ANAHEIM, CALIF. -- The a-blocker arm of a landmark megatrial of antihypertensive therapy has been halted early due to sharp increases in congestive heart failure and stroke.
The National Heart, Lung, and Blood Institute pulled the plug after an interim analysis of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) showed a 25% greater rate of cardiovascular events in patients on doxazosin than in those on chlorthalidone.
"Our recommendation is chlorthalidone, or probably any diuretic, remains the drug of choice for hypertension. Doxazosin is not recommended as first-line therapy for hypertension. These findings are likely to apply to all a-blockers. And until proven otherwise, it seems prudent to at least assume that doxazosin is also inferior as a second- or third-line antihypertensive agent, ALLHAT chair Dr. Curt D. Furberg declared in the first public airing of the results at the annual meeting of the American College of Cardiology.
The ALLHAT data also call into question the long-term safety of using a-blockers in hypertensive patients with benign prostatic hyperplasia, which now certainly warrants investigation, added Dr. Furberg, professor and chairman of public health sciences at Wake Forest University in Winston-Salem, N.C.
The NHLBI-sponsored ALLHAT is a massive randomized, blinded study designed to help sort out existing confusion regarding the appropriate roles of the many available classes of antihypertensive agents.
The study involves 625 North American clinical sites at which 42,448 high-risk hypertensive patients have been randomized to chlorthalidone, the calcium channel blocker amlodipine, the a-blocker doxazosin, or the ACE inhibitor lisinopril. The goal is to learn whether newer antihypertensive agents reduce cardiovascular events, compared with a diuretic.
The 25% increased rate of adverse cardiovascular events at 4 years in the 9,067 patients assigned to doxazosin, compared with the 15,268 randomized to chlorthalidone, was driven largely by a marked disparity in congestive heart failure (CHF). The relative risk of CHF arising during follow-up in the doxazosin group was 2.04. The rate of CHF in the diuretic group was 1% per year and twice that in the a-blocker group. The difference was consistent across all ages, races, and genders and in diabetic as well as nondiabetic patients.
There was also a highly significant 19% increased risk of stroke in the a-blocker-treated patients. The difference in stroke rates broadened over time.
ALLHAT's sheer size engenders great confidence in these conclusions. For example, the finding of increased CHF associated with doxazosin was based upon about 900 incident cases.
Rates of coronary heart disease events- the primary end point in ALLHAT-were identical in the doxazosin and chlorthalidone groups, Dr. Furberg continued.
Patient compliance with the diuretic was superior to that for the a-blocker over the course of follow-up. Moreover, the diuretic provided better hypertension control, with a lower mean systolic blood pressure and less need for step-up medications. And chlorthalidone costs about one-tenth as much as doxazosin does, he said.
He stressed that even though follow-up in the remaining arms of ALLHAT will continue for another couple of years, the trial has already provided physicians with an important lesson: "For some drugs, blood pressure lowering may be an inadequate surrogate for health benefits in hypertension; an antihypertensive agent can have important non-blood pressure actions that may alter the benefits of blood pressure lowering."
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