For many years from the mid-1990s, evidence-minded physicians managing patients with hypertension could be heard to say, "Let’s wait for ALLHAT." In December 2002, the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial arrived (#9). Paper #9 focuses on A for antihypertensive; the LL substudy of lipid lowering, reported in the same issue of JAMA (C.D. Furberg, et al., 288[23]: 2998-3007, 2002) has not yet had the same citation impact.

Designed more than 10 years ago, this study did not include "artans" (see above); nor did it test a beta-blocker. ALLHAT took representatives of three classes of drug (a fourth trial arm, for the alpha-blocker doxazosin, was terminated early), and it asked which would be best, to start with, in a patient with raised blood pressure and at least one other risk factor? The answer was about as unequivocal as you get with clinical trials. Chlorthalidone, a diuretic, was superior to the selected angiotensin-converting enzyme blocker lisinopril and the calcium-channel inhibitor amlodipine. This was a big trial (over 33,000 patients). There were 3,000 primary endpoints, fatal/nonfatal myocardial infarction, and here chlorthalidone held its own, while other results allow the ALLHAT investigators to conclude that thiazide-type diuretics "are unsurpassed in lowering BP, reducing clinical events, and tolerability, and they are less costly." JAMA editorialist Dr. Lawrence J. Appel agreed (JAMA, 288[23]: 3039-42, 2002).

Dr. Appel emphasized the need to disseminate this important result to those who prescribe for hypertension, a process that only begins with publication. In 2003, medical journals have provided a platform for debate on ALLHAT, and the trial has not been without its critics—for example, how sure is extrapolation from one member of a drug class to all members of that class, and how do the results of this trial square with those of a recent Australian trial? Criticism is "a common epilogue to all clinical trials, even the most rigorous," Appel tells Science Watch, but ALLHAT remains a "landmark trial" whose findings are slowly percolating into the prescribing community. Dr. Barry R. Davis, for the ALLHAT team, says much the same. Yes, there had been some "vocal critics," but the paper had been very well received by the academic hypertension community, and the latest U.S. national guidelines "incorporate almost all of ALLHAT’s recommendations." Like Appel, he thinks that prescribing habits are being influenced—and he can prove it. Using an international prescribing database to track prescriptions for diuretics, the ALLHAT Clinical Trials Center in Houston, Texas, has shown that prescriptions for these drugs "increased by over 20% in the first two quarters of 2003."

A 2001 estimate put the annual cost of drugs for hypertension in the U.S. at $15.5 billion, so ALLHAT has important economic as well as clinical consequences. A big potential market usually converts to a willingness in the pharmaceutical industry to commit substantial research budgets to finding new targets for drug treatment and novel agents to hit those targets. In hypertension the latest arrival is the selective aldosterone antagonist. Could it be that from now on novel antihypertensives will have to prove themselves not only against a placebo, which is easy, but also against a good, old-fashioned thiazide?