Antihypertensive Trial Design ALLHAT

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1 1 U.S. Department of Health and Human Services Major Outcomes in High Risk Hypertensive Patients Randomized to Angiotensin-Converting Enzyme Inhibitor or Calcium Channel Blocker vs Diuretic National Institutes of Health The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial () The Collaborative Research Group National Heart, Lung, and Blood Institute Sponsored by the National Heart, Lung, and Blood Institute (NHLBI) JAMA. 2002;288:

2 2 Antihypertensive Trial Design Randomized, double-blind, multi-center clinical trial Determine whether occurrence of fatal CHD or nonfatal MI is lower for high-risk hypertensive patients treated with newer agents (CCB, ACEI, alpha-blocker) compared with a diuretic 42,418 high-risk hypertensive patients 55 years

3 3 Secondary Objectives: Subgroups Pre-specified Age 65+ Women African-Americans Diabetic patients Post-hoc Baseline CHD

4 4 Secondary Outcomes All-cause mortality Stroke Combined CHD nonfatal MI, CHD death, coronary revascularization, hospitalized angina Combined CVD combined CHD, stroke, lower extremity revascularization, treated angina, fatal / hospitalized / treated CHF, hospitalized or outpatient PAD Other renal (reciprocal serum creatinine, ESRD, estimated GFR) and cancer

5 5 Sites in 623 clinical sites United States, Canada, Puerto Rico, US Virgin Islands VA, private & group general medicine practices, community health centers, HMOs, specialty practices Variety of research experience

6 6 High-risk hypertensive patients Randomized Design Consent / Randomize (42,418) of Amlodipine Chlorthalidone Doxazosin Lisinopril Eligible for lipidlowering Not eligible for lipid-lowering Consent / Randomize (10,355) Pravastatin Usual care Follow for CHD and other outcomes until death or end of study (up to 8 yr).

7 7 Inclusion Criteria for Antihypertensive Trial Age/sex: men and women aged > 55 years BP eligibility: Untreated systolic and/or diastolic hypertension ( 140/90 mm Hg but 180/110 mm Hg at two visits) Treated hypertension 160/100 mm Hg on 1-2 antihypertensive drugs at Visit 1 180/110 mm Hg at Visit 2, when medication may have been partially withdrawn No washout period was required in.

8 8 Inclusion Criteria: Risk Factors At least one of the following: Myocardial infarction or stroke: at least 6 months old, or age-indeterminate History of revascularization procedure Major ST segment depression or T-wave inversion Other documented ASCVD

9 9 Inclusion Criteria: Risk Factors At least one of the following (cont.) Type 2 diabetes mellitus HDL cholesterol < 35 mg/dl on any 2 or more determinations in past 5 years Left ventricular hypertrophy (past 2 years) ECG, or echo (septum + posterior wall thickness 25 mm) Current cigarette smoking

10 10 Major Exclusion Criteria MI, stroke, or angina within 6 months Symptomatic CHF or ejection fraction < 35% Known renal insufficiency - creatinine 2 mg/dl Requiring diuretics, CCB, ACEI, or alpha blockers for reasons other than hypertension

11 11 Sample Size Assumptions & Statistical Methods 83% power to detect 16% reduction in risk for primary outcome 2-sided α=.0178 (z=2.37) Accounts for multiple comparisons Analysis according to intent to treat Cumulative event rates Kaplan-Meier Differences between event curves - Log-rank tests & Cox proportional hazards (PH) model PH assumption tested by log-log plots, tests with treatment by time interaction If violated, 2 x 2 table used

12 12 Step 1 Treatment Protocol Step 1 Agent Initial Dose* Dose 1* Dose 2* Dose 3* Chlorthalidone Amlodipine Lisinopril Doxazosin * mg/day

13 13 Step Up Treatment Protocol Step 2 Agents: Dose 1* Dose 2* Dose 3* Reserpine 0.05 qd 0.1 qd 0.2 qd or 0.1 qod Clonidine (oral) 0.1 bid 0.2 bid 0.3 bid Atenolol 25 qd 50 qd 100 qd Step 3 Agent: Hydralazine 25 bid 50 bid 100 bid *All doses in mg

14 14 Safety Outcomes Angioedema Hospitalization for gastrointestinal bleeding Records from the VA hospitalization database Records from the Center for Medicare & Medicaid Services (CMS) database (participants age 65 or older)

