Hypertension is associated with a significantly increased risk of morbidity
and mortality. Only diuretics and β-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.
To compare the effect of doxazosin, an α-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,
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.
A total of 625 centers in the United States and Canada.
A total of 24,335 patients (aged ≥55 years) with hypertension and
at least 1 other coronary heart disease (CHD) risk factor who received either
doxazosin or chlorthalidone.
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.
Main Outcome Measures
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.
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),
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