Health and Human Services National Heart, Lung, and Blood Institute U.S. Department of Health and Human Services National Institutes of Health National Heart, Lung, and Blood Institute ALLHAT Outcomes in High Risk Hypertensives Randomized to CCB vs. ACE Inhibitor in ALLHAT Frans Leenen MD, PhD, Chuke Nwachuku MA, MPH, Dr PH, William Cushman MD, Henry Black MD, Lara Simpson MS, Barry Davis MD, PhD. For the ALLHAT Collaborative Research Group Sponsored by the National Heart, Lung and Blood Institute (NHLBI) www.allhat.org

Primary Objective POST-HOC ANALYSIS ALLHAT Determine whether treatment with the newer agents (CCB, ACEI, alpha-blocker) results in less fatal CHD and nonfatal MI compared with a diuretic POST-HOC ANALYSIS - Comparison of cardiovascular and other outcomes among 18,102 patients randomized to ACEI or dihydropyridine CCB - For sub-groups, emphasis on outcomes in Blacks vs non-Blacks considering the previously reported interaction for several major outcomes with lisinopril.

Hypertension Trial ALLHAT 42,418 high-risk hypertensive patients 90% previously treated 10% untreated STEP 1 AGENTS Chlorthalidone 12.5-25 mg Amlodipine 2.5-10 mg Lisinopril 10-40 mg Doxazosin 1-8 mg This post-hoc comparison is of lisinopril (n=9054, 3210 Blacks) versus amlodipine (n=9048, 3213 Blacks). N=15,255 N=9,048 N=9,054 N=9,061 STEP 2 AND 3 AGENTS (5 years) Atenolol 28.0% Clonidine 10.6% Reserpine 4.3% Hydralazine 10.9%

Baseline Characteristics ALLHAT Amlodipine (n=9048) Lisinopril (n=9054) P value Lisinopril vs. Amlodipine Age in yrs, mean (SD) 66.9 (7.7) 0.83 On antihypertensive meds (%) 8171 (90) 8164 (90) Type 2 diabetes (%) 3323 (37) 3212 (35) 0.08 History of CHD (%) 2202 (24) 2270 (25) 0.25 Cigarette smoker (%) 1980 (22) 1981 (22) 0.90 Female (%) 4280 (47) 4187 (46) 0.15 Blacks (%) 3213 (36) 3210 (35) 0.94 On aspirin (%) 3268 (36) 3258 (36) 0.85 There were no significant differences between the two groups for major baseline characteristics.

Baseline and Follow-up Blood Pressures ALLHAT Baseline and Follow-up Blood Pressures 148 148 148 146 146 146 144 144 144 142 142 142 mm Hg BP mm Hg BP 140 140 140 138 138 138 Amlodipine 136 136 136 134 134 134 Lisinopril 74 76 78 80 82 84 86 86 86 74 76 78 80 82 84 86 84 84 82 82 Mean seated BP at randomization was 146/84 mmHg in both groups. BP deceased progressively but remained higher by 1-1.5 mmHg in the lisinopril compared to the amlodipine arm. mm Hg BP mm Hg BP mm Hg BP 80 80 78 78 76 76 74 74 BL BL BL 3m 3m 3m 6m 6m 6m Y1 Y1 Y1 Y2 Y2 Y2 Y3 Y3 Y3 Y4 Y4 Y4 Number at Risk: Amlodipine 9048 7609 6883 6381 5637 Lisinopril 9054 7521 6700 6076 5325

Baseline and Follow-up BPs by Race ALLHAT Baseline and Follow-up BPs by Race 148 146 Δ=3.4 144 142 mmHg SBP Δ=1.6 140 138 Amlodipine - Blacks Amlodipine - Non-Blacks Lisinopril - Blacks Lisinopril - Non-Blacks 136 134 132 86 84 Δ=1.8 82 Among the pre-specified subgroups, in non-Blacks the two treatments showed only minor (<1 mmHg) differences. In contrast, in Blacks, BP remained higher in the lisinopril arm by 3.4/1.8 mmHg at year 2 and by 1.6/1.1 mmHg at year 4. mmHg DBP 80 Δ=1.1 78 76 Δ=0.5 Δ=0.8 74 BL 3m 6m Y1 Y2 Y3 Y4 Mean # of Meds: Amlodipine Blacks 1.4 1.5 1.6 1.7 Non-Blacks - 1.4 1.5 1.7 1.8 Lisinopril Blacks 1.6 1.8 1.9 2.0 Non-Blacks - 1.4 1.6 1.7 1.8