15 15 Decision to Drop an Arm January 24, 2000 NHLBI Director accepts the recommendation of an independent review group to terminate doxazosin arm Futility of finding a significant difference for primary outcome Statistically significant 25 percent higher rate of major secondary endpoint, combined CVD outcomes

16 16 Cumulative Event Rate C: 15,268 D: 9,067 Cardiovascular Disease Rel Risk 1.25 doxazosin 12,990 7,382 95% CI z = 6.77, p < chlorthalidone 9,443 5,285 Years of Follow-up 4,827 2,654 2,010 1,083 JAMA. 2000;283:

17 17 Cumulative Event Rate C: 15,268 D: 9,067 Heart Failure Rel Risk 2.04 doxazosin 95% CI z = 10.95, p < Years of Follow-up chlorthalidone 9,541 5,531 2,427 13,644 5,457 3,089 1, , JAMA. 2000;283:

18 18 Comparison of Doxazosin with Chlorthalidone - Conclusions Doxazosin is not recommended as firstline therapy in hypertension. does not allow an assessment of the effect of doxazosin compared with placebo on the incidence of CVD. The use of doxazosin as a step-up drug for treating hypertension was not tested in this trial. These findings are likely to apply to all alpha-blockers. JAMA. 2000;283:

19 19 Baseline Characteristics Chlorthalidone 15,255 Amlodipine 9,048 Lisinopril 9,054 Mean SBP/DBP 146 / / / 84 Treated (90%) 145 / / / 84 Untreated (10%) 156 / / / 89 Mean age, y Black, % Women, % Current smoking % History of CHD, % Type 2 diabetes, %

20 20 On Step 1 or Equivalent Treatment by Antihypertensive Treatment Group % Year 2 Years 3 Years 4 Years 5 Years Chlor Aml Lis

21 Full Crossovers by Antihypertensive Treatment Group Chlorthalidone: not on assigned medicine or open-label diuretic, but on open-label calcium channel blocker or ACE-inhibitor Amlodipine: not on assigned medicine or open-label calcium channel blocker, but on open-label diuretic Lisinopril: not on assigned medicine or open-label ACE-inhibitor, but on open-label diuretic % Year 2 Years 3 Years 4 Years 5 Years Chlor Amlodipine Lisinopril

22 22 On Step 2 or Step 3 Treatment by Antihypertensive Treatment Group % Year 2 Years 3 Years 4 Years 5 Years Chlor Aml Lis

23 23 BP Results by Treatment Group Chlorthalidone Amlodipine Lisinopril C A L BL M Y Y Y C A L BL M Y Y Y mm Hg BP 140 mm Hg BP Years Years Compared to chlorthalidone: SBP significantly higher in the amlodipine group (~1 mm Hg) and the lisinopril group (~2 mm Hg). Compared to chlorthalidone: DBP significantly lower in the amlodipine group (~1 mm Hg).

24 24 Biochemical Results Serum cholesterol- mg/dl, mean (SD) Baseline 4 Years Serum potassium mmol/l, mean (SD) Baseline 4 Years Estimated GFR ml/min/1.73m 2,mean (SD) Baseline 4 Years * p<.05 compared to chlorthalidone Ann Intern Med. 1999;130: Chlorthalidone (43.8) (42.1) 4.3 (0.7) 4.1 (0.7) 77.6 (19.7) 70.0 (19.7) Amlodipine (44.1) (41.0)* 4.3 (0.7) 4.4 (0.7)* 78.0 (19.7) 75.1 (20.7)* Lisinopril (42.4) (40.6)* 4.4 (0.7)* 4.5 (0.7)* 77.7 (19.9) 70.7 (20.1)*

25 25 Biochemical Results Fasting Glucose mg/dl Chlorthalidone Amlodipine Lisinopril Total mean (SD) Baseline (58.3) (57.0) (56.1) 4 Years (55.6) (52.0) (51.3)* Among baseline nondiabetics with baseline <126 mg/dl mean (SD) Baseline 93.1 (11.7) 93.0 (11.4) 93.3 (11.8) 4 Years (28.5) (27.7) (19.5)* Diabetes Incidence (follow-up fasting glucose 126 mg/dl) 4 Years 11.6% 9.8%* 8.1%* *p<.05 compared to chlorthalidone

