ALLHAT Major Cardiovascular Events in Hypertensive Patients Randomized to Doxazosin vs Chlorthalidone Final Results From The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) The ALLHAT Collaborative Research Group Sponsored by the National Heart, Lung, and Blood Institute (NHLBI) Hypertension. 2003;42:239-246
Antihypertensive ALLHAT 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
Secondary Objectives: ALLHAT Subgroups Pre-specified – Age 65+ – Women – African-Americans – Diabetic patients Post-hoc – Baseline CHD
Secondary Outcomes ALLHAT • 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 non-hospitalized CHF, hospitalized or outpatient PAD • Other clinical outcomes – renal (reciprocal serum creatinine, ESRD, estimated GFR) and cancer
Sites in ALLHAT ALLHAT • 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
Inclusion Criteria for ALLHAT 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mm Hg on 1-2 antihypertensive drugs at Visit 1 • ≤ 180/110 mm Hg at Visit 2, when medication may have been partially withdrawn – No washout period was required in ALLHAT.
ALLHAT Inclusion Criteria: ALLHAT 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
ALLHAT Inclusion ALLHAT 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
Major Exclusion Criteria ALLHAT • 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
Sample Size Assumptions ALLHAT & Statistical Methods 83% power to detect 16% reduction in risk for primary • outcome – 99% power to detect 20% reduction with the observed event rate 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
Randomized Design of ALLHAT ALLHAT Amlodipine High-risk Chlorthalidone hypertensive Consent / Doxazosin patients Randomize Lisinopril Eligible for lipid- Not eligible for lowering lipid-lowering Consent / Randomize Pravastatin Usual care Follow until death or end of study (4-8 yr, ave 6 yr).
Step 1 ALLHAT Treatment Protocol Step 1 Agent Initial Dose* Dose 1* Dose 2* Dose 3* Chlorthalidone 12.5 12.5 12.5 25 Amlodipine 2.5 2.5 5 10 Lisinopril 10 10 20 40 Doxazosin 1 2 4 8 * mg/day
Step Up ALLHAT 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
Safety Outcomes ALLHAT • 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)
Decision to Drop ALLHAT an ALLHAT 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
Baseline Characteristics ALLHAT Chlorthalidone Doxazosin 15,255 9,061 Mean SBP/DBP 146 / 84 146 / 84 Treated, % 90 90 Mean age, y 67 67 Black, % 35 36 Women, % 47 46 Current smoking % 22 22 ASCVD, % 46 46 Type 2 diabetes, % 36 36
On Step 1 or Equivalent Treatment by ALLHAT Antihypertensive Treatment Group 100.0 80.0 60.0 % 40.0 20.0 0.0 12M 24M 36M 48M 88.2 87.0 86.0 84.8 Chlor 81.3 78.3 75.6 74.0 Dox
Full Crossovers by ALLHAT Antihypertensive Treatment Group Chlorthalidone: not on assigned medicine or open- label diuretic, but on open-label alpha-blocker Doxazosin: not on assigned medicine or open-label alpha-blocker, but on open-label diuretic 25.0 20.0 15.0 % 10.0 5.0 0.0 12M 24M 36M 48M 0.4 0.6 1.0 1.1 Chlor 4.9 6.6 9.0 10.2 Dox
SBP Results by Treatment Group ALLHAT Chlorthalidone Doxazosin 150 BL 6M 1Y 2Y 4Y C 146.2 138.2 136.7 135.8 135.3 D 146.3 141.1 139.8 138.1 137.5 145 mm Hg BP 140 135 130 0 6 12 18 24 30 36 42 48 Months
