 1200 1600 2000 2400 0400 0800 BP (mm Hg) Lacourcière Y et al, in press 160 140 120 100 0 Time Week 12, SBP Effects of Two ARBs Approved for Once Daily Dosing on 24 Hour Blood Pressure (Mancia et al AJC 1999: 84; 28S) Missed Dose Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Do different drug classes have different effects on Daytime vs. Nighttime BP? Meta-Analysis of Effects of Antihypertensive Drug Classes on Daytime & Nighttime BP Weiner, Rieckmann, & Pickering, 2005 Medline search of trials in which effects of antihypertensive drugs on daytime, nighttime, and 24 hr BP were described 55 trials satisfied criteria, & were grouped into 3 classes: ACEI, ARBs, Beta blockers (n=10), CCBs & Diuretics (n=35), and combinations (n=10). Across all studies, the absolute change of daytime BP (14/8 mmHg) was significantly greater than the change of nighttime BP (12.5/4.5 mmHg, p<0.01). The magnitude of the difference between the daytime & nighttime changes did not differ between the groups (p>0.7). Meta-Analysis of Effects of Antihypertensive Drug Classes on Daytime & Nighttime BP Weiner, Rieckmann, & Pickering, 2005 Change of SBP with Treatment mmHg DAY NIGHT Baseline Systolic BP mmHg BP Change mmHg ACEI, ARBs CCBs, Diuretics Meta-Analysis of Effects of Antihypertensive Drug Classes on Daytime & Nighttime BP Weiner, Rieckmann, & Pickering, 2005 Day: B=.07 (p=0.53) Night: B=.04 (p=0.63) Day: B=.55 (p<0.001) Night: B=.55 (p<0.001) Are there class differences in thresholds for lowering BP? (Sekino et al, J Hum Hypertens 1998: 12: 719) Drug Average Effect Threshold BP* on BP Level CBP ABP Daytime Nighttime Nilvadipine -26 -12.5 127 110 Amlodipine -20 -15 127 106 Bisoprolol -19 -12 124 110 Lisinopril -20 -19 97 108 * Estimated from regression line of baseline BP versus change Are there class differences in thresholds for lowering BP? (Sekino et al, J Hum Hypertens 1998: 12: 719) Drug Average Effect Threshold BP* on BP Level CBP ABP Daytime Nighttime Nilvadipine -26 -12.5 127 110 Amlodipine -20 -15 127 106 Bisoprolol -19 -12 124 110 Lisinopril -20 -19 97 108 Combination1 -20 -14 128 106 * Estimated from regression line of baseline BP versus change 1- ACEI + CCB- Fagard et al Am J Hypertens 1993: 6: 648 Diuretics Convert Non-Dippers to Dippers (Uzu & Kimura Circ 1999; 100:1635) Systolic pressure mmHg Day Night No Rx HCTZ No Rx HCTZ Dippers Non-Dippers Diuretics Convert Non-Dippers to Dippers (Uzu & Kimura Circ 1999; 100:1635) Systolic pressure mmHg Day Night No Rx HCTZ No Rx HCTZ Dippers Non-Dippers Regression of Carotid Atherosclerosis by Controlling Morning BP (Marfella et al, Am J Hypertens 2005: 18: 308) Clinic Day Night Morning Carotid IMT 0 -0.02 -0.04 NS NS NS <0.001 <0.02 SBP mmHg IMT mm Regression of Carotid Atherosclerosis by Controlling Morning BP (Marfella et al, Am J Hypertens 2005: 18: 308) Clinic Day Night Morning Carotid IMT 0 -0.02 -0.04 NS NS NS <0.001 <0.02 SBP mmHg IMT mm ?

Slide 26 -

Does the Pattern of Blood Pressure Effects During the Day Matter? Thomas Pickering MD, DPhil Behavioral Cardiovascular Health and Hypertension Program Division of General Medicine Columbia Presbyterian Medical Center New York Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs What is the True Blood Pressure? Clinic BP? Home BP? 24 Hr Average BP? Daytime BP? Nighttime BP? Dipping Pattern? Morning Surge? Variability of BP? Ambulatory BP Differences for Normotensives, and Mild and Established HTN Patients 120- 110- 100- 90- 80- 70- 60- 0- Diastolic Blood Pressure (mm Hg) Clinic Work Home Sleep Normotensives Mild hypertensives Established hypertensives Clinical situations in which the normal diurnal rhythm of BP may be lost Autonomic Dysfunction Syndromes Diabetes Mellitus Renal Failure Secondary forms of hypertension e.g. Cushing’s disease Drugs, e.g. cyclosporine African-American ethnicity Nocturnal BP Changes and CV Mortality: Ohasama study (Ohkubo et al; AJH 1997; 10: 1201) Extreme dippers Dippers Non-dippers Risers Risk of CV Mortality Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Morning Peak of VT Detected by Implanted Cardioverter/Defibrillator (Tofler Circ 1995;92: 1203) Episodes of VT Circadian Rhythm of Ischemic & Hemorrhagic Strokes Gallerani et al, Acta Neurol Scand 1993; 87: 482) % of strokes 1-6 6 -12 12-18 18-24 Hour of day Ischemic Hemorrhagic Analysis of The Influence of the Morning Surge of BP on Stroke Incidence (Kario, Pickering et al, Circ 2003; 107:1401)) Cox regression analysis for clinical stroke events Covariates RR P value Age (10 yrs) 1.80 (1.21-2.69) 0.004 Male gender 1.42 (0.76-2.67) 0.266 BMI 0.98 (0.90-1.07) 0.663 24 hr SBP 1.37 (1.16-1.63 0.003 SCI 4.40 (1.95-10.1) 0.001 Morning BP surge* 1.29 (1.10-1.51) 0.001 Nocturnal BP fall* 0.88 (0.73-1.06) 0.167 Lowest sleep BP 1.05 (0.65-1.71) 0.837 * per 10 mmHg Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Efficacy: telmisartan vs amlodipine using 24-h ABPM Placebo (n=58) Amlodipine (5-10 mg) (n=65) Telmisartan (40-120 mg) (n=62) 0800 1200 1600 2000 2400 0400 0800 BP (mm Hg) Lacourcière Y et al, in press 160 140 120 100 0 Time Week 12, SBP Effects of Two ARBs Approved for Once Daily Dosing on 24 Hour Blood Pressure (Mancia et al AJC 1999: 84; 28S) Missed Dose Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Do different drug classes have different effects on Daytime vs. Nighttime BP? Meta-Analysis of Effects of Antihypertensive Drug Classes on Daytime & Nighttime BP Weiner, Rieckmann, & Pickering, 2005 Medline search of trials in which effects of antihypertensive drugs on daytime, nighttime, and 24 hr BP were described 55 trials satisfied criteria, & were grouped into 3 classes: ACEI, ARBs, Beta blockers (n=10), CCBs & Diuretics (n=35), and combinations (n=10). Across all studies, the absolute change of daytime BP (14/8 mmHg) was significantly greater than the change of nighttime BP (12.5/4.5 mmHg, p<0.01). The magnitude of the difference between the daytime & nighttime changes did not differ between the groups (p>0.7). Meta-Analysis of Effects of Antihypertensive Drug Classes on Daytime & Nighttime BP Weiner, Rieckmann, & Pickering, 2005 Change of SBP with Treatment mmHg DAY NIGHT Baseline Systolic BP mmHg BP Change mmHg ACEI, ARBs CCBs, Diuretics Meta-Analysis of Effects of Antihypertensive Drug Classes on Daytime & Nighttime BP Weiner, Rieckmann, & Pickering, 2005 Day: B=.07 (p=0.53) Night: B=.04 (p=0.63) Day: B=.55 (p<0.001) Night: B=.55 (p<0.001) Are there class differences in thresholds for lowering BP? (Sekino et al, J Hum Hypertens 1998: 12: 719) Drug Average Effect Threshold BP* on BP Level CBP ABP Daytime Nighttime Nilvadipine -26 -12.5 127 110 Amlodipine -20 -15 127 106 Bisoprolol -19 -12 124 110 Lisinopril -20 -19 97 108 * Estimated from regression line of baseline BP versus change Are there class differences in thresholds for lowering BP? (Sekino et al, J Hum Hypertens 1998: 12: 719) Drug Average Effect Threshold BP* on BP Level CBP ABP Daytime Nighttime Nilvadipine -26 -12.5 127 110 Amlodipine -20 -15 127 106 Bisoprolol -19 -12 124 110 Lisinopril -20 -19 97 108 Combination1 -20 -14 128 106 * Estimated from regression line of baseline BP versus change 1- ACEI + CCB- Fagard et al Am J Hypertens 1993: 6: 648 Diuretics Convert Non-Dippers to Dippers (Uzu & Kimura Circ 1999; 100:1635) Systolic pressure mmHg Day Night No Rx HCTZ No Rx HCTZ Dippers Non-Dippers Diuretics Convert Non-Dippers to Dippers (Uzu & Kimura Circ 1999; 100:1635) Systolic pressure mmHg Day Night No Rx HCTZ No Rx HCTZ Dippers Non-Dippers Regression of Carotid Atherosclerosis by Controlling Morning BP (Marfella et al, Am J Hypertens 2005: 18: 308) Clinic Day Night Morning Carotid IMT 0 -0.02 -0.04 NS NS NS <0.001 <0.02 SBP mmHg IMT mm Regression of Carotid Atherosclerosis by Controlling Morning BP (Marfella et al, Am J Hypertens 2005: 18: 308) Clinic Day Night Morning Carotid IMT 0 -0.02 -0.04 NS NS NS <0.001 <0.02 SBP mmHg IMT mm ? Effects of Alpha-Blockade on the Morning Surge of Blood Pressure (Kario, Pickering, et al Am J Hypertens 2004;17; 668) Doxazosin No Rx

Slide 27 -

Does the Pattern of Blood Pressure Effects During the Day Matter? Thomas Pickering MD, DPhil Behavioral Cardiovascular Health and Hypertension Program Division of General Medicine Columbia Presbyterian Medical Center New York Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs What is the True Blood Pressure? Clinic BP? Home BP? 24 Hr Average BP? Daytime BP? Nighttime BP? Dipping Pattern? Morning Surge? Variability of BP? Ambulatory BP Differences for Normotensives, and Mild and Established HTN Patients 120- 110- 100- 90- 80- 70- 60- 0- Diastolic Blood Pressure (mm Hg) Clinic Work Home Sleep Normotensives Mild hypertensives Established hypertensives Clinical situations in which the normal diurnal rhythm of BP may be lost Autonomic Dysfunction Syndromes Diabetes Mellitus Renal Failure Secondary forms of hypertension e.g. Cushing’s disease Drugs, e.g. cyclosporine African-American ethnicity Nocturnal BP Changes and CV Mortality: Ohasama study (Ohkubo et al; AJH 1997; 10: 1201) Extreme dippers Dippers Non-dippers Risers Risk of CV Mortality Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Morning Peak of VT Detected by Implanted Cardioverter/Defibrillator (Tofler Circ 1995;92: 1203) Episodes of VT Circadian Rhythm of Ischemic & Hemorrhagic Strokes Gallerani et al, Acta Neurol Scand 1993; 87: 482) % of strokes 1-6 6 -12 12-18 18-24 Hour of day Ischemic Hemorrhagic Analysis of The Influence of the Morning Surge of BP on Stroke Incidence (Kario, Pickering et al, Circ 2003; 107:1401)) Cox regression analysis for clinical stroke events Covariates RR P value Age (10 yrs) 1.80 (1.21-2.69) 0.004 Male gender 1.42 (0.76-2.67) 0.266 BMI 0.98 (0.90-1.07) 0.663 24 hr SBP 1.37 (1.16-1.63 0.003 SCI 4.40 (1.95-10.1) 0.001 Morning BP surge* 1.29 (1.10-1.51) 0.001 Nocturnal BP fall* 0.88 (0.73-1.06) 0.167 Lowest sleep BP 1.05 (0.65-1.71) 0.837 * per 10 mmHg Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Efficacy: telmisartan vs amlodipine using 24-h ABPM Placebo (n=58) Amlodipine (5-10 mg) (n=65) Telmisartan (40-120 mg) (n=62) 0800 1200 1600 2000 2400 0400 0800 BP (mm Hg) Lacourcière Y et al, in press 160 140 120 100 0 Time Week 12, SBP Effects of Two ARBs Approved for Once Daily Dosing on 24 Hour Blood Pressure (Mancia et al AJC 1999: 84; 28S) Missed Dose Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Do different drug classes have different effects on Daytime vs. Nighttime BP? Meta-Analysis of Effects of Antihypertensive Drug Classes on Daytime & Nighttime BP Weiner, Rieckmann, & Pickering, 2005 Medline search of trials in which effects of antihypertensive drugs on daytime, nighttime, and 24 hr BP were described 55 trials satisfied criteria, & were grouped into 3 classes: ACEI, ARBs, Beta blockers (n=10), CCBs & Diuretics (n=35), and combinations (n=10). Across all studies, the absolute change of daytime BP (14/8 mmHg) was significantly greater than the change of nighttime BP (12.5/4.5 mmHg, p<0.01). The magnitude of the difference between the daytime & nighttime changes did not differ between the groups (p>0.7). Meta-Analysis of Effects of Antihypertensive Drug Classes on Daytime & Nighttime BP Weiner, Rieckmann, & Pickering, 2005 Change of SBP with Treatment mmHg DAY NIGHT Baseline Systolic BP mmHg BP Change mmHg ACEI, ARBs CCBs, Diuretics Meta-Analysis of Effects of Antihypertensive Drug Classes on Daytime & Nighttime BP Weiner, Rieckmann, & Pickering, 2005 Day: B=.07 (p=0.53) Night: B=.04 (p=0.63) Day: B=.55 (p<0.001) Night: B=.55 (p<0.001) Are there class differences in thresholds for lowering BP? (Sekino et al, J Hum Hypertens 1998: 12: 719) Drug Average Effect Threshold BP* on BP Level CBP ABP Daytime Nighttime Nilvadipine -26 -12.5 127 110 Amlodipine -20 -15 127 106 Bisoprolol -19 -12 124 110 Lisinopril -20 -19 97 108 * Estimated from regression line of baseline BP versus change Are there class differences in thresholds for lowering BP? (Sekino et al, J Hum Hypertens 1998: 12: 719) Drug Average Effect Threshold BP* on BP Level CBP ABP Daytime Nighttime Nilvadipine -26 -12.5 127 110 Amlodipine -20 -15 127 106 Bisoprolol -19 -12 124 110 Lisinopril -20 -19 97 108 Combination1 -20 -14 128 106 * Estimated from regression line of baseline BP versus change 1- ACEI + CCB- Fagard et al Am J Hypertens 1993: 6: 648 Diuretics Convert Non-Dippers to Dippers (Uzu & Kimura Circ 1999; 100:1635) Systolic pressure mmHg Day Night No Rx HCTZ No Rx HCTZ Dippers Non-Dippers Diuretics Convert Non-Dippers to Dippers (Uzu & Kimura Circ 1999; 100:1635) Systolic pressure mmHg Day Night No Rx HCTZ No Rx HCTZ Dippers Non-Dippers Regression of Carotid Atherosclerosis by Controlling Morning BP (Marfella et al, Am J Hypertens 2005: 18: 308) Clinic Day Night Morning Carotid IMT 0 -0.02 -0.04 NS NS NS <0.001 <0.02 SBP mmHg IMT mm Regression of Carotid Atherosclerosis by Controlling Morning BP (Marfella et al, Am J Hypertens 2005: 18: 308) Clinic Day Night Morning Carotid IMT 0 -0.02 -0.04 NS NS NS <0.001 <0.02 SBP mmHg IMT mm ? Effects of Alpha-Blockade on the Morning Surge of Blood Pressure (Kario, Pickering, et al Am J Hypertens 2004;17; 668) Doxazosin No Rx Effects of graded release Diltiazem vs. Enalapril on Morning BP (White et al, Am Heart J 2004: 148: 628) Ramipril Diltiazem ER

Slide 28 -

Does the Pattern of Blood Pressure Effects During the Day Matter? Thomas Pickering MD, DPhil Behavioral Cardiovascular Health and Hypertension Program Division of General Medicine Columbia Presbyterian Medical Center New York Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs What is the True Blood Pressure? Clinic BP? Home BP? 24 Hr Average BP? Daytime BP? Nighttime BP? Dipping Pattern? Morning Surge? Variability of BP? Ambulatory BP Differences for Normotensives, and Mild and Established HTN Patients 120- 110- 100- 90- 80- 70- 60- 0- Diastolic Blood Pressure (mm Hg) Clinic Work Home Sleep Normotensives Mild hypertensives Established hypertensives Clinical situations in which the normal diurnal rhythm of BP may be lost Autonomic Dysfunction Syndromes Diabetes Mellitus Renal Failure Secondary forms of hypertension e.g. Cushing’s disease Drugs, e.g. cyclosporine African-American ethnicity Nocturnal BP Changes and CV Mortality: Ohasama study (Ohkubo et al; AJH 1997; 10: 1201) Extreme dippers Dippers Non-dippers Risers Risk of CV Mortality Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Morning Peak of VT Detected by Implanted Cardioverter/Defibrillator (Tofler Circ 1995;92: 1203) Episodes of VT Circadian Rhythm of Ischemic & Hemorrhagic Strokes Gallerani et al, Acta Neurol Scand 1993; 87: 482) % of strokes 1-6 6 -12 12-18 18-24 Hour of day Ischemic Hemorrhagic Analysis of The Influence of the Morning Surge of BP on Stroke Incidence (Kario, Pickering et al, Circ 2003; 107:1401)) Cox regression analysis for clinical stroke events Covariates RR P value Age (10 yrs) 1.80 (1.21-2.69) 0.004 Male gender 1.42 (0.76-2.67) 0.266 BMI 0.98 (0.90-1.07) 0.663 24 hr SBP 1.37 (1.16-1.63 0.003 SCI 4.40 (1.95-10.1) 0.001 Morning BP surge* 1.29 (1.10-1.51) 0.001 Nocturnal BP fall* 0.88 (0.73-1.06) 0.167 Lowest sleep BP 1.05 (0.65-1.71) 0.837 * per 10 mmHg Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Efficacy: telmisartan vs amlodipine using 24-h ABPM Placebo (n=58) Amlodipine (5-10 mg) (n=65) Telmisartan (40-120 mg) (n=62) 0800 1200 1600 2000 2400 0400 0800 BP (mm Hg) Lacourcière Y et al, in press 160 140 120 100 0 Time Week 12, SBP Effects of Two ARBs Approved for Once Daily Dosing on 24 Hour Blood Pressure (Mancia et al AJC 1999: 84; 28S) Missed Dose Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Do different drug classes have different effects on Daytime vs. Nighttime BP? Meta-Analysis of Effects of Antihypertensive Drug Classes on Daytime & Nighttime BP Weiner, Rieckmann, & Pickering, 2005 Medline search of trials in which effects of antihypertensive drugs on daytime, nighttime, and 24 hr BP were described 55 trials satisfied criteria, & were grouped into 3 classes: ACEI, ARBs, Beta blockers (n=10), CCBs & Diuretics (n=35), and combinations (n=10). Across all studies, the absolute change of daytime BP (14/8 mmHg) was significantly greater than the change of nighttime BP (12.5/4.5 mmHg, p<0.01). The magnitude of the difference between the daytime & nighttime changes did not differ between the groups (p>0.7). Meta-Analysis of Effects of Antihypertensive Drug Classes on Daytime & Nighttime BP Weiner, Rieckmann, & Pickering, 2005 Change of SBP with Treatment mmHg DAY NIGHT Baseline Systolic BP mmHg BP Change mmHg ACEI, ARBs CCBs, Diuretics Meta-Analysis of Effects of Antihypertensive Drug Classes on Daytime & Nighttime BP Weiner, Rieckmann, & Pickering, 2005 Day: B=.07 (p=0.53) Night: B=.04 (p=0.63) Day: B=.55 (p<0.001) Night: B=.55 (p<0.001) Are there class differences in thresholds for lowering BP? (Sekino et al, J Hum Hypertens 1998: 12: 719) Drug Average Effect Threshold BP* on BP Level CBP ABP Daytime Nighttime Nilvadipine -26 -12.5 127 110 Amlodipine -20 -15 127 106 Bisoprolol -19 -12 124 110 Lisinopril -20 -19 97 108 * Estimated from regression line of baseline BP versus change Are there class differences in thresholds for lowering BP? (Sekino et al, J Hum Hypertens 1998: 12: 719) Drug Average Effect Threshold BP* on BP Level CBP ABP Daytime Nighttime Nilvadipine -26 -12.5 127 110 Amlodipine -20 -15 127 106 Bisoprolol -19 -12 124 110 Lisinopril -20 -19 97 108 Combination1 -20 -14 128 106 * Estimated from regression line of baseline BP versus change 1- ACEI + CCB- Fagard et al Am J Hypertens 1993: 6: 648 Diuretics Convert Non-Dippers to Dippers (Uzu & Kimura Circ 1999; 100:1635) Systolic pressure mmHg Day Night No Rx HCTZ No Rx HCTZ Dippers Non-Dippers Diuretics Convert Non-Dippers to Dippers (Uzu & Kimura Circ 1999; 100:1635) Systolic pressure mmHg Day Night No Rx HCTZ No Rx HCTZ Dippers Non-Dippers Regression of Carotid Atherosclerosis by Controlling Morning BP (Marfella et al, Am J Hypertens 2005: 18: 308) Clinic Day Night Morning Carotid IMT 0 -0.02 -0.04 NS NS NS <0.001 <0.02 SBP mmHg IMT mm Regression of Carotid Atherosclerosis by Controlling Morning BP (Marfella et al, Am J Hypertens 2005: 18: 308) Clinic Day Night Morning Carotid IMT 0 -0.02 -0.04 NS NS NS <0.001 <0.02 SBP mmHg IMT mm ? Effects of Alpha-Blockade on the Morning Surge of Blood Pressure (Kario, Pickering, et al Am J Hypertens 2004;17; 668) Doxazosin No Rx Effects of graded release Diltiazem vs. Enalapril on Morning BP (White et al, Am Heart J 2004: 148: 628) Ramipril Diltiazem ER Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs

