Module 3 chapter 3a

Important trials in hypertension

Landmark Clinical Trials Hypertension Treatment and Cardiovascular Disease Outcomes 1967 – VA Cooperative Study on DBP 115-129 1970 – VA Cooperative Study on DBP 90-114 1979 – HDFP 1980 – Australian Trial, Oslo Trial 1985 – MRC I, EWPHE 1991 – SHEP, STOP-Hypertension 1992 – MRC II in the elderly 1997 – Syst-Eur 2002 – LIFE 2002 – ALLHAT Landmark Clinical Trials: Hypertension Treatment and Cardiovascular Disease Outcomes A few of the many clinical trials in hypertension are shown on this slide. These trial results have changed our definition of hypertension and for ever altered our clinical management of patients with high blood pressure. Evolving national guidelines in the US and worldwide reflect the lessons learned and the evidence gathered from these and other landmark trials. References: Effects of treatment on morbidity in hypertension. Results in patients with diastolic blood pressures averaging 115 through 129 mm Hg. JAMA 1967; 202 (11):1028-34. Effects of treatment on morbidity in hypertension. II. Results in patients with diastolic blood pressure averaging 90 through 114 mm Hg. JAMA 1970; 213 (7):1143-52. Five-year findings of the hypertension detection and follow-up program. I. Reduction in mortality of persons with high blood pressure, including mild hypertension. Hypertension Detection and Follow-up Program Cooperative Group. JAMA 1979; 242 (23):2562-71. The Australian therapeutic trial in mild hypertension. Report by the Management Committee. Lancet 1980; 1 (8181):1261-7. Helgeland A. Treatment of mild hypertension: a five year controlled drug trial. The Oslo study. Am J Med 1980; 69 (5):725-32. Stamler J, Stamler R, Neaton JD. Blood pressure, systolic and diastolic, and cardiovascular risks. US population data. Arch Intern Med 1993; 153 (5):598-615. MRC trial of treatment of mild hypertension: principal results. Medical Research Council Working Party. Br Med J (Clin Res Ed) 1985; 291 (6488):97-104. Amery A, Birkenhager W, Brixko P et al. Mortality and morbidity results from the European Working Party on High Blood Pressure in the Elderly trial. Lancet 1985; 1 (8442):1349-54. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the Systolic Hypertension in the Elderly Program (SHEP). SHEP Cooperative Research Group. JAMA 1991; 265 (24):3255-64. Dahlof B, Lindholm LH, Hansson L et al. Morbidity and mortality in the Swedish Trial in Old Patients with Hypertension (STOP-Hypertension). Lancet 1991; 338 (8778):1281-5. Medical Research Council trial of treatment of hypertension in older adults: principal results. MRC Working Party. BMJ 1992; 304 (6824):405-12. Staessen JA, Fagard R, Thijs L et al. Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. The Systolic Hypertension in Europe (Syst-Eur) Trial Investigators. Lancet 1997; 350 (9080):757-64. www.hypertensiononline.org

Relative Risk for Coronary Heart Disease Odds ratios and 95% confidence intervals Veterans Administration, 1967 Veterans Administration, 1970 Hypertension Stroke Study, 1974 USPHS Study, 1977 EWPHE Study, 1985 Coope and Warrender, 1986 SHEP Study, 1991 STOP-Hypertension Study, 1991 MRC Study, 1992 Syst-Eur Study, 1997 Total Relative Risk for Coronary Heart Disease This meta-analysis examines the relative risk for coronary heart disease (CHD) events in a variety of placebo control clinical trials. Although individual trials differed in the magnitude of risk reduction, the overall result was a 21% lower risk in total CHD in patients receiving active therapy compared with placebo (95% confidence intervals [CI] 10% to 31%; P<0.001). Fatal CHD was reduced 27% (95% CI 13% to 38%; P<0.001). Overall, 412 CHD events occurred in participants assigned to active treatment and 520 in those assigned to placebo. It should be noted, however, that among these 10 trials, the reduction in risk was only statistically significant for the SHEP study, in which CHD was reduced by 28% (95% CI 6% to 44%). References: He J, Whelton PK. Elevated systolic blood pressure and risk of cardiovascular and renal disease: overview of evidence from observational epidemiologic studies and randomized controlled trials. Am Heart J 1999; 138 (3 Pt 2):211-9. Effects of treatment on morbidity in hypertension. Results in patients with diastolic blood pressures averaging 115 through 129 mm Hg. JAMA 1967; 202 (11):1028-34. Effects of treatment on morbidity in hypertension. II. Results in patients with diastolic blood pressure averaging 90 through 114 mm Hg. JAMA 1970; 213 (7):1143-52. Effect of antihypertensive treatment on stroke recurrence. Hypertension-Stroke Cooperative Study Group. JAMA 1974; 229 (4):409-18. Amery A, Birkenhager W, Brixko P et al. Mortality and morbidity results from the European Working Party on High Blood Pressure in the Elderly trial. Lancet 1985; 1 (8442):1349-54. Coope J, Warrender TS. Randomised trial of treatment of hypertension in elderly patients in primary care. Br Med J (Clin Res Ed) 1986; 293 (6555):1145-51. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the Systolic Hypertension in the Elderly Program (SHEP). SHEP Cooperative Research Group. JAMA 1991; 265 (24):3255-64. Dahlof B, Lindholm LH, Hansson L et al. Morbidity and mortality in the Swedish Trial in Old Patients with Hypertension (STOP-Hypertension). Lancet 1991; 338 (8778):1281-5. Medical Research Council trial of treatment of hypertension in older adults: principal results. MRC Working Party. BMJ 1992; 304 (6824):405-12. Staessen JA, Fagard R, Thijs L et al. Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. The Systolic Hypertension in Europe (Syst-Eur) Trial Investigators. Lancet 1997; 350 (9080):757-64. 0.79 (0.69 to 0.90) 0.5 1 1.5 2 Active treatment better than placebo Active treatment worse than placebo He J, et al. Am Heart J. 1999; 138:211-219. Copyright 1999, Mosby, Inc. www.hypertensiononline.org

Relative Risk for Stroke Odds ratios and 95% confidence intervals Veterans Administration, 1967 Veterans Administration, 1970 Hypertension Stroke Study, 1974 USPHS Study, 1977 EWPHE Study, 1985 Coope and Warrender, 1986 SHEP Study, 1991 STOP-Hypertension Study, 1991 MRC Study, 1992 Syst-Eur Study, 1997 Total Relative Risk for Stroke A similar analysis of stroke risk in this meta-analysis demonstrates a 37% lower risk of stroke in patients receiving active therapy vs. placebo (95% confidence interval [CI] 28% to 45%; P<0.001). Overall, there were 385 strokes in participants allocated to active treatment, and 596 in those assigned to placebo. Out of the 10 trials, the reduction in stroke was statistically significant in 6 of them. References: He J, Whelton PK. Elevated systolic blood pressure and risk of cardiovascular and renal disease: overview of evidence from observational epidemiologic studies and randomized controlled trials. Am Heart J 1999; 138 (3 Pt 2):211-9. Effects of treatment on morbidity in hypertension. Results in patients with diastolic blood pressures averaging 115 through 129 mm Hg. JAMA 1967; 202 (11):1028-34. Effects of treatment on morbidity in hypertension. II. Results in patients with diastolic blood pressure averaging 90 through 114 mm Hg. JAMA 1970; 213 (7):1143-52. Effect of antihypertensive treatment on stroke recurrence. Hypertension-Stroke Cooperative Study Group. JAMA 1974; 229 (4):409-18. Amery A, Birkenhager W, Brixko P et al. Mortality and morbidity results from the European Working Party on High Blood Pressure in the Elderly trial. Lancet 1985; 1 (8442):1349-54. Coope J, Warrender TS. Randomised trial of treatment of hypertension in elderly patients in primary care. Br Med J (Clin Res Ed) 1986; 293 (6555):1145-51. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the Systolic Hypertension in the Elderly Program (SHEP). SHEP Cooperative Research Group. JAMA 1991; 265 (24):3255-64. Dahlof B, Lindholm LH, Hansson L et al. Morbidity and mortality in the Swedish Trial in Old Patients with Hypertension (STOP-Hypertension). Lancet 1991; 338 (8778):1281-5. Medical Research Council trial of treatment of hypertension in older adults: principal results. MRC Working Party. BMJ 1992; 304 (6824):405-12. Staessen JA, Fagard R, Thijs L et al. Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. The Systolic Hypertension in Europe (Syst-Eur) Trial Investigators. Lancet 1997; 350 (9080):757-64. 0.63 (0.55 to 0.72) 0.5 1 1.5 2 Active treatment better than placebo Active treatment worse than placebo He J, et al. Am Heart J. 1999; 138:211-219. Copyright 1999, Mosby, Inc. www.hypertensiononline.org

The Veterans Administration Cooperative Study on Antihypertensive Agents The VA Cooperative Study on Antihypertensive Agents www.hypertensiononline.org

The VA Cooperative Study, 1967 Cohort 143 men Mean age 51 years Eligibility Diastolic BP 115-129 mmHg Design Double blind; placebo control Therapy HCTZ, reserpine, hydralazine Duration 1.5 years BP change -43/30 mmHg The VA Cooperative Study, 1967 The VA Cooperative Study was begun at a time when it was not know whether hypertension therapy was beneficial, of no value, or possibly even harmful. Freis and his VA Cooperative Study Group colleagues designed the first adequately powered placebo-controlled, randomized clinical trial of drug treatment in patients with hypertension. Understandably, they selected patients with fairly severe hypertension—diastolic blood pressures of 115-129 mmHg—for this landmark demonstration study. Active treatment included hydrochlorothiazide, reserpine, and hydralazine hydrochloride. The study was terminated prematurely after only one and a half years because of clear evidence of benefit of treatment and excessive, rapid mortality in the placebo group. This landmark finding precluded any future placebo controlled trials in patients with severe hypertension. Reference: Effects of treatment on morbidity in hypertension. Results in patients with diastolic blood pressures averaging 115 through 129 mm Hg. JAMA 1967; 202(11):1028-34. HCTZ=hydrochlorothiazide VA Cooperative Study Group. JAMA. 1967;202:1028-1034. www.hypertensiononline.org

Change in Systolic BP (mmHg) Change in Diastolic BP (mmHg) The VA Cooperative Study, 1967: Change in Systolic and Diastolic Blood Pressure Placebo Placebo Percent of patients Percent of patients Active drugs Active drugs The VA Cooperative Study, 1967: Change in Systolic and Diastolic Blood Pressure Changes in blood pressure during treatment in the two study arms of the VA Cooperative Study are depicted above. Patients receiving placebo were far more likely to experience a rise in blood pressure and far less likely to have a reduction in blood pressure than those receiving active treatment. In those assigned to active therapy, blood pressure fell on average by 43/30 mmHg. Reference: Effects of treatment on morbidity in hypertension. Results in patients with diastolic blood pressures averaging 115 through 129 mm Hg. JAMA 1967; 202(11):1028-34. -76 -60 -44 -28 -12 12 28 -76 -60 -44 -28 -12 12 28 Decrease (-) (+) Increase Decrease (-) (+) Increase Change in Systolic BP (mmHg) Change in Diastolic BP (mmHg) VA Cooperative Study Group. JAMA. 1967;202:1028-1034. Copyright ©1967, American Medical Association. www.hypertensiononline.org

The VA Cooperative Study, 1967: Assessable Morbid/Fatal Events Placebo n=70 Active Rx* n=73 Accelerated hypertension 12 Stroke 4 1 Coronary event 2 CHF Renal damage Deaths The VA Cooperative Study, 1967: Assessable Morbid/Fatal Events During an average of 11 months of follow-up (2–16 months), far more hypertension-related events occurred in the placebo treated group than in those assigned to active therapy in the VA Cooperative Study. Most notable was the reduction in incidence of accelerated hypertension (12 vs 0). Reference: Effects of treatment on morbidity in hypertension. Results in patients with diastolic blood pressures averaging 115 through 129 mm Hg. JAMA 1967; 202(11):1028-34. *P<0.001 active drug therapy vs placebo VA Cooperative Study Group. JAMA. 1967;202:1028-1034. www.hypertensiononline.org

The VA Cooperative Study, 1967: Conclusions The actively treated group experienced a reduction in multiple hypertension-related endpoints 21 morbid/fatal events on placebo 1 morbid/fatal event on active therapy The VA Cooperative Study, 1967: Conclusions The VA Cooperative Study documented that treatment of severe diastolic hypertension could reduce risk for hypertension-related complications. Although the sample size was small and the follow-up was short, the risk for complications was exquisitely high and the design of the study was sufficiently rigorous to provide a definitive answer. Reference: Effects of treatment on morbidity in hypertension. Results in patients with diastolic blood pressures averaging 115 through 129 mm Hg. JAMA 1967; 202(11):1028-34. VA Cooperative Study Group. JAMA. 1967;202:1028-1034. www.hypertensiononline.org

The VA Cooperative Study, 1970 Cohort 380 men Mean age 50 years Eligibility Diastolic BP 90-114 mmHg Design Double blind; placebo control Therapy HCTZ, reserpine, hydralazine Duration 5.5 years (mean=3.8 yrs) BP change Diastolic BP -19 mmHg The VA Cooperative Study, 1970 The second VA Cooperative Study* involved longer-term follow-up of men with mild-to-moderate hypertension (diastolic blood pressure 90–114 mmHg). As anticipated, because of the lower risks associated with mild-to-moderate hypertension, the study sample was larger (n=380) and the follow-up far longer (mean 3.8 years) than in the earlier VA trial. *this cohort and the severe hypertension cohort reported in 1967 were actually recruited simultaneously and subsequently separated. References: Effects of treatment on morbidity in hypertension. II. Results in patients with diastolic blood pressure averaging 90 through 114 mm Hg. JAMA 1970; 213 (7):1143-52. Effects of treatment on morbidity in hypertension. Results in patients with diastolic blood pressures averaging 115 through 129 mm Hg. JAMA 1967; 202(11):1028-34. VA Cooperative Study Group. JAMA. 1970;213:1143-1152. www.hypertensiononline.org

The VA Cooperative Study, 1970: Assessable Morbid/Fatal Events Placebo n=194 Active Rx* n=186 Accelerated hypertension 4 Stroke 20 5 Total coronary event 13 11 Fatal coronary event 6 Congestive heart failure Renal damage 3 Deaths 19 8 The VA Cooperative Study, 1970: Assessable Morbid/Fatal Events In the second VA Cooperative Study* of patients with mild-to-moderate hypertension, those randomized to active therapy experienced fewer morbid and fatal events than those receiving placebo. Most remarkable was the reduction in those on active therapy compared to placebo in stroke (5 vs 20 events, respectively) and congestive heart failure (0 vs 11 events, respectively). *this cohort and the severe hypertension cohort reported in 1967 were actually recruited simultaneously and subsequently separated. Reference: Effects of treatment on morbidity in hypertension. II. Results in patients with diastolic blood pressure averaging 90 through 114 mm Hg. JAMA 1970; 213 (7):1143-52. *P<0.001 active drug therapy vs placebo VA Cooperative Study Group. JAMA. 1970;213:1143-1152. www.hypertensiononline.org

The VA Cooperative Study, 1970: Conclusions Active treatment reduced fatal and nonfatal endpoints A subsequent analysis revealed that benefits were statistically significant only for those with baseline diastolic blood pressure 105-114 mmHg The VA Cooperative Study, 1970: Conclusions In the second VA Cooperative Study* of patients with mild-to-moderate hypertension Freis and colleagues once again demonstrated the benefits of hypertension treatment. They extended the results of the first VA Cooperative Study to patients with less severe diastolic hypertension. *this cohort and the severe hypertension cohort reported in 1967 were actually recruited simultaneously and subsequently separated. Reference: Effects of treatment on morbidity in hypertension. II. Results in patients with diastolic blood pressure averaging 90 through 114 mm Hg. JAMA 1970; 213 (7):1143-52. Effects of treatment on morbidity in hypertension. 3. Influence of age, diastolic pressure, and prior cardiovascular disease; further analysis of side effects. Circulation 1972; 45 (5):991-1004. VA Cooperative Study Group. Circulation. 1972; 45 (5):991-1004. VA Cooperative Study Group. JAMA. 1970;213:1143-1152. www.hypertensiononline.org

The Systolic Hypertension in Europe (Syst-Eur) Trial, 1997 The Systolic Hypertension in Europe Trial, 1997