Cumulative Event Rates for the Primary Outcome (Fatal CHD or Nonfatal MI) by Treatment Group ALLHAT Years to CHD Event 1 2 3 4 5 6 7 Cumulative CHD Event Rate .04 .08 .12 .16 .2 RR (95% CI) p value L/A 1.01 (0.91-1.11) 0.85 Blacks 1.09 (0.92-1.30) 0.33 Non-Blacks 0.97 (0.86-1.10) 0.66 Amlodipine Lisinopril No significant difference was observed between amlodipine (the red line) and lisinopril (the green line) for the primary outcome. The relative risk was 1.01, with a 95% confidence interval of 0.91-1.11. The number at risk in each interval is the number of persons alive at the start of the interval; those experiencing the outcome or those withdrawn during an interval are removed before the start of the next interval. Those randomized late in the trial (1997-1998) contribute less follow-up time (4-5 years) than those randomized earlier (1994 – 8 years). Thus, at years 4 through 6 the number at risk begin to decline significantly as those randomized later conclude their contribution to the trial. Number at Risk: Amlodipine 9,048 8,576 8,218 7,843 6,824 3,870 1,878 215 Lisinopril 9,054 8,535 8,123 7,711 6,662 3,832 1,770 195

Secondary Endpoints: No Differences Between Treatment Groups For ALLHAT Lisinopril vs. Amlodipine RR (95% CI) P value Combined CHD 1.04 (0.97-1.12) 0.24 All-Cause Mortality 1.05 (0.97-1.13) 0.21 ESRD 0.99 (0.77-1.26) 0.93 Blacks (L vs. A) Non-Blacks (L vs. A) RR (95% CI) P value Combined CHD 1.12 (0.98-1.28) 0.11 1.02 (0.93-1.11) 0.73 All-Cause Mortality 1.01 (0.96-1.23) 0.19 1.03 (0.93-1.13) 0.59 ESRD 1.12 (0.80-1.57) 0.51 0.86 (0.60-1.24) 0.43

Cumulative Event Rates for Stroke by Treatment Group ALLHAT Cumulative Event Rates for Stroke by Treatment Group Cumulative Stroke Rate .02 .04 .06 .08 .1 RR (95% CI) p value L/A 1.23 (1.08-1.41) 0.003 Amlodipine Lisinopril The lisinopril group had a 23% higher risk for stroke than the amlodipine group. The number at risk in each interval is the number of persons alive at the start of the interval; those experiencing the outcome or those withdrawn during an interval are removed before the start of the next interval. Those randomized late in the trial (1997-1998) contribute less follow-up time (4-5 years) than those randomized earlier (1994 – 8 years). Thus, at years 4 through 6 the number at risk begin to decline significantly as those randomized later conclude their contribution to the trial. Years to Stroke 1 2 3 4 5 6 7 Number at risk: Amlodipine 9,048 8,617 8,271 7,949 6,937 3,845 1,813 506 Lisinopril 9,054 8,543 8,172 7,784 6,765 3,891 1,828 949

Cumulative Event Rates for Stroke by Race and Treatment Group ALLHAT Cumulative Event Rates for Stroke by Race and Treatment Group 0.00 0.05 0.10 1 2 3 4 5 6 7 Years to Stroke Amlodipine Lisinopril Blacks 0.00 0.05 0.10 1 2 3 4 5 6 7 Years to Stroke Amlodipine Lisinopril Non-Blacks Cumulative Stroke Rate RR (95%CI) P value L/A 1.51 (1.22-1.86) <0.001 RR (95%CI) P value L/A 1.07 (0.89-1.28) 0.47

Stroke Interaction by Gender and Race ALLHAT Stroke Interaction by Gender and Race Lisinopril versus Amlodipine Blacks Non-Blacks Males Females 6 Yr Event Rate per 100 Pts 9.2 vs 6.7 7.0 vs 4.9 5.2 vs 5.9 5.3 vs 3.7 Δ + 37 % + 45 % - 11 % + 46 % Six-year Kaplan-Meier event rates by race and gender + favors amlodipine - favors lisinopril p=0.02 for interaction of gender within non-blacks

Cumulative Event Rates for Combined CVD by Treatment Group ALLHAT Cumulative Combined CVD Event Rate .1 .2 .3 .4 .5 Number at risk: RR (95% CI) p value L/A 1.06 (1.00-1.12) 0.047 Blacks 1.13 (1.02-1.24) 0.02 Non-Blacks 1.03 (0.96-1.10) 0.47 Amlodipine Lisinopril The lisinopril group had a 6% higher risk of combined CVD (p =0.047) than the amlodipine group. The number at risk in each interval is the number of persons alive at the start of the interval; those experiencing the outcome or those withdrawn during an interval are removed before the start of the next interval. Those randomized late in the trial (1997-1998) contribute less follow-up time (4-5 years) than those randomized earlier (1994 – 8 years). Thus, at years 4 through 6 the number at risk begin to decline significantly as those randomized later conclude their contribution to the trial. Years to Combined CVD Event 1 2 3 4 5 6 7 Amlodipine 9,048 8,118 7,451 6,837 5,724 3,049 1,411 153 Lisinopril 9,054 7,962 7,259 6,631 5,560 3,011 1,375 139