26 26 Follow-Up Chlorthalidone Amlodipine Lisinopril Randomized 15,255 9,048 9,054 Known alive 12,530 (82.1%) 7,479 (82.7%) 7,412 (81.9%) Confirmed deaths 2,203 (14.4%) 1,256 (13.9%) 1,314 (14.5%) Deaths pending confirmation 103 (0.7%) 55 (0.6%) 52 (0.6%) Lost 339 (2.2%) 200 (2.2%) 218 (2.4%) Refused 80 (0.5%) 58 (0.6%) 58 (0.6%) Person-years 99% 99% 99% (% obs/exp)

27 27 Cumulative CHD Event Rate Cumulative Event Rates for the Primary Outcome (Fatal CHD or Nonfatal MI) by Treatment Group A/C L/C RR (95% CI) 0.98 ( ) 0.99 ( ) Chlorthalidone Amlodipine Lisinopril p value Years to CHD Event Number at Risk: Chlorthalidone 15,255 14,477 13,820 13,102 11,362 6,340 2, Amlodipine 9,048 8,576 8,218 7,843 6,824 3,870 1, Lisinopril 9,054 8,535 8,123 7,711 6,662 3,832 1,

28 28 Nonfatal MI + CHD Death Subgroup Comparisons RR (95% CI) Total 0.98 (0.90, 1.07) Age < (0.85, 1.16) Age>= (0.88, 1.08) Men 0.98 (0.87, 1.09) Women 0.99 (0.85, 1.15) Black 1.01 (0.86, 1.18) Non-Black 0.97 (0.87, 1.08) Diabetic 0.99 (0.87, 1.13) Non-Diabetic 0.97 (0.86, 1.09) Amlodipine Better Chlorthalidone Better Total 0.99 (0.91, 1.08) Age < (0.81, 1.12) Age >= (0.91, 1.12) Men 0.94 (0.85, 1.05) Women 1.06 (0.92, 1.23) Black 1.10 (0.94, 1.28) Non-Black 0.94 (0.85, 1.05) Diabetic 1.00 (0.87, 1.14) Non-Diabetic 0.99 (0.88, 1.11) Lisinopril Better Chlorthalidone Better

29 29 Cumulative Event Rates for Stroke by Treatment Group.1 RR (95% CI) p value.08 A/C L/C 0.93 ( ) 1.15 ( ) Cumulative Stroke Rate Chlorthalidone Amlodipine Lisinopril Years to Stroke Number at risk: Chlor 15,255 14,515 13,934 13,309 11,570 6,385 3, Amlo 9,048 8,617 8,271 7,949 6,937 3,845 1, Lisin 9,054 8,543 8,172 7,784 6,765 3,891 1,

30 30 Stroke Subgroup Comparisons RR (95% CI) Total 0.93 (0.82, 1.06) Age < (0.73, 1.19) Age >= (0.81, 1.08) Men 1.00 (0.85, 1.18) Women 0.84 (0.69, 1.03) Black 0.93 (0.76, 1.14) Non-Black 0.93 (0.79, 1.10) Diabetic 0.90 (0.75, 1.08) Non-Diabetic 0.96 (0.81, 1.14) Amlodipine Better Chlorthalidone Better Total 1.15 (1.02, 1.30) Age < (0.97, 1.52) Age >= (0.98, 1.30) Men 1.10 (0.94, 1.29) Women 1.22 (1.01, 1.46) Black 1.40 (1.17, 1.68) Non-Black 1.00 (0.85, 1.17) Diabetic 1.07 (0.90, 1.28) Non-Diabetic 1.23 (1.05, 1.44) Lisinopril Better Chlorthalidone Better P =.01 for interaction

31 Cumulative Event Rates for All-Cause Mortality by Treatment Group A/C L/C RR (95% CI) 0.96 ( ) 1.00 ( ) p value Cumulative Mortality Rate Chlorthalidone Amlodipine Lisinopril Years to Death Number at risk: Chlor 15,255 14,933 14,564 14,077 12, , Amlo 9,048 8,847 8,654 8,391 7,442 4,312 2, Lisin 9,054 8,853 8,612 8,318 7,382 4,304 2,