The Systolic Hypertension in Europe Trial, 1997 Cohort 4,695; 67% women Age  60 yrs old Eligibility Systolic BP 160–219 mmHg and diastolic BP <95 mmHg Design Double blind; placebo control Therapy Nitrendipine (enalapril, HCTZ as Step 2) Duration Median 2 yrs (1-97 months) BP difference -10/5 mmHg The Systolic Hypertension in Europe Trial, 1997 While the Systolic Hypertension in the Elderly Program (SHEP) had previously shown that treatment of isolated systolic hypertension (ISH) was beneficial, a study with a similar design was undertaken in Europe. The Systolic Hypertension in Europe (Syst-Eur) Trial enrolled nearly 5,000 older women and men with stage 2 or greater systolic hypertension and diastolic blood pressure (BP) <95. (SHEP used the more conventional definition of ISH, which required a diastolic BP <90 mmHg.) Like SHEP, Syst-Eur was randomized, double blinded, and placebo controlled. Unlike SHEP, a long-acting dihydropyridine calcium antagonist was used as initial therapy (and other drugs could be added as part of step 2 drug titration). Reference: Staessen JA, Fagard R, Thijs L, Celis H, Arabidze GG, Birkenhager WH, Bulpitt CJ, de Leeuw PW, Dollery CT, Fletcher AE, Forette F, Leonetti G, Nachev C, O'Brien ET, Rosenfeld J, Rodicio JL, Tuomilehto J, Zanchetti A. Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. The Systolic Hypertension in Europe (Syst-Eur) Trial Investigators. Lancet. 1997;350(9080):757-64. Staessen JA, et al. Lancet. 1997;350:757-764. www.hypertensiononline.org

Syst-Eur Mean Sitting Systolic Blood Pressure Placebo (n=2,297) Active treatment (n=2,398) Systolic BP (mmHg) P<0.001 Syst-Eur Mean Sitting Systolic Blood Pressure In Syst-Eur, the mean sitting blood pressure at baseline was 174/86 mmHg for both the placebo and active treatment groups. For patients on active therapy, systolic blood pressures (BP) declined to values close to 150 mmHg. At median follow-up, 21.4% of patients in the placebo group and 43.5% in the active treatment group had reached the target for sitting systolic BP of <150 mmHg (P<0.001). Reference: Staessen JA, Fagard R, Thijs L, Celis H, Arabidze GG, Birkenhager WH, Bulpitt CJ, de Leeuw PW, Dollery CT, Fletcher AE, Forette F, Leonetti G, Nachev C, O'Brien ET, Rosenfeld J, Rodicio JL, Tuomilehto J, Zanchetti A. Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. The Systolic Hypertension in Europe (Syst-Eur) Trial Investigators. Lancet. 1997;350(9080):757-64. 1 2 3 4 Years since randomization Syst-Eur=Systolic Hypertension in Europe Trial Staessen JA, et al. Lancet. 1997;350:757-764. Reprinted with permission from Elsevier Science. www.hypertensiononline.org

Syst-Eur Mean Sitting Diastolic Blood Pressure Diastolic BP (mmHg) Placebo (n=2,297) Syst-Eur Change Mean Sitting Diastolic Blood Pressure At 2 years, sitting diastolic BP had fallen by a mean of 7 mmHg in the active therapy group and by 2 mmHg in the placebo goup in Syst-Eur. For patients on active therapy, diastolic BP declined to just under 80 mmHg. Reference: Staessen JA, Fagard R, Thijs L, Celis H, Arabidze GG, Birkenhager WH, Bulpitt CJ, de Leeuw PW, Dollery CT, Fletcher AE, Forette F, Leonetti G, Nachev C, O'Brien ET, Rosenfeld J, Rodicio JL, Tuomilehto J, Zanchetti A. Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. The Systolic Hypertension in Europe (Syst-Eur) Trial Investigators. Lancet. 1997;350(9080):757-64. Active treatment (n=2,398) 1 2 3 4 Years since randomization Syst-Eur=Systolic Hypertension in Europe Trial Staessen JA, et al. Lancet. 1997;350:757-764. Reprinted with permission from Elsevier Science. www.hypertensiononline.org

Syst-Eur Primary Endpoint Fatal and Nonfatal Stroke Placebo (n=2,297) P=0.003 Active treatment (n=2,398) Events per 100 patients Syst-Eur Primary Endpoint Fatal and Nonfatal Stroke The Syst-Eur primary endpoint was fatal and non-fatal stroke combined. Stroke occurred in 77 patients on placebo and 47 on active therapy. At the recommendation of the data safety and monitoring board the study was terminated prematurely because of a 42% reduction in stroke risk on active therapy. Reference: Staessen JA, Fagard R, Thijs L, Celis H, Arabidze GG, Birkenhager WH, Bulpitt CJ, de Leeuw PW, Dollery CT, Fletcher AE, Forette F, Leonetti G, Nachev C, O'Brien ET, Rosenfeld J, Rodicio JL, Tuomilehto J, Zanchetti A. Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. The Systolic Hypertension in Europe (Syst-Eur) Trial Investigators. Lancet. 1997;350(9080):757-64. 1 3 4 2 Years since randomization Syst-Eur=Systolic Hypertension in Europe Trial Staessen JA, et al. Lancet. 1997;350:757-764. Reprinted with permission from Elsevier Science. www.hypertensiononline.org

Syst-Eur Cardiovascular Disease Endpoints Active therapy vs. placebo 14% risk reduction (95% CI) Percentage relative 30% 29% 31% P<0.001 42% P=0.003 Syst-Eur Cardiovascular Disease Endpoints In addition to the sizable and significant reduction in stroke risk in Syst-Eur, declines of about 1/3 in cardiac endpoints (P=0.03), heart failure (P=NS), and myocardial infarction (P=NS) were observed in the active treatment group. Reference: Staessen JA, Fagard R, Thijs L, Celis H, Arabidze GG, Birkenhager WH, Bulpitt CJ, de Leeuw PW, Dollery CT, Fletcher AE, Forette F, Leonetti G, Nachev C, O'Brien ET, Rosenfeld J, Rodicio JL, Tuomilehto J, Zanchetti A. Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. The Systolic Hypertension in Europe (Syst-Eur) Trial Investigators. Lancet. 1997;350(9080):757-64. Stroke MI CHF All CVD Death MI=myocardial infarction; CHF=congestive heart failure; CVD=cardiovascular disease Syst-Eur=Systolic Hypertension in Europe Trial Staessen JA, et al. Lancet. 1997;350:757-764. www.hypertensiononline.org

Syst-Eur Conclusions Older men and women with isolated systolic hypertension who received active treatment with a dihydropyridine calcium channel blocker experienced fewer strokes and cardiovascular disease (CVD) events than those receiving placebo. Treatment of 1,000 patients for 5 years with this type of regimen could prevent 29 strokes or 53 major CVD endpoints. Syst-Eur Conclusions The conclusions of the Syst-Eur Trial were remarkably similar to those of SHEP. Older men and women primarily with isolated systolic hypertension who received active treatment experienced fewer strokes and cardiovascular disease (CVD) events than those receiving placebo. According to the findings in Syst-Eur, treatment of 1,000 patients for 5 years with this type of regimen could prevent 29 strokes or 53 major CVD endpoints. Reference: Staessen JA, Fagard R, Thijs L, Celis H, Arabidze GG, Birkenhager WH, Bulpitt CJ, de Leeuw PW, Dollery CT, Fletcher AE, Forette F, Leonetti G, Nachev C, O'Brien ET, Rosenfeld J, Rodicio JL, Tuomilehto J, Zanchetti A. Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. The Systolic Hypertension in Europe (Syst-Eur) Trial Investigators. Lancet. 1997;350(9080):757-64. Syst-Eur=Systolic Hypertension in Europe Trial Staessen JA, et al. Lancet. 1997;350:757-764. www.hypertensiononline.org

Allhat trial

The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial ALLHAT study overview Double-blind, randomized trial to determine whether the occurrence of fatal CHD or nonfatal MI is lower for high-risk hypertensive patients treated with newer agents (amlodipine, lisinopril, or doxazosin) compared with a diuretic (chlorthalidone) Cohort 42,418 patients (55 years old) from 623 sites in North America Stage 1 or 2 hypertension 1 additional risk factor for CHD Comparisons between chlorthalidone and amlodipine and chlorthalidone and lisinopril have been reported together, excluding the doxazosin arm (n=9,062), which was terminated early The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) was a randomized, double-blind, multi-center, clinical trial sponsored by the National Heart Lung and Blood Institute (NHLBI). ALLHAT enrolled 42,418 high-risk hypertensive patients ≥55 years old. Participants were recruited between February 1994 and January 1998 at 623 centers in the United States, Canada, Puerto Rico, and the US Virgin Islands. Participants had Stage 1 or 2 hypertension and at least one additional risk factor for coronary heart disease (CHD). Hypertension criteria were either: untreated hypertension [systolic blood pressure (BP) 140–180 mmHg or diastolic BP 90–110 mmHg, but not higher than either systolic BP 180 mmHg or diastolic BP 110 mmHg]; or treated hypertension [on 1–2 antihypertensive drugs at visit 1 and BP ≥160/100 mmHg, or ≥180/110 mm Hg at visit 2, when medication may have been partially withdrawn]. www.hypertensiononline.org ALLHAT Research Group. JAMA. 2002;288:2981-2997.

ALLHAT Study Design Doxazosin n=9,062 Randomized n=42,418 Discontinued early at 3.3 yrs Chlorthalidone n=15,255 Amlodipine n=9,048 Lisinopril n=9,054 n=13,854 2,235 (16.1%) stopped drug n=8,215 1,357 (16.5%) stopped drug n=8,158 1,842 (22.6%) stopped drug YEAR 1 n=6,210 1,873 (30.2%) stopped drug ALLHAT was designed to determine whether the occurrence of fatal CHD or nonfatal myocardial infarction (MI) is lower for high-risk hypertensive patients treated with a calcium channel blocker (CCB), amlodipine; an ACE inhibitor, lisinopril; or an alpha blocker, doxazosin, each compared with diuretic treatment with chlorthalidone. Other, secondary objectives were to examine effects on all-cause mortality, fatal and nonfatal stroke, combined CHD, combined cardiovascular disease (CVD), renal outcomes, and cancer. Individual components of the combined outcomes were pre-specified and examined. The relative benefit of various agents in high-risk subgroups—such as older, black, and diabetic hypertensive persons—also needed to be established. Post-hoc subgroups defined by presence or absence of CHD at baseline were also examined. The doxazosin arm of ALLHAT was terminated early, in January 2000, due to an increased adverse effect of doxazosin compared to diuretic for combined CVD. Data on the doxazosin arm can be found in: ALLHAT Research Group. Major cardiovascular events in hypertensive patients randomized to doxazosin vs chlorthalidone: the antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT). JAMA. 2000;283(15):1967-1975. In the remaining treatment groups, the mean length of follow-up was 4.9 years. A total of 99% of expected person-years were observed. The maximum range of follow-up was 8.0, 7.9, and 8.1 years in the chlorthalidone, amlodipine, and lisinopril groups, respectively. At trial closeout, 419 (2.7%) patients in the chlorthalidone group, 258 (2.8%) in the amlodipine group, and 276 (3.0%) in the lisinopril group were lost to follow-up. n=3,769 1,052 (27.9%) stopped drug n=3,605 1,399 (38.8%) stopped drug YEAR 5 Intent-to-Treat Analysis n=15,255 339 (2.2%) lost to follow-up 80 (0.5%) refused follow-up n=9,048 200 (2.2%) lost to follow-up 58 (0.6%) refused follow-up n=9,054 218 (2.4%) lost to follow-up 58 (0.6%) refused follow-up ALLHAT Research Group. JAMA. 2002;288:2981-2997. www.hypertensiononline.org

ALLHAT Endpoints Primary endpoint Composite of fatal coronary heart disease (CHD) or nonfatal myocardial infarction (MI) Other predefined endpoints all-cause mortality stroke combined CHD – nonfatal MI, CHD death, coronary revascularization, hospitalized angina combined cardiovascular disease – combined CHD, stroke, lower extremity revascularization, treated angina, fatal/ hospitalized/treated congestive heart failure, hospitalized or outpatient peripheral arterial disease other – renal www.hypertensiononline.org ALLHAT Research Group. JAMA. 2002;288:2981-2997.

ALLHAT Baseline Characteristics Chlorthalidone n=15,255 Amlodipine n=9,048 Lisinopril n=9,054 systolic diastolic Mean BP (mmHg) 146 84 Treated (90%) 145 83 Untreated (10%) 156 89 157 90 Mean age (yrs) 67 Black (%) 35 36 Women (%) 47 46 Current smoking (%) 22 History of CHD (%) 26 24 25 Type 2 diabetes (%) 37 There were nearly identical distributions of baseline factors in the three treatment groups. The mean age was 67 years. Of all participants, 35% were black, 47% were women, 22% were current cigarette smokers, 25% had a history of CHD, and 36% were diabetic. Mean seated BP at randomization was about 146/84 mmHg in all three groups, with 90% of participants reporting antihypertensive drug treatment at the time.

ALLHAT Mean Systolic and Diastolic Blood Pressure During Follow-up Chlorthalidone Chlorthalidone Amlodipine Amlodipine Lisinopril Lisinopril Compared to chlorthalidone: SBP significantly higher in amlodipine (~1 mmHg) and lisinopril (~2 mmHg) groups. Compared to chlorthalidone: DBP significantly lower in amlodipine group (~1 mmHg). Systolic BP (mmHg) Diastolic BP (mmHg) Among participants returning for follow-up visits, the mean BP at 1 year was 137/79 mmHg, 138/79 mmHg, and 140/80 mmHg in the chlorthalidone, amlodipine, and lisinopril groups, respectively. At 5 years, the corresponding BPs were 134/75 mmHg, 135/75 mmHg, and 136/75 mmHg. 1 2 3 4 5 6 1 2 3 4 5 6 Follow-up, yrs SBP=systolic blood pressure DBP=diastolic blood pressure www.hypertensiononline.org

ALLHAT BP Controlled to <140/90 mmHg Chlorthalidone Amlodipine Lisinopril † † † *† *† BP <140/90 mmHg % Patients with During follow-up, systolic BP was significantly higher in the amlodipine (~1 mmHg) and lisinopril groups (~2 mmHg) compared to the chlorthalidone group. Diastolic BP was significantly lower in the amlodipine compared to chlorthalidone group (~1 mm Hg). Overall, BP control averaged about 4%–7% better in the chlorthalidone group. At 5 years, BP control to <140/90 mmHg was achieved in 68.2%, 66.3%, and 61.2% of participants in the chlorthalidone, amlodipine, and lisinopril groups, respectively. *P<0.001 for amlodipine vs chlorthalidone †P<0.001 for lisinopril vs chlorthalidone www.hypertensiononline.org ALLHAT Research Group. JAMA. 2002;288:2981-2997.