Slide 29 -

Does the Pattern of Blood Pressure Effects During the Day Matter? Thomas Pickering MD, DPhil Behavioral Cardiovascular Health and Hypertension Program Division of General Medicine Columbia Presbyterian Medical Center New York Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs What is the True Blood Pressure? Clinic BP? Home BP? 24 Hr Average BP? Daytime BP? Nighttime BP? Dipping Pattern? Morning Surge? Variability of BP? Ambulatory BP Differences for Normotensives, and Mild and Established HTN Patients 120- 110- 100- 90- 80- 70- 60- 0- Diastolic Blood Pressure (mm Hg) Clinic Work Home Sleep Normotensives Mild hypertensives Established hypertensives Clinical situations in which the normal diurnal rhythm of BP may be lost Autonomic Dysfunction Syndromes Diabetes Mellitus Renal Failure Secondary forms of hypertension e.g. Cushing’s disease Drugs, e.g. cyclosporine African-American ethnicity Nocturnal BP Changes and CV Mortality: Ohasama study (Ohkubo et al; AJH 1997; 10: 1201) Extreme dippers Dippers Non-dippers Risers Risk of CV Mortality Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Morning Peak of VT Detected by Implanted Cardioverter/Defibrillator (Tofler Circ 1995;92: 1203) Episodes of VT Circadian Rhythm of Ischemic & Hemorrhagic Strokes Gallerani et al, Acta Neurol Scand 1993; 87: 482) % of strokes 1-6 6 -12 12-18 18-24 Hour of day Ischemic Hemorrhagic Analysis of The Influence of the Morning Surge of BP on Stroke Incidence (Kario, Pickering et al, Circ 2003; 107:1401)) Cox regression analysis for clinical stroke events Covariates RR P value Age (10 yrs) 1.80 (1.21-2.69) 0.004 Male gender 1.42 (0.76-2.67) 0.266 BMI 0.98 (0.90-1.07) 0.663 24 hr SBP 1.37 (1.16-1.63 0.003 SCI 4.40 (1.95-10.1) 0.001 Morning BP surge* 1.29 (1.10-1.51) 0.001 Nocturnal BP fall* 0.88 (0.73-1.06) 0.167 Lowest sleep BP 1.05 (0.65-1.71) 0.837 * per 10 mmHg Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Efficacy: telmisartan vs amlodipine using 24-h ABPM Placebo (n=58) Amlodipine (5-10 mg) (n=65) Telmisartan (40-120 mg) (n=62) 0800 1200 1600 2000 2400 0400 0800 BP (mm Hg) Lacourcière Y et al, in press 160 140 120 100 0 Time Week 12, SBP Effects of Two ARBs Approved for Once Daily Dosing on 24 Hour Blood Pressure (Mancia et al AJC 1999: 84; 28S) Missed Dose Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Do different drug classes have different effects on Daytime vs. Nighttime BP? Meta-Analysis of Effects of Antihypertensive Drug Classes on Daytime & Nighttime BP Weiner, Rieckmann, & Pickering, 2005 Medline search of trials in which effects of antihypertensive drugs on daytime, nighttime, and 24 hr BP were described 55 trials satisfied criteria, & were grouped into 3 classes: ACEI, ARBs, Beta blockers (n=10), CCBs & Diuretics (n=35), and combinations (n=10). Across all studies, the absolute change of daytime BP (14/8 mmHg) was significantly greater than the change of nighttime BP (12.5/4.5 mmHg, p<0.01). The magnitude of the difference between the daytime & nighttime changes did not differ between the groups (p>0.7). Meta-Analysis of Effects of Antihypertensive Drug Classes on Daytime & Nighttime BP Weiner, Rieckmann, & Pickering, 2005 Change of SBP with Treatment mmHg DAY NIGHT Baseline Systolic BP mmHg BP Change mmHg ACEI, ARBs CCBs, Diuretics Meta-Analysis of Effects of Antihypertensive Drug Classes on Daytime & Nighttime BP Weiner, Rieckmann, & Pickering, 2005 Day: B=.07 (p=0.53) Night: B=.04 (p=0.63) Day: B=.55 (p<0.001) Night: B=.55 (p<0.001) Are there class differences in thresholds for lowering BP? (Sekino et al, J Hum Hypertens 1998: 12: 719) Drug Average Effect Threshold BP* on BP Level CBP ABP Daytime Nighttime Nilvadipine -26 -12.5 127 110 Amlodipine -20 -15 127 106 Bisoprolol -19 -12 124 110 Lisinopril -20 -19 97 108 * Estimated from regression line of baseline BP versus change Are there class differences in thresholds for lowering BP? (Sekino et al, J Hum Hypertens 1998: 12: 719) Drug Average Effect Threshold BP* on BP Level CBP ABP Daytime Nighttime Nilvadipine -26 -12.5 127 110 Amlodipine -20 -15 127 106 Bisoprolol -19 -12 124 110 Lisinopril -20 -19 97 108 Combination1 -20 -14 128 106 * Estimated from regression line of baseline BP versus change 1- ACEI + CCB- Fagard et al Am J Hypertens 1993: 6: 648 Diuretics Convert Non-Dippers to Dippers (Uzu & Kimura Circ 1999; 100:1635) Systolic pressure mmHg Day Night No Rx HCTZ No Rx HCTZ Dippers Non-Dippers Diuretics Convert Non-Dippers to Dippers (Uzu & Kimura Circ 1999; 100:1635) Systolic pressure mmHg Day Night No Rx HCTZ No Rx HCTZ Dippers Non-Dippers Regression of Carotid Atherosclerosis by Controlling Morning BP (Marfella et al, Am J Hypertens 2005: 18: 308) Clinic Day Night Morning Carotid IMT 0 -0.02 -0.04 NS NS NS <0.001 <0.02 SBP mmHg IMT mm Regression of Carotid Atherosclerosis by Controlling Morning BP (Marfella et al, Am J Hypertens 2005: 18: 308) Clinic Day Night Morning Carotid IMT 0 -0.02 -0.04 NS NS NS <0.001 <0.02 SBP mmHg IMT mm ? Effects of Alpha-Blockade on the Morning Surge of Blood Pressure (Kario, Pickering, et al Am J Hypertens 2004;17; 668) Doxazosin No Rx Effects of graded release Diltiazem vs. Enalapril on Morning BP (White et al, Am Heart J 2004: 148: 628) Ramipril Diltiazem ER Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Effects of Time of Administration of Valsartan on Diurnal Changes of BP (Hermida et al Hypertens 2003: 42:283) P=0.041 P=0.402 P=0.174 Change of SBP mmHg

Slide 30 -

Does the Pattern of Blood Pressure Effects During the Day Matter? Thomas Pickering MD, DPhil Behavioral Cardiovascular Health and Hypertension Program Division of General Medicine Columbia Presbyterian Medical Center New York Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs What is the True Blood Pressure? Clinic BP? Home BP? 24 Hr Average BP? Daytime BP? Nighttime BP? Dipping Pattern? Morning Surge? Variability of BP? Ambulatory BP Differences for Normotensives, and Mild and Established HTN Patients 120- 110- 100- 90- 80- 70- 60- 0- Diastolic Blood Pressure (mm Hg) Clinic Work Home Sleep Normotensives Mild hypertensives Established hypertensives Clinical situations in which the normal diurnal rhythm of BP may be lost Autonomic Dysfunction Syndromes Diabetes Mellitus Renal Failure Secondary forms of hypertension e.g. Cushing’s disease Drugs, e.g. cyclosporine African-American ethnicity Nocturnal BP Changes and CV Mortality: Ohasama study (Ohkubo et al; AJH 1997; 10: 1201) Extreme dippers Dippers Non-dippers Risers Risk of CV Mortality Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Morning Peak of VT Detected by Implanted Cardioverter/Defibrillator (Tofler Circ 1995;92: 1203) Episodes of VT Circadian Rhythm of Ischemic & Hemorrhagic Strokes Gallerani et al, Acta Neurol Scand 1993; 87: 482) % of strokes 1-6 6 -12 12-18 18-24 Hour of day Ischemic Hemorrhagic Analysis of The Influence of the Morning Surge of BP on Stroke Incidence (Kario, Pickering et al, Circ 2003; 107:1401)) Cox regression analysis for clinical stroke events Covariates RR P value Age (10 yrs) 1.80 (1.21-2.69) 0.004 Male gender 1.42 (0.76-2.67) 0.266 BMI 0.98 (0.90-1.07) 0.663 24 hr SBP 1.37 (1.16-1.63 0.003 SCI 4.40 (1.95-10.1) 0.001 Morning BP surge* 1.29 (1.10-1.51) 0.001 Nocturnal BP fall* 0.88 (0.73-1.06) 0.167 Lowest sleep BP 1.05 (0.65-1.71) 0.837 * per 10 mmHg Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Efficacy: telmisartan vs amlodipine using 24-h ABPM Placebo (n=58) Amlodipine (5-10 mg) (n=65) Telmisartan (40-120 mg) (n=62) 0800 1200 1600 2000 2400 0400 0800 BP (mm Hg) Lacourcière Y et al, in press 160 140 120 100 0 Time Week 12, SBP Effects of Two ARBs Approved for Once Daily Dosing on 24 Hour Blood Pressure (Mancia et al AJC 1999: 84; 28S) Missed Dose Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Do different drug classes have different effects on Daytime vs. Nighttime BP? Meta-Analysis of Effects of Antihypertensive Drug Classes on Daytime & Nighttime BP Weiner, Rieckmann, & Pickering, 2005 Medline search of trials in which effects of antihypertensive drugs on daytime, nighttime, and 24 hr BP were described 55 trials satisfied criteria, & were grouped into 3 classes: ACEI, ARBs, Beta blockers (n=10), CCBs & Diuretics (n=35), and combinations (n=10). Across all studies, the absolute change of daytime BP (14/8 mmHg) was significantly greater than the change of nighttime BP (12.5/4.5 mmHg, p<0.01). The magnitude of the difference between the daytime & nighttime changes did not differ between the groups (p>0.7). Meta-Analysis of Effects of Antihypertensive Drug Classes on Daytime & Nighttime BP Weiner, Rieckmann, & Pickering, 2005 Change of SBP with Treatment mmHg DAY NIGHT Baseline Systolic BP mmHg BP Change mmHg ACEI, ARBs CCBs, Diuretics Meta-Analysis of Effects of Antihypertensive Drug Classes on Daytime & Nighttime BP Weiner, Rieckmann, & Pickering, 2005 Day: B=.07 (p=0.53) Night: B=.04 (p=0.63) Day: B=.55 (p<0.001) Night: B=.55 (p<0.001) Are there class differences in thresholds for lowering BP? (Sekino et al, J Hum Hypertens 1998: 12: 719) Drug Average Effect Threshold BP* on BP Level CBP ABP Daytime Nighttime Nilvadipine -26 -12.5 127 110 Amlodipine -20 -15 127 106 Bisoprolol -19 -12 124 110 Lisinopril -20 -19 97 108 * Estimated from regression line of baseline BP versus change Are there class differences in thresholds for lowering BP? (Sekino et al, J Hum Hypertens 1998: 12: 719) Drug Average Effect Threshold BP* on BP Level CBP ABP Daytime Nighttime Nilvadipine -26 -12.5 127 110 Amlodipine -20 -15 127 106 Bisoprolol -19 -12 124 110 Lisinopril -20 -19 97 108 Combination1 -20 -14 128 106 * Estimated from regression line of baseline BP versus change 1- ACEI + CCB- Fagard et al Am J Hypertens 1993: 6: 648 Diuretics Convert Non-Dippers to Dippers (Uzu & Kimura Circ 1999; 100:1635) Systolic pressure mmHg Day Night No Rx HCTZ No Rx HCTZ Dippers Non-Dippers Diuretics Convert Non-Dippers to Dippers (Uzu & Kimura Circ 1999; 100:1635) Systolic pressure mmHg Day Night No Rx HCTZ No Rx HCTZ Dippers Non-Dippers Regression of Carotid Atherosclerosis by Controlling Morning BP (Marfella et al, Am J Hypertens 2005: 18: 308) Clinic Day Night Morning Carotid IMT 0 -0.02 -0.04 NS NS NS <0.001 <0.02 SBP mmHg IMT mm Regression of Carotid Atherosclerosis by Controlling Morning BP (Marfella et al, Am J Hypertens 2005: 18: 308) Clinic Day Night Morning Carotid IMT 0 -0.02 -0.04 NS NS NS <0.001 <0.02 SBP mmHg IMT mm ? Effects of Alpha-Blockade on the Morning Surge of Blood Pressure (Kario, Pickering, et al Am J Hypertens 2004;17; 668) Doxazosin No Rx Effects of graded release Diltiazem vs. Enalapril on Morning BP (White et al, Am Heart J 2004: 148: 628) Ramipril Diltiazem ER Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Effects of Time of Administration of Valsartan on Diurnal Changes of BP (Hermida et al Hypertens 2003: 42:283) P=0.041 P=0.402 P=0.174 Change of SBP mmHg Effects of Time of Administration of Valsartan on Diurnal Changes of BP (Hermida et al Hypertens 2003: 42:283) P=0.041 P=0.402 P=0.174 Change of SBP mmHg “Diovan may be used over a dose range of 80 mg to 320 mg daily, administered once-a-day.”

Slide 31 -

Does the Pattern of Blood Pressure Effects During the Day Matter? Thomas Pickering MD, DPhil Behavioral Cardiovascular Health and Hypertension Program Division of General Medicine Columbia Presbyterian Medical Center New York Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs What is the True Blood Pressure? Clinic BP? Home BP? 24 Hr Average BP? Daytime BP? Nighttime BP? Dipping Pattern? Morning Surge? Variability of BP? Ambulatory BP Differences for Normotensives, and Mild and Established HTN Patients 120- 110- 100- 90- 80- 70- 60- 0- Diastolic Blood Pressure (mm Hg) Clinic Work Home Sleep Normotensives Mild hypertensives Established hypertensives Clinical situations in which the normal diurnal rhythm of BP may be lost Autonomic Dysfunction Syndromes Diabetes Mellitus Renal Failure Secondary forms of hypertension e.g. Cushing’s disease Drugs, e.g. cyclosporine African-American ethnicity Nocturnal BP Changes and CV Mortality: Ohasama study (Ohkubo et al; AJH 1997; 10: 1201) Extreme dippers Dippers Non-dippers Risers Risk of CV Mortality Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Morning Peak of VT Detected by Implanted Cardioverter/Defibrillator (Tofler Circ 1995;92: 1203) Episodes of VT Circadian Rhythm of Ischemic & Hemorrhagic Strokes Gallerani et al, Acta Neurol Scand 1993; 87: 482) % of strokes 1-6 6 -12 12-18 18-24 Hour of day Ischemic Hemorrhagic Analysis of The Influence of the Morning Surge of BP on Stroke Incidence (Kario, Pickering et al, Circ 2003; 107:1401)) Cox regression analysis for clinical stroke events Covariates RR P value Age (10 yrs) 1.80 (1.21-2.69) 0.004 Male gender 1.42 (0.76-2.67) 0.266 BMI 0.98 (0.90-1.07) 0.663 24 hr SBP 1.37 (1.16-1.63 0.003 SCI 4.40 (1.95-10.1) 0.001 Morning BP surge* 1.29 (1.10-1.51) 0.001 Nocturnal BP fall* 0.88 (0.73-1.06) 0.167 Lowest sleep BP 1.05 (0.65-1.71) 0.837 * per 10 mmHg Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Efficacy: telmisartan vs amlodipine using 24-h ABPM Placebo (n=58) Amlodipine (5-10 mg) (n=65) Telmisartan (40-120 mg) (n=62) 0800 1200 1600 2000 2400 0400 0800 BP (mm Hg) Lacourcière Y et al, in press 160 140 120 100 0 Time Week 12, SBP Effects of Two ARBs Approved for Once Daily Dosing on 24 Hour Blood Pressure (Mancia et al AJC 1999: 84; 28S) Missed Dose Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Do different drug classes have different effects on Daytime vs. Nighttime BP? Meta-Analysis of Effects of Antihypertensive Drug Classes on Daytime & Nighttime BP Weiner, Rieckmann, & Pickering, 2005 Medline search of trials in which effects of antihypertensive drugs on daytime, nighttime, and 24 hr BP were described 55 trials satisfied criteria, & were grouped into 3 classes: ACEI, ARBs, Beta blockers (n=10), CCBs & Diuretics (n=35), and combinations (n=10). Across all studies, the absolute change of daytime BP (14/8 mmHg) was significantly greater than the change of nighttime BP (12.5/4.5 mmHg, p<0.01). The magnitude of the difference between the daytime & nighttime changes did not differ between the groups (p>0.7). Meta-Analysis of Effects of Antihypertensive Drug Classes on Daytime & Nighttime BP Weiner, Rieckmann, & Pickering, 2005 Change of SBP with Treatment mmHg DAY NIGHT Baseline Systolic BP mmHg BP Change mmHg ACEI, ARBs CCBs, Diuretics Meta-Analysis of Effects of Antihypertensive Drug Classes on Daytime & Nighttime BP Weiner, Rieckmann, & Pickering, 2005 Day: B=.07 (p=0.53) Night: B=.04 (p=0.63) Day: B=.55 (p<0.001) Night: B=.55 (p<0.001) Are there class differences in thresholds for lowering BP? (Sekino et al, J Hum Hypertens 1998: 12: 719) Drug Average Effect Threshold BP* on BP Level CBP ABP Daytime Nighttime Nilvadipine -26 -12.5 127 110 Amlodipine -20 -15 127 106 Bisoprolol -19 -12 124 110 Lisinopril -20 -19 97 108 * Estimated from regression line of baseline BP versus change Are there class differences in thresholds for lowering BP? (Sekino et al, J Hum Hypertens 1998: 12: 719) Drug Average Effect Threshold BP* on BP Level CBP ABP Daytime Nighttime Nilvadipine -26 -12.5 127 110 Amlodipine -20 -15 127 106 Bisoprolol -19 -12 124 110 Lisinopril -20 -19 97 108 Combination1 -20 -14 128 106 * Estimated from regression line of baseline BP versus change 1- ACEI + CCB- Fagard et al Am J Hypertens 1993: 6: 648 Diuretics Convert Non-Dippers to Dippers (Uzu & Kimura Circ 1999; 100:1635) Systolic pressure mmHg Day Night No Rx HCTZ No Rx HCTZ Dippers Non-Dippers Diuretics Convert Non-Dippers to Dippers (Uzu & Kimura Circ 1999; 100:1635) Systolic pressure mmHg Day Night No Rx HCTZ No Rx HCTZ Dippers Non-Dippers Regression of Carotid Atherosclerosis by Controlling Morning BP (Marfella et al, Am J Hypertens 2005: 18: 308) Clinic Day Night Morning Carotid IMT 0 -0.02 -0.04 NS NS NS <0.001 <0.02 SBP mmHg IMT mm Regression of Carotid Atherosclerosis by Controlling Morning BP (Marfella et al, Am J Hypertens 2005: 18: 308) Clinic Day Night Morning Carotid IMT 0 -0.02 -0.04 NS NS NS <0.001 <0.02 SBP mmHg IMT mm ? Effects of Alpha-Blockade on the Morning Surge of Blood Pressure (Kario, Pickering, et al Am J Hypertens 2004;17; 668) Doxazosin No Rx Effects of graded release Diltiazem vs. Enalapril on Morning BP (White et al, Am Heart J 2004: 148: 628) Ramipril Diltiazem ER Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Effects of Time of Administration of Valsartan on Diurnal Changes of BP (Hermida et al Hypertens 2003: 42:283) P=0.041 P=0.402 P=0.174 Change of SBP mmHg Effects of Time of Administration of Valsartan on Diurnal Changes of BP (Hermida et al Hypertens 2003: 42:283) P=0.041 P=0.402 P=0.174 Change of SBP mmHg “Diovan may be used over a dose range of 80 mg to 320 mg daily, administered once-a-day.”

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Does the Pattern of Blood Pressure Effects During the Day Matter? Thomas Pickering MD, DPhil Behavioral Cardiovascular Health and Hypertension Program Division of General Medicine Columbia Presbyterian Medical Center New York Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs What is the True Blood Pressure? Clinic BP? Home BP? 24 Hr Average BP? Daytime BP? Nighttime BP? Dipping Pattern? Morning Surge? Variability of BP? Ambulatory BP Differences for Normotensives, and Mild and Established HTN Patients 120- 110- 100- 90- 80- 70- 60- 0- Diastolic Blood Pressure (mm Hg) Clinic Work Home Sleep Normotensives Mild hypertensives Established hypertensives Clinical situations in which the normal diurnal rhythm of BP may be lost Autonomic Dysfunction Syndromes Diabetes Mellitus Renal Failure Secondary forms of hypertension e.g. Cushing’s disease Drugs, e.g. cyclosporine African-American ethnicity Nocturnal BP Changes and CV Mortality: Ohasama study (Ohkubo et al; AJH 1997; 10: 1201) Extreme dippers Dippers Non-dippers Risers Risk of CV Mortality Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Morning Peak of VT Detected by Implanted Cardioverter/Defibrillator (Tofler Circ 1995;92: 1203) Episodes of VT Circadian Rhythm of Ischemic & Hemorrhagic Strokes Gallerani et al, Acta Neurol Scand 1993; 87: 482) % of strokes 1-6 6 -12 12-18 18-24 Hour of day Ischemic Hemorrhagic Analysis of The Influence of the Morning Surge of BP on Stroke Incidence (Kario, Pickering et al, Circ 2003; 107:1401)) Cox regression analysis for clinical stroke events Covariates RR P value Age (10 yrs) 1.80 (1.21-2.69) 0.004 Male gender 1.42 (0.76-2.67) 0.266 BMI 0.98 (0.90-1.07) 0.663 24 hr SBP 1.37 (1.16-1.63 0.003 SCI 4.40 (1.95-10.1) 0.001 Morning BP surge* 1.29 (1.10-1.51) 0.001 Nocturnal BP fall* 0.88 (0.73-1.06) 0.167 Lowest sleep BP 1.05 (0.65-1.71) 0.837 * per 10 mmHg Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Efficacy: telmisartan vs amlodipine using 24-h ABPM Placebo (n=58) Amlodipine (5-10 mg) (n=65) Telmisartan (40-120 mg) (n=62) 0800 1200 1600 2000 2400 0400 0800 BP (mm Hg) Lacourcière Y et al, in press 160 140 120 100 0 Time Week 12, SBP Effects of Two ARBs Approved for Once Daily Dosing on 24 Hour Blood Pressure (Mancia et al AJC 1999: 84; 28S) Missed Dose Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Do different drug classes have different effects on Daytime vs. Nighttime BP? Meta-Analysis of Effects of Antihypertensive Drug Classes on Daytime & Nighttime BP Weiner, Rieckmann, & Pickering, 2005 Medline search of trials in which effects of antihypertensive drugs on daytime, nighttime, and 24 hr BP were described 55 trials satisfied criteria, & were grouped into 3 classes: ACEI, ARBs, Beta blockers (n=10), CCBs & Diuretics (n=35), and combinations (n=10). Across all studies, the absolute change of daytime BP (14/8 mmHg) was significantly greater than the change of nighttime BP (12.5/4.5 mmHg, p<0.01). The magnitude of the difference between the daytime & nighttime changes did not differ between the groups (p>0.7). Meta-Analysis of Effects of Antihypertensive Drug Classes on Daytime & Nighttime BP Weiner, Rieckmann, & Pickering, 2005 Change of SBP with Treatment mmHg DAY NIGHT Baseline Systolic BP mmHg BP Change mmHg ACEI, ARBs CCBs, Diuretics Meta-Analysis of Effects of Antihypertensive Drug Classes on Daytime & Nighttime BP Weiner, Rieckmann, & Pickering, 2005 Day: B=.07 (p=0.53) Night: B=.04 (p=0.63) Day: B=.55 (p<0.001) Night: B=.55 (p<0.001) Are there class differences in thresholds for lowering BP? (Sekino et al, J Hum Hypertens 1998: 12: 719) Drug Average Effect Threshold BP* on BP Level CBP ABP Daytime Nighttime Nilvadipine -26 -12.5 127 110 Amlodipine -20 -15 127 106 Bisoprolol -19 -12 124 110 Lisinopril -20 -19 97 108 * Estimated from regression line of baseline BP versus change Are there class differences in thresholds for lowering BP? (Sekino et al, J Hum Hypertens 1998: 12: 719) Drug Average Effect Threshold BP* on BP Level CBP ABP Daytime Nighttime Nilvadipine -26 -12.5 127 110 Amlodipine -20 -15 127 106 Bisoprolol -19 -12 124 110 Lisinopril -20 -19 97 108 Combination1 -20 -14 128 106 * Estimated from regression line of baseline BP versus change 1- ACEI + CCB- Fagard et al Am J Hypertens 1993: 6: 648 Diuretics Convert Non-Dippers to Dippers (Uzu & Kimura Circ 1999; 100:1635) Systolic pressure mmHg Day Night No Rx HCTZ No Rx HCTZ Dippers Non-Dippers Diuretics Convert Non-Dippers to Dippers (Uzu & Kimura Circ 1999; 100:1635) Systolic pressure mmHg Day Night No Rx HCTZ No Rx HCTZ Dippers Non-Dippers Regression of Carotid Atherosclerosis by Controlling Morning BP (Marfella et al, Am J Hypertens 2005: 18: 308) Clinic Day Night Morning Carotid IMT 0 -0.02 -0.04 NS NS NS <0.001 <0.02 SBP mmHg IMT mm Regression of Carotid Atherosclerosis by Controlling Morning BP (Marfella et al, Am J Hypertens 2005: 18: 308) Clinic Day Night Morning Carotid IMT 0 -0.02 -0.04 NS NS NS <0.001 <0.02 SBP mmHg IMT mm ? Effects of Alpha-Blockade on the Morning Surge of Blood Pressure (Kario, Pickering, et al Am J Hypertens 2004;17; 668) Doxazosin No Rx Effects of graded release Diltiazem vs. Enalapril on Morning BP (White et al, Am Heart J 2004: 148: 628) Ramipril Diltiazem ER Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Effects of Time of Administration of Valsartan on Diurnal Changes of BP (Hermida et al Hypertens 2003: 42:283) P=0.041 P=0.402 P=0.174 Change of SBP mmHg Effects of Time of Administration of Valsartan on Diurnal Changes of BP (Hermida et al Hypertens 2003: 42:283) P=0.041 P=0.402 P=0.174 Change of SBP mmHg “Diovan may be used over a dose range of 80 mg to 320 mg daily, administered once-a-day.”