DBP Results by Treatment Group ALLHAT Chlorthalidone Doxazosin 90 BL 6M 1Y 2Y 4Y C 84 80.1 79.2 78.2 76.4 85 D 83.9 80 79.3 78.2 76.4 mm Hg BP 80 75 70 0 6 12 18 24 30 36 42 48 Months
Vital Status by Antihypertensive ALLHAT Treatment Group Chlorthalidone Doxazosin N 15,255 9,061 Lost to follow-up 545 (3.6%) 361 (4.0%) Deaths 1,258 (8.2%) 769 (8.5%) Observed / expected 95% 95% person-years
Combined CVD Rates by ALLHAT ALLHAT Treatment Group RR (95% CI) p value .4 D/C 1.20 (1.13 – 1.27) <0.001 Combined CVD Event Rate .3 Chlorthalidone Doxazosin .2 .1 0 0 1 2 3 4 5 Years to Combined CVD Event
RR and 95% CI for ALLHAT Combined CVD Total Total 1.20 (1.13, 1.27) 1.20 (1.13, 1.27) Age < 65 Age < 65 1.15 (1.04, 1.27) 1.15 (1.04, 1.27) Age >= 65 Age >= 65 1.23 (1.14, 1.32) 1.23 (1.14, 1.32) Men Men 1.21 (1.13, 1.30) 1.21 (1.13, 1.30) Women Women 1.17 (1.07, 1.29) 1.17 (1.07, 1.29) Black Black 1.28 (1.16, 1.42) 1.28 (1.16, 1.42) Non-Black Non-Black 1.16 (1.09, 1.25) 1.16 (1.09, 1.25) Diabetic Diabetic 1.22 (1.11, 1.33) 1.22 (1.11, 1.33) Nondiabetic Nondiabetic 1.19 (1.10, 1.28) 1.19 (1.10, 1.28) Untreated Untreated 1.39 (1.14, 1.70) 1.39 (1.14, 1.70) Treated Treated 1.18 (1.11, 1.26) 1.18 (1.11, 1.26) CHD CHD 1.14 (1.04, 1.25) 1.14 (1.04, 1.25) No CHD No CHD 1.24 (1.15, 1.34) 0.33 0.50 1 2 3 Favors Doxazosin Favors Chlorthalidone
Heart Failure Rates by ALLHAT ALLHAT Treatment Group RR (95% CI) p value .15 D/C 1.80 (1.61- 2.02) <0.001 Cumulative HF Rate .1 Chlorthalidone Doxazosin .05 0 0 1 2 3 4 5 Years to HF
RR and 95% CI for ALLHAT Heart Failure Total Total 1.80 (1.61, 2.02) 1.80 (1.61, 2.02) Age < 65 Age < 65 1.76 (1.40, 2.22) 1.76 (1.40, 2.22) Age >= 65 Age >= 65 1.89 (1.65, 2.17) 1.89 (1.65, 2.17) Men Men 1.89 (1.62, 2.20) 1.89 (1.62, 2.20) Women Women 1.78 (1.49, 2.14) 1.78 (1.49, 2.14) Black Black 1.84 (1.51, 2.24) 1.84 (1.51, 2.24) Non Non -Black -Black 1.85 (1.60, 2.14) 1.85 (1.60, 2.14) Diabetic Diabetic 1.85 (1.56, 2.19) 1.85 (1.56, 2.19) Nondiabetic Nondiabetic 1.88 (1.60, 2.20) 1.88 (1.60, 2.20) Untreated Untreated 1.54 (0.98, 2.42) 1.54 (0.98, 2.42) Treated Treated 1.87 (1.66, 2.11) 1.87 (1.66, 2.11) CHD CHD 1.75 (1.46, 2.11) 1.75 (1.46, 2.11) No CHD No CHD 1.91 (1.64, 2.22) 1.91 (1.64, 2.22) 0.33 0.33 0.50 0.50 1 1 2 2 3 3 Favors Doxazosin Favors Chlorthalidone
Stroke Rates by ALLHAT ALLHAT Treatment Group RR (95% CI) p value .08 D/C 1.26 (1.10 – 1.46) 0.001 Cumulative Stroke Rate .06 Chlorthalidone Doxazosin .04 .02 0 0 1 2 3 4 5 Years to Stroke
STROKE ALLHAT Total 1.26 (1.00 - 1.46) Age<65 1.22 (0.93 - 1.61) Age>=65 1.28 (1.08 - 1.51) Men 0.32 (0.10 - 1.59) Women 1.18 (0.94 - 1.49) Black 1.38 (1.10 - 1.73) Non-Black 1.18 (0.98 - 1.42) Diabetic 1.21 (0.98 - 1.51) 1.32 (1.09 - 1.60) Non-Diabetic Untreated 1.60 (0.99 - 2.59) Treated 1.23 (1.06 - 1.43) CHD 1.23 (0.96 - 1.58) No CHD 1.27 (1.07 - 1.52) 0.50 1 2 Favors Doxazosin Favors Chlorthalidone
CHD Rates by ALLHAT ALLHAT Treatment Group RR (95% CI) p value .12 D/C 1.03 (0.92 – 1.15) 0.62 Cumulative CHD Event Rate .09 Chlorthalidone Doxazosin .06 .03 0 0 1 2 3 4 5 Years to CHD Event
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