ALLHAT Treatment and Blood Pressure Control 1 Drug 2 Drugs 3 Drugs 2.0 1.7 1.4 1.3 Patients (%) Average # of drugs The number of patients requiring multiple drugs increased every year during the study. At 5 years, 63% of patients were on 2 or more antihypertensive agents. At baseline, the proportion of participants at or below the BP goal of <140/90 mmHg was ~27%. At 5 years, 66% of patients in all three treatment groups had achieved the goal blood pressure. 6 mos 1 yr 3 yr 5 yr Blood pressure controlled <140/90 mmHg 49.8% 55.2% 62.3% 65.6% Cushman WC, et al. J Clin Hypertens. 2002;4:393-405. www.hypertensiononline.org

ALLHAT Primary Outcome by Treatment Group Chlorthalidone Amlodipine Lisinopril Cumulative Fatal CHD and Nonfatal MI event rate (%) No significant difference was observed between amlodipine and chlorthalidone for the primary composite endpoint of CHD death and nonfatal MI. The relative risk for amlodipine compared to chlorthalidone was 0.98, with a 95% confidence interval of 0.90–1.07. No significant difference was observed between lisinopril and chlorthalidone for the primary outcome, either. The relative risk was 0.99, with a 95% confidence interval of 0.91–1.08. 1 2 3 4 5 6 7 Time to event, yrs No. at Risk Chlorthalidone Amlodipine Lisinopril 15255 9048 9054 14477 8576 8535 13820 8218 8123 13102 7843 7711 11362 6824 6662 6340 3870 3832 2956 1878 1770 209 215 195 ALLHAT Research Group. JAMA. 2002;288:2981-2997. Copyright ©2002, American Medical Association. www.hypertensiononline.org

ALLHAT CHD Death and Nonfatal MI Relative Risk (95% CI) TOTAL 0.98 (0.90-1.07) 0.99 (0.91-1.08) Age <65 (0.85-1.16) 0.95 (0.81-1.12) Age 65 0.97 (0.88-1.08) 1.01 (0.91-1.12) Men (0.87-1.09) 0.94 (0.85-1.05) Women (0.85-1.15) 1.06 (0.92-1.23) Black (0.86-1.18) 1.10 (0.94-1.28) Nonblack (0.87-1.08) Diabetic (0.87-1.13) 1.00 (0.87-1.14) Nondiabetic (0.86-1.09) (0.88-1.11) Favors amlodipine Favors chlorthalidone Favors lisinopril Favors chlorthalidone The results for the primary endpoint were consistent for both treatment comparisons across the pre-defined subgroups. 0.5 1 2 0.5 1 2 ALLHAT Research Group. JAMA. 2002;288:2981-2997. Copyright ©2002, American Medical Association. www.hypertensiononline.org

ALLHAT All-Cause Mortality Relative Risk (95% CI) TOTAL 0.96 (0.89-1.02) 1.00 (0.94-1.08) Age <65 (0.83-1.10) 0.93 (0.81-1.08) Age 65 (0.88-1.03) 1.03 (0.95-1.12) Men 0.95 (0.87-1.04) 0.99 (0.91-1.08) Women (0.86-1.07) 1.02 (0.91-1.13) Black 0.97 (0.87-1.09) 1.06 (0.95-1.18) Nonblack 0.94 (0.87-1.03) (0.89-1.06) Diabetic (0.87-1.07) Nondiabetic (0.91-1.09) Favors amlodipine Favors chlorthalidone Favors lisinopril Favors chlorthalidone For the secondary endpoint of all-cause mortality, neither amlodipine nor lisinopril compared to chlorthalidone was statistically significant. There were no differences across the pre-specified subgroups. 0.5 1 2 0.5 1 2 ALLHAT Research Group. JAMA. 2002;288:2981-2997. Copyright ©2002, American Medical Association. www.hypertensiononline.org

ALLHAT Combined CV Disease Relative Risk (95% CI) TOTAL 1.04 (0.99-1.09) 1.10 (1.05-1.16) Age <65 1.03 (0.94-1.12) 1.05 (0.97-1.15) Age 65 (0.99-1.12) 1.13 (1.06-1.20) Men (0.98-1.11) 1.08 (1.02-1.15) Women (0.96-1.13) 1.12 (1.03-1.21) Black 1.06 (0.96-1.16) 1.19 (1.09-1.30) Nonblack (0.97-1.10) (1.00-1.13) Diabetic (0.98-1.15) (1.00-1.17) Nondiabetic 1.02 (0.96-1.09) (1.05-1.19) Favors amlodipine Favors chlorthalidone Favors lisinopril Favors chlorthalidone For the secondary endpoint of combined CVD, amlodipine compared to chlorthalidone was not statistically significant. However, the lisinopril group had a 10% higher risk of combined CVD (P<0.001), with a 6-year absolute risk difference of 2.4%. There was no difference across the pre-defined subgroups for amlodipine compared to chlorthalidone. There was a significant differential effect with lisinopril compared to chlorthalidone for race (P=0.04). The relative risk for CVD for blacks was 1.19 (P<0.001) and was 1.06 for non-blacks (P=0.05). 0.5 1 2 0.5 1 2 ALLHAT Research Group. JAMA. 2002;288:2981-2997. Copyright ©2002, American Medical Association. www.hypertensiononline.org

ALLHAT Stroke by Treatment Group Chlorthalidone Amlodipine Lisinopril Cumulative event rate (%) There was no difference between the amlodipine and chlorthalidone groups for the secondary endpoint of stroke. However, the lisinopril group had a 15% higher risk for stroke than the chlorthalidone group (P=0.02). 1 2 3 4 5 6 7 Time to event, yrs No. at Risk Chlorthalidone Amlodipine Lisinopril 15255 9048 9054 14515 8617 8543 13934 8271 8172 13309 7949 7784 11570 6937 6765 6385 3845 3891 3217 1813 1828 567 506 949 ALLHAT Research Group. JAMA. 2002;288:2981-2997. Copyright ©2002, American Medical Association. www.hypertensiononline.org

Favors chlorthalidone Favors chlorthalidone ALLHAT Stroke Relative Risk (95% CI) TOTAL 0.93 (0.82-1.06) 1.15 (1.02-1.30) Age <65 (0.73-1.19) 1.21 (0.97-1.52) Age 65 (0.81-1.08) 1.13 (0.98-1.30) Men 1.00 (0.85-1.18) 1.10 (0.94-1.29) Women 0.84 (0.69-1.03) 1.22 (1.01-1.46) Black (0.76-1.14) 1.40 (1.17-1.68) Nonblack (0.79-1.10) (0.85-1.17) Diabetic 0.90 (0.75-1.08) 1.07 (0.90-1.28) Nondiabetic 0.96 (0.81-1.14) 1.23 (1.05-1.44) Favors amlodipine Favors chlorthalidone Favors lisinopril Favors chlorthalidone There was no difference across the pre-defined subgroups for amlodipine compared to chlorthalidone. The relative risk for stroke with lisinopril compared to chlorthalidone was 1.40 for blacks (P<0.001) and 1.00 for non-blacks (P=NS). 0.5 1 2 0.5 1 2 ALLHAT Research Group. JAMA. 2002;288:2981-2997. Copyright ©2002, American Medical Association. www.hypertensiononline.org

ALLHAT Heart Failure by Treatment Group P<0.001 for chlorthalidone vs amlodipine and chlorthalidone vs lisinopril Chlorthalidone Amlodipine Lisinopril Cumulative event rate (%) There was a 38% higher risk for the secondary endpoint of heart failure (HF) with amlodipine compared to chlorthalidone (P<0.001), with a 6-year absolute risk difference of 2.5%. The lisinopril group had a 19% higher risk of HF (P<0.001). 1 2 3 4 5 6 7 No. at Risk Chlorthalidone Amlodipine Lisinopril Time to event, yrs 15255 9048 9054 14528 8535 8496 13898 8185 8096 13224 7801 7689 11511 6785 6698 6369 3775 3789 3016 1780 1837 384 210 313 ALLHAT Research Group. JAMA. 2002;288:2981-2997. Copyright ©2002, American Medical Association. www.hypertensiononline.org

Favors chlorthalidone Favors chlorthalidone ALLHAT Heart Failure Relative Risk (95% CI) TOTAL 1.38 (1.25-1.52) 1.20 (1.09-1.34) Age <65 1.51 (1.25-1.82) 1.23 (1.01-1.50) Age 65 1.33 (1.18-1.49) (1.06-1.35) Men 1.41 (1.24-1.61) 1.19 (1.03-1.36) Women (1.14-1.55) (1.05-1.43) Black 1.47 (1.24-1.74) 1.32 (1.11-1.58) Nonblack (1.18-1.51) 1.15 (1.01-1.30) Diabetic 1.42 (1.23-1.64) 1.22 (1.05-1.42) Nondiabetic (1.16-1.52) (1.04-1.38) Favors amlodipine Favors chlorthalidone Favors lisinopril Favors chlorthalidone The increased risk for HF with amlodipine and lisinopril was consistent across all subgroups. 0.5 1 2 0.5 1 2 ALLHAT Research Group. JAMA. 2002;288:2981-2997. Copyright ©2002, American Medical Association. www.hypertensiononline.org

ALLHAT Conclusions Better control of systolic BP was achieved with chlorthalidone than with amlodipine or lisinopril There were no differences in risk for CHD death/nonfatal MI between chlorthalidone and amlodipine or lisinopril In secondary endpoints, chlorthalidone was associated with lower risk for stroke, combined CVD, and HF compared with lisinopril HF compared with amlodipine The overall BP control rate in ALLHAT of 66% was determined primarily by the rate of control of systolic BP. Diastolic BP was controlled in 92% of participants, but systolic BP was controlled in only 67%. BP control required an average of ≥2 drugs in 63% of the participants, primarily to control systolic BP. There were no differences in risk noted between chlorthalidone and amlodipine or lisinorpil for the primary composite endpoint of fatal CHD and nonfatal MI. However, there was increased risk for the secondary endpoints of stroke, combined CVD, and HF with lisinopril, and for HF with amlodipine. MI=myocardial infarction CHD=coronary heart disease HF=heart failure ALLHAT Research Group. JAMA. 2002;288:2981-2997.

ALLHAT Implications Unless contraindicated, or unless specific indications are present that would favor use of another drug class, diuretics should be the initial drug of choice in antihypertensive regimens Only 30 percent of patients achieve both systolic BP <140 mmHg and diastolic BP <90 mmHg on monotherapy Many high-risk hypertensive patients will require 2 or more drugs for BP control The results of ALLHAT indicate that thiazide-type diuretics should be considered first for pharmacologic therapy in patients with hypertension. The diuretic used in ALLHAT was chlorthalidone. The effects of chlorthalidone vs. hydrochlorothiazide, the thiazide diuretic most commonly prescribed in the United States, on mortality or cardiovascular outcomes in hypertensive patients have never been compared directly as noted in a recent review comparing the similarities and differences of the two drugs. References ALLHAT Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. 2002 Dec 18;288(23):2981-97. Cushman WC, Ford CE, Cutler JA, Margolis KL, Davis BR, Grimm RH, Black HR, Hamilton BP, Holland J, Nwachuku C, Papademetriou V, Probstfield J, Wright JT Jr, Alderman MH, Weiss RJ, Piller L, Bettencourt J, Walsh SM. Success and predictors of blood pressure control in diverse North American settings: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). J Clin Hypertens (Greenwich). 2002 Nov-Dec;4(6):393-405. Carter BL, ME Ernst, Cohen JD. Hydrochlorothiazide versus chlorthalidone: Evidence supporting their interchangability. Hypertension. 2004; 43 (1): 4-9. www.hypertensiononline.org ALLHAT Research Group. JAMA. 2002;288:2981-2997.

Second Australian National Blood Pressure Study ANBP2 Conducted by the High Blood Pressure Research Council of Australia in conjunction with Australia’s General Practitioners

Background Treatment of hypertension based on diuretics and/or beta blockers provides a definite outcome benefit Additional benefit beyond that resulting from blood pressure reduction may result with therapy based on agents inhibiting the renin-angiotensin system ANBP2 New Engl J Med, 2003;348:583-92.

Antihypertensive Drug Use in Australia

Background No outcome data with ACE inhibitor based regimens Potential benefits include Reduction in LVH Improved survival with cardiac failure Enhanced insulin sensitivity Lipid “neutrality” Will outcome be the same better or worse than those of published studies? ANBP2

Main Aim To determine in hypertensive patients aged 65-84 years whether there is any difference in total cardiovascular events (fatal and non-fatal) over a 5 year treatment period between treatment with either a diuretic-based regimen or an ACE inhibitor-based regimen ANBP2 New Engl J Med, 2003;348:583-92.

P prospective R randomised O open label B blinded E endpoints Study Design P prospective R randomised O open label B blinded E endpoints Features Intention to treat General practice based 600 practices 6000 patients Recruitment: 2.5 years ANBP2 New Engl J Med, 2003;348:583-92.

Study Organisation (HBPRCA) General Practice Data monitoring Management Committee (HBPRCA) Sub Committees General Practice Data monitoring End - point Audit Substudies: ABPM, LVH, Genetic, Health Econ National Centre (BMRI) Regional Centers SA QLD VIC NSW WA Data Management Centre (Uni of Adelaide) ANBP2

Study Subjects Inclusion Criteria Exclusion Criteria Men and women 65 - 84 years Previously treated or newly diagnosed hypertensives Untreated sitting SBP > 160 and/or DBP > 90 mmHg Able to give consent and to attend GP practice No recent cardiovascular morbidity Exclusion Criteria Any cardiovascular end-point in the past 6 months Dementia Plasma creatinine > 0.2 mmol/L Any life threatening illness (unlikely to survive 5 years) Unwillingness of GP to enter subject into study Unable to attend GP practice Absolute contraindication to ACE or diuretic ANBP2 New Engl J Med, 2003;348:583-92.

Study Protocol Blood Pressure Screening Randomisation Follow-Up 3 visits conducted by Study Nurses 3 measurements (average of 2nd and 3rd) Mercury sphygmomanometer Entry BP - average of 2nd and 3rd visit readings Randomisation Central - Data Management Centre (Adelaide) Stratified for age (> or  75) Follow-Up GP manages patient according to usual practice Conform (where possible) to randomisation arm Achieve subject goal BP At least 2 visits per year ANBP2 New Engl J Med, 2003;348:583-92.

Study Drug Treatments ACE Inhibitor Group Diuretic Group Step 1. ACE Inhibitor (enalapril recommended) Step 2. Beta or alpha blocker or calcium antagonist Step 3. Drug from class not used in Step 2 or diuretic Step 4. Drug from class not used in step 2 or 3 Diuretic Group Step 1. Thiazide type diuretic (low dose) Step 3. Drug from class not used in Step 2 ANBP2 New Engl J Med, 2003;348:583-92.

Study End-points Obtained by study nurses from GP case notes, hospital case records and death certificates End-point Committee (blinded to treatment allocation) evaluated all data relating to potential study end-points Primary Outcome: All cardiovascular events (initial and subsequent) or death from any cause – ‘total burden of cardiovascular disease’ Any first event or death – ‘event-free survival’ Cause-specific first events ANBP2 New Engl J Med, 2003;348:583-92.

End-points myocardial infarction (fatal and non-fatal) sudden or rapid or ‘other’ cardiac death coronary events resulting in coronary therapeutic procedures cardiac failure (fatal or non-fatal) stroke (fatal or non-fatal) transient cerebral ischaemic attacks acute non-coronary or non-cerebral vascular occlusion other vascular deaths dissecting or ruptured aortic aneurysm ANBP2 New Engl J Med, 2003;348:583-92.

Data Analysis Wei-Lin-Weissfeld method for multiple failure time data Multivariate proportional hazards (Cox) models incorporating: Wei-Lin-Weissfeld method for multiple failure time data Li-Lagakos application of WLW method to analyse recurrent event data with a terminating event Robust variance estimation Validation by simulation Proportional hazards (Cox) models for cause-specific first events ANBP2 New Engl J Med, 2003;348:583-92.

GP Involvement in ANBP2 2681 - GPs 1594 - Practices 500 299 472 361 224 361 200 390 270 958 601 ANBP2 New Engl J Med, 2003;348:583-92.

ANBP2 Subject Recruitment Screened - 54288 Randomised - 6083 Rate - 11% 14669 1310 9% 7530 849 11% 7607 672 7448 763 10% 17145 2489 15% ANBP2

Study profile 54288 screened 25805 ineligible 16899 unwilling to participate 5501 did not meet inclusion criteria ~ 3 yrs 6083 randomised ACE 3044 Diuretic 3039 ITT* analysis Observation Time Median 4.1 yrs Patient yrs 24702 0 No Vital Status 2 ACE 3044 Diuretic 3037 ANBP2 New Engl J Med, 2003;348:583-92. * Intention to treat

Baseline data ACE Diuretic (3044) (3039) Male: Female 50:50 48:52 (3044) (3039) Male: Female 50:50 48:52 Age (yr) 72.0 71.9 Blood Pressure (mmHg) 167 ± 13 168 ± 13 91 ± 8 91 ± 8 Previously Treated 62% 62% Body Mass Index (kg/m2) 27 ± 4 27 ± 4 Current Smokers 7% 7% Physically Active 78% 76% ANBP2 New Engl J Med, 2003;348:583-92.

Baseline data ACE Diuretic (3044) (3039) Coronary Heart Disease 8% 8% (3044) (3039) Coronary Heart Disease 8% 8% Cerebrovascular Disease 5% 5% Diabetes Mellitus 8% 7% Hypercholesterolaemia 38% 36% - lipid lowering drugs 13% 13% ANBP2 New Engl J Med, 2003;348:583-92.