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Does the Pattern of Blood Pressure Effects During the Day Matter? Thomas Pickering MD, DPhil Behavioral Cardiovascular Health and Hypertension Program Division of General Medicine Columbia Presbyterian Medical Center New York Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs What is the True Blood Pressure? Clinic BP? Home BP? 24 Hr Average BP? Daytime BP? Nighttime BP? Dipping Pattern? Morning Surge? Variability of BP? Ambulatory BP Differences for Normotensives, and Mild and Established HTN Patients 120- 110- 100- 90- 80- 70- 60- 0- Diastolic Blood Pressure (mm Hg) Clinic Work Home Sleep Normotensives Mild hypertensives Established hypertensives Clinical situations in which the normal diurnal rhythm of BP may be lost Autonomic Dysfunction Syndromes Diabetes Mellitus Renal Failure Secondary forms of hypertension e.g. Cushing’s disease Drugs, e.g. cyclosporine African-American ethnicity Nocturnal BP Changes and CV Mortality: Ohasama study (Ohkubo et al; AJH 1997; 10: 1201) Extreme dippers Dippers Non-dippers Risers Risk of CV Mortality Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Morning Peak of VT Detected by Implanted Cardioverter/Defibrillator (Tofler Circ 1995;92: 1203) Episodes of VT Circadian Rhythm of Ischemic & Hemorrhagic Strokes Gallerani et al, Acta Neurol Scand 1993; 87: 482) % of strokes 1-6 6 -12 12-18 18-24 Hour of day Ischemic Hemorrhagic Analysis of The Influence of the Morning Surge of BP on Stroke Incidence (Kario, Pickering et al, Circ 2003; 107:1401)) Cox regression analysis for clinical stroke events Covariates RR P value Age (10 yrs) 1.80 (1.21-2.69) 0.004 Male gender 1.42 (0.76-2.67) 0.266 BMI 0.98 (0.90-1.07) 0.663 24 hr SBP 1.37 (1.16-1.63 0.003 SCI 4.40 (1.95-10.1) 0.001 Morning BP surge* 1.29 (1.10-1.51) 0.001 Nocturnal BP fall* 0.88 (0.73-1.06) 0.167 Lowest sleep BP 1.05 (0.65-1.71) 0.837 * per 10 mmHg Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Efficacy: telmisartan vs amlodipine using 24-h ABPM Placebo (n=58) Amlodipine (5-10 mg) (n=65) Telmisartan (40-120 mg) (n=62) 0800 1200 1600 2000 2400 0400 0800 BP (mm Hg) Lacourcière Y et al, in press 160 140 120 100 0 Time Week 12, SBP Effects of Two ARBs Approved for Once Daily Dosing on 24 Hour Blood Pressure (Mancia et al AJC 1999: 84; 28S) Missed Dose Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Do different drug classes have different effects on Daytime vs. Nighttime BP? Meta-Analysis of Effects of Antihypertensive Drug Classes on Daytime & Nighttime BP Weiner, Rieckmann, & Pickering, 2005 Medline search of trials in which effects of antihypertensive drugs on daytime, nighttime, and 24 hr BP were described 55 trials satisfied criteria, & were grouped into 3 classes: ACEI, ARBs, Beta blockers (n=10), CCBs & Diuretics (n=35), and combinations (n=10). Across all studies, the absolute change of daytime BP (14/8 mmHg) was significantly greater than the change of nighttime BP (12.5/4.5 mmHg, p<0.01). The magnitude of the difference between the daytime & nighttime changes did not differ between the groups (p>0.7). Meta-Analysis of Effects of Antihypertensive Drug Classes on Daytime & Nighttime BP Weiner, Rieckmann, & Pickering, 2005 Change of SBP with Treatment mmHg DAY NIGHT Baseline Systolic BP mmHg BP Change mmHg ACEI, ARBs CCBs, Diuretics Meta-Analysis of Effects of Antihypertensive Drug Classes on Daytime & Nighttime BP Weiner, Rieckmann, & Pickering, 2005 Day: B=.07 (p=0.53) Night: B=.04 (p=0.63) Day: B=.55 (p<0.001) Night: B=.55 (p<0.001) Are there class differences in thresholds for lowering BP? (Sekino et al, J Hum Hypertens 1998: 12: 719) Drug Average Effect Threshold BP* on BP Level CBP ABP Daytime Nighttime Nilvadipine -26 -12.5 127 110 Amlodipine -20 -15 127 106 Bisoprolol -19 -12 124 110 Lisinopril -20 -19 97 108 * Estimated from regression line of baseline BP versus change Are there class differences in thresholds for lowering BP? (Sekino et al, J Hum Hypertens 1998: 12: 719) Drug Average Effect Threshold BP* on BP Level CBP ABP Daytime Nighttime Nilvadipine -26 -12.5 127 110 Amlodipine -20 -15 127 106 Bisoprolol -19 -12 124 110 Lisinopril -20 -19 97 108 Combination1 -20 -14 128 106 * Estimated from regression line of baseline BP versus change 1- ACEI + CCB- Fagard et al Am J Hypertens 1993: 6: 648 Diuretics Convert Non-Dippers to Dippers (Uzu & Kimura Circ 1999; 100:1635) Systolic pressure mmHg Day Night No Rx HCTZ No Rx HCTZ Dippers Non-Dippers Diuretics Convert Non-Dippers to Dippers (Uzu & Kimura Circ 1999; 100:1635) Systolic pressure mmHg Day Night No Rx HCTZ No Rx HCTZ Dippers Non-Dippers Regression of Carotid Atherosclerosis by Controlling Morning BP (Marfella et al, Am J Hypertens 2005: 18: 308) Clinic Day Night Morning Carotid IMT 0 -0.02 -0.04 NS NS NS <0.001 <0.02 SBP mmHg IMT mm Regression of Carotid Atherosclerosis by Controlling Morning BP (Marfella et al, Am J Hypertens 2005: 18: 308) Clinic Day Night Morning Carotid IMT 0 -0.02 -0.04 NS NS NS <0.001 <0.02 SBP mmHg IMT mm ? Effects of Alpha-Blockade on the Morning Surge of Blood Pressure (Kario, Pickering, et al Am J Hypertens 2004;17; 668) Doxazosin No Rx Effects of graded release Diltiazem vs. Enalapril on Morning BP (White et al, Am Heart J 2004: 148: 628) Ramipril Diltiazem ER Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Effects of Time of Administration of Valsartan on Diurnal Changes of BP (Hermida et al Hypertens 2003: 42:283) P=0.041 P=0.402 P=0.174 Change of SBP mmHg Effects of Time of Administration of Valsartan on Diurnal Changes of BP (Hermida et al Hypertens 2003: 42:283) P=0.041 P=0.402 P=0.174 Change of SBP mmHg “Diovan may be used over a dose range of 80 mg to 320 mg daily, administered once-a-day.” Conclusions: Does the Pattern of Blood Pressure Effects During the Day Matter? There is a pronounced diurnal rhythm of BP and cardiovascular events, with a peak of both in the morning hours, and a decrease during the night. In some categories of patients the normal dipping pattern of BP is lost or reversed; this may be associated with increased risk. Drugs approved for once daily dose may have different durations of action, particularly after missed doses. Most classes of antihypertensive drugs lower daytime BP more than nighttime BP. The effects of CCBs may be more closely related to baseline BP than ARBs/ACEI.

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Does the Pattern of Blood Pressure Effects During the Day Matter? Thomas Pickering MD, DPhil Behavioral Cardiovascular Health and Hypertension Program Division of General Medicine Columbia Presbyterian Medical Center New York Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs What is the True Blood Pressure? Clinic BP? Home BP? 24 Hr Average BP? Daytime BP? Nighttime BP? Dipping Pattern? Morning Surge? Variability of BP? Ambulatory BP Differences for Normotensives, and Mild and Established HTN Patients 120- 110- 100- 90- 80- 70- 60- 0- Diastolic Blood Pressure (mm Hg) Clinic Work Home Sleep Normotensives Mild hypertensives Established hypertensives Clinical situations in which the normal diurnal rhythm of BP may be lost Autonomic Dysfunction Syndromes Diabetes Mellitus Renal Failure Secondary forms of hypertension e.g. Cushing’s disease Drugs, e.g. cyclosporine African-American ethnicity Nocturnal BP Changes and CV Mortality: Ohasama study (Ohkubo et al; AJH 1997; 10: 1201) Extreme dippers Dippers Non-dippers Risers Risk of CV Mortality Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Morning Peak of VT Detected by Implanted Cardioverter/Defibrillator (Tofler Circ 1995;92: 1203) Episodes of VT Circadian Rhythm of Ischemic & Hemorrhagic Strokes Gallerani et al, Acta Neurol Scand 1993; 87: 482) % of strokes 1-6 6 -12 12-18 18-24 Hour of day Ischemic Hemorrhagic Analysis of The Influence of the Morning Surge of BP on Stroke Incidence (Kario, Pickering et al, Circ 2003; 107:1401)) Cox regression analysis for clinical stroke events Covariates RR P value Age (10 yrs) 1.80 (1.21-2.69) 0.004 Male gender 1.42 (0.76-2.67) 0.266 BMI 0.98 (0.90-1.07) 0.663 24 hr SBP 1.37 (1.16-1.63 0.003 SCI 4.40 (1.95-10.1) 0.001 Morning BP surge* 1.29 (1.10-1.51) 0.001 Nocturnal BP fall* 0.88 (0.73-1.06) 0.167 Lowest sleep BP 1.05 (0.65-1.71) 0.837 * per 10 mmHg Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Efficacy: telmisartan vs amlodipine using 24-h ABPM Placebo (n=58) Amlodipine (5-10 mg) (n=65) Telmisartan (40-120 mg) (n=62) 0800 1200 1600 2000 2400 0400 0800 BP (mm Hg) Lacourcière Y et al, in press 160 140 120 100 0 Time Week 12, SBP Effects of Two ARBs Approved for Once Daily Dosing on 24 Hour Blood Pressure (Mancia et al AJC 1999: 84; 28S) Missed Dose Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Do different drug classes have different effects on Daytime vs. Nighttime BP? Meta-Analysis of Effects of Antihypertensive Drug Classes on Daytime & Nighttime BP Weiner, Rieckmann, & Pickering, 2005 Medline search of trials in which effects of antihypertensive drugs on daytime, nighttime, and 24 hr BP were described 55 trials satisfied criteria, & were grouped into 3 classes: ACEI, ARBs, Beta blockers (n=10), CCBs & Diuretics (n=35), and combinations (n=10). Across all studies, the absolute change of daytime BP (14/8 mmHg) was significantly greater than the change of nighttime BP (12.5/4.5 mmHg, p<0.01). The magnitude of the difference between the daytime & nighttime changes did not differ between the groups (p>0.7). Meta-Analysis of Effects of Antihypertensive Drug Classes on Daytime & Nighttime BP Weiner, Rieckmann, & Pickering, 2005 Change of SBP with Treatment mmHg DAY NIGHT Baseline Systolic BP mmHg BP Change mmHg ACEI, ARBs CCBs, Diuretics Meta-Analysis of Effects of Antihypertensive Drug Classes on Daytime & Nighttime BP Weiner, Rieckmann, & Pickering, 2005 Day: B=.07 (p=0.53) Night: B=.04 (p=0.63) Day: B=.55 (p<0.001) Night: B=.55 (p<0.001) Are there class differences in thresholds for lowering BP? (Sekino et al, J Hum Hypertens 1998: 12: 719) Drug Average Effect Threshold BP* on BP Level CBP ABP Daytime Nighttime Nilvadipine -26 -12.5 127 110 Amlodipine -20 -15 127 106 Bisoprolol -19 -12 124 110 Lisinopril -20 -19 97 108 * Estimated from regression line of baseline BP versus change Are there class differences in thresholds for lowering BP? (Sekino et al, J Hum Hypertens 1998: 12: 719) Drug Average Effect Threshold BP* on BP Level CBP ABP Daytime Nighttime Nilvadipine -26 -12.5 127 110 Amlodipine -20 -15 127 106 Bisoprolol -19 -12 124 110 Lisinopril -20 -19 97 108 Combination1 -20 -14 128 106 * Estimated from regression line of baseline BP versus change 1- ACEI + CCB- Fagard et al Am J Hypertens 1993: 6: 648 Diuretics Convert Non-Dippers to Dippers (Uzu & Kimura Circ 1999; 100:1635) Systolic pressure mmHg Day Night No Rx HCTZ No Rx HCTZ Dippers Non-Dippers Diuretics Convert Non-Dippers to Dippers (Uzu & Kimura Circ 1999; 100:1635) Systolic pressure mmHg Day Night No Rx HCTZ No Rx HCTZ Dippers Non-Dippers Regression of Carotid Atherosclerosis by Controlling Morning BP (Marfella et al, Am J Hypertens 2005: 18: 308) Clinic Day Night Morning Carotid IMT 0 -0.02 -0.04 NS NS NS <0.001 <0.02 SBP mmHg IMT mm Regression of Carotid Atherosclerosis by Controlling Morning BP (Marfella et al, Am J Hypertens 2005: 18: 308) Clinic Day Night Morning Carotid IMT 0 -0.02 -0.04 NS NS NS <0.001 <0.02 SBP mmHg IMT mm ? Effects of Alpha-Blockade on the Morning Surge of Blood Pressure (Kario, Pickering, et al Am J Hypertens 2004;17; 668) Doxazosin No Rx Effects of graded release Diltiazem vs. Enalapril on Morning BP (White et al, Am Heart J 2004: 148: 628) Ramipril Diltiazem ER Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Effects of Time of Administration of Valsartan on Diurnal Changes of BP (Hermida et al Hypertens 2003: 42:283) P=0.041 P=0.402 P=0.174 Change of SBP mmHg Effects of Time of Administration of Valsartan on Diurnal Changes of BP (Hermida et al Hypertens 2003: 42:283) P=0.041 P=0.402 P=0.174 Change of SBP mmHg “Diovan may be used over a dose range of 80 mg to 320 mg daily, administered once-a-day.” Conclusions: Does the Pattern of Blood Pressure Effects During the Day Matter? There is a pronounced diurnal rhythm of BP and cardiovascular events, with a peak of both in the morning hours, and a decrease during the night. In some categories of patients the normal dipping pattern of BP is lost or reversed; this may be associated with increased risk. Drugs approved for once daily dose may have different durations of action, particularly after missed doses. Most classes of antihypertensive drugs lower daytime BP more than nighttime BP. The effects of CCBs may be more closely related to baseline BP than ARBs/ACEI. Conclusions: Does the Pattern of Blood Pressure Effects During the Day Matter? 6. Different antihypertensive drugs may have different effects on the morning surge of BP. 7. With some antihypertensive drugs the time of dosing may have significant effects on the diurnal pattern of BP. 8. The implications of these time-dependent differences of antihypertensive drugs for CV morbidity are largely unknown, and need to be more fully investigated. 9. Implications of BP-independent effects of antihypertensive drugs based on small differences of clinic BP may be unwarranted.

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Does the Pattern of Blood Pressure Effects During the Day Matter? Thomas Pickering MD, DPhil Behavioral Cardiovascular Health and Hypertension Program Division of General Medicine Columbia Presbyterian Medical Center New York Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs What is the True Blood Pressure? Clinic BP? Home BP? 24 Hr Average BP? Daytime BP? Nighttime BP? Dipping Pattern? Morning Surge? Variability of BP? Ambulatory BP Differences for Normotensives, and Mild and Established HTN Patients 120- 110- 100- 90- 80- 70- 60- 0- Diastolic Blood Pressure (mm Hg) Clinic Work Home Sleep Normotensives Mild hypertensives Established hypertensives Clinical situations in which the normal diurnal rhythm of BP may be lost Autonomic Dysfunction Syndromes Diabetes Mellitus Renal Failure Secondary forms of hypertension e.g. Cushing’s disease Drugs, e.g. cyclosporine African-American ethnicity Nocturnal BP Changes and CV Mortality: Ohasama study (Ohkubo et al; AJH 1997; 10: 1201) Extreme dippers Dippers Non-dippers Risers Risk of CV Mortality Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Morning Peak of VT Detected by Implanted Cardioverter/Defibrillator (Tofler Circ 1995;92: 1203) Episodes of VT Circadian Rhythm of Ischemic & Hemorrhagic Strokes Gallerani et al, Acta Neurol Scand 1993; 87: 482) % of strokes 1-6 6 -12 12-18 18-24 Hour of day Ischemic Hemorrhagic Analysis of The Influence of the Morning Surge of BP on Stroke Incidence (Kario, Pickering et al, Circ 2003; 107:1401)) Cox regression analysis for clinical stroke events Covariates RR P value Age (10 yrs) 1.80 (1.21-2.69) 0.004 Male gender 1.42 (0.76-2.67) 0.266 BMI 0.98 (0.90-1.07) 0.663 24 hr SBP 1.37 (1.16-1.63 0.003 SCI 4.40 (1.95-10.1) 0.001 Morning BP surge* 1.29 (1.10-1.51) 0.001 Nocturnal BP fall* 0.88 (0.73-1.06) 0.167 Lowest sleep BP 1.05 (0.65-1.71) 0.837 * per 10 mmHg Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Efficacy: telmisartan vs amlodipine using 24-h ABPM Placebo (n=58) Amlodipine (5-10 mg) (n=65) Telmisartan (40-120 mg) (n=62) 0800 1200 1600 2000 2400 0400 0800 BP (mm Hg) Lacourcière Y et al, in press 160 140 120 100 0 Time Week 12, SBP Effects of Two ARBs Approved for Once Daily Dosing on 24 Hour Blood Pressure (Mancia et al AJC 1999: 84; 28S) Missed Dose Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Do different drug classes have different effects on Daytime vs. Nighttime BP? Meta-Analysis of Effects of Antihypertensive Drug Classes on Daytime & Nighttime BP Weiner, Rieckmann, & Pickering, 2005 Medline search of trials in which effects of antihypertensive drugs on daytime, nighttime, and 24 hr BP were described 55 trials satisfied criteria, & were grouped into 3 classes: ACEI, ARBs, Beta blockers (n=10), CCBs & Diuretics (n=35), and combinations (n=10). Across all studies, the absolute change of daytime BP (14/8 mmHg) was significantly greater than the change of nighttime BP (12.5/4.5 mmHg, p<0.01). The magnitude of the difference between the daytime & nighttime changes did not differ between the groups (p>0.7). Meta-Analysis of Effects of Antihypertensive Drug Classes on Daytime & Nighttime BP Weiner, Rieckmann, & Pickering, 2005 Change of SBP with Treatment mmHg DAY NIGHT Baseline Systolic BP mmHg BP Change mmHg ACEI, ARBs CCBs, Diuretics Meta-Analysis of Effects of Antihypertensive Drug Classes on Daytime & Nighttime BP Weiner, Rieckmann, & Pickering, 2005 Day: B=.07 (p=0.53) Night: B=.04 (p=0.63) Day: B=.55 (p<0.001) Night: B=.55 (p<0.001) Are there class differences in thresholds for lowering BP? (Sekino et al, J Hum Hypertens 1998: 12: 719) Drug Average Effect Threshold BP* on BP Level CBP ABP Daytime Nighttime Nilvadipine -26 -12.5 127 110 Amlodipine -20 -15 127 106 Bisoprolol -19 -12 124 110 Lisinopril -20 -19 97 108 * Estimated from regression line of baseline BP versus change Are there class differences in thresholds for lowering BP? (Sekino et al, J Hum Hypertens 1998: 12: 719) Drug Average Effect Threshold BP* on BP Level CBP ABP Daytime Nighttime Nilvadipine -26 -12.5 127 110 Amlodipine -20 -15 127 106 Bisoprolol -19 -12 124 110 Lisinopril -20 -19 97 108 Combination1 -20 -14 128 106 * Estimated from regression line of baseline BP versus change 1- ACEI + CCB- Fagard et al Am J Hypertens 1993: 6: 648 Diuretics Convert Non-Dippers to Dippers (Uzu & Kimura Circ 1999; 100:1635) Systolic pressure mmHg Day Night No Rx HCTZ No Rx HCTZ Dippers Non-Dippers Diuretics Convert Non-Dippers to Dippers (Uzu & Kimura Circ 1999; 100:1635) Systolic pressure mmHg Day Night No Rx HCTZ No Rx HCTZ Dippers Non-Dippers Regression of Carotid Atherosclerosis by Controlling Morning BP (Marfella et al, Am J Hypertens 2005: 18: 308) Clinic Day Night Morning Carotid IMT 0 -0.02 -0.04 NS NS NS <0.001 <0.02 SBP mmHg IMT mm Regression of Carotid Atherosclerosis by Controlling Morning BP (Marfella et al, Am J Hypertens 2005: 18: 308) Clinic Day Night Morning Carotid IMT 0 -0.02 -0.04 NS NS NS <0.001 <0.02 SBP mmHg IMT mm ? Effects of Alpha-Blockade on the Morning Surge of Blood Pressure (Kario, Pickering, et al Am J Hypertens 2004;17; 668) Doxazosin No Rx Effects of graded release Diltiazem vs. Enalapril on Morning BP (White et al, Am Heart J 2004: 148: 628) Ramipril Diltiazem ER Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Effects of Time of Administration of Valsartan on Diurnal Changes of BP (Hermida et al Hypertens 2003: 42:283) P=0.041 P=0.402 P=0.174 Change of SBP mmHg Effects of Time of Administration of Valsartan on Diurnal Changes of BP (Hermida et al Hypertens 2003: 42:283) P=0.041 P=0.402 P=0.174 Change of SBP mmHg “Diovan may be used over a dose range of 80 mg to 320 mg daily, administered once-a-day.” Conclusions: Does the Pattern of Blood Pressure Effects During the Day Matter? There is a pronounced diurnal rhythm of BP and cardiovascular events, with a peak of both in the morning hours, and a decrease during the night. In some categories of patients the normal dipping pattern of BP is lost or reversed; this may be associated with increased risk. Drugs approved for once daily dose may have different durations of action, particularly after missed doses. Most classes of antihypertensive drugs lower daytime BP more than nighttime BP. The effects of CCBs may be more closely related to baseline BP than ARBs/ACEI. Conclusions: Does the Pattern of Blood Pressure Effects During the Day Matter? 6. Different antihypertensive drugs may have different effects on the morning surge of BP. 7. With some antihypertensive drugs the time of dosing may have significant effects on the diurnal pattern of BP. 8. The implications of these time-dependent differences of antihypertensive drugs for CV morbidity are largely unknown, and need to be more fully investigated. 9. Implications of BP-independent effects of antihypertensive drugs based on small differences of clinic BP may be unwarranted. Duration of Action by Trough:Peak Ratio 0 Hours after dosing 24 Peak Trough Blood Pressure Change mmHg Placebo Drug