32 32 All-Cause Mortality Subgroup Comparisons RR (95% CI) Total 0.96 (0.89, 1.02) Age < (0.83, 1.10) Age >= (0.88, 1.03) Men 0.95 (0.87, 1.04) Women 0.96 (0.86, 1.07) Black 0.97 (0.87, 1.09) Non-Black 0.94 (0.87, 1.03) Diabetic 0.96 (0.87, 1.07) Non-Diabetic 0.95 (0.87, 1.04) Amlodipine Better Chlorthalidone Better Total 1.00 (0.94, 1.08) Age < (0.81, 1.08) Age >= (0.95, 1.12) Men 0.99 (0.91, 1.08) Women 1.02 (0.91, 1.13) Black 1.06 (0.95, 1.18) Non-Black 0.97 (0.89, 1.06) Diabetic 1.02 (0.91, 1.13) Non-Diabetic 1.00 (0.91, 1.09) Lisinopril Better Chlorthalidone Better

33 33 Cumulative Event Rates for Combined CVD by Treatment Group.5 RR (95% CI) p value A/C 1.04 ( ) 0.12 Cumulative Combined CVD Event Rate L/C 1.10 ( ) Chlorthalidone Amlodipine Lisinopril < Years to Combined CVD Event Number at risk: Chlor 15,255 13,752 12,594 11,517 9,643 5,167 2, Amlo 9,048 8,118 7,451 6,837 5,724 3,049 1, Lisin 9,054 7,962 7,259 6,631 5,560 3,011 1,

34 34 Combined CVD Subgroup Comparisons RR (95% CI) Total 1.04 (0.99, 1.09) Age < (0.94, 1.12) Age >= (0.99, 1.12) Men 1.04 (0.98, 1.11) Women 1.04 (0.96, 1.13) Black 1.06 (0.96, 1.16) Non-Black 1.04 (0.97, 1.10) Diabetic 1.06 (0.98, 1.15) Non-Diabetic 1.02 (0.96, 1.09) Amlodipine Better Chlorthalidone Better Total 1.10 (1.05, 1.16) Age < (0.97, 1.15) Age >= (1.06, 1.20) Men 1.08 (1.02, 1.15) Women 1.12 (1.03, 1.21) Black 1.19 (1.09, 1.30) Non-Black 1.06 (1.00, 1.13) Diabetic 1.08 (1.00, 1.17) Non-Diabetic 1.12 (1.05, 1.19) Lisinopril Better Chlorthalidone Better P =.04 for interaction

35 35 Cumulative Event Rates for Heart Failure by Treatment Group.15 A/C RR (95% CI) 1.38 ( ) p value <.001 L/C 1.19 ( ) <.001 Cumulative CHF Rate Chlorthalidone Amlodipine Lisinopril Years to HF Number at risk: Chlor 15,255 14,528 13,898 13,224 11,511 6,369 3, Amlo 9,048 8,535 8,185 7,801 6,785 3,775 1, Lisin 9,054 8,496 8,096 7,689 6,698 3,789 1,

36 36 Heart Failure Subgroup Comparisons RR (95% CI) Total 1.38 (1.25, 1.52) Age < (1.25, 1.82) Age >= (1.18, 1.49) Men 1.41 (1.24, 1.61) Women 1.33 (1.14, 1.55) Black 1.47 (1.24, 1.74) Non-Black 1.33 (1.18, 1.51) Diabetic 1.42 (1.23, 1.64) Non-Diabetic 1.33 (1.16, 1.52) Amlodipine Better Chlorthalidone Better Total 1.20 (1.09, 1.34) Age < (1.01, 1.50) Age >= (1.06, 1.35) Men 1.19 (1.03, 1.36) Women 1.23 (1.05, 1.43) Black 1.32 (1.11, 1.58) Non-Black 1.15 (1.01, 1.30) Diabetic 1.22 (1.05, 1.42) Non-Diabetic 1.20 (1.04, 1.38) Lisinopril Better Chlorthalidone Better

37 37 Overall Conclusions Because of the superiority of thiazide-type diuretics in preventing one or more major forms of CVD and their lower cost, they should be the drugs of choice for first-step antihypertensive drug therapy.

38 38 Other Conclusions Neither amlodipine (representing CCB) nor lisinopril (representing ACEI) was superior to chlorthalidone (representing thiazide-type diuretics) in preventing major coronary events or increasing overall survival. Although chlorthalidone did not differ from amlodipine in overall CVD event prevention, it was superior to amlodipine (by about onefourth) in preventing heart failure, overall and for hospitalized or fatal cases.

39 39 Other Conclusions Chlorthalidone was superior to lisinopril in preventing aggregate CV events, principally stroke, HF, angina, and coronary revascularization Chlorthalidone was superior to doxazosin (representing alpha-blockers) in preventing CV events, including both HF and other CVD.