Drug treatments At Randomisation At Study End ACE Diuretic ACE Diuretic (3044) (3039) (3044) (3039) Allocated Therapy 83% 83% 58% 62% Monotherapy 82% 82% 65% 67%  3 agents 6% 5% No drugs 16% 15% 4% 3% ANBP2 New Engl J Med, 2003;348:583-92.

Antihypertensive Medication Use at Study End ACE Diuretic ACE 58 18 Beta Blocker 11 14 Ca Blocker 23 25 Diuretic 24 62 Single Drug 65 67 2 Drugs 25 25 3 + Drugs 6 5 Data represent % ANBP2 New Engl J Med, 2003;348:583-92.

In-study blood pressure -26 mmHg -12 mmHg ANBP2 New Engl J Med, 2003;348:583-92.

Primary Result ACE Diuretic Event n Rate n Rate HR (95%CI) p All cardiovascular 692 55.8 732 59.5 0.89 (0.79,1.00) 0.05 events or any death First cardiovascular 490 41.9 529 45.7 0.89 (0.79,1.01) 0.06 event or death Death 195 15.7 210 17.1 0.90 (0.75,1.09) 0.27 Rate per 1000 patient years Adjusted for age, gender ANBP2 New Engl J Med, 2003;348:583-92.

Primary Result ANBP2 Rate per 1000 patient years Adjusted for age, gender ANBP2

Cause-specific first events Remember this is cause specific so do not translate hazard reductions to risk reductions. All subjects - first any events ANBP2 New Engl J Med, 2003;348:583-92.

Cause-specific fatal events Remember this is cause specific so do not translate hazard reductions to risk reductions. All subjects - fatal events ANBP2 New Engl J Med, 2003;348:583-92.

Cause-specific non-fatal events Remember this is cause specific so do not translate hazard reductions to risk reductions. All subjects - first non-fatal events New Engl J Med, 2003;348:583-92. ANBP2

Summary 11% reduction in total cardiovascular events (or death from any cause) with ACE inhibitor treatment 11% reduction in first events with ACE inhibitor treatment 17% reduction in total events in males and no effect in females ANBP2 New Engl J Med, 2003;348:583-92.

Summary No difference between treatments total or cardiovascular mortality all cerebrovascular events all coronary events With ACE inhibitor treatment reduction in first non-fatal cardiovascular events (HR 0.86) reduction in non-fatal myocardial infarctions (HR 0.68) increase in fatal strokes (HR 1.91) cause-specific effects only in males ANBP2 New Engl J Med, 2003;348:583-92.

Conclusion Initiation of antihypertensive treatment in older patients with an ACE inhibitor particularly in males has a modest but definite outcome advantage over a diuretic despite a similar reduction in blood pressure ANBP2 New Engl J Med, 2003;348:583-92.

Camelot

Invest study

International Verapamil-Trandolapril Study (INVEST) Overview Prospective, Randomized, Open, Blinded End-Point Evaluation (PROBE) trial comparing verapamil- vs. atenolol-based treatment strategies Designed to determine if one treatment strategy was equivalent to the other in reducing all-cause mortality, nonfatal myocardial infarction, or stroke Men and women (n=22,576) ≥ 50 years of age with hypertension and coronary artery disease The patient population was selected to reflect the composition of a primary care practice including women, diabetics, ethnic minorities, and the elderly The International Verapamil-Trandolapril Study (INVEST) is the largest clinical study to date of patients with both hypertension and coronary artery disease. This prospective, randomized, open, blinded-end point evaluation (PROBE) trial included a total of 22,576 men and women, aged 50 and over, recruited from primary care settings in 862 sites in 14 countries.   All patients had hypertension as defined by the Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI) of ≥ 140 mmHg systolic and ≥ 90 mmHg diastolic. In addition, all patients had documented, clinically stable coronary artery disease. The trial was designed to determine if a verapamil-based treatment strategy was equivalent to an atenolol-based treatment strategy for reducing all-cause mortality, nonfatal myocardial infarction, or nonfatal stroke in hypertensive patients with coronary artery disease. The trial steering committee decided prior to trial initiation that a 20% difference in the primary outcome would be considered clinically significant. The equivalence bound for the risk ratio was thus established with a confidence interval of 1.20 to 0.83. Pepine CJ, et al. JAMA. 2003;290:2805-2816

International Verapamil-Trandolapril Study (INVEST) Treatment strategies Calcium antagonist strategy (CAS) using verapamil-SR Non-calcium antagonist strategy (NCAS) using atenolol Addition of trandolapril to the regimen of patients with concomitant diabetes, renal failure, or heart failure was recommended Additional antihypertensive therapy was allowed to achieve and maintain goal blood pressure It was anticipated that multiple drugs would be required to control blood pressure at the JNC VI goals. Eligible patients were randomized to therapy with verapamil-SR, a non-dihydropyridine calcium antagonist, or with atenolol, a beta-blocker. Eligible patients who were taking antihypertensive medications prior to the trial were switched to verapamil-SR or atenolol without placebo washout. Slide 4 (Invest Study Design) provides details about the sequence in which additional drugs could be added to the initial protocol-specified drug. Because previous trials have demonstrated that the use of angiotensin converting enzyme inhibitors was associated with a reduced risk of cardiovascular or renal events in patients with diabetes, chronic kidney disease, or heart failure, it was recommended that trandolapril be added to the treatment regimens of patients with any of these conditions. Pepine CJ, et al. JAMA. 2003;290:2805-2816

INVEST: Primary and Secondary Endpoints Primary composite endpoint First occurrence of Death (all-cause), or Nonfatal myocardial infarction, or Nonfatal stroke Secondary endpoints Each of the above as individual endpoints Cardiovascular death Time to most serious event (death, then MI, then stroke) Angina Cardiovascular hospitalizations Blood pressure control Cancer, Alzheimer’s disease, Parkinson’s disease, and gastrointestinal bleeding New diagnosis of diabetes mellitus The primary endpoint of this trial was cumulative all-cause mortality, nonfatal myocardial infarction, and nonfatal stroke. Each of the components of the primary endpoint assessed individually were the main secondary endpoints. Other pre-specified secondary endpoints included death specifically from cardiovascular causes, time to most serious event (death, nonfatal MI, nonfatal stroke in descending order of seriousness), angina, hospitalizations for cardiovascular events such as new or worsening heart failure, coronary artery revascularization, etc., blood pressure control according to JNC VI guidelines, the occurrence of any cancer, Alzheimer’s disease, Parkinson’s disease and gastrointestinal bleeding. During the early recruitment phase, new diagnosis of diabetes was added as a pre-specified secondary endpoint. Pepine CJ, et al. JAMA. 2003;290:2805-2816

Calcium Antagonist Strategy Non-Calcium Antagonist Strategy INVEST: Design Calcium Antagonist Strategy Non-Calcium Antagonist Strategy Verapamil-SR 240 mg/d, plus trandolapril 2 mg/d for patients with diabetes, renal impairment, or heart failure* Atenolol 50 mg/d, plus trandolapril 2 mg/d for patients with diabetes, renal impairment, or heart failure Step 1 Step 2 Add Drug Verapamil-SR 240 mg/d, plus trandolapril 2 mg/d Atenolol 50 mg/d, plus hydrochlorothiazide 25 mg/d Step 3 Increase Dose Verapamil-SR 180 mg twice daily, plus trandolapril 2 mg twice daily Atenolol 50 mg twice daily, plus hydrochlorothiazide 25 mg twice daily Verapamil-SR 180 mg twice daily, plus trandolapril 2 mg twice daily, plus hydrochlorothiazide 25 mg/d Atenolol 50 mg twice daily, plus hydrochlorothiazide 25 mg twice daily, plus trandolapril 2 mg/d Step 4 Add Drug The objective of INVEST was to lower blood pressure to levels recommended by JNC VI guidelines. Accordingly, investigators aimed for blood pressure levels below 140/90 mmHg for patients with hypertension and 130/85 mmHg for hypertensive patients with renal impairment or diabetes.   A multidrug approach was used to reach the target blood pressure goals in each of two treatment groups. In the first, treatment was initiated with verapamil-SR. If adequate blood pressure control was not achieved, trandolapril was added to the regimen. Physicians could then increase the dosage of both agents, and if necessary, add the diuretic hydrochlorothiazide (HCTZ). Treatment in the second arm was initiated with the beta blocker atenolol, and HCTZ was added on as needed. Dosage increases of both agents were followed by the addition of trandolapril to the regimen as needed to achieve goal blood pressure. In both treatment groups, the final step was the use of maximum tolerated doses of the protocol-specified drugs with the addition of nonstudy antihypertensive agents as necessary. It was recommended that trandolapril be added to the Step 1 treatments in both groups for all patients with diabetes, renal disease, or heart failure. Patients were evaluated every six weeks during the first six months of treatment, followed by biannual visits until two years following enrollment of the last patient. Patients were followed for a mean of 2.7 years. Maximum tolerated dose and/or add nonstudy antihypertensive medication Maximum Treatment Maximum tolerated dose and/or add nonstudy antihypertensive medication The drugs, order of addition, and recommended doses for each step of each strategy are summarized. Nonstudy antihypertensive drugs could be added to control blood pressure except for β-blockers in those assigned to the calcium antagonist strategy and calcium antagonists for those assigned to the non-calcium antagonist strategy. Titration ranges: atenolol, 25-200 mg/d; hydrochlorothiazide, 12.5-100 mg/d; trandolapril, 1-8 mg/d; and verapamil sustained release (Verapamil-SR), 120-480 mg/d. *For patients with creatinine levels of ≥2.0 mg/dL (≥1.77 mol/L), the recommended starting dose was 0.5 mg/d of trandolapril. Pepine CJ, et al. JAMA. 2003;290:2805-2816

INVEST: Baseline Demographics Calcium Antagonist Strategy (n=11,267) Non-Calcium Antagonist Strategy (n=11,309) Mean age (yrs) 66.0 66.1 Women (%) 51.9 52.3 Race/ethnicity (%) White 48.5 48.3 Hispanic 35.7 35.6 Black 13.4 13.5 Asian 0.6 0.8 Other 1.9 Mean BMI (kg/m2) 29.1 29.2 The distribution of demographic characteristics of patients at baseline was approximately equal in the two treatment arms. It should be noted; however, that the INVEST trial included a significant percentage of women, elderly, and nonwhite participants, which is expected to render the results applicable to patients seen in a typical primary care setting. BMI = Body Mass Index Pepine CJ, et al. JAMA. 2003;290:2805-2816

INVEST: Baseline Conditions (expressed as percentages) Calcium Antagonist Strategy (n=11,267) Non-Calcium Antagonist Strategy (n=11,309) Myocardial infarction 32.1 31.8 Abnormal angiogram 38.9 39.5 Concordant stress abnormalities 21.3 21.1 Angina pectoris 66.2 67.0 CABG or PCI 27.3 Stroke 5.3 5.0 Left ventricular hypertrophy 21.5 22.3 Unstable angina > 1 mo ago 11.4 11.5 Arrhythmia 7.1 Heart failure (class I-III) 5.5 5.6 History of smoking 46.6 46.0 Diabetes* 28.1 28.6 Hypercholesterolemia* 55.9 55.6 The specific conditions of patients at baseline were nearly equivalent across the two treatment groups. All patients had documented coronary artery disease. Of these, more than 70% had a prior myocardial infarction, history of MI, or angiographic abnormalities. In addition, many patients had additional risk factors for coronary artery disease; including a history of smoking (46%), diabetes (28%), or hypercholesterolemia (56%). *History of or currently taking antidiabetic or lipid-lowering medications CABG= Coronary Artery Bypass Graft(s); PCI= Percutaneous Coronary Interventions Pepine CJ, et al. JAMA. 2003;290:2805-2816

INVEST: Baseline Medications (expressed as percentages) Calcium Antagonist Strategy (n=11,267) Non-Calcium Antagonist Strategy (n=11,309) Aspirin or other antiplatelet drugs 57.0 56.4 Other NSAIDS 17.6 17.9 Antidiabetic medications 22.1 22.9 Lipid-lowering agent 36.8 36.6 Nitrates 35.4 Potassium supplements 6.9 Hormone replacement* 17.7 18.5 The use of medications at baseline for conditions other than hypertension was also evenly balanced between the CAS and NCAS groups. *Data for women only (n=5,850 for CAS; 5,920 for NCAS) NSAIDS = Nonsteroidal anti-inflammatory drugs Pepine CJ, et al. JAMA. 2003;290:2805-2816

INVEST: Baseline Blood Pressures Calcium Antagonist Strategy Non-Calcium Antagonist Strategy Antihypertensive Medication Use (n=9,758) (n=9,791) Mean systolic blood pressure (mmHg) 149.5 Mean diastolic blood pressure (mmHg) 86.3 Blood pressure controlled (%) Systolic 24.4 24.1 Diastolic 53.7 54.2 Both 22.1 21.6 No Antihypertensive Medication Use (n=1,509) (n=1,518) 159.2 160.1 92.9 92.6 Average values for both systolic and diastolic blood pressure were similar in the two groups at baseline, whether the patients were or were not already taking antihypertensive medications at the time of enrollment. Average blood pressure was approximately 10/5 mmHg higher in patients not taking antihypertensive medications than in those already receiving antihypertensive medication. Of those patients taking antihypertensive medications at the time of enrollment, only 4,267 or 22% had blood pressure controlled according to JNC-VI criteria. Pepine CJ, et al. JAMA. 2003;290:2805-2816

INVEST: Protocol-Specified Drug Use at 12 and 24 Months Verapamil-SR Atenolol Trandolapril Hydrochlorothiazide 12 Months 24 Months *P<0.001 *P<0.001 * * * * Patients (%) At the 24-month follow-up, 81.5% of patients in the CAS group were taking verapamil-SR and 77.5% of patients in the NCAS group were taking atenolol. At both the 12- and 24-month follow-ups, the use of trandolapril and hydrochlorothiazide differed significantly in the two treatment strategies; more patients were receiving trandolapril in the CAS group than in the NCAS group, and more patients in the NCAS group were receiving hydrochlorothiazide than in the CAS group. Pepine CJ, et al. JAMA. 2003;290:2805-2816

INVEST: Number of Protocol-Specified Drugs at 24 Months Patients (%) 1 Drugs The distribution of the number of protocol-specified drugs was similar between the CAS and NCAS groups, although the component drugs in each regimen were different as noted on the previous slide. At 24 months, more than two-thirds of patients in each group were treated with two or more protocol-specified drugs. 0 Drugs Pepine CJ, et al. JAMA. 2003;290:2805-2816

INVEST: Mean Systolic and Diastolic Blood Pressure During Study Calcium Antagonist Strategy (CAS) Non-Calcium Antagonist Strategy (NCAS) Systolic Blood Pressure Level (mmHg) Diastolic Blood Pressure This graph shows the mean systolic and diastolic blood pressures for patients in each treatment arm during the 48 months after randomization. The numbers of subjects at each observation are indicated below the graph. The mean reduction in blood pressures was similar in each treatment group at all observations. Ninety percent of the maximum reduction in systolic blood pressure and 100% of the maximum reduction in diastolic blood pressure were achieved during the first six months of treatment. Level (mmHg) 6 12 18 24 30 36 42 48 Time, mo No. of Pts. CAS NCAS 11267 11309 8558 8573 8639 8694 7758 7710 7842 7850 5721 5834 3659 3679 1458 1473 796 817 Pepine CJ, et al. JAMA. 2003;290:2805-2816

INVEST: Patients with Controlled BP by Treatment Group at 24 Months BP Control Criteria Calcium Antagonist Strategy Non-Calcium Antagonist Strategy P Value SBP <140 mmHg and DBP <90 mmHg 72% 71% 0.18 JNC-VI SBP goals achieved * 65% 64% 0.23 JNC-VI DBP goals achieved † 89% 88% 0.46 The goal of SBP <140 mmHg and DBP <90 mmHg was achieved by approximately 71% of all patients. Rates for SBP and DBP control using JNC VI criteria are included in the above table. The number of patients who achieved these goals for systolic and diastolic blood pressures were approximately 65% and 88%, respectively, with no significant difference between the treatment groups. *SBP <140 mmHg for hypertensives and <130 mmHg for diabetes mellitus or renal impairment DBP <90 mmHg for hypertensives and <85 mmHg for diabetes mellitus or renal impairment Pepine CJ, et al. JAMA. 2003;290:2805-2816