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Does the Pattern of Blood Pressure Effects During the Day Matter? Thomas Pickering MD, DPhil Behavioral Cardiovascular Health and Hypertension Program Division of General Medicine Columbia Presbyterian Medical Center New York Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs What is the True Blood Pressure? Clinic BP? Home BP? 24 Hr Average BP? Daytime BP? Nighttime BP? Dipping Pattern? Morning Surge? Variability of BP? Ambulatory BP Differences for Normotensives, and Mild and Established HTN Patients 120- 110- 100- 90- 80- 70- 60- 0- Diastolic Blood Pressure (mm Hg) Clinic Work Home Sleep Normotensives Mild hypertensives Established hypertensives Clinical situations in which the normal diurnal rhythm of BP may be lost Autonomic Dysfunction Syndromes Diabetes Mellitus Renal Failure Secondary forms of hypertension e.g. Cushing’s disease Drugs, e.g. cyclosporine African-American ethnicity Nocturnal BP Changes and CV Mortality: Ohasama study (Ohkubo et al; AJH 1997; 10: 1201) Extreme dippers Dippers Non-dippers Risers Risk of CV Mortality Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Morning Peak of VT Detected by Implanted Cardioverter/Defibrillator (Tofler Circ 1995;92: 1203) Episodes of VT Circadian Rhythm of Ischemic & Hemorrhagic Strokes Gallerani et al, Acta Neurol Scand 1993; 87: 482) % of strokes 1-6 6 -12 12-18 18-24 Hour of day Ischemic Hemorrhagic Analysis of The Influence of the Morning Surge of BP on Stroke Incidence (Kario, Pickering et al, Circ 2003; 107:1401)) Cox regression analysis for clinical stroke events Covariates RR P value Age (10 yrs) 1.80 (1.21-2.69) 0.004 Male gender 1.42 (0.76-2.67) 0.266 BMI 0.98 (0.90-1.07) 0.663 24 hr SBP 1.37 (1.16-1.63 0.003 SCI 4.40 (1.95-10.1) 0.001 Morning BP surge* 1.29 (1.10-1.51) 0.001 Nocturnal BP fall* 0.88 (0.73-1.06) 0.167 Lowest sleep BP 1.05 (0.65-1.71) 0.837 * per 10 mmHg Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Efficacy: telmisartan vs amlodipine using 24-h ABPM Placebo (n=58) Amlodipine (5-10 mg) (n=65) Telmisartan (40-120 mg) (n=62) 0800 1200 1600 2000 2400 0400 0800 BP (mm Hg) Lacourcière Y et al, in press 160 140 120 100 0 Time Week 12, SBP Effects of Two ARBs Approved for Once Daily Dosing on 24 Hour Blood Pressure (Mancia et al AJC 1999: 84; 28S) Missed Dose Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Do different drug classes have different effects on Daytime vs. Nighttime BP? Meta-Analysis of Effects of Antihypertensive Drug Classes on Daytime & Nighttime BP Weiner, Rieckmann, & Pickering, 2005 Medline search of trials in which effects of antihypertensive drugs on daytime, nighttime, and 24 hr BP were described 55 trials satisfied criteria, & were grouped into 3 classes: ACEI, ARBs, Beta blockers (n=10), CCBs & Diuretics (n=35), and combinations (n=10). Across all studies, the absolute change of daytime BP (14/8 mmHg) was significantly greater than the change of nighttime BP (12.5/4.5 mmHg, p<0.01). The magnitude of the difference between the daytime & nighttime changes did not differ between the groups (p>0.7). Meta-Analysis of Effects of Antihypertensive Drug Classes on Daytime & Nighttime BP Weiner, Rieckmann, & Pickering, 2005 Change of SBP with Treatment mmHg DAY NIGHT Baseline Systolic BP mmHg BP Change mmHg ACEI, ARBs CCBs, Diuretics Meta-Analysis of Effects of Antihypertensive Drug Classes on Daytime & Nighttime BP Weiner, Rieckmann, & Pickering, 2005 Day: B=.07 (p=0.53) Night: B=.04 (p=0.63) Day: B=.55 (p<0.001) Night: B=.55 (p<0.001) Are there class differences in thresholds for lowering BP? (Sekino et al, J Hum Hypertens 1998: 12: 719) Drug Average Effect Threshold BP* on BP Level CBP ABP Daytime Nighttime Nilvadipine -26 -12.5 127 110 Amlodipine -20 -15 127 106 Bisoprolol -19 -12 124 110 Lisinopril -20 -19 97 108 * Estimated from regression line of baseline BP versus change Are there class differences in thresholds for lowering BP? (Sekino et al, J Hum Hypertens 1998: 12: 719) Drug Average Effect Threshold BP* on BP Level CBP ABP Daytime Nighttime Nilvadipine -26 -12.5 127 110 Amlodipine -20 -15 127 106 Bisoprolol -19 -12 124 110 Lisinopril -20 -19 97 108 Combination1 -20 -14 128 106 * Estimated from regression line of baseline BP versus change 1- ACEI + CCB- Fagard et al Am J Hypertens 1993: 6: 648 Diuretics Convert Non-Dippers to Dippers (Uzu & Kimura Circ 1999; 100:1635) Systolic pressure mmHg Day Night No Rx HCTZ No Rx HCTZ Dippers Non-Dippers Diuretics Convert Non-Dippers to Dippers (Uzu & Kimura Circ 1999; 100:1635) Systolic pressure mmHg Day Night No Rx HCTZ No Rx HCTZ Dippers Non-Dippers Regression of Carotid Atherosclerosis by Controlling Morning BP (Marfella et al, Am J Hypertens 2005: 18: 308) Clinic Day Night Morning Carotid IMT 0 -0.02 -0.04 NS NS NS <0.001 <0.02 SBP mmHg IMT mm Regression of Carotid Atherosclerosis by Controlling Morning BP (Marfella et al, Am J Hypertens 2005: 18: 308) Clinic Day Night Morning Carotid IMT 0 -0.02 -0.04 NS NS NS <0.001 <0.02 SBP mmHg IMT mm ? Effects of Alpha-Blockade on the Morning Surge of Blood Pressure (Kario, Pickering, et al Am J Hypertens 2004;17; 668) Doxazosin No Rx Effects of graded release Diltiazem vs. Enalapril on Morning BP (White et al, Am Heart J 2004: 148: 628) Ramipril Diltiazem ER Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Effects of Time of Administration of Valsartan on Diurnal Changes of BP (Hermida et al Hypertens 2003: 42:283) P=0.041 P=0.402 P=0.174 Change of SBP mmHg Effects of Time of Administration of Valsartan on Diurnal Changes of BP (Hermida et al Hypertens 2003: 42:283) P=0.041 P=0.402 P=0.174 Change of SBP mmHg “Diovan may be used over a dose range of 80 mg to 320 mg daily, administered once-a-day.” Conclusions: Does the Pattern of Blood Pressure Effects During the Day Matter? There is a pronounced diurnal rhythm of BP and cardiovascular events, with a peak of both in the morning hours, and a decrease during the night. In some categories of patients the normal dipping pattern of BP is lost or reversed; this may be associated with increased risk. Drugs approved for once daily dose may have different durations of action, particularly after missed doses. Most classes of antihypertensive drugs lower daytime BP more than nighttime BP. The effects of CCBs may be more closely related to baseline BP than ARBs/ACEI. Conclusions: Does the Pattern of Blood Pressure Effects During the Day Matter? 6. Different antihypertensive drugs may have different effects on the morning surge of BP. 7. With some antihypertensive drugs the time of dosing may have significant effects on the diurnal pattern of BP. 8. The implications of these time-dependent differences of antihypertensive drugs for CV morbidity are largely unknown, and need to be more fully investigated. 9. Implications of BP-independent effects of antihypertensive drugs based on small differences of clinic BP may be unwarranted. Duration of Action by Trough:Peak Ratio 0 Hours after dosing 24 Peak Trough Blood Pressure Change mmHg Placebo Drug Peak Trough Smoothness Index: mean change/SD Trough:peak ratio Change of systolic pressure mmHg Hours since drug dosing Trough:Peak Ratio vs Smoothness Index for defining drug effects on 24 hour BP (Omboni et al BPM, 1998; 3:201)

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Does the Pattern of Blood Pressure Effects During the Day Matter? Thomas Pickering MD, DPhil Behavioral Cardiovascular Health and Hypertension Program Division of General Medicine Columbia Presbyterian Medical Center New York Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs What is the True Blood Pressure? Clinic BP? Home BP? 24 Hr Average BP? Daytime BP? Nighttime BP? Dipping Pattern? Morning Surge? Variability of BP? Ambulatory BP Differences for Normotensives, and Mild and Established HTN Patients 120- 110- 100- 90- 80- 70- 60- 0- Diastolic Blood Pressure (mm Hg) Clinic Work Home Sleep Normotensives Mild hypertensives Established hypertensives Clinical situations in which the normal diurnal rhythm of BP may be lost Autonomic Dysfunction Syndromes Diabetes Mellitus Renal Failure Secondary forms of hypertension e.g. Cushing’s disease Drugs, e.g. cyclosporine African-American ethnicity Nocturnal BP Changes and CV Mortality: Ohasama study (Ohkubo et al; AJH 1997; 10: 1201) Extreme dippers Dippers Non-dippers Risers Risk of CV Mortality Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Morning Peak of VT Detected by Implanted Cardioverter/Defibrillator (Tofler Circ 1995;92: 1203) Episodes of VT Circadian Rhythm of Ischemic & Hemorrhagic Strokes Gallerani et al, Acta Neurol Scand 1993; 87: 482) % of strokes 1-6 6 -12 12-18 18-24 Hour of day Ischemic Hemorrhagic Analysis of The Influence of the Morning Surge of BP on Stroke Incidence (Kario, Pickering et al, Circ 2003; 107:1401)) Cox regression analysis for clinical stroke events Covariates RR P value Age (10 yrs) 1.80 (1.21-2.69) 0.004 Male gender 1.42 (0.76-2.67) 0.266 BMI 0.98 (0.90-1.07) 0.663 24 hr SBP 1.37 (1.16-1.63 0.003 SCI 4.40 (1.95-10.1) 0.001 Morning BP surge* 1.29 (1.10-1.51) 0.001 Nocturnal BP fall* 0.88 (0.73-1.06) 0.167 Lowest sleep BP 1.05 (0.65-1.71) 0.837 * per 10 mmHg Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Efficacy: telmisartan vs amlodipine using 24-h ABPM Placebo (n=58) Amlodipine (5-10 mg) (n=65) Telmisartan (40-120 mg) (n=62) 0800 1200 1600 2000 2400 0400 0800 BP (mm Hg) Lacourcière Y et al, in press 160 140 120 100 0 Time Week 12, SBP Effects of Two ARBs Approved for Once Daily Dosing on 24 Hour Blood Pressure (Mancia et al AJC 1999: 84; 28S) Missed Dose Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Do different drug classes have different effects on Daytime vs. Nighttime BP? Meta-Analysis of Effects of Antihypertensive Drug Classes on Daytime & Nighttime BP Weiner, Rieckmann, & Pickering, 2005 Medline search of trials in which effects of antihypertensive drugs on daytime, nighttime, and 24 hr BP were described 55 trials satisfied criteria, & were grouped into 3 classes: ACEI, ARBs, Beta blockers (n=10), CCBs & Diuretics (n=35), and combinations (n=10). Across all studies, the absolute change of daytime BP (14/8 mmHg) was significantly greater than the change of nighttime BP (12.5/4.5 mmHg, p<0.01). The magnitude of the difference between the daytime & nighttime changes did not differ between the groups (p>0.7). Meta-Analysis of Effects of Antihypertensive Drug Classes on Daytime & Nighttime BP Weiner, Rieckmann, & Pickering, 2005 Change of SBP with Treatment mmHg DAY NIGHT Baseline Systolic BP mmHg BP Change mmHg ACEI, ARBs CCBs, Diuretics Meta-Analysis of Effects of Antihypertensive Drug Classes on Daytime & Nighttime BP Weiner, Rieckmann, & Pickering, 2005 Day: B=.07 (p=0.53) Night: B=.04 (p=0.63) Day: B=.55 (p<0.001) Night: B=.55 (p<0.001) Are there class differences in thresholds for lowering BP? (Sekino et al, J Hum Hypertens 1998: 12: 719) Drug Average Effect Threshold BP* on BP Level CBP ABP Daytime Nighttime Nilvadipine -26 -12.5 127 110 Amlodipine -20 -15 127 106 Bisoprolol -19 -12 124 110 Lisinopril -20 -19 97 108 * Estimated from regression line of baseline BP versus change Are there class differences in thresholds for lowering BP? (Sekino et al, J Hum Hypertens 1998: 12: 719) Drug Average Effect Threshold BP* on BP Level CBP ABP Daytime Nighttime Nilvadipine -26 -12.5 127 110 Amlodipine -20 -15 127 106 Bisoprolol -19 -12 124 110 Lisinopril -20 -19 97 108 Combination1 -20 -14 128 106 * Estimated from regression line of baseline BP versus change 1- ACEI + CCB- Fagard et al Am J Hypertens 1993: 6: 648 Diuretics Convert Non-Dippers to Dippers (Uzu & Kimura Circ 1999; 100:1635) Systolic pressure mmHg Day Night No Rx HCTZ No Rx HCTZ Dippers Non-Dippers Diuretics Convert Non-Dippers to Dippers (Uzu & Kimura Circ 1999; 100:1635) Systolic pressure mmHg Day Night No Rx HCTZ No Rx HCTZ Dippers Non-Dippers Regression of Carotid Atherosclerosis by Controlling Morning BP (Marfella et al, Am J Hypertens 2005: 18: 308) Clinic Day Night Morning Carotid IMT 0 -0.02 -0.04 NS NS NS <0.001 <0.02 SBP mmHg IMT mm Regression of Carotid Atherosclerosis by Controlling Morning BP (Marfella et al, Am J Hypertens 2005: 18: 308) Clinic Day Night Morning Carotid IMT 0 -0.02 -0.04 NS NS NS <0.001 <0.02 SBP mmHg IMT mm ? Effects of Alpha-Blockade on the Morning Surge of Blood Pressure (Kario, Pickering, et al Am J Hypertens 2004;17; 668) Doxazosin No Rx Effects of graded release Diltiazem vs. Enalapril on Morning BP (White et al, Am Heart J 2004: 148: 628) Ramipril Diltiazem ER Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Effects of Time of Administration of Valsartan on Diurnal Changes of BP (Hermida et al Hypertens 2003: 42:283) P=0.041 P=0.402 P=0.174 Change of SBP mmHg Effects of Time of Administration of Valsartan on Diurnal Changes of BP (Hermida et al Hypertens 2003: 42:283) P=0.041 P=0.402 P=0.174 Change of SBP mmHg “Diovan may be used over a dose range of 80 mg to 320 mg daily, administered once-a-day.” Conclusions: Does the Pattern of Blood Pressure Effects During the Day Matter? There is a pronounced diurnal rhythm of BP and cardiovascular events, with a peak of both in the morning hours, and a decrease during the night. In some categories of patients the normal dipping pattern of BP is lost or reversed; this may be associated with increased risk. Drugs approved for once daily dose may have different durations of action, particularly after missed doses. Most classes of antihypertensive drugs lower daytime BP more than nighttime BP. The effects of CCBs may be more closely related to baseline BP than ARBs/ACEI. Conclusions: Does the Pattern of Blood Pressure Effects During the Day Matter? 6. Different antihypertensive drugs may have different effects on the morning surge of BP. 7. With some antihypertensive drugs the time of dosing may have significant effects on the diurnal pattern of BP. 8. The implications of these time-dependent differences of antihypertensive drugs for CV morbidity are largely unknown, and need to be more fully investigated. 9. Implications of BP-independent effects of antihypertensive drugs based on small differences of clinic BP may be unwarranted. Duration of Action by Trough:Peak Ratio 0 Hours after dosing 24 Peak Trough Blood Pressure Change mmHg Placebo Drug Peak Trough Smoothness Index: mean change/SD Trough:peak ratio Change of systolic pressure mmHg Hours since drug dosing Trough:Peak Ratio vs Smoothness Index for defining drug effects on 24 hour BP (Omboni et al BPM, 1998; 3:201) Prognostic Significance of Non-Dipping (Verdecchia et al, BPM 1996; 1 (Suppl 2) ;S81) Covariate Relative Risk Men Women Age>60 7.39 2.44 Diabetes 2.23 2.30 24 hr SBP>median - 3.90 Non-dipper 1.96 1.70 1522 subjects followed for 4.2 years after ABPM

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Does the Pattern of Blood Pressure Effects During the Day Matter? Thomas Pickering MD, DPhil Behavioral Cardiovascular Health and Hypertension Program Division of General Medicine Columbia Presbyterian Medical Center New York Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs What is the True Blood Pressure? Clinic BP? Home BP? 24 Hr Average BP? Daytime BP? Nighttime BP? Dipping Pattern? Morning Surge? Variability of BP? Ambulatory BP Differences for Normotensives, and Mild and Established HTN Patients 120- 110- 100- 90- 80- 70- 60- 0- Diastolic Blood Pressure (mm Hg) Clinic Work Home Sleep Normotensives Mild hypertensives Established hypertensives Clinical situations in which the normal diurnal rhythm of BP may be lost Autonomic Dysfunction Syndromes Diabetes Mellitus Renal Failure Secondary forms of hypertension e.g. Cushing’s disease Drugs, e.g. cyclosporine African-American ethnicity Nocturnal BP Changes and CV Mortality: Ohasama study (Ohkubo et al; AJH 1997; 10: 1201) Extreme dippers Dippers Non-dippers Risers Risk of CV Mortality Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Morning Peak of VT Detected by Implanted Cardioverter/Defibrillator (Tofler Circ 1995;92: 1203) Episodes of VT Circadian Rhythm of Ischemic & Hemorrhagic Strokes Gallerani et al, Acta Neurol Scand 1993; 87: 482) % of strokes 1-6 6 -12 12-18 18-24 Hour of day Ischemic Hemorrhagic Analysis of The Influence of the Morning Surge of BP on Stroke Incidence (Kario, Pickering et al, Circ 2003; 107:1401)) Cox regression analysis for clinical stroke events Covariates RR P value Age (10 yrs) 1.80 (1.21-2.69) 0.004 Male gender 1.42 (0.76-2.67) 0.266 BMI 0.98 (0.90-1.07) 0.663 24 hr SBP 1.37 (1.16-1.63 0.003 SCI 4.40 (1.95-10.1) 0.001 Morning BP surge* 1.29 (1.10-1.51) 0.001 Nocturnal BP fall* 0.88 (0.73-1.06) 0.167 Lowest sleep BP 1.05 (0.65-1.71) 0.837 * per 10 mmHg Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Efficacy: telmisartan vs amlodipine using 24-h ABPM Placebo (n=58) Amlodipine (5-10 mg) (n=65) Telmisartan (40-120 mg) (n=62) 0800 1200 1600 2000 2400 0400 0800 BP (mm Hg) Lacourcière Y et al, in press 160 140 120 100 0 Time Week 12, SBP Effects of Two ARBs Approved for Once Daily Dosing on 24 Hour Blood Pressure (Mancia et al AJC 1999: 84; 28S) Missed Dose Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Do different drug classes have different effects on Daytime vs. Nighttime BP? Meta-Analysis of Effects of Antihypertensive Drug Classes on Daytime & Nighttime BP Weiner, Rieckmann, & Pickering, 2005 Medline search of trials in which effects of antihypertensive drugs on daytime, nighttime, and 24 hr BP were described 55 trials satisfied criteria, & were grouped into 3 classes: ACEI, ARBs, Beta blockers (n=10), CCBs & Diuretics (n=35), and combinations (n=10). Across all studies, the absolute change of daytime BP (14/8 mmHg) was significantly greater than the change of nighttime BP (12.5/4.5 mmHg, p<0.01). The magnitude of the difference between the daytime & nighttime changes did not differ between the groups (p>0.7). Meta-Analysis of Effects of Antihypertensive Drug Classes on Daytime & Nighttime BP Weiner, Rieckmann, & Pickering, 2005 Change of SBP with Treatment mmHg DAY NIGHT Baseline Systolic BP mmHg BP Change mmHg ACEI, ARBs CCBs, Diuretics Meta-Analysis of Effects of Antihypertensive Drug Classes on Daytime & Nighttime BP Weiner, Rieckmann, & Pickering, 2005 Day: B=.07 (p=0.53) Night: B=.04 (p=0.63) Day: B=.55 (p<0.001) Night: B=.55 (p<0.001) Are there class differences in thresholds for lowering BP? (Sekino et al, J Hum Hypertens 1998: 12: 719) Drug Average Effect Threshold BP* on BP Level CBP ABP Daytime Nighttime Nilvadipine -26 -12.5 127 110 Amlodipine -20 -15 127 106 Bisoprolol -19 -12 124 110 Lisinopril -20 -19 97 108 * Estimated from regression line of baseline BP versus change Are there class differences in thresholds for lowering BP? (Sekino et al, J Hum Hypertens 1998: 12: 719) Drug Average Effect Threshold BP* on BP Level CBP ABP Daytime Nighttime Nilvadipine -26 -12.5 127 110 Amlodipine -20 -15 127 106 Bisoprolol -19 -12 124 110 Lisinopril -20 -19 97 108 Combination1 -20 -14 128 106 * Estimated from regression line of baseline BP versus change 1- ACEI + CCB- Fagard et al Am J Hypertens 1993: 6: 648 Diuretics Convert Non-Dippers to Dippers (Uzu & Kimura Circ 1999; 100:1635) Systolic pressure mmHg Day Night No Rx HCTZ No Rx HCTZ Dippers Non-Dippers Diuretics Convert Non-Dippers to Dippers (Uzu & Kimura Circ 1999; 100:1635) Systolic pressure mmHg Day Night No Rx HCTZ No Rx HCTZ Dippers Non-Dippers Regression of Carotid Atherosclerosis by Controlling Morning BP (Marfella et al, Am J Hypertens 2005: 18: 308) Clinic Day Night Morning Carotid IMT 0 -0.02 -0.04 NS NS NS <0.001 <0.02 SBP mmHg IMT mm Regression of Carotid Atherosclerosis by Controlling Morning BP (Marfella et al, Am J Hypertens 2005: 18: 308) Clinic Day Night Morning Carotid IMT 0 -0.02 -0.04 NS NS NS <0.001 <0.02 SBP mmHg IMT mm ? Effects of Alpha-Blockade on the Morning Surge of Blood Pressure (Kario, Pickering, et al Am J Hypertens 2004;17; 668) Doxazosin No Rx Effects of graded release Diltiazem vs. Enalapril on Morning BP (White et al, Am Heart J 2004: 148: 628) Ramipril Diltiazem ER Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Effects of Time of Administration of Valsartan on Diurnal Changes of BP (Hermida et al Hypertens 2003: 42:283) P=0.041 P=0.402 P=0.174 Change of SBP mmHg Effects of Time of Administration of Valsartan on Diurnal Changes of BP (Hermida et al Hypertens 2003: 42:283) P=0.041 P=0.402 P=0.174 Change of SBP mmHg “Diovan may be used over a dose range of 80 mg to 320 mg daily, administered once-a-day.” Conclusions: Does the Pattern of Blood Pressure Effects During the Day Matter? There is a pronounced diurnal rhythm of BP and cardiovascular events, with a peak of both in the morning hours, and a decrease during the night. In some categories of patients the normal dipping pattern of BP is lost or reversed; this may be associated with increased risk. Drugs approved for once daily dose may have different durations of action, particularly after missed doses. Most classes of antihypertensive drugs lower daytime BP more than nighttime BP. The effects of CCBs may be more closely related to baseline BP than ARBs/ACEI. Conclusions: Does the Pattern of Blood Pressure Effects During the Day Matter? 6. Different antihypertensive drugs may have different effects on the morning surge of BP. 7. With some antihypertensive drugs the time of dosing may have significant effects on the diurnal pattern of BP. 8. The implications of these time-dependent differences of antihypertensive drugs for CV morbidity are largely unknown, and need to be more fully investigated. 9. Implications of BP-independent effects of antihypertensive drugs based on small differences of clinic BP may be unwarranted. Duration of Action by Trough:Peak Ratio 0 Hours after dosing 24 Peak Trough Blood Pressure Change mmHg Placebo Drug Peak Trough Smoothness Index: mean change/SD Trough:peak ratio Change of systolic pressure mmHg Hours since drug dosing Trough:Peak Ratio vs Smoothness Index for defining drug effects on 24 hour BP (Omboni et al BPM, 1998; 3:201) Prognostic Significance of Non-Dipping (Verdecchia et al, BPM 1996; 1 (Suppl 2) ;S81) Covariate Relative Risk Men Women Age>60 7.39 2.44 Diabetes 2.23 2.30 24 hr SBP>median - 3.90 Non-dipper 1.96 1.70 1522 subjects followed for 4.2 years after ABPM Effects of ACEI and CCB on Low and High Ambulatory BP in 3 Studies Study Effect of Drug on Systolic ABP mmHg ACEI CCB ABP Lo ABP Hi ABP Lo ABP Hi Ashida -7.6 -8.9 -3.8 -12.7 Herpin -7 -9 -1 -7 Kristensen -14.5 -16.6 -2.7 -10.1 Ashida et al AJC 1990: 66: 498. N=41; ACEI = Enalapril; CCB= Nifedipine SR Herpin et al AJC 1992: 69: 923. N=236; ACEI = Various; CCB = Various. Kristensen et al BPM; 1998; 3: 116. N=96; ACEI = Benazepril; CCB = Felodipine ER

