Major Cardiovascular Events in Hypertensive Patients Randomized to Doxazosin vs Chlorthalidone: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) | Acute Coronary Syndromes | JAMA | JAMA Network
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Original Contribution
April 19, 2000

Major Cardiovascular Events in Hypertensive Patients Randomized to Doxazosin vs Chlorthalidone: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)

Author Affiliations

ALLHAT Officers and Coordinators: Curt D. Furberg, MD, PhD, Jackson T. Wright, MD, PhD, Barry R. Davis, MD, PhD, Jeffrey A. Cutler, MD, MPH, Michael Alderman, MD, Henry Black, MD, William Cushman, MD, Richard Grimm, MD, PhD, L. Julian Haywood, MD, Franz Leenen, MD, Suzanne Oparil, MD, H. Mitchell Perry, MD, Jeffrey Probstfield, MD, Paul Whelton, MD, MSc, Gerald Payne, MD, Chuke Nwachuku, MA, MPH, David Gordon, MD, PhD, Michael Proschan, PhD, Peter Frommer, MD, Paula Einhorn, MD, MS, C. Morton Hawkins, ScD, Charles Ford, PhD, Sara Pressel, MS, Linda Piller, MD, MPH, Christine Lusk, MPH, Judy Bettencourt, Barbara Kimmel, MS, Therese Geraci, MSN, RN, CS, Sandra Walsh, RN, Mahboob Rahman, MD, Anne Juratovac, RN, Robert Pospisil, RN, Kim Brennan, Lillian Carroll, MA, RN, Sheila Sullivan, Gail Barone, RN, Rudell Christian, MPH, Sharon Feldman, MPH, Tracy Lucente, MPH, C. E. Lewis, MD, MSPH, Kim Jenkins, MPH, Peggy McDowell, RN, Janice Johnson, Connie Kingry, RN, BSN, Rebecca Letterer, RN, BSN, Karen Margolis, MD, Leslie Holland, Brenda Jaeger-Fox, Jeffrey Williamson, MD, MHS, Gail Louis, RN, Pamela Ragusa, RN, BSN, Angela Williard, RN, BSN, R. Sue Ferguson, RN, Joanna Tanner, John Eckfeldt, MD, PhD, Richard Crow, MD, John Pelosi, MS.

JAMA. 2000;283(15):1967-1975. doi:10.1001/jama.283.15.1967

Context 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.

Objective 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, and lisinopril.

Design 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.

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

Participants 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.

Interventions 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.

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.

Conclusion 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.