INVEST: Primary Composite Endpoint by Treatment Group Calcium Antagonist Strategy (CAS) Non-Calcium Antagonist Strategy (NCAS) RR = 0.98 (0.90 – 1.06) Cumulative % Log-Rank P=.57 During follow-up evaluations over 60 months, the time to first primary composite endpoint (all-cause mortality, nonfatal MI, or nonfatal stroke) was the same for the CAS and NCAS treatment groups. 6 12 18 24 36 48 54 42 60 30 No. at Risk CAS NCAS Time, mo 11267 11309 10921 10991 10716 10785 10512 10536 10008 10048 6612 6604 3738 3706 1568 1563 974 960 393 390 35 33 Pepine CJ, et al. JAMA. 2003;290:2805-2816

INVEST: Primary and Secondary Outcomes by Treatment Group Calcium Antagonist Strategy (n=11,267) Non-Calcium Antagonist Strategy (n=11,309) No. (%) Rate per 1,000 patient years Rate per 1,000 patient years First event* 1,119 (9.93) 36 1,150 (10.17) 37 Death 873 (7.75) 28 893 (7.90) 29 Nonfatal MI 151 (1.34) 5 153 (1.35) Nonfatal stroke 131 (1.16) 4 148 (1.31) Cardiovascular death 431 (3.83) 14 431 (3.81) Cardiovascular hospitalization 726 (6.44) 24 709 (6.27) 23 Neither the primary composite endpoint (all-cause death, nonfatal myocardial infarction, and nonfatal stroke) nor the secondary outcomes (time to first event, cardiovascular-related death or cardiovascular-related hospitalizations) were significantly different between the treatment groups. * Primary Outcome = first occurrence of death, nonfatal MI, or nonfatal stroke Pepine CJ, et al. JAMA. 2003;290:2805-2816

INVEST: Relative Risk of Primary and Secondary Outcomes RR (95% CI) First event* 0.98 (0.90 – 1.06) Death 0.98 (0.90 – 1.07) Nonfatal MI 0.99 (0.79 – 1.24) Nonfatal stroke 0.89 (0.70 – 1.12) Cardiovascular death 1.00 (0.88 – 1.14) Cardiovascular hospitalization 1.03 (0.93 – 1.14) Favors CAS Favors NCAS The relative risks (RR) of the primary and secondary outcomes also revealed no significant differences between the CAS and NCAS treatment groups. Note the narrow confidence interval for the primary composite endpoint (“First Event”), which indicates no clinically important difference between the two treatment groups. CAS = Calcium Antagonist Strategy NCAS = Non-Calcium Antagonist Strategy 0.6 0.8 1.0 1.2 1.4 RR (95% CI) * Primary Outcome = first occurrence of death, nonfatal MI, or nonfatal stroke Pepine CJ, et al. JAMA. 2003;290:2805-2816

INVEST: Primary Composite Endpoint in Subgroups by Treatment Strategy Clinical Characteristics Age ≤70 Age >70 Female Male White Black Hispanic Other ethnicities Diabetes No diabetes Hypercholesterolemia No hypercholesterolemia Favors CAS Favors NCAS Even patients with prior myocardial infarction and coronary revascularization had similar primary outcomes. However, patients with congestive heart failure at baseline had fewer primary events in the NCAS regimen than in the CAS regimen. 0.8 1.0 1.4 1.6 1.8 1.2 0.6 0.4 RR (95% CI) CAS = Calcium Antagonist Strategy NCAS = Non-Calcium Antagonist Strategy Pepine CJ, et al. JAMA. 2003;290:2805-2816

INVEST: Primary Composite Endpoint in Subgroups by Treatment Strategy Cardiovascular Conditions Prior myocardial infarction No prior myocardial infarction Congestive heart failure No congestive heart failure Revascularization No revascularization Left ventricular hypertrophy No left ventricular hypertrophy Favors CAS Favors NCAS During follow-up examinations, a significantly greater number of new cases of diabetes was diagnosed in the NCAS group. However, the difference (1.2 %) is absolute risk of new onset diabetes between the two treatment groups was small. A preliminary analysis suggested that either the non-dihydropyridine calcium antagonist (verapamil-SR) or the ACE inhibitor (trandolapril) in the CAS group might have provided protection against new-onset diabetes, while the diuretic (hydrochlorothiazide) and/or beta-blocker (atenolol) in the NCAS group might have increased the risk. 0.8 1.0 1.4 1.6 1.8 1.2 0.6 0.4 RR (95% CI) CAS = Calcium Antagonist Strategy NCAS = Non-Calcium Antagonist Strategy Pepine CJ, et al. JAMA. 2003;290:2805-2816

INVEST: New Onset of Diabetes During Study RR = 0.85 (0.77 – 0.95) 8.23 7.03 Patients (%) Pepine CJ, et al. JAMA. 2003;290:2805-2816

INVEST: Summary The verapamil-based regimen (calcium antagonist strategy) and the atenolol-based regimen (non- calcium antagonist strategy) on the primary composite endpoint of all-cause mortality, nonfatal MI, or nonfatal stroke were similar The verapamil- and atenolol-based regimens showed similar efficacy in blood pressure control, cardiovascular death, and cardiovascular hospitalizations The verapamil-based regimen was associated with a small but significantly lower incidence of new onset diabetes Pepine CJ, et al. JAMA. 2003;290:2805-2816

INVEST: Conclusions for the Clinician The verapamil-based regimen (calcium antagonist strategy) was as effective as the atenolol-based regimen (non-calcium antagonist strategy) in reducing morbidity and mortality in patients with both hypertension and coronary artery disease Multi-drug treatment regimens can achieve goal blood pressures in a majority of patients with hypertension and coronary artery disease Benefits with each treatment regimen were observed in all study subgroups (women, ethnic minorities, elderly, and diabetics) Pepine CJ, et al. JAMA. 2003;290:2805-2816

LIFE STUDY

Losartan Intervention For Endpoint Reduction in Hypertension Study LIFE Study Overview Double-blind, randomized trial to compare the effects of losartan and atenolol on cardiovascular morbidity and mortality in high-risk patients with hypertension and left ventricular hypertrophy (LVH) Population 9,193 patients (55 to 80 years old) from 945 sites in 7 countries previously treated or untreated essential hypertension (systolic BP 160–200 mmHg or diastolic BP 95–115 mmHg) ECG LVH 1,195 patients (13%) had diabetes at baseline Losartan Intervention For Endpoints Reduction in Hypertension Study The Losartan Intervention For Endpoint (LIFE) reduction in hypertension study was a double-blind, randomized, parallel-group trial to compare the effects of losartan and atenolol on cardiovascular morbidity and mortality in 9,193 high-risk hypertensive patients (systolic BP 160-200 mmHg or diastolic BP 95-115 mmHg) with left ventricular hypertrophy (LVH) determined by electrocardiography (ECG). The LVH measure used in the study was the product of QRS duration (in msec) and Cornell voltage (the sum of R wave in AVL plus S wave in V3 with adjustment of 8 mm in women) using partition value of >2440 mm X msec (for patients recruited after April 30, 1996 (n=7,708), Cornell voltage adjustment was reduced to 6 mm in women, and Sokolow-Lyon voltage of greater than 38 mm was accepted as an alternative measure of the presence of LVH). The LIFE study was designed to last until at least 1,040 patients experienced a primary endpoint (at least 4 years after the last patient was enrolled), for a relative difference between treatment groups of at least 15% with 80% power with a two-sided 5% level of significance. The planned sample size was 8,300 patients. Analysis of cardiovascular endpoints was by intention to treat. The differences between treatment groups for clinical events were assessed by a Cox regression model with degree of LVH (using the Cornell voltage duration product as a continuous variable) and the Framingham coronary heart disease risk score defined by baseline characteristics as covariates. A secondary unadjusted analysis was conducted to validate the adjusted results. References: Dahlof B, Devereux RB, Kjeldsen SE, Julius S, Beevers G, Faire U, Fyhrquist F, Ibsen H, Kristiansson K, Lederballe-Pedersen O, Lindholm LH, Nieminen MS, Omvik P, Oparil S, Wedel H. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet. 2002;359:995-1003. Lindholm LH, Ibsen H, Dahlof B, Devereux RB, Beevers G, Faire U, Fyhrquist F, Julius S, Kjeldsen SE, Kristiansson K, Lederballe-Pedersen O, Nieminen MS, Omvik P, Oparil S, Wedel H, Aurup P, Edelman J, Snapinn S. Cardiovascular morbidity and mortality in patients with diabetes in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet. 2002;359:1004-1010. Dahlof B, Devereux R, de Faire U, Fyhrquist F, Hedner T, Ibsen H, Julius S, Kjeldsen S, Kristianson K, Lederballe-Pedersen O, Lindholm LH, Nieminen MS, Omvik P, Oparil S, Wedel H. The Losartan Intervention For Endpoint reduction (LIFE) in Hypertension study: rationale, design, and methods. The LIFE Study Group. Am J Hypertens. 1997;10(7 Pt 1):705-713. Kjeldsen SE, Dahlof B, Devereux RB, Julius S, de Faire U, Fyhrquist F, Ibsen H, Kristianson K, Lindholm LH, Lindholm LH, Nieminen MS, Omvik P, Oparil S, Wedel H. Lowering of blood pressure and predictors of response in patients with left ventricular hypertrophy: the LIFE study. Losartan Intervention For Endpoint. Am J Hypertens. 2000;13(8):899-906. www.hypertensiononline.org Dahlof B, et al. Lancet. 2002;359:995-1003.

LIFE Study Design 44 withdrew consent 57 vital status only Assessed for eligibility n=10,780 Ineligible (n=1,558) failed protocol criteria (n=1,343) unwilling to participate (n=215) Randomized n=9,222 Excluded for irregularities (n=29) Losartan n=4,605 Atenolol n=4,588 4,605 available for intention-to-treat analyses 44 withdrew consent 57 vital status only 4 lost to follow-up 4,588 available for intention-to-treat analyses 34 withdrew consent 50 vital status only 8 lost to follow-up www.hypertensiononline.org Dahlof B, et al. Lancet. 2002;359:995-1003.

LIFE Study Endpoints* Primary Endpoint Composite of cardiovascular mortality, fatal and non-fatal myocardial infarction, and fatal and non-fatal stroke Other predefined endpoints total mortality angina pectoris† heart failure† coronary or peripheral revascularization procedures resuscitated cardiac arrest new-onset diabetes mellitus The LIFE study primary endpoint was a composite of cardiovascular mortality, fatal and non-fatal myocardial infarction, and fatal and non-fatal stroke. Other predefined endpoints included total mortality, angina pectoris, heart failure, revascularization, resuscitated cardiac arrest, and new-onset diabetes mellitus. Patients who experienced more than one endpoint were counted in all relevant categories; however where multiple endpoint events occurred in patients, only the first event was counted in the endpoint component analyses. Investigator-reported endpoints disapproved by the endpoint classification committee were not included. *Each endpoint includes only first event; patients could appear in more than one category. †Requiring hospital admission www.hypertensiononline.org Dahlof B, et al. Lancet. 2002;359:995-1003.

LIFE Study Distribution of 9,193 Participants Among 7 Countries Finland 16% Iceland 1% Denmark 15% Norway 15% United States 19% Patients were enrolled between June 1995 and May 2, 1997 from 945 centers in 7 countries, including Norway (n=1,415), Sweden (n=2,245), Finland (n=1,485), Iceland (n=133), Denmark (n=1,391), the United Kingdom (n=817), and the United States (n=1,707). Follow-up of endpoints was stopped when sufficient endpoints for study power were reached on September 16, 2001 (for a mean follow-up of 4.8 years, SD 0.9). Sweden 24% United Kingdom 9% www.hypertensiononline.org Dahlof B, et al. Lancet. 2002;359:995-1003.

Titration to target blood pressure <140/90 mmHg LIFE Study Dosing Losartan 100 mg + HCTZ 12.5-25 mg + others* Titration to target blood pressure <140/90 mmHg Losartan 100 mg + HCTZ 12.5 mg Losartan 50 mg + HCTZ 12.5 mg Losartan 50 mg Placebo Atenolol 50 mg Atenolol 50 mg + HCTZ 12.5 mg Atenolol 100 mg + HCTZ 12.5 mg After a 2-week single-blind placebo run-in period, patients entered a minimum 4-year active treatment period. Antihypertensive therapy was titrated as shown above to achieve a goal blood pressure of less than 140/90 mmHg. Patients initially received losartan 50 mg or atenolol 50 mg. After 2 months, hydrochlorothiazide (HCTZ) 12.5 mg was added if blood pressure was not at, or below, goal blood pressure. After 4 months, the dose of losartan or atenolol was doubled to 100 mg plus HCTZ 12.5 mg if blood pressure was still inadequately controlled. At month 6, additional open-label antihypertensive medication, including upward titration of HCTZ, was added in order to reach goal blood pressure. If blood pressure was 160/95 mmHg, upward titration with additional open-label therapy was mandatory. Atenolol 100 mg + HCTZ 12.5-25 mg + others* 14 7 1 1 2 4 6 1 1.5 2 2.5 3 3.5 4 5 DAY MONTH YEAR *Other antihypertensives excluding ACEIs, AII antagonists, beta-blockers www.hypertensiononline.org Dahlof B, et al. Lancet. 2002;359:995-1003.

LIFE Study Baseline Characteristics* (1) Losartan group n=4,605 Atenolol group (n=4,588) Age (yrs) 66.9 Female (%) 54 BMI (kg/m2) 28 Blood pressure (mmHg) 174.3/97.9 174.5/97.7 Heart rate (bpm) 73.9 73.7 Cornell product (mm x msec) 2834.4 2824.1 Sokolow-Lyon (mm) 30 30.1 Framingham risk score (%) 22 Smokers (%) 16 17 The losartan-based and atenolol-based treatment groups were very well-matched with respect to baseline characteristics. There were no significant differences between the treatment groups in any of the observed baseline characteristics. *P=NS for all comparisons www.hypertensiononline.org Dahlof B, et al. Lancet. 2002;359:995-1003.

LIFE Study Baseline Characteristics* (2) Losartan (n=4,605) Atenolol (n=4,588) Medical History Diabetes mellitus 13 % Isolated systolic hypertension (>160/<90 mmHg) 14 % 15 % Coronary heart disease 17 % Cerebrovascular disease 8 % Peripheral vascular disease 6 % 5 % Atrial fibrillation 3 % 4 % *P=NS for all comparisons www.hypertensiononline.org Dahlof B, et al. Lancet. 2002;359:995-1003.

LIFE Study Distribution of Therapy* Losartan (mean dosage 82 mg) 50 mg only 50 mg + additional drugs* Off study drugs 100 mg with or without additional drugs* Alone Atenolol (mean dosage 79 mg) With HCTZ only With other drugs only At the end of follow-up or occurrence of first primary endpoint, most of the patients in both randomized treatment groups had been titrated to losartan 100 mg, or atenolol 100 mg, plus HCTZ and other study drugs (excluding ACE inhibitors, angiotensin receptor blockers, and beta-blockers) in an effort to control their blood pressure to <140/90 mmHg. The majority of patients in both treatment groups received HCTZ 12.5 mg per day, or more. Approximately 25% of patients in both the losartan-based and atenolol-based treatment groups were off the study drug at the end of follow-up or occurrence of first primary endpoint. Only about 10% of all patients in each treatment group were still receiving the initial drug dose of losartan 50 mg or atenolol 50 mg. With HCTZ and other drugs *At endpoint or end of follow-up www.hypertensiononline.org Dahlof B, et al. Lancet. 2002;359:995-1003.

LIFE Study Blood Pressure and Heart Rate Results Losartan (n=4,605) Atenolol (n=4,588) SBP last visit (mmHg) 144.1 145.4 Change in SBP* -30.2 -29.1 DBP last visit (mmHg) 81.3 80.9 Change in DBP -16.6 -16.8 MAP last visit (mmHg) 102.2 102.4 BP <140/<90 (%) 48 45 SBP <140 mmHg (%) 49 46 DBP < 90 mmHg (%) 87 89 Change in HR (bpm)† -1.8 -7.7 Blood pressure was reduced substantially during the LIFE study in both the losartan-based and atenolol-based treatment groups. Baseline blood pressures for the losartan and atenolol groups were systolic 174.3 mmHg and 174.5 mmHg, and diastolic 97.9 mmHg and 97.7 mmHg, respectively. Sitting systolic pressure (SBP) at the end of follow-up, or at last visit before a primary endpoint occurred, fell by 30.2 mmHg in the losartan group and 29.1 mmHg in the atenolol group (P=0.017). Sitting diastolic pressure (DBP) was reduced by 16.6 mmHg and 16.8 mmHg, respectively (P=0.37). Mean blood pressures at last visit were 144.1/81.3 mmHg and 145.4/80.9 mmHg in the losartan and atenolol groups, respectively. There were 2,196 patients in the losartan group (48%) and 2,051 in the atenolol group (45%) who achieved a blood pressure of 140/90 mmHg. Systolic pressure of 140 mmHg was reached in 2,268 (49%) and 2,099 (46%) patients in the two groups, respectively. The most substantial impact was seen in diastolic blood pressure, which was reduced to 90 mmHg in 4,017 (87%) and 4,067 (89%) patients in the losartan and atenolol groups, respectively. *P=0.017 †P<0.0001 www.hypertensiononline.org Dahlof B, et al. Lancet. 2002;359:995-1003.