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Does the Pattern of Blood Pressure Effects During the Day Matter? Thomas Pickering MD, DPhil Behavioral Cardiovascular Health and Hypertension Program Division of General Medicine Columbia Presbyterian Medical Center New York Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs What is the True Blood Pressure? Clinic BP? Home BP? 24 Hr Average BP? Daytime BP? Nighttime BP? Dipping Pattern? Morning Surge? Variability of BP? Ambulatory BP Differences for Normotensives, and Mild and Established HTN Patients 120- 110- 100- 90- 80- 70- 60- 0- Diastolic Blood Pressure (mm Hg) Clinic Work Home Sleep Normotensives Mild hypertensives Established hypertensives Clinical situations in which the normal diurnal rhythm of BP may be lost Autonomic Dysfunction Syndromes Diabetes Mellitus Renal Failure Secondary forms of hypertension e.g. Cushing’s disease Drugs, e.g. cyclosporine African-American ethnicity Nocturnal BP Changes and CV Mortality: Ohasama study (Ohkubo et al; AJH 1997; 10: 1201) Extreme dippers Dippers Non-dippers Risers Risk of CV Mortality Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Morning Peak of VT Detected by Implanted Cardioverter/Defibrillator (Tofler Circ 1995;92: 1203) Episodes of VT Circadian Rhythm of Ischemic & Hemorrhagic Strokes Gallerani et al, Acta Neurol Scand 1993; 87: 482) % of strokes 1-6 6 -12 12-18 18-24 Hour of day Ischemic Hemorrhagic Analysis of The Influence of the Morning Surge of BP on Stroke Incidence (Kario, Pickering et al, Circ 2003; 107:1401)) Cox regression analysis for clinical stroke events Covariates RR P value Age (10 yrs) 1.80 (1.21-2.69) 0.004 Male gender 1.42 (0.76-2.67) 0.266 BMI 0.98 (0.90-1.07) 0.663 24 hr SBP 1.37 (1.16-1.63 0.003 SCI 4.40 (1.95-10.1) 0.001 Morning BP surge* 1.29 (1.10-1.51) 0.001 Nocturnal BP fall* 0.88 (0.73-1.06) 0.167 Lowest sleep BP 1.05 (0.65-1.71) 0.837 * per 10 mmHg Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Efficacy: telmisartan vs amlodipine using 24-h ABPM Placebo (n=58) Amlodipine (5-10 mg) (n=65) Telmisartan (40-120 mg) (n=62) 0800 1200 1600 2000 2400 0400 0800 BP (mm Hg) Lacourcière Y et al, in press 160 140 120 100 0 Time Week 12, SBP Effects of Two ARBs Approved for Once Daily Dosing on 24 Hour Blood Pressure (Mancia et al AJC 1999: 84; 28S) Missed Dose Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Do different drug classes have different effects on Daytime vs. Nighttime BP? Meta-Analysis of Effects of Antihypertensive Drug Classes on Daytime & Nighttime BP Weiner, Rieckmann, & Pickering, 2005 Medline search of trials in which effects of antihypertensive drugs on daytime, nighttime, and 24 hr BP were described 55 trials satisfied criteria, & were grouped into 3 classes: ACEI, ARBs, Beta blockers (n=10), CCBs & Diuretics (n=35), and combinations (n=10). Across all studies, the absolute change of daytime BP (14/8 mmHg) was significantly greater than the change of nighttime BP (12.5/4.5 mmHg, p<0.01). The magnitude of the difference between the daytime & nighttime changes did not differ between the groups (p>0.7). Meta-Analysis of Effects of Antihypertensive Drug Classes on Daytime & Nighttime BP Weiner, Rieckmann, & Pickering, 2005 Change of SBP with Treatment mmHg DAY NIGHT Baseline Systolic BP mmHg BP Change mmHg ACEI, ARBs CCBs, Diuretics Meta-Analysis of Effects of Antihypertensive Drug Classes on Daytime & Nighttime BP Weiner, Rieckmann, & Pickering, 2005 Day: B=.07 (p=0.53) Night: B=.04 (p=0.63) Day: B=.55 (p<0.001) Night: B=.55 (p<0.001) Are there class differences in thresholds for lowering BP? (Sekino et al, J Hum Hypertens 1998: 12: 719) Drug Average Effect Threshold BP* on BP Level CBP ABP Daytime Nighttime Nilvadipine -26 -12.5 127 110 Amlodipine -20 -15 127 106 Bisoprolol -19 -12 124 110 Lisinopril -20 -19 97 108 * Estimated from regression line of baseline BP versus change Are there class differences in thresholds for lowering BP? (Sekino et al, J Hum Hypertens 1998: 12: 719) Drug Average Effect Threshold BP* on BP Level CBP ABP Daytime Nighttime Nilvadipine -26 -12.5 127 110 Amlodipine -20 -15 127 106 Bisoprolol -19 -12 124 110 Lisinopril -20 -19 97 108 Combination1 -20 -14 128 106 * Estimated from regression line of baseline BP versus change 1- ACEI + CCB- Fagard et al Am J Hypertens 1993: 6: 648 Diuretics Convert Non-Dippers to Dippers (Uzu & Kimura Circ 1999; 100:1635) Systolic pressure mmHg Day Night No Rx HCTZ No Rx HCTZ Dippers Non-Dippers Diuretics Convert Non-Dippers to Dippers (Uzu & Kimura Circ 1999; 100:1635) Systolic pressure mmHg Day Night No Rx HCTZ No Rx HCTZ Dippers Non-Dippers Regression of Carotid Atherosclerosis by Controlling Morning BP (Marfella et al, Am J Hypertens 2005: 18: 308) Clinic Day Night Morning Carotid IMT 0 -0.02 -0.04 NS NS NS <0.001 <0.02 SBP mmHg IMT mm Regression of Carotid Atherosclerosis by Controlling Morning BP (Marfella et al, Am J Hypertens 2005: 18: 308) Clinic Day Night Morning Carotid IMT 0 -0.02 -0.04 NS NS NS <0.001 <0.02 SBP mmHg IMT mm ? Effects of Alpha-Blockade on the Morning Surge of Blood Pressure (Kario, Pickering, et al Am J Hypertens 2004;17; 668) Doxazosin No Rx Effects of graded release Diltiazem vs. Enalapril on Morning BP (White et al, Am Heart J 2004: 148: 628) Ramipril Diltiazem ER Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Effects of Time of Administration of Valsartan on Diurnal Changes of BP (Hermida et al Hypertens 2003: 42:283) P=0.041 P=0.402 P=0.174 Change of SBP mmHg Effects of Time of Administration of Valsartan on Diurnal Changes of BP (Hermida et al Hypertens 2003: 42:283) P=0.041 P=0.402 P=0.174 Change of SBP mmHg “Diovan may be used over a dose range of 80 mg to 320 mg daily, administered once-a-day.” Conclusions: Does the Pattern of Blood Pressure Effects During the Day Matter? There is a pronounced diurnal rhythm of BP and cardiovascular events, with a peak of both in the morning hours, and a decrease during the night. In some categories of patients the normal dipping pattern of BP is lost or reversed; this may be associated with increased risk. Drugs approved for once daily dose may have different durations of action, particularly after missed doses. Most classes of antihypertensive drugs lower daytime BP more than nighttime BP. The effects of CCBs may be more closely related to baseline BP than ARBs/ACEI. Conclusions: Does the Pattern of Blood Pressure Effects During the Day Matter? 6. Different antihypertensive drugs may have different effects on the morning surge of BP. 7. With some antihypertensive drugs the time of dosing may have significant effects on the diurnal pattern of BP. 8. The implications of these time-dependent differences of antihypertensive drugs for CV morbidity are largely unknown, and need to be more fully investigated. 9. Implications of BP-independent effects of antihypertensive drugs based on small differences of clinic BP may be unwarranted. Duration of Action by Trough:Peak Ratio 0 Hours after dosing 24 Peak Trough Blood Pressure Change mmHg Placebo Drug Peak Trough Smoothness Index: mean change/SD Trough:peak ratio Change of systolic pressure mmHg Hours since drug dosing Trough:Peak Ratio vs Smoothness Index for defining drug effects on 24 hour BP (Omboni et al BPM, 1998; 3:201) Prognostic Significance of Non-Dipping (Verdecchia et al, BPM 1996; 1 (Suppl 2) ;S81) Covariate Relative Risk Men Women Age>60 7.39 2.44 Diabetes 2.23 2.30 24 hr SBP>median - 3.90 Non-dipper 1.96 1.70 1522 subjects followed for 4.2 years after ABPM Effects of ACEI and CCB on Low and High Ambulatory BP in 3 Studies Study Effect of Drug on Systolic ABP mmHg ACEI CCB ABP Lo ABP Hi ABP Lo ABP Hi Ashida -7.6 -8.9 -3.8 -12.7 Herpin -7 -9 -1 -7 Kristensen -14.5 -16.6 -2.7 -10.1 Ashida et al AJC 1990: 66: 498. N=41; ACEI = Enalapril; CCB= Nifedipine SR Herpin et al AJC 1992: 69: 923. N=236; ACEI = Various; CCB = Various. Kristensen et al BPM; 1998; 3: 116. N=96; ACEI = Benazepril; CCB = Felodipine ER Effects of ACEI and CCB on Clinic SBP in Low and High Ambulatory BP Groups in 3 Studies Study Effect of Drug on Systolic CBP mmHg ACEI CCB ABP Lo ABP Hi ABP Lo ABP Hi Ashida -6.5 -9.5 -11 -16 Herpin -13 -9 -13 -7 Kristensen NA NA NA NA Ashida et al AJC 1990: 66: 498. N=41; ACEI = Enalapril; CCB= Nifedipine SR Herpin et al AJC 1992: 69: 923. N=236; ACEI = Various; CCB = Various. Kristensen et al BPM; 1998; 3: 116. N=96; ACEI = Benazepril; CCB = Felodipine ER

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Does the Pattern of Blood Pressure Effects During the Day Matter? Thomas Pickering MD, DPhil Behavioral Cardiovascular Health and Hypertension Program Division of General Medicine Columbia Presbyterian Medical Center New York Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs What is the True Blood Pressure? Clinic BP? Home BP? 24 Hr Average BP? Daytime BP? Nighttime BP? Dipping Pattern? Morning Surge? Variability of BP? Ambulatory BP Differences for Normotensives, and Mild and Established HTN Patients 120- 110- 100- 90- 80- 70- 60- 0- Diastolic Blood Pressure (mm Hg) Clinic Work Home Sleep Normotensives Mild hypertensives Established hypertensives Clinical situations in which the normal diurnal rhythm of BP may be lost Autonomic Dysfunction Syndromes Diabetes Mellitus Renal Failure Secondary forms of hypertension e.g. Cushing’s disease Drugs, e.g. cyclosporine African-American ethnicity Nocturnal BP Changes and CV Mortality: Ohasama study (Ohkubo et al; AJH 1997; 10: 1201) Extreme dippers Dippers Non-dippers Risers Risk of CV Mortality Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Morning Peak of VT Detected by Implanted Cardioverter/Defibrillator (Tofler Circ 1995;92: 1203) Episodes of VT Circadian Rhythm of Ischemic & Hemorrhagic Strokes Gallerani et al, Acta Neurol Scand 1993; 87: 482) % of strokes 1-6 6 -12 12-18 18-24 Hour of day Ischemic Hemorrhagic Analysis of The Influence of the Morning Surge of BP on Stroke Incidence (Kario, Pickering et al, Circ 2003; 107:1401)) Cox regression analysis for clinical stroke events Covariates RR P value Age (10 yrs) 1.80 (1.21-2.69) 0.004 Male gender 1.42 (0.76-2.67) 0.266 BMI 0.98 (0.90-1.07) 0.663 24 hr SBP 1.37 (1.16-1.63 0.003 SCI 4.40 (1.95-10.1) 0.001 Morning BP surge* 1.29 (1.10-1.51) 0.001 Nocturnal BP fall* 0.88 (0.73-1.06) 0.167 Lowest sleep BP 1.05 (0.65-1.71) 0.837 * per 10 mmHg Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Efficacy: telmisartan vs amlodipine using 24-h ABPM Placebo (n=58) Amlodipine (5-10 mg) (n=65) Telmisartan (40-120 mg) (n=62) 0800 1200 1600 2000 2400 0400 0800 BP (mm Hg) Lacourcière Y et al, in press 160 140 120 100 0 Time Week 12, SBP Effects of Two ARBs Approved for Once Daily Dosing on 24 Hour Blood Pressure (Mancia et al AJC 1999: 84; 28S) Missed Dose Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Do different drug classes have different effects on Daytime vs. Nighttime BP? Meta-Analysis of Effects of Antihypertensive Drug Classes on Daytime & Nighttime BP Weiner, Rieckmann, & Pickering, 2005 Medline search of trials in which effects of antihypertensive drugs on daytime, nighttime, and 24 hr BP were described 55 trials satisfied criteria, & were grouped into 3 classes: ACEI, ARBs, Beta blockers (n=10), CCBs & Diuretics (n=35), and combinations (n=10). Across all studies, the absolute change of daytime BP (14/8 mmHg) was significantly greater than the change of nighttime BP (12.5/4.5 mmHg, p<0.01). The magnitude of the difference between the daytime & nighttime changes did not differ between the groups (p>0.7). Meta-Analysis of Effects of Antihypertensive Drug Classes on Daytime & Nighttime BP Weiner, Rieckmann, & Pickering, 2005 Change of SBP with Treatment mmHg DAY NIGHT Baseline Systolic BP mmHg BP Change mmHg ACEI, ARBs CCBs, Diuretics Meta-Analysis of Effects of Antihypertensive Drug Classes on Daytime & Nighttime BP Weiner, Rieckmann, & Pickering, 2005 Day: B=.07 (p=0.53) Night: B=.04 (p=0.63) Day: B=.55 (p<0.001) Night: B=.55 (p<0.001) Are there class differences in thresholds for lowering BP? (Sekino et al, J Hum Hypertens 1998: 12: 719) Drug Average Effect Threshold BP* on BP Level CBP ABP Daytime Nighttime Nilvadipine -26 -12.5 127 110 Amlodipine -20 -15 127 106 Bisoprolol -19 -12 124 110 Lisinopril -20 -19 97 108 * Estimated from regression line of baseline BP versus change Are there class differences in thresholds for lowering BP? (Sekino et al, J Hum Hypertens 1998: 12: 719) Drug Average Effect Threshold BP* on BP Level CBP ABP Daytime Nighttime Nilvadipine -26 -12.5 127 110 Amlodipine -20 -15 127 106 Bisoprolol -19 -12 124 110 Lisinopril -20 -19 97 108 Combination1 -20 -14 128 106 * Estimated from regression line of baseline BP versus change 1- ACEI + CCB- Fagard et al Am J Hypertens 1993: 6: 648 Diuretics Convert Non-Dippers to Dippers (Uzu & Kimura Circ 1999; 100:1635) Systolic pressure mmHg Day Night No Rx HCTZ No Rx HCTZ Dippers Non-Dippers Diuretics Convert Non-Dippers to Dippers (Uzu & Kimura Circ 1999; 100:1635) Systolic pressure mmHg Day Night No Rx HCTZ No Rx HCTZ Dippers Non-Dippers Regression of Carotid Atherosclerosis by Controlling Morning BP (Marfella et al, Am J Hypertens 2005: 18: 308) Clinic Day Night Morning Carotid IMT 0 -0.02 -0.04 NS NS NS <0.001 <0.02 SBP mmHg IMT mm Regression of Carotid Atherosclerosis by Controlling Morning BP (Marfella et al, Am J Hypertens 2005: 18: 308) Clinic Day Night Morning Carotid IMT 0 -0.02 -0.04 NS NS NS <0.001 <0.02 SBP mmHg IMT mm ? Effects of Alpha-Blockade on the Morning Surge of Blood Pressure (Kario, Pickering, et al Am J Hypertens 2004;17; 668) Doxazosin No Rx Effects of graded release Diltiazem vs. Enalapril on Morning BP (White et al, Am Heart J 2004: 148: 628) Ramipril Diltiazem ER Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Effects of Time of Administration of Valsartan on Diurnal Changes of BP (Hermida et al Hypertens 2003: 42:283) P=0.041 P=0.402 P=0.174 Change of SBP mmHg Effects of Time of Administration of Valsartan on Diurnal Changes of BP (Hermida et al Hypertens 2003: 42:283) P=0.041 P=0.402 P=0.174 Change of SBP mmHg “Diovan may be used over a dose range of 80 mg to 320 mg daily, administered once-a-day.” Conclusions: Does the Pattern of Blood Pressure Effects During the Day Matter? There is a pronounced diurnal rhythm of BP and cardiovascular events, with a peak of both in the morning hours, and a decrease during the night. In some categories of patients the normal dipping pattern of BP is lost or reversed; this may be associated with increased risk. Drugs approved for once daily dose may have different durations of action, particularly after missed doses. Most classes of antihypertensive drugs lower daytime BP more than nighttime BP. The effects of CCBs may be more closely related to baseline BP than ARBs/ACEI. Conclusions: Does the Pattern of Blood Pressure Effects During the Day Matter? 6. Different antihypertensive drugs may have different effects on the morning surge of BP. 7. With some antihypertensive drugs the time of dosing may have significant effects on the diurnal pattern of BP. 8. The implications of these time-dependent differences of antihypertensive drugs for CV morbidity are largely unknown, and need to be more fully investigated. 9. Implications of BP-independent effects of antihypertensive drugs based on small differences of clinic BP may be unwarranted. Duration of Action by Trough:Peak Ratio 0 Hours after dosing 24 Peak Trough Blood Pressure Change mmHg Placebo Drug Peak Trough Smoothness Index: mean change/SD Trough:peak ratio Change of systolic pressure mmHg Hours since drug dosing Trough:Peak Ratio vs Smoothness Index for defining drug effects on 24 hour BP (Omboni et al BPM, 1998; 3:201) Prognostic Significance of Non-Dipping (Verdecchia et al, BPM 1996; 1 (Suppl 2) ;S81) Covariate Relative Risk Men Women Age>60 7.39 2.44 Diabetes 2.23 2.30 24 hr SBP>median - 3.90 Non-dipper 1.96 1.70 1522 subjects followed for 4.2 years after ABPM Effects of ACEI and CCB on Low and High Ambulatory BP in 3 Studies Study Effect of Drug on Systolic ABP mmHg ACEI CCB ABP Lo ABP Hi ABP Lo ABP Hi Ashida -7.6 -8.9 -3.8 -12.7 Herpin -7 -9 -1 -7 Kristensen -14.5 -16.6 -2.7 -10.1 Ashida et al AJC 1990: 66: 498. N=41; ACEI = Enalapril; CCB= Nifedipine SR Herpin et al AJC 1992: 69: 923. N=236; ACEI = Various; CCB = Various. Kristensen et al BPM; 1998; 3: 116. N=96; ACEI = Benazepril; CCB = Felodipine ER Effects of ACEI and CCB on Clinic SBP in Low and High Ambulatory BP Groups in 3 Studies Study Effect of Drug on Systolic CBP mmHg ACEI CCB ABP Lo ABP Hi ABP Lo ABP Hi Ashida -6.5 -9.5 -11 -16 Herpin -13 -9 -13 -7 Kristensen NA NA NA NA Ashida et al AJC 1990: 66: 498. N=41; ACEI = Enalapril; CCB= Nifedipine SR Herpin et al AJC 1992: 69: 923. N=236; ACEI = Various; CCB = Various. Kristensen et al BPM; 1998; 3: 116. N=96; ACEI = Benazepril; CCB = Felodipine ER 80 100 90 110 120 130 140 150 160 Extreme dippers Dippers Non-dippers Risers Daytime BP Reduction 8 / 7 7 / 7 11 / 8 10 / 8 p<0.001 p<0.001 p<0.001 N.S. n = 18 n = 46 n = 48 n = 6 mmHg Blood pressure level

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Does the Pattern of Blood Pressure Effects During the Day Matter? Thomas Pickering MD, DPhil Behavioral Cardiovascular Health and Hypertension Program Division of General Medicine Columbia Presbyterian Medical Center New York Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs What is the True Blood Pressure? Clinic BP? Home BP? 24 Hr Average BP? Daytime BP? Nighttime BP? Dipping Pattern? Morning Surge? Variability of BP? Ambulatory BP Differences for Normotensives, and Mild and Established HTN Patients 120- 110- 100- 90- 80- 70- 60- 0- Diastolic Blood Pressure (mm Hg) Clinic Work Home Sleep Normotensives Mild hypertensives Established hypertensives Clinical situations in which the normal diurnal rhythm of BP may be lost Autonomic Dysfunction Syndromes Diabetes Mellitus Renal Failure Secondary forms of hypertension e.g. Cushing’s disease Drugs, e.g. cyclosporine African-American ethnicity Nocturnal BP Changes and CV Mortality: Ohasama study (Ohkubo et al; AJH 1997; 10: 1201) Extreme dippers Dippers Non-dippers Risers Risk of CV Mortality Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Morning Peak of VT Detected by Implanted Cardioverter/Defibrillator (Tofler Circ 1995;92: 1203) Episodes of VT Circadian Rhythm of Ischemic & Hemorrhagic Strokes Gallerani et al, Acta Neurol Scand 1993; 87: 482) % of strokes 1-6 6 -12 12-18 18-24 Hour of day Ischemic Hemorrhagic Analysis of The Influence of the Morning Surge of BP on Stroke Incidence (Kario, Pickering et al, Circ 2003; 107:1401)) Cox regression analysis for clinical stroke events Covariates RR P value Age (10 yrs) 1.80 (1.21-2.69) 0.004 Male gender 1.42 (0.76-2.67) 0.266 BMI 0.98 (0.90-1.07) 0.663 24 hr SBP 1.37 (1.16-1.63 0.003 SCI 4.40 (1.95-10.1) 0.001 Morning BP surge* 1.29 (1.10-1.51) 0.001 Nocturnal BP fall* 0.88 (0.73-1.06) 0.167 Lowest sleep BP 1.05 (0.65-1.71) 0.837 * per 10 mmHg Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Efficacy: telmisartan vs amlodipine using 24-h ABPM Placebo (n=58) Amlodipine (5-10 mg) (n=65) Telmisartan (40-120 mg) (n=62) 0800 1200 1600 2000 2400 0400 0800 BP (mm Hg) Lacourcière Y et al, in press 160 140 120 100 0 Time Week 12, SBP Effects of Two ARBs Approved for Once Daily Dosing on 24 Hour Blood Pressure (Mancia et al AJC 1999: 84; 28S) Missed Dose Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Do different drug classes have different effects on Daytime vs. Nighttime BP? Meta-Analysis of Effects of Antihypertensive Drug Classes on Daytime & Nighttime BP Weiner, Rieckmann, & Pickering, 2005 Medline search of trials in which effects of antihypertensive drugs on daytime, nighttime, and 24 hr BP were described 55 trials satisfied criteria, & were grouped into 3 classes: ACEI, ARBs, Beta blockers (n=10), CCBs & Diuretics (n=35), and combinations (n=10). Across all studies, the absolute change of daytime BP (14/8 mmHg) was significantly greater than the change of nighttime BP (12.5/4.5 mmHg, p<0.01). The magnitude of the difference between the daytime & nighttime changes did not differ between the groups (p>0.7). Meta-Analysis of Effects of Antihypertensive Drug Classes on Daytime & Nighttime BP Weiner, Rieckmann, & Pickering, 2005 Change of SBP with Treatment mmHg DAY NIGHT Baseline Systolic BP mmHg BP Change mmHg ACEI, ARBs CCBs, Diuretics Meta-Analysis of Effects of Antihypertensive Drug Classes on Daytime & Nighttime BP Weiner, Rieckmann, & Pickering, 2005 Day: B=.07 (p=0.53) Night: B=.04 (p=0.63) Day: B=.55 (p<0.001) Night: B=.55 (p<0.001) Are there class differences in thresholds for lowering BP? (Sekino et al, J Hum Hypertens 1998: 12: 719) Drug Average Effect Threshold BP* on BP Level CBP ABP Daytime Nighttime Nilvadipine -26 -12.5 127 110 Amlodipine -20 -15 127 106 Bisoprolol -19 -12 124 110 Lisinopril -20 -19 97 108 * Estimated from regression line of baseline BP versus change Are there class differences in thresholds for lowering BP? (Sekino et al, J Hum Hypertens 1998: 12: 719) Drug Average Effect Threshold BP* on BP Level CBP ABP Daytime Nighttime Nilvadipine -26 -12.5 127 110 Amlodipine -20 -15 127 106 Bisoprolol -19 -12 124 110 Lisinopril -20 -19 97 108 Combination1 -20 -14 128 106 * Estimated from regression line of baseline BP versus change 1- ACEI + CCB- Fagard et al Am J Hypertens 1993: 6: 648 Diuretics Convert Non-Dippers to Dippers (Uzu & Kimura Circ 1999; 100:1635) Systolic pressure mmHg Day Night No Rx HCTZ No Rx HCTZ Dippers Non-Dippers Diuretics Convert Non-Dippers to Dippers (Uzu & Kimura Circ 1999; 100:1635) Systolic pressure mmHg Day Night No Rx HCTZ No Rx HCTZ Dippers Non-Dippers Regression of Carotid Atherosclerosis by Controlling Morning BP (Marfella et al, Am J Hypertens 2005: 18: 308) Clinic Day Night Morning Carotid IMT 0 -0.02 -0.04 NS NS NS <0.001 <0.02 SBP mmHg IMT mm Regression of Carotid Atherosclerosis by Controlling Morning BP (Marfella et al, Am J Hypertens 2005: 18: 308) Clinic Day Night Morning Carotid IMT 0 -0.02 -0.04 NS NS NS <0.001 <0.02 SBP mmHg IMT mm ? Effects of Alpha-Blockade on the Morning Surge of Blood Pressure (Kario, Pickering, et al Am J Hypertens 2004;17; 668) Doxazosin No Rx Effects of graded release Diltiazem vs. Enalapril on Morning BP (White et al, Am Heart J 2004: 148: 628) Ramipril Diltiazem ER Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Effects of Time of Administration of Valsartan on Diurnal Changes of BP (Hermida et al Hypertens 2003: 42:283) P=0.041 P=0.402 P=0.174 Change of SBP mmHg Effects of Time of Administration of Valsartan on Diurnal Changes of BP (Hermida et al Hypertens 2003: 42:283) P=0.041 P=0.402 P=0.174 Change of SBP mmHg “Diovan may be used over a dose range of 80 mg to 320 mg daily, administered once-a-day.” Conclusions: Does the Pattern of Blood Pressure Effects During the Day Matter? There is a pronounced diurnal rhythm of BP and cardiovascular events, with a peak of both in the morning hours, and a decrease during the night. In some categories of patients the normal dipping pattern of BP is lost or reversed; this may be associated with increased risk. Drugs approved for once daily dose may have different durations of action, particularly after missed doses. Most classes of antihypertensive drugs lower daytime BP more than nighttime BP. The effects of CCBs may be more closely related to baseline BP than ARBs/ACEI. Conclusions: Does the Pattern of Blood Pressure Effects During the Day Matter? 6. Different antihypertensive drugs may have different effects on the morning surge of BP. 7. With some antihypertensive drugs the time of dosing may have significant effects on the diurnal pattern of BP. 8. The implications of these time-dependent differences of antihypertensive drugs for CV morbidity are largely unknown, and need to be more fully investigated. 9. Implications of BP-independent effects of antihypertensive drugs based on small differences of clinic BP may be unwarranted. Duration of Action by Trough:Peak Ratio 0 Hours after dosing 24 Peak Trough Blood Pressure Change mmHg Placebo Drug Peak Trough Smoothness Index: mean change/SD Trough:peak ratio Change of systolic pressure mmHg Hours since drug dosing Trough:Peak Ratio vs Smoothness Index for defining drug effects on 24 hour BP (Omboni et al BPM, 1998; 3:201) Prognostic Significance of Non-Dipping (Verdecchia et al, BPM 1996; 1 (Suppl 2) ;S81) Covariate Relative Risk Men Women Age>60 7.39 2.44 Diabetes 2.23 2.30 24 hr SBP>median - 3.90 Non-dipper 1.96 1.70 1522 subjects followed for 4.2 years after ABPM Effects of ACEI and CCB on Low and High Ambulatory BP in 3 Studies Study Effect of Drug on Systolic ABP mmHg ACEI CCB ABP Lo ABP Hi ABP Lo ABP Hi Ashida -7.6 -8.9 -3.8 -12.7 Herpin -7 -9 -1 -7 Kristensen -14.5 -16.6 -2.7 -10.1 Ashida et al AJC 1990: 66: 498. N=41; ACEI = Enalapril; CCB= Nifedipine SR Herpin et al AJC 1992: 69: 923. N=236; ACEI = Various; CCB = Various. Kristensen et al BPM; 1998; 3: 116. N=96; ACEI = Benazepril; CCB = Felodipine ER Effects of ACEI and CCB on Clinic SBP in Low and High Ambulatory BP Groups in 3 Studies Study Effect of Drug on Systolic CBP mmHg ACEI CCB ABP Lo ABP Hi ABP Lo ABP Hi Ashida -6.5 -9.5 -11 -16 Herpin -13 -9 -13 -7 Kristensen NA NA NA NA Ashida et al AJC 1990: 66: 498. N=41; ACEI = Enalapril; CCB= Nifedipine SR Herpin et al AJC 1992: 69: 923. N=236; ACEI = Various; CCB = Various. Kristensen et al BPM; 1998; 3: 116. N=96; ACEI = Benazepril; CCB = Felodipine ER 80 100 90 110 120 130 140 150 160 Extreme dippers Dippers Non-dippers Risers Daytime BP Reduction 8 / 7 7 / 7 11 / 8 10 / 8 p<0.001 p<0.001 p<0.001 N.S. n = 18 n = 46 n = 48 n = 6 mmHg Blood pressure level Extreme dippers Dippers Non-dippers Reverse dippers Nighttime BP Reduction 4 / 2 1 / 2 18 /12 12 / 9 p<0.001 N.S. p<0.01 n = 18 n = 46 n = 48 n = 6 mmHg Blood pressure level