Other Components of Combined CVD ALLHAT Other Components of Combined CVD Amlodipine Lisinopril Lisinopril vs Amlodipine No. of Total Events 6-yr rate per 100 Persons (SE) 6-yr rate per 100 RR (95% CI) P Value Heart failure 706 10.2 (0.4) 612 8.7 (0.4) 0.87 (0.78-0.96)* 0.007 Hospitalized/fatal heart failure 578 8.4 (0.4) 471 6.9 (0.4) 0.81 (0.72-0.9)* <0.001 Angina (hospitalized or treated) 950 12.6 (0.4) 1019 13.6 (0.4) 1.09 (1.00-1.19) 0.055 Angina (hospitalized) 630 693 9.6 (0.4) 1.12 (1.00-1.24) 0.045 Coronary revascularizations 725 10.0 (0.4) 718 1.00 (0.91-1.11) 0.943 Peripheral arterial disease (hospitalized or fatal) 265 3.7 (0.2) 311 4.7 (0.4) 1.19 (1.01-1.40) 0.036 * 2X2 table RR rather than Cox PH

Cumulative Event Rates for Heart Failure by Treatment Group ALLHAT Cumulative Event Rates for Heart Failure by Treatment Group Cumulative HF Rate .03 .06 .09 .12 .15 RR (95% CI) p value L/A 0.87 (0.78-0.96) 0.007 Blacks 0.89 (0.75-1.06) 0.18 Non-Blacks 0.85 (0.75-0.97) 0.02 Amlodipine Lisinopril The amlodipine group had a 13% higher risk of HF (p=.007) (RR calculated from a 2x2 table rather than Cox PH). The number at risk in each interval is the number of persons alive at the start of the interval; those experiencing the outcome or those withdrawn during an interval are removed before the start of the next interval. Those randomized late in the trial (1997-1998) contribute less follow-up time (4-5 years) than those randomized earlier (1994 – 8 years). Thus, at years 4 through 6 the number at risk begin to decline significantly as those randomized later conclude their contribution to the trial. Years to HF 1 2 3 4 5 6 7 Number at risk: Amlodipine 9,048 8,535 8,185 7,801 6,785 3,775 1,780 210 Lisinopril 9,054 8,496 8,096 7,689 6,698 3,789 1,837 313

Lisinopril vs. Amlodipine ALLHAT Safety Parameters Lisinopril vs. Amlodipine RR (95% CI) P value Cancer 1.01 (0.91-1.12) 0.91 GI Bleed 1.20 (1.06-1.37) 0.004 Blacks (L vs. A) Non-Blacks (L vs. A) RR (95% CI) P value Cancer 1.06 (0.89-1.26) 0.54 0.98 (0.86-1.12) 0.75 GI Bleed 1.28 (1.04-1.56) 0.02 1.16 (0.99-1.36) 0.07 Lisinopril (n) Amlodipine (n) P value Angioedema 38 3 <0.001 Blacks (n) Non-Blacks (n) Lisinopril Amlodipine P Angioedema 23 2 <0.001 15 1

Summary Lisinopril vs. Amlodipine ALLHAT Summary Lisinopril vs. Amlodipine Non-Blacks Blacks SBP Control <+0.5 mmHg + 2-3 mmHg # antihypertensive drugs similar + 0.3 CHD, Combined CHD, Mortality, ESRD, cancer similar Stroke similar but men -11%, women +46% + 45% Combined CVD HF similar - 15% + 13% - 11% GI Bleed + 16% + 28% Angioedema > >> +favors amlodipine - favors lisinopril

ALLHAT Conclusions Non-Black Older Hypertensives At apparently equivalent BP control, most outcomes are similar on lisinopril vs. amlodipine-initiated treatment except for less HF on lisinopril more strokes (in women), GI bleed, and angioedema on lisinopril Black Older Hypertensives Several outcomes are similar on lisinopril vs. amlodipine-initiated treatment, but Less HF on lisinopril Less BP control and more cardiovascular events, including stroke, on lisinopril more GI bleeds and angioedema on lisinopril Clinical Implications ALLHAT was not designed to identify the best step-one drug alternative if a thiazide-type diuretic cannot be used. However, considering the totality of the outcome measures, amlodipine would appear to have an advantage over lisinopril, particularly in Blacks and Women, but this depends on how clinicians weigh outcomes that favor the respective arms.