LIFE Study Blood Pressure During Follow-up Systolic Mean Arterial mmHg Diastolic Losartan Atenolol 6 12 18 24 30 36 42 48 54 Study Month Dahlof B, et al. Lancet. 2002;359:995-1003. Reprinted with permission from Elsevier Science. www.hypertensiononline.org

LIFE Study Primary Composite Endpoint 16 Intention-to-treat 14 Adjusted risk reduction 13·0%, P=0·021 Unadjusted risk reduction 14·6%, P=0·009 12 10 Atenolol Proportion of patients with first event (%) 8 Losartan 6 4 The LIFE study primary endpoint was a composite of cardiovascular mortality, fatal and non-fatal myocardial infarction, and fatal and non-fatal stroke. Other predefined endpoints included total mortality, angina pectoris, heart failure, revascularization, resuscitated cardiac arrest, and new-onset diabetes mellitus. Patients who experienced more than one endpoint were counted in all relevant categories; however, where multiple endpoint events occurred in patients, only the first event was counted in the endpoint component analyses. For the losartan compared to atenolol treatment group, there was a 13% adjusted relative risk reduction for the primary composite endpoint (P=0.021). 2 Study Month 6 12 18 24 30 36 42 48 54 60 66 Losartan (n) 4605 4524 4460 4392 4312 4247 4189 4112 4047 3897 1889 901 Atenolol (n) 4588 4494 4414 4349 4289 4205 4135 4066 3992 3821 1854 876 Dahlof B, et al. Lancet. 2002;359:995-1003. Reprinted with permission from Elsevier Science. www.hypertensiononline.org

LIFE Study Cardiovascular Mortality 8 Intention-to-treat 7 Adjusted risk reduction 11·4%, P=0·21 Unadjusted risk reduction 13·3%, P=0·14 6 5 Atenolol Proportion of patients with first event (%) 4 Losartan 3 There was no significant difference between the losartan and atenolol treatment groups in adjusted relative risk for the primary endpoint component of cardiovascular mortality. 2 1 6 12 18 24 30 36 42 48 54 60 66 Study Month Dahlof B, et al. Lancet. 2002;359:995-1003. Reprinted with permission from Elsevier Science. www.hypertensiononline.org

LIFE Study Fatal and Non-Fatal Myocardial Infarction 7 Intention-to-treat 6 Adjusted Risk Reduction -7·3%, P=0·49 Unadjusted Risk Reduction -5·0%, P=0·63 5 Losartan Proportion of patients with first event (%) 4 3 Atenolol 2 There was no significant difference between the losartan and atenolol treatment groups in adjusted relative risk for the primary endpoint component of fatal and non-fatal myocardial infarction. 1 6 12 18 24 30 36 42 48 54 60 66 Study Month Dahlof B, et al. Lancet. 2002;359:995-1003. Reprinted with permission from Elsevier Science. www.hypertensiononline.org

LIFE Study Fatal and Non-Fatal Stroke 8 Intention-to-treat Adjusted risk reduction 24·9%, P=0·001 Unadjusted risk reduction 25·8%, P=0·0006 7 6 Atenolol 5 Proportion of patients with first event (%) 4 Losartan 3 With losartan compared to atenolol there was a 24.9% adjusted relative risk reduction for the primary endpoint component of fatal and non-fatal stroke (P=0.001). 2 1 6 12 18 24 30 36 42 48 54 60 66 Study Month Dahlof B, et al. Lancet. 2002;359:995-1003. Reprinted with permission from Elsevier Science. www.hypertensiononline.org

LIFE Study New-Onset Diabetes 10 1 2 3 4 5 6 7 8 9 Intention-to-treat Adjusted risk reduction 25%, P=0·001 Unadjusted risk reduction 25%, P=0·001 Atenolol Proportion of patients with first event (%) Losartan One of the predefined study endpoints was new-onset diabetes mellitus. The adjusted risk reduction for new-onset diabetes with losartan compared to atenolol was 25% (P=0.001). The unusual non-linear shape of the lines on this graph are the result of periodic diagnosis of new-onset diabetes at clinic visits rather than continuously, as with other endpoints. 6 12 18 24 36 42 48 54 60 66 30 Study Month Dahlof B, et al. Lancet. 2002;359:995-1003. Presented by B Dahlof at the American College of Cardiology Scientific Sessions Late-Breaking Clinical Trials III, 2002. www.hypertensiononline.org

LIFE Study Discontinuation Rates Due to Adverse Events (AE) 20 P<0.0001 16 Atenolol 12 P<0.0001 Losartan Proportion of patients who dropped-out because of AE (%) 8 LIFE study discontinuation due to adverse events was more prevalent in the atenolol group than in the losartan group. 4 P=0.006 Serious, drug-related All Drug-related Dahlof B, et al. Lancet. 2002;359:995-1003. Reprinted with permission from Elsevier Science. www.hypertensiononline.org

LIFE Study Change in Cornell Voltage Duration Product and Sokolow-Lyon Cornell Product Sokolow-Lyon -2 -4 -6 -8 Change from baseline (%) -10 P<0.0001 Regression of LVH (defined either by Cornell product or Sokolow-Lyon voltage) occurred in both treatment arms, but was greater in the losartan than in the atenolol group. -12 -14 Losartan -16 Atenolol P<0.0001 -18 Dahlof B, et al. Lancet. 2002;359:995-1003. Reprinted with permission from Elsevier Science. www.hypertensiononline.org

LIFE Study Diabetes Subgroup Primary Composite Endpoint 24 Adjusted risk reduction 24·5%, P=0·031 Unadjusted risk reduction 26.7%, P=0·017 20 16 Atenolol Proportion of patients with first event (%) Losartan 12 8 In the LIFE study diabetic subgroup (n=1,195), there was a 24.5% adjusted risk reduction for the primary composite endpoint (P=0.031). For the primary endpoint components, losartan compared to atenolol produced a 37% reduction in cardiovascular mortality (P=0.028); a 21% reduction in all stroke (P=NS); and a 17% reduction in all myocardial infarction (P=NS). There was a 39% reduction in all-cause mortality (P=0.002), and a 41% reduction in heart failure (P=0.019) with losartan compared to atenolol. (For the entire LIFE study patient population the differences between the treatment groups for all-cause mortality and heart failure were not significant.) 4 6 12 18 24 36 42 48 54 60 66 30 Study Month Losartan (n) 586 569 558 548 532 520 513 501 484 459 237 127 Atenolol (n) 609 588 562 552 540 527 507 486 472 434 204 99 Lindholm LH, et al. Lancet. 2002;359:1004-1010. Reprinted with permission from Elsevier Science. www.hypertensiononline.org

LIFE Study Diabetes Subgroup Primary Composite Endpoint and Components No. of events P value Adjusted hazard ratio (95% CI) Endpoints Composite 242 0.031 CV Death 99 0.028 Stroke 116 NS Myocardial infarction 91 NS Total Mortality 167 0.002 0.5 1 1.5 Favors losartan Favors atenolol Lindholm LH, et al. Lancet. 2002;359:1004-1010. Presented by B Dahlof at the American College of Cardiology Scientific Sessions Late-Breaking Clinical Trials III, 2002. www.hypertensiononline.org

LIFE Study Diabetes Subgroup Total Mortality 24 Adjusted risk reduction 38·7%, P=0·002 Unadjusted risk reduction 40·1%, P=0·001 20 16 Atenolol Proportion of patients with first event(%) 12 8 Losartan 4 6 12 18 24 36 42 48 54 60 66 30 Study Month Lindholm LH, et al. Lancet. 2002;359:1004-1010. Reprinted with permission from Elsevier Science. www.hypertensiononline.org

LIFE Study Summary Losartan-based compared with atenolol-based antihypertensive therapy was associated with: A reduction in the combined primary endpoint of cardiovascular death, stroke or MI (-13%) fewer strokes (-25%) similar blood pressure reduction Losartan reduced the rate of new-onset diabetes (-25%) In the diabetic subgroup, losartan reduced the rate of: combined endpoint of cardiovascular death, stroke and MI (-25%) all-cause mortality (-39%) Dahlof B, et al. Lancet. 2002;359:995-1003. Lindholm LH, et al. Lancet. 2002;359:1004-1010. www.hypertensiononline.org

LIFE Study Conclusions Losartan reduced the combined risk of cardiovascular morbidity and mortality compared to atenolol with benefits not explained by blood pressure reduction Losartan reduced the rate of new-onset diabetes Losartan was significantly better tolerated than atenolol Among diabetics, losartan reduced cardiovascular morbidity and mortality Dahlof B, et al. Lancet. 2002;359:995-1003. Lindholm LH, et al. Lancet. 2002;359:1004-1010. www.hypertensiononline.org

LIFE Study Isolated Systolic Hypertension Subgroup Overview Double-blind, randomized trial to compare the effects of losartan and atenolol on cardiovascular morbidity and mortality in patients with isolated systolic hypertension who were a subgroup of high-risk hypertensive patients in the LIFE study (n=9,193) Cohort 1,326 patients (55 to 80 years old) from 945 sites in 7 countries who were enrolled in the LIFE study Isolated systolic hypertension systolic blood pressure 160–200 mmHg diastolic blood pressure <90 mmHg previously treated or untreated ECG criteria for LVH The Losartan Intervention For Endpoint (LIFE) reduction in hypertension study was a double-blind, randomized, parallel-group trial to compare the effects of losartan and atenolol on cardiovascular morbidity and mortality in 9,193 high-risk hypertensive patients (systolic BP 160-200 mmHg or diastolic BP 95-115 mmHg), 55 to 80 years old, with left ventricular hypertrophy (LVH) determined by electrocardiography (ECG). (SEE Hypertension Online Late Breaking Trials: LIFE) The LIFE study primary endpoint was a composite of cardiovascular mortality, fatal and non-fatal myocardial infarction, and fatal and non-fatal stroke. Other predefined endpoints were the components of the composite endpoint, in addition to total mortality, angina pectoris, heart failure, revascularization, resuscitated cardiac arrest, and new-onset diabetes mellitus. Patients who experienced more than one endpoint were counted in all relevant categories; however where multiple endpoint events occurred in patients, only the first event was counted in the endpoint component analyses. Investigator-reported endpoints disapproved by the endpoint classification committee were not included. The pre-specified data analysis plan for the LIFE study included a component for conducting endpoint analyses in a subgroup of patients with isolated systolic hypertension (ISH). The 1,326 patients included in the LIFE-ISH substudy had systolic blood pressure of 160 to 200 mmHg and diastolic blood pressure of less than 90 mmHg at baseline. The same composite endpoint and components, along with the other predefined endpoints, were also considered in the LIFE-ISH subgroup. LIFE=Losartan Intervention for Endpoints Dahlof B, et al. Am J Hypertens. 1997;10:705-713. Kjeldsen SE, et al. JAMA. 2002;228:1491-1498. www.hypertensiononline.org

LIFE Study ISH Subgroup Design Assessed for eligibility n=10,778 Ineligible (n=1,556) Did not meet protocol criteria (n=1,341) Unwilling to participate (n=215) Randomized n=9,222 Excluded for irregularities (n=29) Isolated systolic hypertension n=1,326 Losartan n=660 Atenolol n=666 Of the 1,326 patients who met the criteria for isolated systolic hypertension (ISH), were eligible to participate, and had not been excluded because of procedural irregularities, 660 were randomized to losartan-based therapy and 666 to atenolol-based therapy. According to intention-to-treat criteria, data from all patients who had received at least one dose of blinded study medication were included in the analysis. Approximately the same percentage of patients were lost to follow-up in the LIFE-ISH sub-study (0/660 in the losartan group; 2/666 in the atenolol group) as in the main LIFE trial (4/4,605 in the losartan group and 8/4,588 in the atenolol group). After a 2-week single-blind placebo run-in period, patients entered a minimum 4-year active treatment period. Antihypertensive therapy was titrated as shown above to achieve a goal systolic blood pressure of less than 140 mmHg. Patients initially received losartan 50 mg or atenolol 50 mg. After 2 months, hydrochlorothiazide (HCTZ) 12.5 mg was added if blood pressure was not at, or below, goal blood pressure. After 4 months, the dose of losartan or atenolol was doubled to 100 mg plus HCTZ 12.5 mg if blood pressure was still inadequately controlled. At month 6, additional open-label antihypertensive medication, including upward titration of HCTZ, was added in order to reach goal blood pressure. 650 available for intention-to-treat analyses Vital status only (n=12) Withdrawn consent (n=10) Lost to follow-up (n=0) 659 available for intention-to-treat analyses Vital status only (n=8) Withdrawn consent (n=5) Lost to follow-up (n=2) Isolated systolic hypertension (ISH) defined as systolic blood pressure 160 mmHg, with diastolic blood pressure <90 mmHg. www.hypertensiononline.org Kjeldsen SE, et al. JAMA. 2002;228:1491-1498.

LIFE Study ISH Subgroup Baseline Characteristics Losartan n=660 Atenolol n=666 Age (yrs) 70.2 70.4 Female (n) 388 408 Blood pressure (mmHg) 174.2/83.0 174.5/82.3 Heart rate (bpm) 71.5 Body mass index (kg/m2) 27.2 27.7 Current smokers (n) 95 102 Framingham risk score (%) 23 24 Cornell VD Product (mm  msec) 2772 2820 Sokolow-Lyon Voltage (mm) 30.8 31.4 The losartan-based and atenolol-based treatment groups were well-matched with respect to baseline characteristics and medical history. www.hypertensiononline.org Kjeldsen SE, et al. JAMA. 2002;228:1491-1498.

LIFE Study ISH Subgroup Medical History Losartan n=660 Atenolol n=666 n % Previously untreated hypertension 233 35.3 211 31.7 Coronary heart disease 158 23.9 140 21.0 Cerebrovascular disease 70 10.6 86 12.9 Peripheral vascular disease 57 8.6 55 8.3 Atrial fibrillation 28 4.2 39 5.9 Diabetes 103 15.6 131 19.7 www.hypertensiononline.org Kjeldsen SE, et al. JAMA. 2002;228:1491-1498.

LIFE Study ISH Subgroup Drug Use at Endpoint or Termination Losartan (%) Atenolol (%) 50 mg (total) 30.4 30.9 Alone 9.8 8.7 50 mg plus other therapy* 20.6 22.2 100 mg (total) 44.1 36.8 2.3 1.4 With HCTZ only 16.1 13.5 With other therapy only 3.6 2.6 With HCTZ & other 22.1 19.4 Off study therapy 25.5 32.3 Mean follow-up time from randomization to death, attrition, or the end of the study was 4.7 years. Patients in the losartan and atenolol groups continued therapy 83.7% and 74.9% of the follow-up time, respectively. The mean final losartan dose was 79 mg; the mean final atenolol dose was 76 mg. The majority of patients received combination therapy. Patients taking losartan were more likely to continue therapy than those taking atenolol. At the end of the trial, 25.5% of the losartan group and 32.3% of the atenolol group were not taking study medication. As with all intent-to-treat analyses in clinical trials, the loss of patients on treatment may reduce a greater, true difference between the observed effects, which could have been demonstrated if all patients remained on study therapy. *including hydrochlorothiazide (HCTZ) www.hypertensiononline.org Kjeldsen SE, et al. JAMA. 2002;228:1491-1498.