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Does the Pattern of Blood Pressure Effects During the Day Matter? Thomas Pickering MD, DPhil Behavioral Cardiovascular Health and Hypertension Program Division of General Medicine Columbia Presbyterian Medical Center New York Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs What is the True Blood Pressure? Clinic BP? Home BP? 24 Hr Average BP? Daytime BP? Nighttime BP? Dipping Pattern? Morning Surge? Variability of BP? Ambulatory BP Differences for Normotensives, and Mild and Established HTN Patients 120- 110- 100- 90- 80- 70- 60- 0- Diastolic Blood Pressure (mm Hg) Clinic Work Home Sleep Normotensives Mild hypertensives Established hypertensives Clinical situations in which the normal diurnal rhythm of BP may be lost Autonomic Dysfunction Syndromes Diabetes Mellitus Renal Failure Secondary forms of hypertension e.g. Cushing’s disease Drugs, e.g. cyclosporine African-American ethnicity Nocturnal BP Changes and CV Mortality: Ohasama study (Ohkubo et al; AJH 1997; 10: 1201) Extreme dippers Dippers Non-dippers Risers Risk of CV Mortality Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Morning Peak of VT Detected by Implanted Cardioverter/Defibrillator (Tofler Circ 1995;92: 1203) Episodes of VT Circadian Rhythm of Ischemic & Hemorrhagic Strokes Gallerani et al, Acta Neurol Scand 1993; 87: 482) % of strokes 1-6 6 -12 12-18 18-24 Hour of day Ischemic Hemorrhagic Analysis of The Influence of the Morning Surge of BP on Stroke Incidence (Kario, Pickering et al, Circ 2003; 107:1401)) Cox regression analysis for clinical stroke events Covariates RR P value Age (10 yrs) 1.80 (1.21-2.69) 0.004 Male gender 1.42 (0.76-2.67) 0.266 BMI 0.98 (0.90-1.07) 0.663 24 hr SBP 1.37 (1.16-1.63 0.003 SCI 4.40 (1.95-10.1) 0.001 Morning BP surge* 1.29 (1.10-1.51) 0.001 Nocturnal BP fall* 0.88 (0.73-1.06) 0.167 Lowest sleep BP 1.05 (0.65-1.71) 0.837 * per 10 mmHg Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Efficacy: telmisartan vs amlodipine using 24-h ABPM Placebo (n=58) Amlodipine (5-10 mg) (n=65) Telmisartan (40-120 mg) (n=62) 0800 1200 1600 2000 2400 0400 0800 BP (mm Hg) Lacourcière Y et al, in press 160 140 120 100 0 Time Week 12, SBP Effects of Two ARBs Approved for Once Daily Dosing on 24 Hour Blood Pressure (Mancia et al AJC 1999: 84; 28S) Missed Dose Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Do different drug classes have different effects on Daytime vs. Nighttime BP? Meta-Analysis of Effects of Antihypertensive Drug Classes on Daytime & Nighttime BP Weiner, Rieckmann, & Pickering, 2005 Medline search of trials in which effects of antihypertensive drugs on daytime, nighttime, and 24 hr BP were described 55 trials satisfied criteria, & were grouped into 3 classes: ACEI, ARBs, Beta blockers (n=10), CCBs & Diuretics (n=35), and combinations (n=10). Across all studies, the absolute change of daytime BP (14/8 mmHg) was significantly greater than the change of nighttime BP (12.5/4.5 mmHg, p<0.01). The magnitude of the difference between the daytime & nighttime changes did not differ between the groups (p>0.7). Meta-Analysis of Effects of Antihypertensive Drug Classes on Daytime & Nighttime BP Weiner, Rieckmann, & Pickering, 2005 Change of SBP with Treatment mmHg DAY NIGHT Baseline Systolic BP mmHg BP Change mmHg ACEI, ARBs CCBs, Diuretics Meta-Analysis of Effects of Antihypertensive Drug Classes on Daytime & Nighttime BP Weiner, Rieckmann, & Pickering, 2005 Day: B=.07 (p=0.53) Night: B=.04 (p=0.63) Day: B=.55 (p<0.001) Night: B=.55 (p<0.001) Are there class differences in thresholds for lowering BP? (Sekino et al, J Hum Hypertens 1998: 12: 719) Drug Average Effect Threshold BP* on BP Level CBP ABP Daytime Nighttime Nilvadipine -26 -12.5 127 110 Amlodipine -20 -15 127 106 Bisoprolol -19 -12 124 110 Lisinopril -20 -19 97 108 * Estimated from regression line of baseline BP versus change Are there class differences in thresholds for lowering BP? (Sekino et al, J Hum Hypertens 1998: 12: 719) Drug Average Effect Threshold BP* on BP Level CBP ABP Daytime Nighttime Nilvadipine -26 -12.5 127 110 Amlodipine -20 -15 127 106 Bisoprolol -19 -12 124 110 Lisinopril -20 -19 97 108 Combination1 -20 -14 128 106 * Estimated from regression line of baseline BP versus change 1- ACEI + CCB- Fagard et al Am J Hypertens 1993: 6: 648 Diuretics Convert Non-Dippers to Dippers (Uzu & Kimura Circ 1999; 100:1635) Systolic pressure mmHg Day Night No Rx HCTZ No Rx HCTZ Dippers Non-Dippers Diuretics Convert Non-Dippers to Dippers (Uzu & Kimura Circ 1999; 100:1635) Systolic pressure mmHg Day Night No Rx HCTZ No Rx HCTZ Dippers Non-Dippers Regression of Carotid Atherosclerosis by Controlling Morning BP (Marfella et al, Am J Hypertens 2005: 18: 308) Clinic Day Night Morning Carotid IMT 0 -0.02 -0.04 NS NS NS <0.001 <0.02 SBP mmHg IMT mm Regression of Carotid Atherosclerosis by Controlling Morning BP (Marfella et al, Am J Hypertens 2005: 18: 308) Clinic Day Night Morning Carotid IMT 0 -0.02 -0.04 NS NS NS <0.001 <0.02 SBP mmHg IMT mm ? Effects of Alpha-Blockade on the Morning Surge of Blood Pressure (Kario, Pickering, et al Am J Hypertens 2004;17; 668) Doxazosin No Rx Effects of graded release Diltiazem vs. Enalapril on Morning BP (White et al, Am Heart J 2004: 148: 628) Ramipril Diltiazem ER Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Effects of Time of Administration of Valsartan on Diurnal Changes of BP (Hermida et al Hypertens 2003: 42:283) P=0.041 P=0.402 P=0.174 Change of SBP mmHg Effects of Time of Administration of Valsartan on Diurnal Changes of BP (Hermida et al Hypertens 2003: 42:283) P=0.041 P=0.402 P=0.174 Change of SBP mmHg “Diovan may be used over a dose range of 80 mg to 320 mg daily, administered once-a-day.” Conclusions: Does the Pattern of Blood Pressure Effects During the Day Matter? There is a pronounced diurnal rhythm of BP and cardiovascular events, with a peak of both in the morning hours, and a decrease during the night. In some categories of patients the normal dipping pattern of BP is lost or reversed; this may be associated with increased risk. Drugs approved for once daily dose may have different durations of action, particularly after missed doses. Most classes of antihypertensive drugs lower daytime BP more than nighttime BP. The effects of CCBs may be more closely related to baseline BP than ARBs/ACEI. Conclusions: Does the Pattern of Blood Pressure Effects During the Day Matter? 6. Different antihypertensive drugs may have different effects on the morning surge of BP. 7. With some antihypertensive drugs the time of dosing may have significant effects on the diurnal pattern of BP. 8. The implications of these time-dependent differences of antihypertensive drugs for CV morbidity are largely unknown, and need to be more fully investigated. 9. Implications of BP-independent effects of antihypertensive drugs based on small differences of clinic BP may be unwarranted. Duration of Action by Trough:Peak Ratio 0 Hours after dosing 24 Peak Trough Blood Pressure Change mmHg Placebo Drug Peak Trough Smoothness Index: mean change/SD Trough:peak ratio Change of systolic pressure mmHg Hours since drug dosing Trough:Peak Ratio vs Smoothness Index for defining drug effects on 24 hour BP (Omboni et al BPM, 1998; 3:201) Prognostic Significance of Non-Dipping (Verdecchia et al, BPM 1996; 1 (Suppl 2) ;S81) Covariate Relative Risk Men Women Age>60 7.39 2.44 Diabetes 2.23 2.30 24 hr SBP>median - 3.90 Non-dipper 1.96 1.70 1522 subjects followed for 4.2 years after ABPM Effects of ACEI and CCB on Low and High Ambulatory BP in 3 Studies Study Effect of Drug on Systolic ABP mmHg ACEI CCB ABP Lo ABP Hi ABP Lo ABP Hi Ashida -7.6 -8.9 -3.8 -12.7 Herpin -7 -9 -1 -7 Kristensen -14.5 -16.6 -2.7 -10.1 Ashida et al AJC 1990: 66: 498. N=41; ACEI = Enalapril; CCB= Nifedipine SR Herpin et al AJC 1992: 69: 923. N=236; ACEI = Various; CCB = Various. Kristensen et al BPM; 1998; 3: 116. N=96; ACEI = Benazepril; CCB = Felodipine ER Effects of ACEI and CCB on Clinic SBP in Low and High Ambulatory BP Groups in 3 Studies Study Effect of Drug on Systolic CBP mmHg ACEI CCB ABP Lo ABP Hi ABP Lo ABP Hi Ashida -6.5 -9.5 -11 -16 Herpin -13 -9 -13 -7 Kristensen NA NA NA NA Ashida et al AJC 1990: 66: 498. N=41; ACEI = Enalapril; CCB= Nifedipine SR Herpin et al AJC 1992: 69: 923. N=236; ACEI = Various; CCB = Various. Kristensen et al BPM; 1998; 3: 116. N=96; ACEI = Benazepril; CCB = Felodipine ER 80 100 90 110 120 130 140 150 160 Extreme dippers Dippers Non-dippers Risers Daytime BP Reduction 8 / 7 7 / 7 11 / 8 10 / 8 p<0.001 p<0.001 p<0.001 N.S. n = 18 n = 46 n = 48 n = 6 mmHg Blood pressure level Extreme dippers Dippers Non-dippers Reverse dippers Nighttime BP Reduction 4 / 2 1 / 2 18 /12 12 / 9 p<0.001 N.S. p<0.01 n = 18 n = 46 n = 48 n = 6 mmHg Blood pressure level SBP change (mmHg) -50 -40 -30 -20 -10 0 10 20 30 40 50 90 100 110 120 130 140 150 160 170 180 190 200 Baseline SBP (mmHg) Y = 51 - .42 X r = .45, p<.0001 Nighttime BP Daytime BP Y = 46 - .36 X r = .44, p<.0001 n=118 Effect of Doxazosin on Daytime and Nighttime BPs Kario, Schwartz, Pickering, Hypertension 2000; 35: 787-94.

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Does the Pattern of Blood Pressure Effects During the Day Matter? Thomas Pickering MD, DPhil Behavioral Cardiovascular Health and Hypertension Program Division of General Medicine Columbia Presbyterian Medical Center New York Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs What is the True Blood Pressure? Clinic BP? Home BP? 24 Hr Average BP? Daytime BP? Nighttime BP? Dipping Pattern? Morning Surge? Variability of BP? Ambulatory BP Differences for Normotensives, and Mild and Established HTN Patients 120- 110- 100- 90- 80- 70- 60- 0- Diastolic Blood Pressure (mm Hg) Clinic Work Home Sleep Normotensives Mild hypertensives Established hypertensives Clinical situations in which the normal diurnal rhythm of BP may be lost Autonomic Dysfunction Syndromes Diabetes Mellitus Renal Failure Secondary forms of hypertension e.g. Cushing’s disease Drugs, e.g. cyclosporine African-American ethnicity Nocturnal BP Changes and CV Mortality: Ohasama study (Ohkubo et al; AJH 1997; 10: 1201) Extreme dippers Dippers Non-dippers Risers Risk of CV Mortality Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Morning Peak of VT Detected by Implanted Cardioverter/Defibrillator (Tofler Circ 1995;92: 1203) Episodes of VT Circadian Rhythm of Ischemic & Hemorrhagic Strokes Gallerani et al, Acta Neurol Scand 1993; 87: 482) % of strokes 1-6 6 -12 12-18 18-24 Hour of day Ischemic Hemorrhagic Analysis of The Influence of the Morning Surge of BP on Stroke Incidence (Kario, Pickering et al, Circ 2003; 107:1401)) Cox regression analysis for clinical stroke events Covariates RR P value Age (10 yrs) 1.80 (1.21-2.69) 0.004 Male gender 1.42 (0.76-2.67) 0.266 BMI 0.98 (0.90-1.07) 0.663 24 hr SBP 1.37 (1.16-1.63 0.003 SCI 4.40 (1.95-10.1) 0.001 Morning BP surge* 1.29 (1.10-1.51) 0.001 Nocturnal BP fall* 0.88 (0.73-1.06) 0.167 Lowest sleep BP 1.05 (0.65-1.71) 0.837 * per 10 mmHg Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Efficacy: telmisartan vs amlodipine using 24-h ABPM Placebo (n=58) Amlodipine (5-10 mg) (n=65) Telmisartan (40-120 mg) (n=62) 0800 1200 1600 2000 2400 0400 0800 BP (mm Hg) Lacourcière Y et al, in press 160 140 120 100 0 Time Week 12, SBP Effects of Two ARBs Approved for Once Daily Dosing on 24 Hour Blood Pressure (Mancia et al AJC 1999: 84; 28S) Missed Dose Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Do different drug classes have different effects on Daytime vs. Nighttime BP? Meta-Analysis of Effects of Antihypertensive Drug Classes on Daytime & Nighttime BP Weiner, Rieckmann, & Pickering, 2005 Medline search of trials in which effects of antihypertensive drugs on daytime, nighttime, and 24 hr BP were described 55 trials satisfied criteria, & were grouped into 3 classes: ACEI, ARBs, Beta blockers (n=10), CCBs & Diuretics (n=35), and combinations (n=10). Across all studies, the absolute change of daytime BP (14/8 mmHg) was significantly greater than the change of nighttime BP (12.5/4.5 mmHg, p<0.01). The magnitude of the difference between the daytime & nighttime changes did not differ between the groups (p>0.7). Meta-Analysis of Effects of Antihypertensive Drug Classes on Daytime & Nighttime BP Weiner, Rieckmann, & Pickering, 2005 Change of SBP with Treatment mmHg DAY NIGHT Baseline Systolic BP mmHg BP Change mmHg ACEI, ARBs CCBs, Diuretics Meta-Analysis of Effects of Antihypertensive Drug Classes on Daytime & Nighttime BP Weiner, Rieckmann, & Pickering, 2005 Day: B=.07 (p=0.53) Night: B=.04 (p=0.63) Day: B=.55 (p<0.001) Night: B=.55 (p<0.001) Are there class differences in thresholds for lowering BP? (Sekino et al, J Hum Hypertens 1998: 12: 719) Drug Average Effect Threshold BP* on BP Level CBP ABP Daytime Nighttime Nilvadipine -26 -12.5 127 110 Amlodipine -20 -15 127 106 Bisoprolol -19 -12 124 110 Lisinopril -20 -19 97 108 * Estimated from regression line of baseline BP versus change Are there class differences in thresholds for lowering BP? (Sekino et al, J Hum Hypertens 1998: 12: 719) Drug Average Effect Threshold BP* on BP Level CBP ABP Daytime Nighttime Nilvadipine -26 -12.5 127 110 Amlodipine -20 -15 127 106 Bisoprolol -19 -12 124 110 Lisinopril -20 -19 97 108 Combination1 -20 -14 128 106 * Estimated from regression line of baseline BP versus change 1- ACEI + CCB- Fagard et al Am J Hypertens 1993: 6: 648 Diuretics Convert Non-Dippers to Dippers (Uzu & Kimura Circ 1999; 100:1635) Systolic pressure mmHg Day Night No Rx HCTZ No Rx HCTZ Dippers Non-Dippers Diuretics Convert Non-Dippers to Dippers (Uzu & Kimura Circ 1999; 100:1635) Systolic pressure mmHg Day Night No Rx HCTZ No Rx HCTZ Dippers Non-Dippers Regression of Carotid Atherosclerosis by Controlling Morning BP (Marfella et al, Am J Hypertens 2005: 18: 308) Clinic Day Night Morning Carotid IMT 0 -0.02 -0.04 NS NS NS <0.001 <0.02 SBP mmHg IMT mm Regression of Carotid Atherosclerosis by Controlling Morning BP (Marfella et al, Am J Hypertens 2005: 18: 308) Clinic Day Night Morning Carotid IMT 0 -0.02 -0.04 NS NS NS <0.001 <0.02 SBP mmHg IMT mm ? Effects of Alpha-Blockade on the Morning Surge of Blood Pressure (Kario, Pickering, et al Am J Hypertens 2004;17; 668) Doxazosin No Rx Effects of graded release Diltiazem vs. Enalapril on Morning BP (White et al, Am Heart J 2004: 148: 628) Ramipril Diltiazem ER Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Effects of Time of Administration of Valsartan on Diurnal Changes of BP (Hermida et al Hypertens 2003: 42:283) P=0.041 P=0.402 P=0.174 Change of SBP mmHg Effects of Time of Administration of Valsartan on Diurnal Changes of BP (Hermida et al Hypertens 2003: 42:283) P=0.041 P=0.402 P=0.174 Change of SBP mmHg “Diovan may be used over a dose range of 80 mg to 320 mg daily, administered once-a-day.” Conclusions: Does the Pattern of Blood Pressure Effects During the Day Matter? There is a pronounced diurnal rhythm of BP and cardiovascular events, with a peak of both in the morning hours, and a decrease during the night. In some categories of patients the normal dipping pattern of BP is lost or reversed; this may be associated with increased risk. Drugs approved for once daily dose may have different durations of action, particularly after missed doses. Most classes of antihypertensive drugs lower daytime BP more than nighttime BP. The effects of CCBs may be more closely related to baseline BP than ARBs/ACEI. Conclusions: Does the Pattern of Blood Pressure Effects During the Day Matter? 6. Different antihypertensive drugs may have different effects on the morning surge of BP. 7. With some antihypertensive drugs the time of dosing may have significant effects on the diurnal pattern of BP. 8. The implications of these time-dependent differences of antihypertensive drugs for CV morbidity are largely unknown, and need to be more fully investigated. 9. Implications of BP-independent effects of antihypertensive drugs based on small differences of clinic BP may be unwarranted. Duration of Action by Trough:Peak Ratio 0 Hours after dosing 24 Peak Trough Blood Pressure Change mmHg Placebo Drug Peak Trough Smoothness Index: mean change/SD Trough:peak ratio Change of systolic pressure mmHg Hours since drug dosing Trough:Peak Ratio vs Smoothness Index for defining drug effects on 24 hour BP (Omboni et al BPM, 1998; 3:201) Prognostic Significance of Non-Dipping (Verdecchia et al, BPM 1996; 1 (Suppl 2) ;S81) Covariate Relative Risk Men Women Age>60 7.39 2.44 Diabetes 2.23 2.30 24 hr SBP>median - 3.90 Non-dipper 1.96 1.70 1522 subjects followed for 4.2 years after ABPM Effects of ACEI and CCB on Low and High Ambulatory BP in 3 Studies Study Effect of Drug on Systolic ABP mmHg ACEI CCB ABP Lo ABP Hi ABP Lo ABP Hi Ashida -7.6 -8.9 -3.8 -12.7 Herpin -7 -9 -1 -7 Kristensen -14.5 -16.6 -2.7 -10.1 Ashida et al AJC 1990: 66: 498. N=41; ACEI = Enalapril; CCB= Nifedipine SR Herpin et al AJC 1992: 69: 923. N=236; ACEI = Various; CCB = Various. Kristensen et al BPM; 1998; 3: 116. N=96; ACEI = Benazepril; CCB = Felodipine ER Effects of ACEI and CCB on Clinic SBP in Low and High Ambulatory BP Groups in 3 Studies Study Effect of Drug on Systolic CBP mmHg ACEI CCB ABP Lo ABP Hi ABP Lo ABP Hi Ashida -6.5 -9.5 -11 -16 Herpin -13 -9 -13 -7 Kristensen NA NA NA NA Ashida et al AJC 1990: 66: 498. N=41; ACEI = Enalapril; CCB= Nifedipine SR Herpin et al AJC 1992: 69: 923. N=236; ACEI = Various; CCB = Various. Kristensen et al BPM; 1998; 3: 116. N=96; ACEI = Benazepril; CCB = Felodipine ER 80 100 90 110 120 130 140 150 160 Extreme dippers Dippers Non-dippers Risers Daytime BP Reduction 8 / 7 7 / 7 11 / 8 10 / 8 p<0.001 p<0.001 p<0.001 N.S. n = 18 n = 46 n = 48 n = 6 mmHg Blood pressure level Extreme dippers Dippers Non-dippers Reverse dippers Nighttime BP Reduction 4 / 2 1 / 2 18 /12 12 / 9 p<0.001 N.S. p<0.01 n = 18 n = 46 n = 48 n = 6 mmHg Blood pressure level SBP change (mmHg) -50 -40 -30 -20 -10 0 10 20 30 40 50 90 100 110 120 130 140 150 160 170 180 190 200 Baseline SBP (mmHg) Y = 51 - .42 X r = .45, p<.0001 Nighttime BP Daytime BP Y = 46 - .36 X r = .44, p<.0001 n=118 Effect of Doxazosin on Daytime and Nighttime BPs Kario, Schwartz, Pickering, Hypertension 2000; 35: 787-94. Effects of Time of Administration of CCBs on Diurnal Changes of BP (Lemmer BPM 1996: 1;169) Drug Dose Effect on BP Time Day Night 24 hr Pattern Amlodipine (1) AM Unchanged PM Unchanged Isradipine (2) AM Unchanged PM Unchanged Nifedipine GITS (3) AM Unchanged PM Unchanged Nitrendipine (4) AM Unchanged PM Unchanged 1. Mengden J Hypertens 1992:10 (supp 4); S136 2. Fogari Br J Clin Pharm 1993: 35:51 3. Lemmer Naunyn- Schmiederberg Arch Pharm 1994; 349(supp); R141 4. Meilhac Therapie 1992: 47: 205