40 40 Other Conclusions Given the large sample size, almost all biochemical differences between treatment groups at 4 years were statistically significant. Total cholesterol 1-2 mg/dl higher in chlorthalidone compared to amlodipine and lisinopril. Serum potassium mmol/l lower in chlorthalidone compared to amlodipine and lisinopril. Potassium <3.5 mmol/l 6-8% higher among those randomized to chlorthalidone Fasting glucose 3 mg/dl higher in chlorthalidone than amlodipine group, 5 mg/dl higher in chlorthalidone than lisinopril group.

41 41 Other Conclusions Among nondiabetic participants, incidence of fasting glucose 126 mg/dl at 4 years was 1.8% higher in chlorthalidone vs amlodipine, and 3.5% higher in chlorthalidone vs lisinopril. Estimated GFR decreased by 7-8 units at 4 years in chlorthalidone and lisinopril arms, but decreased only by about 3 units in the amlodipine arm. Overall, metabolic differences did not translate into more adverse cardiovascular events, or into higher all-cause mortality, with chlorthalidone.

42 42 Further Conclusions: Amlodipine versus Chlorthalidone Drug tolerance and blood pressure control were similar (and high): The percent of participants who remained on the assigned drug or another of the same class was essentially identical (80% of those attending the 5- year visit) Mean SBP averaged about 1 mm Hg higher, and mean DBP about 1 mm Hg lower, in the amlodipine group BP control averaged about 2% better in the chlorthalidone group, reaching 68% after 5 years

43 43 Further Conclusions: Amlodipine versus Chlorthalidone There were no differences for other secondary outcomes: Cardiovascular stroke, angina, coronary revascularization, peripheral arterial disease End stage renal disease Cancer incidence and mortality Hospitalization for gastrointestinal bleeding (in a subset of the cohort) All-cause mortality

44 44 Further Conclusions: Amlodipine versus Chlorthalidone Results for all cited outcomes were consistent for major (pre-specified) subgroups: Men and women Black and nonblack participants Older and younger participants (<65 and 65+) Diabetic and non-diabetic participants

45 45 Further Conclusions: Lisinopril versus Chlorthalidone Drug tolerance and blood pressure control were better with chlorthalidone, especially for black patients: The percent of participants remaining on lisinopril or another ACEI averaged about 5-6% less than participants assigned to the diuretic About 6-8% more of the participants in the lisinopril group than those in the chlorthalidone group required additional antihypertensive drugs

46 46 Further Conclusions: Lisinopril versus Chlorthalidone Mean SBP averaged about 2 mm Hg higher in the lisinopril than the chlorthalidone group (4 mm Hg for blacks); mean DBPs were equivalent BP control averaged about 4-7% better in the chlorthalidone group Of patients in the lisinopril group who remained on an ACEI, 19% were also on a diuretic at 5 years

47 47 Further Conclusions: Lisinopril versus Chlorthalidone There were no differences for other secondary outcomes peripheral arterial disease end stage renal disease cancer incidence and mortality all-cause mortality

48 48 Further Conclusions: Lisinopril versus Chlorthalidone Results were consistent for all outcomes by age, gender, race, and diabetic status, except for stroke and CVD, where there was significant heterogeneity by race (p=.01 and p=.04, respectively) Among black participants assigned to lisinopril, the stroke rate was increased 40% compared to the chlorthalidone group. (No difference among nonblack participants.) The combined CVD rate was increased 19% in blacks and by 6% in whites. Angiodema, a rare adverse effect, was more frequent with lisinopril, especially in blacks

49 49 Antihypertensive Trial: Implications Diuretics should be the drug of choice for first step therapy of hypertension For the patient who cannot take a diuretic (which should be an unusual circumstance), CCB s and ACEI s may be considered. Most hypertensive patients require more than one drug. Diuretics should generally be part of the antihypertensive regimen. Lifestyle advice should also be provided.

50 50 Angioedema Total Blacks Nonblacks Chlorthalidone 8 / 15,255 2 / 5,369 6 / 9, % <0.1% 0.1% Lisinopril 38 / 9, / 3, / 5, % 0.7% 0.3% p<.001 p<.001 p=.002 There were 3 cases (<0.1%) of angioedema in the amlodipine group (comparison to chlorthalidone not significant).