LIFE Study ISH Subgroup Composite of CV Death, Stroke, and MI Unadjusted relative risk=29%; P=0.02 Adjusted relative risk reduction=25%; P=0.06 18 16 14 12 Endpoint rate (%) 10 8 6 The primary composite endpoint of cardiovascular death, stroke, and myocardial infarction was reduced by 29% in the losartan group compared to the atenolol group (P=0.02). But, the mean sitting blood pressure levels at the last visit were 146/75 in the losartan and 146/74 in the atenolol group (P=0.67, systolic; P=0.04 diastolic). Adjustment for non-significant differences in blood pressure, as a time-varying covariate, and for a non-significant difference in Framingham risk scores changed the primary outcome. The adjusted relative risk of the primary composite endpoint was reduced by 25% in the losartan group compared to the atenolol group, which was not significant (P=0.06). The event rates per 1,000 patient-years were 25.1 with losartan and 35.4 with atenolol. Atenolol 4 Losartan 2 6 12 18 24 30 36 42 48 54 60 66 Study month CV=cardiovascular MI=myocardial infarction Kjeldsen SE, et al. JAMA. 2002;228:1491-1498. Copyright 2002, American Medical Association. www.hypertensiononline.org

LIFE Study ISH Subgroup Cardiovascular Mortality 10 Unadjusted relative risk reduction=49%; P=0.004 Adjusted relative risk reduction=46%; P=0.01 8 6 Endpoint rate (%) 4 Cardiovascular (CV) mortality was reduced by 46% in the losartan-treated compared to atenolol-treated patients (P=0.01). There were 27 patients in the losartan group (4.1%) compared to 52 in the atenolol group (7.8%) who died of CV causes. The event rates per 1,000 person-years for CV mortality were 8.7 compared to 16.9 for losartan and atenolol, respectively. Atenolol 2 Losartan 6 12 18 24 30 36 42 48 54 60 66 Study month Kjeldsen SE, et al. JAMA. 2002;228:1491-1498. Copyright 2002, American Medical Association. www.hypertensiononline.org

LIFE Study ISH Subgroup Fatal and Non-fatal Stroke Unadjusted relative risk reduction=44%; P=0.008 Adjusted relative risk reduction=40%; P=0.02 10 8 6 Endpoint rate (%) 4 The composite endpoint component of stroke was also significantly reduced in the losartan group. The adjusted relative risk reduction for stroke was 40% with losartan compared to atenolol (P=0.02). There were 32 stroke events in the losartan-treated patients (4.8%) compared to 56 in the atenolol-treated patients (8.4%). The event rates for stroke per 1,000 person-years were 10.6 for losartan and 18.9 for atenolol. Atenolol 2 Losartan 6 12 18 24 30 36 42 48 54 60 66 Study month Kjeldsen SE, et al. JAMA. 2002;228:1491-1498. Copyright 2002, American Medical Association. www.hypertensiononline.org

LIFE Study ISH Subgroup Fatal and Non-fatal Myocardial Infarction 10 Unadjusted relative risk reduction=14%; P=0.54 Adjusted relative risk reduction=11%; P=0.64 8 6 Endpoint rate (%) 4 The adjusted relative risk of myocardial infarction was reduced by 11% in the losartan group compared to the atenolol group. The difference between the groups was not significant. 2 Atenolol Losartan 6 12 18 24 30 36 42 48 54 60 66 Study month Kjeldsen SE, et al. JAMA. 2002;228:1491-1498. Copyright 2002, American Medical Association. www.hypertensiononline.org

LIFE Study ISH Subgroup Total Mortality 18 Unadjusted relative risk reduction=30%; P=0.03 Adjusted relative risk reduction=28%; P=0.046 16 14 12 10 Endpoint rate (%) 8 6 Total mortality was reduced by 28% with losartan compared to atenolol (P=0.046). The event rate per 1,000 person-years for total mortality was 21.2% in the losartan group compared to 30.2 in the atenolol group. There were 66 deaths with losartan (10%) compared to 93 with atenolol (14%). 4 Atenolol Losartan 2 6 12 18 24 30 36 42 48 54 60 66 Study month Kjeldsen SE, et al. JAMA. 2002;228:1491-1498. Copyright 2002, American Medical Association. www.hypertensiononline.org

LIFE Study ISH Subgroup New-Onset Diabetes 12 Unadjusted relative risk reduction=37%; P=0.04 Adjusted relative risk reduction=38%; P=0.04 10 8 6 Endpoint rate (%) 4 One of the predefined study endpoints was new-onset diabetes as determined by 1985 World Health Organization criteria. Losartan compared to atenolol reduced the adjusted relative risk of new-onset diabetes by 38% (P=0.04) in patients without diabetes at randomization (losartan n=557; atenolol n=535). The event rates for new cases of diabetes were 12.6 per 1,000 patient-years with losartan compared to 20.1 per 1,000 patient-years with atenolol. There were 32 patients in the losartan group (5.8%) and 48 in the atenolol group (9%) who developed diabetes. Atenolol 2 Losartan 6 12 18 24 30 36 42 48 54 60 66 Study month www.hypertensiononline.org Kjeldsen SE, et al. JAMA. 2002;228:1491-1498.

LIFE Study ISH Subgroup Blood Pressure During Follow-up 180 Atenolol Losartan 160 Mean BP reduction=28/9 mmHg 140 Systolic 120 mmHg 100 Mean Arterial The mean sitting blood pressures at the end of follow-up or first primary endpoint were reduced by 28/9 mmHg in both the losartan and atenolol groups. A blood pressure of less that 140/90 mmHg was achieved in 44.4% of those taking losartan and in 42.9% of those taking atenolol. The mean blood pressure at last visit was 146/75 mmHg in the losartan group and 146/74 mmHg in the atenolol group; the mean arterial pressure was 98 mmHg in both groups; and the mean pulse pressure was 71 mmHg in the losartan group and 73 mmHg in the atenolol group. 80 Diastolic 60 40 6 12 18 24 30 36 42 48 54 Study month Kjeldsen SE, et al. JAMA. 2002;228:1491-1498. Copyright 2002, American Medical Association. www.hypertensiononline.org

LIFE Study ISH Subgroup ECG-LVH Regression Cornell VD Product Sokolow-Lyon -63* -2 -4 -6 -211* -2.3* Change from baseline (%) -8 P<0.001 The LVH measure used in LIFE was the product of QRS duration (in msec) and Cornell voltage (the sum of R wave in AVL plus S wave in V3 with adjustment of 8 mm in women) using partition value of >2440 mm X msec (for patients recruited after April 30, 1996 (n=7,708), Cornell voltage adjustment was reduced to 6 mm in women, and Sokolow-Lyon voltage of greater than 38 mm was accepted as an alternative measure of the presence of LVH). ECGs were evaluated at a central facility and had to meet both the Cornell voltage duration product (product of QRS duration times Cornell voltage, with a 6 mm adjustment for women and a partition value of >2440 mm x ms) and the Sokolow-Lyon voltage criteria of 38 mm for left ventricular hypertrophy. There was a significantly greater reduction in both the Cornell VD Product (211 vs 63 mm x ms) and in the Sokolow-Lyon values (3.9 vs 2.3 mm) in patients in the losartan group compared to those in the atenolol group. -10 Losartan -3.9* -12 Atenolol -14 P<0.001 *absolute change from baseline www.hypertensiononline.org Kjeldsen SE, et al. JAMA. 2002;228:1491-1498.

LIFE Study ISH Subgroup Discontinuation Due to Adverse Events 25 P=0.002 Losartan 20 Atenolol 15 P<0.001 due to adverse event (%) Patients discontinued 10 P=0.18 Discontinuations from the study either by a patient or a patient’s physician for any reason, or for an adverse event thought to be related to drug therapy, were fewer among patients in the losartan group than in the atenolol group. The differences between the two treatment groups in the number of patients who were discontinued due to serious adverse events for any reason or for suspected drug-related adverse events were not significant. 5 P=0.84 All Drug-related Serious Serious, drug-related www.hypertensiononline.org Kjeldsen SE, et al. JAMA. 2002;228:1491-1498.

LIFE Study ISH Subgroup Summary Losartan was not significantly different from atenolol against the combined primary endpoint of cardiovascular (CV) death, stroke and myocardial infarction (P=0.06) in patients with isolated systolic hypertension (ISH) after adjustment for blood pressure and Framingham risk score Losartan vs. atenolol decreased CV mortality (P=0.01) and stroke (P=0.02) but not MI (P=0.64) in patients with ISH Losartan induced stronger regression of left ventricular hypertrophy (LVH) than atenolol Cornell VD Product P<0.001 Sokolow-Lyon P<0.001 Losartan compared to atenolol reduced the rate of new onset diabetes (P=0.04) In patients with ISH, although the lower CV event rate (composite of CV death, stroke and MI) for losartan compared to atenolol did not reach significance after adjustments for blood pressure and Framingham risk scores (P=0.06), CV mortality (P=0.01) and stroke (P=0.02) were lower with losartan. Losartan induced stronger regression of LVH than atenolol. Losartan compared to atenolol reduced the rate of new-onset diabetes (P=0.04) as defined by 1985 World Health Organization criteria early in the study or by the 1999 WHO criteria later in the trial. Lars H, Lindholm LH, Ibsen H, Borch-Johnsen K, et al for the Life study group. Risk of new-onset diabetes in the Losartan Intervention For Endpoint reduction in hypertension study. J Hypertens 2002; 20: 1879-1886. www.hypertensiononline.org Kjeldsen SE, et al. JAMA. 2002;228:1491-1498.

LIFE Study ISH Subgroup Conclusions The greater effect of treatment with losartan vs. atenolol on combined CV mortality, stroke and MI in patients with isolated systolic hypertension (ISH) (RRR = 25%) compared to the larger LIFE study cohort (RRR = 13%) suggested a particular cardiovascular protective effect of losartan in ISH Losartan achieved the same level of blood pressure reduction as atenolol Losartan was significantly better tolerated than atenolol These results suggest that losartan-based compared to atenolol-based therapy may be preferred in patients with isolated systolic hypertension and left ventricular hypertrophy It is currently not known whether losartan is superior to diuretics, calcium channel blockers, or other first-line treatments of isolated systolic hypertension. The interaction between treatment with losartan and ISH suggested a particular CV protective effect of losartan in ISH. Losartan achieved the same level of blood pressure reduction as atenolol and was significantly better tolerated. These results suggest that losartan-based therapy may be preferred to atenolol-based therapy in the management of patients with ISH and LVH. It is currently not known whether losartan is superior to diuretics, calcium channel blockers, or other first-line treatments of isolated systolic hypertension. RRR = relative risk reduction www.hypertensiononline.org Kjeldsen SE, et al. JAMA. 2002;228:1491-1498.

ACCOMPLISH STUDY

Avoiding Cardiovascular Events through COMbination Therapy in Patients LIving with Systolic Hypertension Kenneth Jamerson1, George L. Bakris2, Bjorn Dahlof3, Bertram Pitt1, Eric J. Velazquez4, and Michael A. Weber5 for the ACCOMPLISH Investigators University of Michigan Health System, Ann Arbor, MI1; University of Chicago-Pritzker School of Medicine, Chicago, IL2; Sahlgrenska University Hospital, Gothenburg, Sweden3; Duke University School of Medicine, Durham, NC4; SUNY Downstate Medical College, Brooklyn, NY5 167

ACCOMPLISH: A Novel Hypertension Trial Traditional approach to hypertension management: Initiate monotherapy then sequentially add medications to achieve target BP ACCOMPLISH: Initiate single tablet combination therapy in high-risk hypertension Specific combinations may confer target organ protection in addition to their BP- lowering effects

ACCOMPLISH Hypothesis ACCOMPLISH will test a new strategy for the treatment of hypertension – the first outcomes trial to compare initial therapy with two different combinations The combination of benazepril and amlodipine will reduce cardiovascular morbidity and mortality in patients with high-risk hypertension by 15% when compared to the combination of benazepril and HCTZ

Primary Endpoint Primary Endpoint Cardiovascular Mortality and Morbidity, defined as: Cardiovascular death Non-fatal myocardial infarction Non-fatal stroke Hospitalization for unstable angina Coronary revascularization procedure (PCI or CABG) Resuscitated sudden death Jamerson KA et al. Am J Hypertens. 2003;16(part2)193A. 170

Targeted Population for Recruitment into the ACCOMPLISH Study Men or women age ≥ 55 years SBP ≥ 160 mmHg or currently on antihypertensive therapy Evidence of cardiovascular or renal disease or target organ damage

ACCOMPLISH Patients Were Receiving Significant Medical Management at Baseline 78% of patients on ACEI or ARB 67% of patients on lipid-lowering agents 63% of patients on anti-platelet therapy Mean LDL 101.6 mg/dl

Baseline Traits of the ACCOMPLISH Cohort 50% of patients were obese 60% of patients had Diabetes Mellitus 97% of patients were treated previously for hypertension 74% of patients were treated with ≥ 2 antihypertensive agents Only 37.5% of patients were controlled to <140/90 mmHg

ACCOMPLISH: Design Randomization 14 Days Day 1 Month 1 Month 2 Month 3 Free add-on antihypertensive agents* Amlodipine 10 + benazepril 40 mg Amlodipine 5 mg + benazepril 40 mg Amlodipine 5 mg + benazepril 20 mg Screening Randomization Benazepril 20 mg + HCTZ 12.5 mg Benazepril 40 mg + HCTZ 12.5 mg Benazepril 40 mg + HCTZ 25 mg Titrated to achieve BP<140/90 mmHg; <130/80 mmHg in patients with diabetes or renal insufficiency Patients will be randomized to amlodipine/benazepril 5/20 mg or benazepril/HCTZ 20/12.5 mg, and will have their doses force-titrated to standard maintenance doses of amlodipine/benazepril 5/40 mg, and benazepril/HCTZ 40/12.5 mg during the first 2 months. The doses can be increased to 10/40 mg or 40/25 mg, respectively, and after 3 months other antihypertensive agents (excluding the drug classes involved in the primary treatments) may be added to achieve blood pressure <140/90 mmHg (<130/80 mmHg for patients with diabetes or renal insufficiency). Investigators will be strongly encouraged to reach target blood pressure in all patients. Patients will be seen at 3 months, 6 months, and thereafter at 6-month intervals until the end of the trial.1 (Jamerson et al. Am J Hypertens. 2004;17: Page 796-A) ACCOMPLISH is an event-driven trial: patients will be treated until 1,642 primary cardiovascular events have been reported. It is estimated this will take approximately 5 years, including the 18 months of recruitment. 1. Jamerson KA, Bakris GL, Wun CC, et al. Rationale and design of the Avoiding Cardiovascular events through COMbination therapy in Patients LIving with Systolic Hypertension (ACCOMPLISH) trial: the first randomized controlled trial to compare the clinical outcome effects of first-line combination therapies in hypertension. Am J Hypertens. 2004;17:793–801. Free add-on antihypertensive agents* 14 Days Day 1 Month 1 Month 2 Month 3 Year 5 *Beta blockers; alpha blockers; clonidine; (loop diuretics). Jamerson KA et al. Am J Hypertens. 2003;16(part2)193A 174

Baseline Demographics ACEI / HCTZ N=5741 (%) CCB / ACEI N=5721 (%) Gender Male Female 3509 (61.1) 2226 (38.8) 3436 (60.1) 2283 (39.9) Race Caucasian Black Asian Other 4789 (83.4) 699 (12.2) 27 (0.5) 220 (3.8) 4814 (84.1) 675 (11.8) 22 (0.4) 208 (3.6) Age Mean (years) < 70 ≥ 70 68.3 3407 (59.3) 2328 (40.6) 68.4 3367 (58.9) 2351 (41.1) Region Nordic countries* United States 1676 (29.2) 4059 (70.7) 1677 (29.3) 4042 (70.7) *Denmark, Finland, Norway or Sweden

Systolic Blood Pressure Over Time ACEI / HCTZ N=5733 CCB / ACEI N=5713 mm Hg 130mmHg Difference of 0.7 mmHg p<0.05* 129.3 mmHg Month 5731 5387 5206 4999 4804 4285 2520 1045 5709 5377 5154 4980 4831 4286 2594 1075 Patients *Mean values are taken at 30 months F/U visit DBP: 71.1 DBP: 72.8

ACCOMPLISH: Exceptional Control Rates with Initial Combination Therapy 90 81.7 78.5 80 70 60 Control rate (%) 50 40 Baseline Control Rates 37.2 37.9 30 20 10 ACEI / HCTZ N=5733 CCB / ACEI N=5713 P<0.001 at 30 months follow-up Control defined as <140/90 mmHg