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Does the Pattern of Blood Pressure Effects During the Day Matter? Thomas Pickering MD, DPhil Behavioral Cardiovascular Health and Hypertension Program Division of General Medicine Columbia Presbyterian Medical Center New York Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs What is the True Blood Pressure? Clinic BP? Home BP? 24 Hr Average BP? Daytime BP? Nighttime BP? Dipping Pattern? Morning Surge? Variability of BP? Ambulatory BP Differences for Normotensives, and Mild and Established HTN Patients 120- 110- 100- 90- 80- 70- 60- 0- Diastolic Blood Pressure (mm Hg) Clinic Work Home Sleep Normotensives Mild hypertensives Established hypertensives Clinical situations in which the normal diurnal rhythm of BP may be lost Autonomic Dysfunction Syndromes Diabetes Mellitus Renal Failure Secondary forms of hypertension e.g. Cushing’s disease Drugs, e.g. cyclosporine African-American ethnicity Nocturnal BP Changes and CV Mortality: Ohasama study (Ohkubo et al; AJH 1997; 10: 1201) Extreme dippers Dippers Non-dippers Risers Risk of CV Mortality Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Morning Peak of VT Detected by Implanted Cardioverter/Defibrillator (Tofler Circ 1995;92: 1203) Episodes of VT Circadian Rhythm of Ischemic & Hemorrhagic Strokes Gallerani et al, Acta Neurol Scand 1993; 87: 482) % of strokes 1-6 6 -12 12-18 18-24 Hour of day Ischemic Hemorrhagic Analysis of The Influence of the Morning Surge of BP on Stroke Incidence (Kario, Pickering et al, Circ 2003; 107:1401)) Cox regression analysis for clinical stroke events Covariates RR P value Age (10 yrs) 1.80 (1.21-2.69) 0.004 Male gender 1.42 (0.76-2.67) 0.266 BMI 0.98 (0.90-1.07) 0.663 24 hr SBP 1.37 (1.16-1.63 0.003 SCI 4.40 (1.95-10.1) 0.001 Morning BP surge* 1.29 (1.10-1.51) 0.001 Nocturnal BP fall* 0.88 (0.73-1.06) 0.167 Lowest sleep BP 1.05 (0.65-1.71) 0.837 * per 10 mmHg Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Efficacy: telmisartan vs amlodipine using 24-h ABPM Placebo (n=58) Amlodipine (5-10 mg) (n=65) Telmisartan (40-120 mg) (n=62) 0800 1200 1600 2000 2400 0400 0800 BP (mm Hg) Lacourcière Y et al, in press 160 140 120 100 0 Time Week 12, SBP Effects of Two ARBs Approved for Once Daily Dosing on 24 Hour Blood Pressure (Mancia et al AJC 1999: 84; 28S) Missed Dose Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Do different drug classes have different effects on Daytime vs. Nighttime BP? Meta-Analysis of Effects of Antihypertensive Drug Classes on Daytime & Nighttime BP Weiner, Rieckmann, & Pickering, 2005 Medline search of trials in which effects of antihypertensive drugs on daytime, nighttime, and 24 hr BP were described 55 trials satisfied criteria, & were grouped into 3 classes: ACEI, ARBs, Beta blockers (n=10), CCBs & Diuretics (n=35), and combinations (n=10). Across all studies, the absolute change of daytime BP (14/8 mmHg) was significantly greater than the change of nighttime BP (12.5/4.5 mmHg, p<0.01). The magnitude of the difference between the daytime & nighttime changes did not differ between the groups (p>0.7). Meta-Analysis of Effects of Antihypertensive Drug Classes on Daytime & Nighttime BP Weiner, Rieckmann, & Pickering, 2005 Change of SBP with Treatment mmHg DAY NIGHT Baseline Systolic BP mmHg BP Change mmHg ACEI, ARBs CCBs, Diuretics Meta-Analysis of Effects of Antihypertensive Drug Classes on Daytime & Nighttime BP Weiner, Rieckmann, & Pickering, 2005 Day: B=.07 (p=0.53) Night: B=.04 (p=0.63) Day: B=.55 (p<0.001) Night: B=.55 (p<0.001) Are there class differences in thresholds for lowering BP? (Sekino et al, J Hum Hypertens 1998: 12: 719) Drug Average Effect Threshold BP* on BP Level CBP ABP Daytime Nighttime Nilvadipine -26 -12.5 127 110 Amlodipine -20 -15 127 106 Bisoprolol -19 -12 124 110 Lisinopril -20 -19 97 108 * Estimated from regression line of baseline BP versus change Are there class differences in thresholds for lowering BP? (Sekino et al, J Hum Hypertens 1998: 12: 719) Drug Average Effect Threshold BP* on BP Level CBP ABP Daytime Nighttime Nilvadipine -26 -12.5 127 110 Amlodipine -20 -15 127 106 Bisoprolol -19 -12 124 110 Lisinopril -20 -19 97 108 Combination1 -20 -14 128 106 * Estimated from regression line of baseline BP versus change 1- ACEI + CCB- Fagard et al Am J Hypertens 1993: 6: 648 Diuretics Convert Non-Dippers to Dippers (Uzu & Kimura Circ 1999; 100:1635) Systolic pressure mmHg Day Night No Rx HCTZ No Rx HCTZ Dippers Non-Dippers Diuretics Convert Non-Dippers to Dippers (Uzu & Kimura Circ 1999; 100:1635) Systolic pressure mmHg Day Night No Rx HCTZ No Rx HCTZ Dippers Non-Dippers Regression of Carotid Atherosclerosis by Controlling Morning BP (Marfella et al, Am J Hypertens 2005: 18: 308) Clinic Day Night Morning Carotid IMT 0 -0.02 -0.04 NS NS NS <0.001 <0.02 SBP mmHg IMT mm Regression of Carotid Atherosclerosis by Controlling Morning BP (Marfella et al, Am J Hypertens 2005: 18: 308) Clinic Day Night Morning Carotid IMT 0 -0.02 -0.04 NS NS NS <0.001 <0.02 SBP mmHg IMT mm ? Effects of Alpha-Blockade on the Morning Surge of Blood Pressure (Kario, Pickering, et al Am J Hypertens 2004;17; 668) Doxazosin No Rx Effects of graded release Diltiazem vs. Enalapril on Morning BP (White et al, Am Heart J 2004: 148: 628) Ramipril Diltiazem ER Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Effects of Time of Administration of Valsartan on Diurnal Changes of BP (Hermida et al Hypertens 2003: 42:283) P=0.041 P=0.402 P=0.174 Change of SBP mmHg Effects of Time of Administration of Valsartan on Diurnal Changes of BP (Hermida et al Hypertens 2003: 42:283) P=0.041 P=0.402 P=0.174 Change of SBP mmHg “Diovan may be used over a dose range of 80 mg to 320 mg daily, administered once-a-day.” Conclusions: Does the Pattern of Blood Pressure Effects During the Day Matter? There is a pronounced diurnal rhythm of BP and cardiovascular events, with a peak of both in the morning hours, and a decrease during the night. In some categories of patients the normal dipping pattern of BP is lost or reversed; this may be associated with increased risk. Drugs approved for once daily dose may have different durations of action, particularly after missed doses. Most classes of antihypertensive drugs lower daytime BP more than nighttime BP. The effects of CCBs may be more closely related to baseline BP than ARBs/ACEI. Conclusions: Does the Pattern of Blood Pressure Effects During the Day Matter? 6. Different antihypertensive drugs may have different effects on the morning surge of BP. 7. With some antihypertensive drugs the time of dosing may have significant effects on the diurnal pattern of BP. 8. The implications of these time-dependent differences of antihypertensive drugs for CV morbidity are largely unknown, and need to be more fully investigated. 9. Implications of BP-independent effects of antihypertensive drugs based on small differences of clinic BP may be unwarranted. Duration of Action by Trough:Peak Ratio 0 Hours after dosing 24 Peak Trough Blood Pressure Change mmHg Placebo Drug Peak Trough Smoothness Index: mean change/SD Trough:peak ratio Change of systolic pressure mmHg Hours since drug dosing Trough:Peak Ratio vs Smoothness Index for defining drug effects on 24 hour BP (Omboni et al BPM, 1998; 3:201) Prognostic Significance of Non-Dipping (Verdecchia et al, BPM 1996; 1 (Suppl 2) ;S81) Covariate Relative Risk Men Women Age>60 7.39 2.44 Diabetes 2.23 2.30 24 hr SBP>median - 3.90 Non-dipper 1.96 1.70 1522 subjects followed for 4.2 years after ABPM Effects of ACEI and CCB on Low and High Ambulatory BP in 3 Studies Study Effect of Drug on Systolic ABP mmHg ACEI CCB ABP Lo ABP Hi ABP Lo ABP Hi Ashida -7.6 -8.9 -3.8 -12.7 Herpin -7 -9 -1 -7 Kristensen -14.5 -16.6 -2.7 -10.1 Ashida et al AJC 1990: 66: 498. N=41; ACEI = Enalapril; CCB= Nifedipine SR Herpin et al AJC 1992: 69: 923. N=236; ACEI = Various; CCB = Various. Kristensen et al BPM; 1998; 3: 116. N=96; ACEI = Benazepril; CCB = Felodipine ER Effects of ACEI and CCB on Clinic SBP in Low and High Ambulatory BP Groups in 3 Studies Study Effect of Drug on Systolic CBP mmHg ACEI CCB ABP Lo ABP Hi ABP Lo ABP Hi Ashida -6.5 -9.5 -11 -16 Herpin -13 -9 -13 -7 Kristensen NA NA NA NA Ashida et al AJC 1990: 66: 498. N=41; ACEI = Enalapril; CCB= Nifedipine SR Herpin et al AJC 1992: 69: 923. N=236; ACEI = Various; CCB = Various. Kristensen et al BPM; 1998; 3: 116. N=96; ACEI = Benazepril; CCB = Felodipine ER 80 100 90 110 120 130 140 150 160 Extreme dippers Dippers Non-dippers Risers Daytime BP Reduction 8 / 7 7 / 7 11 / 8 10 / 8 p<0.001 p<0.001 p<0.001 N.S. n = 18 n = 46 n = 48 n = 6 mmHg Blood pressure level Extreme dippers Dippers Non-dippers Reverse dippers Nighttime BP Reduction 4 / 2 1 / 2 18 /12 12 / 9 p<0.001 N.S. p<0.01 n = 18 n = 46 n = 48 n = 6 mmHg Blood pressure level SBP change (mmHg) -50 -40 -30 -20 -10 0 10 20 30 40 50 90 100 110 120 130 140 150 160 170 180 190 200 Baseline SBP (mmHg) Y = 51 - .42 X r = .45, p<.0001 Nighttime BP Daytime BP Y = 46 - .36 X r = .44, p<.0001 n=118 Effect of Doxazosin on Daytime and Nighttime BPs Kario, Schwartz, Pickering, Hypertension 2000; 35: 787-94. Effects of Time of Administration of CCBs on Diurnal Changes of BP (Lemmer BPM 1996: 1;169) Drug Dose Effect on BP Time Day Night 24 hr Pattern Amlodipine (1) AM Unchanged PM Unchanged Isradipine (2) AM Unchanged PM Unchanged Nifedipine GITS (3) AM Unchanged PM Unchanged Nitrendipine (4) AM Unchanged PM Unchanged 1. Mengden J Hypertens 1992:10 (supp 4); S136 2. Fogari Br J Clin Pharm 1993: 35:51 3. Lemmer Naunyn- Schmiederberg Arch Pharm 1994; 349(supp); R141 4. Meilhac Therapie 1992: 47: 205 Effects of Time of Administration of ACEIs on Diurnal Changes of BP (Lemmer BPM 1996: 1;169) Drug Dose Effect on BP Time Day Night 24 hr Pattern Benazepril (1) AM Nearly Unchanged PM Changed Enalapril (2) AM Nearly Unchanged PM Changed Quinapril (3) AM Nearly Unchanged PM Changed 1. Palatini Int J Clin Pharm Ther Toxicol 1993:31:295 2. Witte Clin Pharm Ther 1993: 54:177 3. Paltini Clin Pharm Ther 1992; 52: 378

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Does the Pattern of Blood Pressure Effects During the Day Matter? Thomas Pickering MD, DPhil Behavioral Cardiovascular Health and Hypertension Program Division of General Medicine Columbia Presbyterian Medical Center New York Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs What is the True Blood Pressure? Clinic BP? Home BP? 24 Hr Average BP? Daytime BP? Nighttime BP? Dipping Pattern? Morning Surge? Variability of BP? Ambulatory BP Differences for Normotensives, and Mild and Established HTN Patients 120- 110- 100- 90- 80- 70- 60- 0- Diastolic Blood Pressure (mm Hg) Clinic Work Home Sleep Normotensives Mild hypertensives Established hypertensives Clinical situations in which the normal diurnal rhythm of BP may be lost Autonomic Dysfunction Syndromes Diabetes Mellitus Renal Failure Secondary forms of hypertension e.g. Cushing’s disease Drugs, e.g. cyclosporine African-American ethnicity Nocturnal BP Changes and CV Mortality: Ohasama study (Ohkubo et al; AJH 1997; 10: 1201) Extreme dippers Dippers Non-dippers Risers Risk of CV Mortality Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Morning Peak of VT Detected by Implanted Cardioverter/Defibrillator (Tofler Circ 1995;92: 1203) Episodes of VT Circadian Rhythm of Ischemic & Hemorrhagic Strokes Gallerani et al, Acta Neurol Scand 1993; 87: 482) % of strokes 1-6 6 -12 12-18 18-24 Hour of day Ischemic Hemorrhagic Analysis of The Influence of the Morning Surge of BP on Stroke Incidence (Kario, Pickering et al, Circ 2003; 107:1401)) Cox regression analysis for clinical stroke events Covariates RR P value Age (10 yrs) 1.80 (1.21-2.69) 0.004 Male gender 1.42 (0.76-2.67) 0.266 BMI 0.98 (0.90-1.07) 0.663 24 hr SBP 1.37 (1.16-1.63 0.003 SCI 4.40 (1.95-10.1) 0.001 Morning BP surge* 1.29 (1.10-1.51) 0.001 Nocturnal BP fall* 0.88 (0.73-1.06) 0.167 Lowest sleep BP 1.05 (0.65-1.71) 0.837 * per 10 mmHg Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Efficacy: telmisartan vs amlodipine using 24-h ABPM Placebo (n=58) Amlodipine (5-10 mg) (n=65) Telmisartan (40-120 mg) (n=62) 0800 1200 1600 2000 2400 0400 0800 BP (mm Hg) Lacourcière Y et al, in press 160 140 120 100 0 Time Week 12, SBP Effects of Two ARBs Approved for Once Daily Dosing on 24 Hour Blood Pressure (Mancia et al AJC 1999: 84; 28S) Missed Dose Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Do different drug classes have different effects on Daytime vs. Nighttime BP? Meta-Analysis of Effects of Antihypertensive Drug Classes on Daytime & Nighttime BP Weiner, Rieckmann, & Pickering, 2005 Medline search of trials in which effects of antihypertensive drugs on daytime, nighttime, and 24 hr BP were described 55 trials satisfied criteria, & were grouped into 3 classes: ACEI, ARBs, Beta blockers (n=10), CCBs & Diuretics (n=35), and combinations (n=10). Across all studies, the absolute change of daytime BP (14/8 mmHg) was significantly greater than the change of nighttime BP (12.5/4.5 mmHg, p<0.01). The magnitude of the difference between the daytime & nighttime changes did not differ between the groups (p>0.7). Meta-Analysis of Effects of Antihypertensive Drug Classes on Daytime & Nighttime BP Weiner, Rieckmann, & Pickering, 2005 Change of SBP with Treatment mmHg DAY NIGHT Baseline Systolic BP mmHg BP Change mmHg ACEI, ARBs CCBs, Diuretics Meta-Analysis of Effects of Antihypertensive Drug Classes on Daytime & Nighttime BP Weiner, Rieckmann, & Pickering, 2005 Day: B=.07 (p=0.53) Night: B=.04 (p=0.63) Day: B=.55 (p<0.001) Night: B=.55 (p<0.001) Are there class differences in thresholds for lowering BP? (Sekino et al, J Hum Hypertens 1998: 12: 719) Drug Average Effect Threshold BP* on BP Level CBP ABP Daytime Nighttime Nilvadipine -26 -12.5 127 110 Amlodipine -20 -15 127 106 Bisoprolol -19 -12 124 110 Lisinopril -20 -19 97 108 * Estimated from regression line of baseline BP versus change Are there class differences in thresholds for lowering BP? (Sekino et al, J Hum Hypertens 1998: 12: 719) Drug Average Effect Threshold BP* on BP Level CBP ABP Daytime Nighttime Nilvadipine -26 -12.5 127 110 Amlodipine -20 -15 127 106 Bisoprolol -19 -12 124 110 Lisinopril -20 -19 97 108 Combination1 -20 -14 128 106 * Estimated from regression line of baseline BP versus change 1- ACEI + CCB- Fagard et al Am J Hypertens 1993: 6: 648 Diuretics Convert Non-Dippers to Dippers (Uzu & Kimura Circ 1999; 100:1635) Systolic pressure mmHg Day Night No Rx HCTZ No Rx HCTZ Dippers Non-Dippers Diuretics Convert Non-Dippers to Dippers (Uzu & Kimura Circ 1999; 100:1635) Systolic pressure mmHg Day Night No Rx HCTZ No Rx HCTZ Dippers Non-Dippers Regression of Carotid Atherosclerosis by Controlling Morning BP (Marfella et al, Am J Hypertens 2005: 18: 308) Clinic Day Night Morning Carotid IMT 0 -0.02 -0.04 NS NS NS <0.001 <0.02 SBP mmHg IMT mm Regression of Carotid Atherosclerosis by Controlling Morning BP (Marfella et al, Am J Hypertens 2005: 18: 308) Clinic Day Night Morning Carotid IMT 0 -0.02 -0.04 NS NS NS <0.001 <0.02 SBP mmHg IMT mm ? Effects of Alpha-Blockade on the Morning Surge of Blood Pressure (Kario, Pickering, et al Am J Hypertens 2004;17; 668) Doxazosin No Rx Effects of graded release Diltiazem vs. Enalapril on Morning BP (White et al, Am Heart J 2004: 148: 628) Ramipril Diltiazem ER Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Effects of Time of Administration of Valsartan on Diurnal Changes of BP (Hermida et al Hypertens 2003: 42:283) P=0.041 P=0.402 P=0.174 Change of SBP mmHg Effects of Time of Administration of Valsartan on Diurnal Changes of BP (Hermida et al Hypertens 2003: 42:283) P=0.041 P=0.402 P=0.174 Change of SBP mmHg “Diovan may be used over a dose range of 80 mg to 320 mg daily, administered once-a-day.” Conclusions: Does the Pattern of Blood Pressure Effects During the Day Matter? There is a pronounced diurnal rhythm of BP and cardiovascular events, with a peak of both in the morning hours, and a decrease during the night. In some categories of patients the normal dipping pattern of BP is lost or reversed; this may be associated with increased risk. Drugs approved for once daily dose may have different durations of action, particularly after missed doses. Most classes of antihypertensive drugs lower daytime BP more than nighttime BP. The effects of CCBs may be more closely related to baseline BP than ARBs/ACEI. Conclusions: Does the Pattern of Blood Pressure Effects During the Day Matter? 6. Different antihypertensive drugs may have different effects on the morning surge of BP. 7. With some antihypertensive drugs the time of dosing may have significant effects on the diurnal pattern of BP. 8. The implications of these time-dependent differences of antihypertensive drugs for CV morbidity are largely unknown, and need to be more fully investigated. 9. Implications of BP-independent effects of antihypertensive drugs based on small differences of clinic BP may be unwarranted. Duration of Action by Trough:Peak Ratio 0 Hours after dosing 24 Peak Trough Blood Pressure Change mmHg Placebo Drug Peak Trough Smoothness Index: mean change/SD Trough:peak ratio Change of systolic pressure mmHg Hours since drug dosing Trough:Peak Ratio vs Smoothness Index for defining drug effects on 24 hour BP (Omboni et al BPM, 1998; 3:201) Prognostic Significance of Non-Dipping (Verdecchia et al, BPM 1996; 1 (Suppl 2) ;S81) Covariate Relative Risk Men Women Age>60 7.39 2.44 Diabetes 2.23 2.30 24 hr SBP>median - 3.90 Non-dipper 1.96 1.70 1522 subjects followed for 4.2 years after ABPM Effects of ACEI and CCB on Low and High Ambulatory BP in 3 Studies Study Effect of Drug on Systolic ABP mmHg ACEI CCB ABP Lo ABP Hi ABP Lo ABP Hi Ashida -7.6 -8.9 -3.8 -12.7 Herpin -7 -9 -1 -7 Kristensen -14.5 -16.6 -2.7 -10.1 Ashida et al AJC 1990: 66: 498. N=41; ACEI = Enalapril; CCB= Nifedipine SR Herpin et al AJC 1992: 69: 923. N=236; ACEI = Various; CCB = Various. Kristensen et al BPM; 1998; 3: 116. N=96; ACEI = Benazepril; CCB = Felodipine ER Effects of ACEI and CCB on Clinic SBP in Low and High Ambulatory BP Groups in 3 Studies Study Effect of Drug on Systolic CBP mmHg ACEI CCB ABP Lo ABP Hi ABP Lo ABP Hi Ashida -6.5 -9.5 -11 -16 Herpin -13 -9 -13 -7 Kristensen NA NA NA NA Ashida et al AJC 1990: 66: 498. N=41; ACEI = Enalapril; CCB= Nifedipine SR Herpin et al AJC 1992: 69: 923. N=236; ACEI = Various; CCB = Various. Kristensen et al BPM; 1998; 3: 116. N=96; ACEI = Benazepril; CCB = Felodipine ER 80 100 90 110 120 130 140 150 160 Extreme dippers Dippers Non-dippers Risers Daytime BP Reduction 8 / 7 7 / 7 11 / 8 10 / 8 p<0.001 p<0.001 p<0.001 N.S. n = 18 n = 46 n = 48 n = 6 mmHg Blood pressure level Extreme dippers Dippers Non-dippers Reverse dippers Nighttime BP Reduction 4 / 2 1 / 2 18 /12 12 / 9 p<0.001 N.S. p<0.01 n = 18 n = 46 n = 48 n = 6 mmHg Blood pressure level SBP change (mmHg) -50 -40 -30 -20 -10 0 10 20 30 40 50 90 100 110 120 130 140 150 160 170 180 190 200 Baseline SBP (mmHg) Y = 51 - .42 X r = .45, p<.0001 Nighttime BP Daytime BP Y = 46 - .36 X r = .44, p<.0001 n=118 Effect of Doxazosin on Daytime and Nighttime BPs Kario, Schwartz, Pickering, Hypertension 2000; 35: 787-94. Effects of Time of Administration of CCBs on Diurnal Changes of BP (Lemmer BPM 1996: 1;169) Drug Dose Effect on BP Time Day Night 24 hr Pattern Amlodipine (1) AM Unchanged PM Unchanged Isradipine (2) AM Unchanged PM Unchanged Nifedipine GITS (3) AM Unchanged PM Unchanged Nitrendipine (4) AM Unchanged PM Unchanged 1. Mengden J Hypertens 1992:10 (supp 4); S136 2. Fogari Br J Clin Pharm 1993: 35:51 3. Lemmer Naunyn- Schmiederberg Arch Pharm 1994; 349(supp); R141 4. Meilhac Therapie 1992: 47: 205 Effects of Time of Administration of ACEIs on Diurnal Changes of BP (Lemmer BPM 1996: 1;169) Drug Dose Effect on BP Time Day Night 24 hr Pattern Benazepril (1) AM Nearly Unchanged PM Changed Enalapril (2) AM Nearly Unchanged PM Changed Quinapril (3) AM Nearly Unchanged PM Changed 1. Palatini Int J Clin Pharm Ther Toxicol 1993:31:295 2. Witte Clin Pharm Ther 1993: 54:177 3. Paltini Clin Pharm Ther 1992; 52: 378 Effects of Time of Administration of Trandolapril on Diurnal Changes of BP (Poirier J Clin Pharm 1993: 33:832) Change of SBP mmHg

