Major cardiovascular events in hypertensive patients randomized to doxazosin vs chlorthalidone: the antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT). ALLHAT Collaborative Research Group.
BACKGROUND
Hypertension is associated with a significantly increased risk of morbidity and mortality. Only diuretics and beta-blockers have been shown to reduce this risk in long-term clinical trials. Whether newer antihypertensive agents reduce the incidence of cardiovascular disease (CVD) is unknown.


OBJECTIVE
To compare the effect of doxazosin, an alpha-blocker, with chlorthalidone, a diuretic, on incidence of CVD in patients with hypertension as part of a study of 4 types of antihypertensive drugs: chlorthalidone, doxazosin, amlodipine, and lisinopril.


METHODS
Randomized, double-blind, active-controlled clinical trial, the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial, initiated in February 1994. In January 2000, after an interim analysis, an independent data review committee recommended discontinuing the doxazosin treatment arm based on comparisons with chlorthalidone. Therefore, outcomes data presented herein reflect follow-up through December 1999.


METHODS
A total of 625 centers in the United States and Canada.


METHODS
A total of 24,335 patients (aged > or = 55 years) with hypertension and at least 1 other coronary heart disease (CHD) risk factor who received either doxazosin or chlorthalidone.


METHODS
Participants were randomly assigned to receive chlorthalidone, 12.5 to 25 mg/d (n=15,268), or doxazosin, 2 to 8 mg/d (n=9067), for a planned follow-up of 4 to 8 years.


METHODS
The primary outcome measure was fatal CHD or nonfatal myocardial infarction (MI), analyzed by intent to treat; secondary outcome measures included all-cause mortality, stroke, and combined CVD (CHD death, nonfatal MI, stroke, angina, coronary revascularization, congestive heart failure [CHF], and peripheral arterial disease); compared by the chlorthalidone group vs the doxazosin group.


RESULTS
Median follow-up was 3.3 years. A total of 365 patients in the doxazosin group and 608 in the chlorthalidone group had fatal CHD or nonfatal MI, with no difference in risk between the groups (relative risk [RR], 1.03; 95% confidence interval [CI], 0.90-1.17; P=.71). Total mortality did not differ between the doxazosin and chlorthalidone arms (4-year rates, 9.62% and 9.08%, respectively; RR, 1.03; 95% CI, 0.90-1.15; P=.56.) The doxazosin arm, compared with the chlorthalidone arm, had a higher risk of stroke (RR, 1.19; 95% CI, 1.01-1.40; P=.04) and combined CVD (4-year rates, 25.45% vs 21.76%; RR, 1.25; 95% CI, 1.17-1.33; P<.001). Considered separately, CHF risk was doubled (4-year rates, 8.13% vs 4.45%; RR, 2.04; 95% CI, 1.79-2.32; P<.001); RRs for angina, coronary revascularization, and peripheral arterial disease were 1.16 (P<.001), 1.15 (P=.05), and 1.07 (P=.50), respectively.


CONCLUSIONS
Our data indicate that compared with doxazosin, chlorthalidone yields essentially equal risk of CHD death/nonfatal MI but significantly reduces the risk of combined CVD events, particularly CHF, in high-risk hypertensive patients.
D000317:Adrenergic alpha-Antagonists / Q000627:therapeutic use*; D000368:Aged; D017311:Amlodipine / Q000627:therapeutic use; D000924:Anticholesteremic Agents / Q000627:therapeutic use*; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D002318:Cardiovascular Diseases / Q000453:epidemiology* / Q000517:prevention & control*; D002752:Chlorthalidone / Q000627:therapeutic use*; D004232:Diuretics / Q000627:therapeutic use*; D004311:Double-Blind Method; D017292:Doxazosin / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D006973:Hypertension / Q000188:drug therapy*; D017706:Lisinopril / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000453:epidemiology / Q000517:prevention & control; D016016:Proportional Hazards Models; D012306:Risk; D016019:Survival Analysis
D000317:Adrenergic alpha-Antagonists; D000924:Anticholesteremic Agents; D000959:Antihypertensive Agents; D004232:Diuretics; D017311:Amlodipine; D017706:Lisinopril; D017292:Doxazosin; D002752:Chlorthalidone