Low Pill Burden in ACCOMPLISH ACEI / HCTZ N=5733 CCB / ACEI N=5713 Study Medication Only Study + 1 Add-on Study + ≥ 2 Add-on Drug Interruption Study Medication Only Study + 1 Add-on Study + ≥ 2 Add-on Drug Interruption Includes patients receiving beta blockers, alpha blockers, clonidine, loop diuretics. The number of patients with free add-on antihypertensive agents only include those patients who has reached dose level 3. At 30 month follow-up

DSMB Oct 17 2007 Pre-specified efficacy boundary was crossed with 60% of the expected trial information Executive Committee accepted the recommendation Last patient last visit was Jan 24, 2008 Total of 1176 unique patients with events 95.3% of primary events are adjudicated

Kaplan Meier for Primary Endpoint ACEI / HCTZ CCB / ACEI 20% Risk Reduction 650 526 Cumulative event rate p = 0 .0 2 Time to 1st CV morbidity/mortality (days) HR (95% CI): 0.80 (0.72, 0.90) INTERIM RESULTS Mar 08 180

Primary Endpoint and Components Incidence of adjudicated primary endpoints, based upon cut-off analysis date 3/24/2008 (Intent-to-treat population) Risk Ratio (95%) Composite CV mortality/morbidity Cardiovascular mortality Non-fatal MI Non-fatal stroke Hospitalization for unstable angina Coronary revascularization procedure Resuscitated sudden death 0.5 1.0 2.0 0.80 (0.72–0.90) 0.81 (0.62-1.06) 0.81 (0.63-1.05) 0.87 (0.67-1.13) 0.74 (0.49-1.11) 0.85 (0.74-0.99) 1.75 (0.73-4.17) Favors CCB / ACEI Favors ACEI / HCTZ INTERIM RESULTS Mar 08 181 181 181

Primary and Other Endpoints Incidence of adjudicated primary endpoints, based upon cut-off analysis date 3/24/2008 (Intent-to-treat population) Risk Ratio (95%) Composite CV mortality/morbidity Primary w/o revascularization Hard CV endpoint (CV death, non-fatal MI, non-fatal stroke) All cause mortality 0.80 (0.72– 0.90) 0.79 (0.68– 0.92) 0.80 (0.68– 0.94) 0.90 (0.75– 1.08) 0.5 1.0 2.0 Favors CCB / ACEI Favors ACEI / HCTZ INTERIM RESULTS Mar 08 182 182

Summary Single tablet combination therapy was initiated in 11,462 high risk hypertensive patients After mean follow-up of 39 months, The combination of ACEI / CCB was superior to ACEI / diuretic CV morbidity / mortality was reduced by 20% (p=0.0002) Hard CV Endpoint (CV death, stroke and MI) was reduced by 20% (p=0.007)

Summary (cont’d) Prior to study entry, 97% of patients were on antihypertensive medication, 74% receiving > 2 therapies After mean follow up of 30 months, Overall BP control rates increased from 37% to 80% Mean SBP decreased from 145 to <130 mmHg 50% of participants required only one tablet

Conclusions ACCOMPLISH achieved exceptional BP control with combination therapy providing a new option for cardiovascular risk reduction to millions of patients with hypertension. The results of ACCOMPLISH provide compelling evidence for initial combination therapy with ACEI / CCB and challenge current diuretic-based guidelines.

Treatment of uncomplicated hypertension: Implications on the management of hypertension

Need for ASCOT – BPLA ASCOT – BPLA Results of ASCOT – BPLA Implications

A large majority of hypertensive patients require combination treatment … Required 2 or more drugs for blood pressure control Lancet 2005; 366: 895–906. Lancet 1998;351:1755-1762.

And yet ...up to ASCOT...no study assessed treatment regimens...for example... ...Second step drugs were common to randomized groups in effect...only the initial treatment was randomly compared JAMA 2002;288:2981-97 NEJM 2003;348:583-92

By contrast... Randomized to… And in the 9/10 uncontrolled patients Addition of Doxazosin GITS in both the groups …the comparison was therefore between treatment regimens… Amlodipine + perindopril versus Atenolol + diuretic Lancet 2005; 366: 895–906 At present therefore..only two drug regimens have been properly assessed

End points To assess nonfatal MI and fatal CHD with a standard anti-hypertensive regimen (beta blocker + diuretic combination) with a more contemporary regimen (Amlodipine + Perindopril combination) All-cause mortality Total CV mortality Total stroke Total heart failure All CV events and procedures Total coronary events including silent MI Development of diabetes mellitus Renal impairment All major study end points among specific subgroups ASCOT-BPLA Lancet 2005; 366: 895–906.

Inclusion criteria Hypertension at baseline BP > 160/100 mmHg untreated or > 140/90 mmHg treated with one or more drugs Patients aged 40-79 years Patients with 3 or more risk factors for a future cardiovascular event Male sex Age > 55 years LVH NIDDM Smoking ECG abnormalities History of cerebrovascular event History of early CHD in first-degree relative Plasma TC/ HDL ratio > 6 Peripheral vascular disease Microalbuminuria / proteinuria ASCOT-BPLA Lancet 2005; 366: 895–906.

Risk factors at baseline 6 11 22 23 33 62 81 84 100 10 20 30 40 50 60 70 80 90 Peripheral vascular disease LVH 26 Type 2 diabetes 27 Family history of early coronary disease Microalbumin/proteinuria Age ≥ 55 years Hypertension Male Smoker 14 Plasma LDL > 6 ECG abnormalities Previous CVA ASCOT-BPLA Lancet 2005; 366: 895–906.

Baseline characteristics Amlodipine + Perindopril b-blocker+ diuretic combination combination Demographics and clinical characteristics n = 9639 n = 9618 Woman 2258 (23.4%) 2257 (23.5%) White 9187 (95.3%) 9170 (95.3%) Current smoker 3168 (32.9%) 3110 (32.3%) Age (years) 63.0 (8.5) 63.0 (8.5) SBP (mm Hg) 164.1 (18.1) 163.9 (18.0) DBP (mm Hg) 94.8 (10.4) 94.5 (10.4) Heart rate (bpm) 71.9 (12.7) 71.8 (12.6) BMI (kg/m2) 28.7 (4.6) 28.7 (4.5) Risk factors 3.7 (0.9) 3.7 (0.9) Drug therapy Previous antihypertensive treatments 0 1841 (19.1%) 1825 (19.0%) 1 4280 (44.4%) 4283 (44.5%) ≥ 2 3518 (36.5%) 3510 (36.5%) Lipid-lowering therapy 1009 (10.5%) 980 (10.2%) Aspirin 1810 (18.8%) 1801 (18.7%) ASCOT-BPLA Lancet 2005; 366: 895–906.

Data Safety Monitoring Board In October 2004 the DSMB recommended that the BP arm of ASCOT should be stopped on account of concerns that those patients receiving b-blocker + diuretic combination would continue to be disadvantaged compared with the Amlodipine + Perindopril combination. The Steering Committee endorsed the recommendation of the DSMB, and trial closure began in December 2004 after a median follow-up period of 5.4 years. ASCOT-BPLA Lancet 2005; 366: 895–906.

Possible to achieve guideline BP levels b-blocker + diuretic combination Amlodipine + Perindopril combination P<0.0001 ASCOT-BPLA Lancet 2005; 366: 895–906.

All-cause mortality b-blocker + diuretic combination Amlodipine + Perindopril combination -11% P<0.0247 ASCOT-BPLA Lancet 2005; 366: 895–906.

Nonfatal MI and CHD death b-blocker + diuretic combination Amlodipine + Perindopril combination -10% P=0.1052 ASCOT-BPLA Lancet 2005; 366: 895–906.

Superior reduction in Cardiovascular mortality… b-blocker + diuretic combination Amlodipine + Perindopril combination -24% P=0.001 … with Amlodipine + Perindopril combination ASCOT-BPLA Lancet 2005; 366: 895–906.

Superior reduction in Stroke… b-blocker + diuretic combination Amlodipine + Perindopril combination -23% P=0.0003 … with Amlodipine + Perindopril combination ASCOT-BPLA Lancet 2005; 366: 895–906.

Amlodipine + Perindopril combination… b-blocker + diuretic combination Amlodipine + Perindopril combination -30% P<0.0001 …prevents new onset of diabetes ASCOT-BPLA Lancet 2005; 366: 895–906.

Superior reduction with Amlodipine + Perindopril combination on all end-points better b-blocker + diuretic combination better ASCOT-BPLA Lancet 2005; 366: 895–906.

Despite good BP control combination with the newer treatment (Amlodipine + Perindopril) yielded better outcomes than combination with traditional treatment (b-blockers + diuretic) Nonfatal MI +CHD death -10% 0.12 Cardiovascular mortality -24% < 0.001 Total mortality -11% < 0.001 Total coronary events -13% 0.005 Fatal and nonfatal strokes -23% < 0.001 Total CV events and procedures -16% < 0.001 New onset of diabetes -30% < 0.001 ASCOT-BPLA Lancet 2005; 366: 895–906.

Conclusion For the first time ever, a new combination of antihypertensives, (Amlodipine + Perindopril) demonstrated a reduction in mortality and cardiovascular events in comparison with (-blockers + diuretics) therapy in hypertensive patients. No other combination of CCB + ACEI or ARBs has demonstrated such an effect so far This should lead to modification of antihypertensive treatment in large populations of hypertensive patients. ASCOT-BPLA Lancet 2005; 366: 895–906.

Hyvet trial

Blood Pressure Lowering Therapy Evidence: Primary Prevention Hypertension in the Very Elderly (HYVET) Trial 3,845 patients >80 years with SBP >160 mm Hg randomized to treatment to indapamide (1.5 mg) and perindopril (2-4 mg if needed) vs. placebo for 2 years Blood pressure control in patients >80 years of age provides benefit Rate/1000 patient years (%) P=0.06 P=0.05 P=0.02 P<0.001 (Primary end point) The HYVET trial enrolled 3845 patients from Europe, China, Australasia, and Tunisia who were 80 years of age or older and had a sustained systolic blood pressure of 160 mm Hg or more. Patients were randomly assigned to receive either the diuretic indapamide (sustained release, 1.5 mg) or matching placebo. The angiotensin-converting–enzyme inhibitor perindopril (2 or 4 mg), or matching placebo, was added if necessary to achieve the target blood pressure of 150/80 mm Hg. The primary end point was fatal or nonfatal stroke. At 2 years, 25.8%, 23.9%, and 49.5% of patients in the active-treatment group were receiving indapamide alone, indapamide and perindopril (2 mg), and indapamide and perindopril (4 mg), respectively; 14.2%, 13.4%, and 71.8% of patients in the placebo group, respectively, were receiving the corresponding placebos. At 2 years, the mean blood pressure while sitting was 15.0/6.1 mm Hg lower in the active-treatment group than in the placebo group. In an intention-to-treat analysis, active treatment was associated with a 30% reduction in the rate of fatal or nonfatal stroke (95% confidence interval [CI], –1 to 51; P=0.06), a 39% reduction in the rate of death from stroke (95% CI, 1 to 62; P=0.05), a 21% reduction in the rate of death from any cause (95% CI, 4 to 35; P=0.02), a 23% reduction in the rate of death from cardiovascular causes (95% CI, –1 to 40; P=0.06), and a 64% reduction in the rate of heart failure (95% CI, 42 to 78; P<0.001). Fewer serious adverse events were also reported in the active-treatment group (358, vs. 448 in the placebo group; P=0.001). CV=Cardiovascular, CVA=Stroke Source: Beckett NS et al. NEJM 2008;358:1887-98

Value trial

Blood Pressure Lowering Therapy Evidence: Secondary Prevention Valsartan Antihypertensive Long-Term Use Evaluation (VALUE) Trial 15,245 patients with untreated HTN and high CV risk randomized to a BP lowering strategy with valsartan (160 mg) or amlodipine (10 mg) for 4.2 years Both blood pressure lowering regimens provide similar efficacy Primary cardiac composite endpoint Cardiac mortality Cardiac morbidity All myocardial infarction All congestive heart failure All stroke All-cause death New-onset diabetes The VALUE trial sought to investigate differing effects of valsartan and amlodipine on cardiac morbidity and mortality in patients with hypertension given the same level of blood pressure control. The primary end point was a composite of cardiac mortality and morbidity. Amlodipine resulted in a greater reduction in blood pressure after one month and one year compared to valsartan. Despite this, there were no differences in the primary composite endpoint between the two treatments. There were, however, fewer cases of new onset diabetes mellitus in the valsartan arm. Overall: Valsartan and amlodipine are equally efficacious in reducing CVD risk in hypertensive patients. 0.5 1 2 Favors valsartan Favors amlodipine CV=Cardiovascular Source: Julius S et al. Lancet 2004;363:2022-2031 208

Hot trial

Hypertension Optimal Treatment (HOT) Study Blood Pressure Lowering Therapy Evidence: Effect of Intensive Blood Pressure Control Hypertension Optimal Treatment (HOT) Study 18,790 patients with a baseline diastolic BP of 100-115 mm Hg randomized to a target diastolic BP of <90 mm Hg, <85 mm Hg, or <80 mm Hg More intensive blood pressure control provides greater benefit in diabetics Diastolic BP goal Patients without Diabetes Major CV events per 1000 patient-years Patients with The importance of reducing diastolic BP in patients with diabetes mellitus was demonstrated in the Hypertension Optimal Treatment (HOT) trial. In the HOT trial, 18,790 patients with hypertension and a diastolic BP between 100 and 115 mm Hg were randomized to 1 of 3 target diastolic BP groups: 90 mm Hg, 85 mm Hg, or 80 mm Hg. A subgroup of 1501 patients had DM at baseline. A 5-step treatment regimen that started with felodipine was used to lower BP. At the study end, 78% of patients were still taking felodipine, usually with an angiotensin converting enzyme inhibitor (41%) or a -blocker (28%). The incidence of major CV events (MI, stroke, CV mortality) did not differ significantly among the 3 target BP groups in patients who did not have diabetes. Events per 1000 patient-years were 9.9, 10.0, and 9.3 for the 90 mm Hg, 85 mm Hg, or 80 mm Hg groups, respectively. In patients with diabetes mellitus, however, there was a 51% reduction in major CV events in the target group 80 mm compared with target group 90 mm (P for trend = .005). Events per 1000 patient-years were 24.4, 18.6, and 11.9 (P=0.005 for trend) for those with diabetes in the 90 mm Hg, 85 mm Hg, or 80 mm Hg groups, respectively. Source: Hansson L et al. Lancet. 1998;351:1755-1762.

Accord bpla trial

Nonfatal MI, nonfatal stroke, or CV death Blood Pressure Lowering Therapy Evidence: Effect of Intensive Blood Pressure Control Action to Control Cardiovascular Risk in Diabetes (ACCORD) Blood Pressure Trial 4,733 diabetic patients randomized to intensive BP control (target SBP <120 mm Hg) or standard BP control (target SBP <140 mm Hg) for 4.7 years Intensive BP control in DM does not reduce a composite of adverse CV events, but does reduce the rate of stroke HR=0.88 95% CI (0.73-1.06) HR=0.59 95% CI (0.39-0.89) Nonfatal MI, nonfatal stroke, or CV death Total stroke In the ACCORD BP trial, 4,733 diabetic patients were randomized, in a non-blinded fashion, to an intensive BP-lowering regimen with a target systolic BP goal of <120 mm Hg—with patients on average taking three and a half antihypertensives—or standard BP lowering, where the goal was <140 mm Hg. The primary composite outcome was nonfatal MI, nonfatal stroke, or death from cardiovascular causes, and the mean follow-up was 4.7 years. After one year, the mean systolic pressure was 119.3 mm Hg in the intensive-BP-lowering group and 133.5 mm Hg in the standard group. There was no significant difference in the primary end point between the groups. There was also no difference between the groups in terms of pre-specified secondary end points (except stroke), including the primary outcome plus revascularization or nonfatal heart failure; major coronary disease events; and fatal or nonfatal heart failure. There was a significant difference in stroke (41% relative risk reduction) between the intensive and standard BP-lowering arms. Those assigned to the intensive-therapy group were more likely to suffer adverse events due to antihypertensive therapy—3.3% compared with 1.3% in the standard-therapy group (p<0.001). BP=Blood pressure, DM=Diabetes mellitus, HR=Hazard ratio, SBP=Systolic blood pressure ACCORD study group. NEJM 2010;362:1575-85.

End of module 3 chapter 3a