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Does the Pattern of Blood Pressure Effects During the Day Matter? Thomas Pickering MD, DPhil Behavioral Cardiovascular Health and Hypertension Program Division of General Medicine Columbia Presbyterian Medical Center New York Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs What is the True Blood Pressure? Clinic BP? Home BP? 24 Hr Average BP? Daytime BP? Nighttime BP? Dipping Pattern? Morning Surge? Variability of BP? Ambulatory BP Differences for Normotensives, and Mild and Established HTN Patients 120- 110- 100- 90- 80- 70- 60- 0- Diastolic Blood Pressure (mm Hg) Clinic Work Home Sleep Normotensives Mild hypertensives Established hypertensives Clinical situations in which the normal diurnal rhythm of BP may be lost Autonomic Dysfunction Syndromes Diabetes Mellitus Renal Failure Secondary forms of hypertension e.g. Cushing’s disease Drugs, e.g. cyclosporine African-American ethnicity Nocturnal BP Changes and CV Mortality: Ohasama study (Ohkubo et al; AJH 1997; 10: 1201) Extreme dippers Dippers Non-dippers Risers Risk of CV Mortality Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Morning Peak of VT Detected by Implanted Cardioverter/Defibrillator (Tofler Circ 1995;92: 1203) Episodes of VT Circadian Rhythm of Ischemic & Hemorrhagic Strokes Gallerani et al, Acta Neurol Scand 1993; 87: 482) % of strokes 1-6 6 -12 12-18 18-24 Hour of day Ischemic Hemorrhagic Analysis of The Influence of the Morning Surge of BP on Stroke Incidence (Kario, Pickering et al, Circ 2003; 107:1401)) Cox regression analysis for clinical stroke events Covariates RR P value Age (10 yrs) 1.80 (1.21-2.69) 0.004 Male gender 1.42 (0.76-2.67) 0.266 BMI 0.98 (0.90-1.07) 0.663 24 hr SBP 1.37 (1.16-1.63 0.003 SCI 4.40 (1.95-10.1) 0.001 Morning BP surge* 1.29 (1.10-1.51) 0.001 Nocturnal BP fall* 0.88 (0.73-1.06) 0.167 Lowest sleep BP 1.05 (0.65-1.71) 0.837 * per 10 mmHg Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Efficacy: telmisartan vs amlodipine using 24-h ABPM Placebo (n=58) Amlodipine (5-10 mg) (n=65) Telmisartan (40-120 mg) (n=62) 0800 1200 1600 2000 2400 0400 0800 BP (mm Hg) Lacourcière Y et al, in press 160 140 120 100 0 Time Week 12, SBP Effects of Two ARBs Approved for Once Daily Dosing on 24 Hour Blood Pressure (Mancia et al AJC 1999: 84; 28S) Missed Dose Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Do different drug classes have different effects on Daytime vs. Nighttime BP? Meta-Analysis of Effects of Antihypertensive Drug Classes on Daytime & Nighttime BP Weiner, Rieckmann, & Pickering, 2005 Medline search of trials in which effects of antihypertensive drugs on daytime, nighttime, and 24 hr BP were described 55 trials satisfied criteria, & were grouped into 3 classes: ACEI, ARBs, Beta blockers (n=10), CCBs & Diuretics (n=35), and combinations (n=10). Across all studies, the absolute change of daytime BP (14/8 mmHg) was significantly greater than the change of nighttime BP (12.5/4.5 mmHg, p<0.01). The magnitude of the difference between the daytime & nighttime changes did not differ between the groups (p>0.7). Meta-Analysis of Effects of Antihypertensive Drug Classes on Daytime & Nighttime BP Weiner, Rieckmann, & Pickering, 2005 Change of SBP with Treatment mmHg DAY NIGHT Baseline Systolic BP mmHg BP Change mmHg ACEI, ARBs CCBs, Diuretics Meta-Analysis of Effects of Antihypertensive Drug Classes on Daytime & Nighttime BP Weiner, Rieckmann, & Pickering, 2005 Day: B=.07 (p=0.53) Night: B=.04 (p=0.63) Day: B=.55 (p<0.001) Night: B=.55 (p<0.001) Are there class differences in thresholds for lowering BP? (Sekino et al, J Hum Hypertens 1998: 12: 719) Drug Average Effect Threshold BP* on BP Level CBP ABP Daytime Nighttime Nilvadipine -26 -12.5 127 110 Amlodipine -20 -15 127 106 Bisoprolol -19 -12 124 110 Lisinopril -20 -19 97 108 * Estimated from regression line of baseline BP versus change Are there class differences in thresholds for lowering BP? (Sekino et al, J Hum Hypertens 1998: 12: 719) Drug Average Effect Threshold BP* on BP Level CBP ABP Daytime Nighttime Nilvadipine -26 -12.5 127 110 Amlodipine -20 -15 127 106 Bisoprolol -19 -12 124 110 Lisinopril -20 -19 97 108 Combination1 -20 -14 128 106 * Estimated from regression line of baseline BP versus change 1- ACEI + CCB- Fagard et al Am J Hypertens 1993: 6: 648 Diuretics Convert Non-Dippers to Dippers (Uzu & Kimura Circ 1999; 100:1635) Systolic pressure mmHg Day Night No Rx HCTZ No Rx HCTZ Dippers Non-Dippers Diuretics Convert Non-Dippers to Dippers (Uzu & Kimura Circ 1999; 100:1635) Systolic pressure mmHg Day Night No Rx HCTZ No Rx HCTZ Dippers Non-Dippers Regression of Carotid Atherosclerosis by Controlling Morning BP (Marfella et al, Am J Hypertens 2005: 18: 308) Clinic Day Night Morning Carotid IMT 0 -0.02 -0.04 NS NS NS <0.001 <0.02 SBP mmHg IMT mm Regression of Carotid Atherosclerosis by Controlling Morning BP (Marfella et al, Am J Hypertens 2005: 18: 308) Clinic Day Night Morning Carotid IMT 0 -0.02 -0.04 NS NS NS <0.001 <0.02 SBP mmHg IMT mm ? Effects of Alpha-Blockade on the Morning Surge of Blood Pressure (Kario, Pickering, et al Am J Hypertens 2004;17; 668) Doxazosin No Rx Effects of graded release Diltiazem vs. Enalapril on Morning BP (White et al, Am Heart J 2004: 148: 628) Ramipril Diltiazem ER Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Effects of Time of Administration of Valsartan on Diurnal Changes of BP (Hermida et al Hypertens 2003: 42:283) P=0.041 P=0.402 P=0.174 Change of SBP mmHg Effects of Time of Administration of Valsartan on Diurnal Changes of BP (Hermida et al Hypertens 2003: 42:283) P=0.041 P=0.402 P=0.174 Change of SBP mmHg “Diovan may be used over a dose range of 80 mg to 320 mg daily, administered once-a-day.” Conclusions: Does the Pattern of Blood Pressure Effects During the Day Matter? There is a pronounced diurnal rhythm of BP and cardiovascular events, with a peak of both in the morning hours, and a decrease during the night. In some categories of patients the normal dipping pattern of BP is lost or reversed; this may be associated with increased risk. Drugs approved for once daily dose may have different durations of action, particularly after missed doses. Most classes of antihypertensive drugs lower daytime BP more than nighttime BP. The effects of CCBs may be more closely related to baseline BP than ARBs/ACEI. Conclusions: Does the Pattern of Blood Pressure Effects During the Day Matter? 6. Different antihypertensive drugs may have different effects on the morning surge of BP. 7. With some antihypertensive drugs the time of dosing may have significant effects on the diurnal pattern of BP. 8. The implications of these time-dependent differences of antihypertensive drugs for CV morbidity are largely unknown, and need to be more fully investigated. 9. Implications of BP-independent effects of antihypertensive drugs based on small differences of clinic BP may be unwarranted. Duration of Action by Trough:Peak Ratio 0 Hours after dosing 24 Peak Trough Blood Pressure Change mmHg Placebo Drug Peak Trough Smoothness Index: mean change/SD Trough:peak ratio Change of systolic pressure mmHg Hours since drug dosing Trough:Peak Ratio vs Smoothness Index for defining drug effects on 24 hour BP (Omboni et al BPM, 1998; 3:201) Prognostic Significance of Non-Dipping (Verdecchia et al, BPM 1996; 1 (Suppl 2) ;S81) Covariate Relative Risk Men Women Age>60 7.39 2.44 Diabetes 2.23 2.30 24 hr SBP>median - 3.90 Non-dipper 1.96 1.70 1522 subjects followed for 4.2 years after ABPM Effects of ACEI and CCB on Low and High Ambulatory BP in 3 Studies Study Effect of Drug on Systolic ABP mmHg ACEI CCB ABP Lo ABP Hi ABP Lo ABP Hi Ashida -7.6 -8.9 -3.8 -12.7 Herpin -7 -9 -1 -7 Kristensen -14.5 -16.6 -2.7 -10.1 Ashida et al AJC 1990: 66: 498. N=41; ACEI = Enalapril; CCB= Nifedipine SR Herpin et al AJC 1992: 69: 923. N=236; ACEI = Various; CCB = Various. Kristensen et al BPM; 1998; 3: 116. N=96; ACEI = Benazepril; CCB = Felodipine ER Effects of ACEI and CCB on Clinic SBP in Low and High Ambulatory BP Groups in 3 Studies Study Effect of Drug on Systolic CBP mmHg ACEI CCB ABP Lo ABP Hi ABP Lo ABP Hi Ashida -6.5 -9.5 -11 -16 Herpin -13 -9 -13 -7 Kristensen NA NA NA NA Ashida et al AJC 1990: 66: 498. N=41; ACEI = Enalapril; CCB= Nifedipine SR Herpin et al AJC 1992: 69: 923. N=236; ACEI = Various; CCB = Various. Kristensen et al BPM; 1998; 3: 116. N=96; ACEI = Benazepril; CCB = Felodipine ER 80 100 90 110 120 130 140 150 160 Extreme dippers Dippers Non-dippers Risers Daytime BP Reduction 8 / 7 7 / 7 11 / 8 10 / 8 p<0.001 p<0.001 p<0.001 N.S. n = 18 n = 46 n = 48 n = 6 mmHg Blood pressure level Extreme dippers Dippers Non-dippers Reverse dippers Nighttime BP Reduction 4 / 2 1 / 2 18 /12 12 / 9 p<0.001 N.S. p<0.01 n = 18 n = 46 n = 48 n = 6 mmHg Blood pressure level SBP change (mmHg) -50 -40 -30 -20 -10 0 10 20 30 40 50 90 100 110 120 130 140 150 160 170 180 190 200 Baseline SBP (mmHg) Y = 51 - .42 X r = .45, p<.0001 Nighttime BP Daytime BP Y = 46 - .36 X r = .44, p<.0001 n=118 Effect of Doxazosin on Daytime and Nighttime BPs Kario, Schwartz, Pickering, Hypertension 2000; 35: 787-94. Effects of Time of Administration of CCBs on Diurnal Changes of BP (Lemmer BPM 1996: 1;169) Drug Dose Effect on BP Time Day Night 24 hr Pattern Amlodipine (1) AM Unchanged PM Unchanged Isradipine (2) AM Unchanged PM Unchanged Nifedipine GITS (3) AM Unchanged PM Unchanged Nitrendipine (4) AM Unchanged PM Unchanged 1. Mengden J Hypertens 1992:10 (supp 4); S136 2. Fogari Br J Clin Pharm 1993: 35:51 3. Lemmer Naunyn- Schmiederberg Arch Pharm 1994; 349(supp); R141 4. Meilhac Therapie 1992: 47: 205 Effects of Time of Administration of ACEIs on Diurnal Changes of BP (Lemmer BPM 1996: 1;169) Drug Dose Effect on BP Time Day Night 24 hr Pattern Benazepril (1) AM Nearly Unchanged PM Changed Enalapril (2) AM Nearly Unchanged PM Changed Quinapril (3) AM Nearly Unchanged PM Changed 1. Palatini Int J Clin Pharm Ther Toxicol 1993:31:295 2. Witte Clin Pharm Ther 1993: 54:177 3. Paltini Clin Pharm Ther 1992; 52: 378 Effects of Time of Administration of Trandolapril on Diurnal Changes of BP (Poirier J Clin Pharm 1993: 33:832) Change of SBP mmHg Question: If you were allowed just one reading over 24 hours to predict CV morbidity, which would you choose? Gosse et al, J Hum Hypertens 2001; 15: 413 Awake Awake Sleep Going to bed Arising Evening BP Lowest BP Preawake BP Morning BP

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Does the Pattern of Blood Pressure Effects During the Day Matter? Thomas Pickering MD, DPhil Behavioral Cardiovascular Health and Hypertension Program Division of General Medicine Columbia Presbyterian Medical Center New York Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs What is the True Blood Pressure? Clinic BP? Home BP? 24 Hr Average BP? Daytime BP? Nighttime BP? Dipping Pattern? Morning Surge? Variability of BP? Ambulatory BP Differences for Normotensives, and Mild and Established HTN Patients 120- 110- 100- 90- 80- 70- 60- 0- Diastolic Blood Pressure (mm Hg) Clinic Work Home Sleep Normotensives Mild hypertensives Established hypertensives Clinical situations in which the normal diurnal rhythm of BP may be lost Autonomic Dysfunction Syndromes Diabetes Mellitus Renal Failure Secondary forms of hypertension e.g. Cushing’s disease Drugs, e.g. cyclosporine African-American ethnicity Nocturnal BP Changes and CV Mortality: Ohasama study (Ohkubo et al; AJH 1997; 10: 1201) Extreme dippers Dippers Non-dippers Risers Risk of CV Mortality Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Morning Peak of VT Detected by Implanted Cardioverter/Defibrillator (Tofler Circ 1995;92: 1203) Episodes of VT Circadian Rhythm of Ischemic & Hemorrhagic Strokes Gallerani et al, Acta Neurol Scand 1993; 87: 482) % of strokes 1-6 6 -12 12-18 18-24 Hour of day Ischemic Hemorrhagic Analysis of The Influence of the Morning Surge of BP on Stroke Incidence (Kario, Pickering et al, Circ 2003; 107:1401)) Cox regression analysis for clinical stroke events Covariates RR P value Age (10 yrs) 1.80 (1.21-2.69) 0.004 Male gender 1.42 (0.76-2.67) 0.266 BMI 0.98 (0.90-1.07) 0.663 24 hr SBP 1.37 (1.16-1.63 0.003 SCI 4.40 (1.95-10.1) 0.001 Morning BP surge* 1.29 (1.10-1.51) 0.001 Nocturnal BP fall* 0.88 (0.73-1.06) 0.167 Lowest sleep BP 1.05 (0.65-1.71) 0.837 * per 10 mmHg Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Efficacy: telmisartan vs amlodipine using 24-h ABPM Placebo (n=58) Amlodipine (5-10 mg) (n=65) Telmisartan (40-120 mg) (n=62) 0800 1200 1600 2000 2400 0400 0800 BP (mm Hg) Lacourcière Y et al, in press 160 140 120 100 0 Time Week 12, SBP Effects of Two ARBs Approved for Once Daily Dosing on 24 Hour Blood Pressure (Mancia et al AJC 1999: 84; 28S) Missed Dose Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Do different drug classes have different effects on Daytime vs. Nighttime BP? Meta-Analysis of Effects of Antihypertensive Drug Classes on Daytime & Nighttime BP Weiner, Rieckmann, & Pickering, 2005 Medline search of trials in which effects of antihypertensive drugs on daytime, nighttime, and 24 hr BP were described 55 trials satisfied criteria, & were grouped into 3 classes: ACEI, ARBs, Beta blockers (n=10), CCBs & Diuretics (n=35), and combinations (n=10). Across all studies, the absolute change of daytime BP (14/8 mmHg) was significantly greater than the change of nighttime BP (12.5/4.5 mmHg, p<0.01). The magnitude of the difference between the daytime & nighttime changes did not differ between the groups (p>0.7). Meta-Analysis of Effects of Antihypertensive Drug Classes on Daytime & Nighttime BP Weiner, Rieckmann, & Pickering, 2005 Change of SBP with Treatment mmHg DAY NIGHT Baseline Systolic BP mmHg BP Change mmHg ACEI, ARBs CCBs, Diuretics Meta-Analysis of Effects of Antihypertensive Drug Classes on Daytime & Nighttime BP Weiner, Rieckmann, & Pickering, 2005 Day: B=.07 (p=0.53) Night: B=.04 (p=0.63) Day: B=.55 (p<0.001) Night: B=.55 (p<0.001) Are there class differences in thresholds for lowering BP? (Sekino et al, J Hum Hypertens 1998: 12: 719) Drug Average Effect Threshold BP* on BP Level CBP ABP Daytime Nighttime Nilvadipine -26 -12.5 127 110 Amlodipine -20 -15 127 106 Bisoprolol -19 -12 124 110 Lisinopril -20 -19 97 108 * Estimated from regression line of baseline BP versus change Are there class differences in thresholds for lowering BP? (Sekino et al, J Hum Hypertens 1998: 12: 719) Drug Average Effect Threshold BP* on BP Level CBP ABP Daytime Nighttime Nilvadipine -26 -12.5 127 110 Amlodipine -20 -15 127 106 Bisoprolol -19 -12 124 110 Lisinopril -20 -19 97 108 Combination1 -20 -14 128 106 * Estimated from regression line of baseline BP versus change 1- ACEI + CCB- Fagard et al Am J Hypertens 1993: 6: 648 Diuretics Convert Non-Dippers to Dippers (Uzu & Kimura Circ 1999; 100:1635) Systolic pressure mmHg Day Night No Rx HCTZ No Rx HCTZ Dippers Non-Dippers Diuretics Convert Non-Dippers to Dippers (Uzu & Kimura Circ 1999; 100:1635) Systolic pressure mmHg Day Night No Rx HCTZ No Rx HCTZ Dippers Non-Dippers Regression of Carotid Atherosclerosis by Controlling Morning BP (Marfella et al, Am J Hypertens 2005: 18: 308) Clinic Day Night Morning Carotid IMT 0 -0.02 -0.04 NS NS NS <0.001 <0.02 SBP mmHg IMT mm Regression of Carotid Atherosclerosis by Controlling Morning BP (Marfella et al, Am J Hypertens 2005: 18: 308) Clinic Day Night Morning Carotid IMT 0 -0.02 -0.04 NS NS NS <0.001 <0.02 SBP mmHg IMT mm ? Effects of Alpha-Blockade on the Morning Surge of Blood Pressure (Kario, Pickering, et al Am J Hypertens 2004;17; 668) Doxazosin No Rx Effects of graded release Diltiazem vs. Enalapril on Morning BP (White et al, Am Heart J 2004: 148: 628) Ramipril Diltiazem ER Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs Effects of Time of Administration of Valsartan on Diurnal Changes of BP (Hermida et al Hypertens 2003: 42:283) P=0.041 P=0.402 P=0.174 Change of SBP mmHg Effects of Time of Administration of Valsartan on Diurnal Changes of BP (Hermida et al Hypertens 2003: 42:283) P=0.041 P=0.402 P=0.174 Change of SBP mmHg “Diovan may be used over a dose range of 80 mg to 320 mg daily, administered once-a-day.” Conclusions: Does the Pattern of Blood Pressure Effects During the Day Matter? There is a pronounced diurnal rhythm of BP and cardiovascular events, with a peak of both in the morning hours, and a decrease during the night. In some categories of patients the normal dipping pattern of BP is lost or reversed; this may be associated with increased risk. Drugs approved for once daily dose may have different durations of action, particularly after missed doses. Most classes of antihypertensive drugs lower daytime BP more than nighttime BP. The effects of CCBs may be more closely related to baseline BP than ARBs/ACEI. Conclusions: Does the Pattern of Blood Pressure Effects During the Day Matter? 6. Different antihypertensive drugs may have different effects on the morning surge of BP. 7. With some antihypertensive drugs the time of dosing may have significant effects on the diurnal pattern of BP. 8. The implications of these time-dependent differences of antihypertensive drugs for CV morbidity are largely unknown, and need to be more fully investigated. 9. Implications of BP-independent effects of antihypertensive drugs based on small differences of clinic BP may be unwarranted. Duration of Action by Trough:Peak Ratio 0 Hours after dosing 24 Peak Trough Blood Pressure Change mmHg Placebo Drug Peak Trough Smoothness Index: mean change/SD Trough:peak ratio Change of systolic pressure mmHg Hours since drug dosing Trough:Peak Ratio vs Smoothness Index for defining drug effects on 24 hour BP (Omboni et al BPM, 1998; 3:201) Prognostic Significance of Non-Dipping (Verdecchia et al, BPM 1996; 1 (Suppl 2) ;S81) Covariate Relative Risk Men Women Age>60 7.39 2.44 Diabetes 2.23 2.30 24 hr SBP>median - 3.90 Non-dipper 1.96 1.70 1522 subjects followed for 4.2 years after ABPM Effects of ACEI and CCB on Low and High Ambulatory BP in 3 Studies Study Effect of Drug on Systolic ABP mmHg ACEI CCB ABP Lo ABP Hi ABP Lo ABP Hi Ashida -7.6 -8.9 -3.8 -12.7 Herpin -7 -9 -1 -7 Kristensen -14.5 -16.6 -2.7 -10.1 Ashida et al AJC 1990: 66: 498. N=41; ACEI = Enalapril; CCB= Nifedipine SR Herpin et al AJC 1992: 69: 923. N=236; ACEI = Various; CCB = Various. Kristensen et al BPM; 1998; 3: 116. N=96; ACEI = Benazepril; CCB = Felodipine ER Effects of ACEI and CCB on Clinic SBP in Low and High Ambulatory BP Groups in 3 Studies Study Effect of Drug on Systolic CBP mmHg ACEI CCB ABP Lo ABP Hi ABP Lo ABP Hi Ashida -6.5 -9.5 -11 -16 Herpin -13 -9 -13 -7 Kristensen NA NA NA NA Ashida et al AJC 1990: 66: 498. N=41; ACEI = Enalapril; CCB= Nifedipine SR Herpin et al AJC 1992: 69: 923. N=236; ACEI = Various; CCB = Various. Kristensen et al BPM; 1998; 3: 116. N=96; ACEI = Benazepril; CCB = Felodipine ER 80 100 90 110 120 130 140 150 160 Extreme dippers Dippers Non-dippers Risers Daytime BP Reduction 8 / 7 7 / 7 11 / 8 10 / 8 p<0.001 p<0.001 p<0.001 N.S. n = 18 n = 46 n = 48 n = 6 mmHg Blood pressure level Extreme dippers Dippers Non-dippers Reverse dippers Nighttime BP Reduction 4 / 2 1 / 2 18 /12 12 / 9 p<0.001 N.S. p<0.01 n = 18 n = 46 n = 48 n = 6 mmHg Blood pressure level SBP change (mmHg) -50 -40 -30 -20 -10 0 10 20 30 40 50 90 100 110 120 130 140 150 160 170 180 190 200 Baseline SBP (mmHg) Y = 51 - .42 X r = .45, p<.0001 Nighttime BP Daytime BP Y = 46 - .36 X r = .44, p<.0001 n=118 Effect of Doxazosin on Daytime and Nighttime BPs Kario, Schwartz, Pickering, Hypertension 2000; 35: 787-94. Effects of Time of Administration of CCBs on Diurnal Changes of BP (Lemmer BPM 1996: 1;169) Drug Dose Effect on BP Time Day Night 24 hr Pattern Amlodipine (1) AM Unchanged PM Unchanged Isradipine (2) AM Unchanged PM Unchanged Nifedipine GITS (3) AM Unchanged PM Unchanged Nitrendipine (4) AM Unchanged PM Unchanged 1. Mengden J Hypertens 1992:10 (supp 4); S136 2. Fogari Br J Clin Pharm 1993: 35:51 3. Lemmer Naunyn- Schmiederberg Arch Pharm 1994; 349(supp); R141 4. Meilhac Therapie 1992: 47: 205 Effects of Time of Administration of ACEIs on Diurnal Changes of BP (Lemmer BPM 1996: 1;169) Drug Dose Effect on BP Time Day Night 24 hr Pattern Benazepril (1) AM Nearly Unchanged PM Changed Enalapril (2) AM Nearly Unchanged PM Changed Quinapril (3) AM Nearly Unchanged PM Changed 1. Palatini Int J Clin Pharm Ther Toxicol 1993:31:295 2. Witte Clin Pharm Ther 1993: 54:177 3. Paltini Clin Pharm Ther 1992; 52: 378 Effects of Time of Administration of Trandolapril on Diurnal Changes of BP (Poirier J Clin Pharm 1993: 33:832) Change of SBP mmHg Question: If you were allowed just one reading over 24 hours to predict CV morbidity, which would you choose? Gosse et al, J Hum Hypertens 2001; 15: 413 Awake Awake Sleep Going to bed Arising Evening BP Lowest BP Preawake BP Morning BP Factors Influencing Dipping Status Physical activity during day Sleep duration and quality Ethnicity Sympathetic nervous system Glucocorticoids Sodium/volume factors Renal disease Diabetes