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Diuretics Best at Lowering Coronary Risk in Hypertensive Patients

Amlodipine and lisinopril were both associated with worse cardiovascular outcomes in hypertensive patients than were less expensive diuretics.

That, according to the results of the long-awaited Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) trial reported in the Dec. 18 issue of The Journal of the American Medical Association. The editorialist agrees that diuretics are best for first-line treatment, but he points out that we still need more data to go beyond first-line treatment, and that the most important next step is to educate physicians about therapeutic options.

"The results of ALLHAT indicate that thiazide-type diuretics should be considered first for pharmacologic therapy in patients with hypertension," write Jackson T. Wright, Jr., MD, PhD, from Case Western Reserve University in Cleveland, and colleagues. "They are unsurpassed in lowering blood pressure, reducing clinical events, and tolerability, and they are less costly."

From February 1994 through March 2002, ALLHAT enrolled 33,357 subjects aged 55 years or older with hypertension and at least one other risk factor for coronary heart disease (CHD) from 623 centers in the U.S., Canada, and the U.S. Virgin Islands.

This randomized, double-blind trial compared the occurrence of fatal CHD or nonfatal myocardial infarction (MI) in high-risk hypertensive patients treated with the calcium channel blocker amlodipine, 2.5 to 10 mg/day (n = 9,048), the angiotensin-converting enzyme inhibitor lisinopril, 10 to 40 mg/day (n = 9,054), or the thiazide diuretic chlorthalidone, 12.5 to 25 mg/day (n = 15,255).

During follow-up of four to eight years (mean, 4.9 years), the primary outcome of combined fatal CHD or nonfatal MI occurred in 2,956 subjects. The six-year rate of the primary outcome was similar in all three groups: 11.3% for amlodipine, 11.4% for lisinopril, and 11.5% for chlorthalidone. All-cause mortality did not differ among the groups.

Although chlorthalidone did not differ from amlodipine in overall CHD prevention, six-year rate of heart failure was higher with amlodipine (10.2% vs. 7.7%; relative ratio, 1.38; 95% confidence interval, 1.25 - 1.52). Chlorthalidone was superior to lisinopril in lowering blood pressure and in six-year rates of combined cardiovascular disease (30.9% vs. 33.3%), stroke (5.6% vs. 6.3%), heart failure (7.7% vs. 8.7%), angina, and coronary revascularization.

"Since a large proportion of participants required more than one drug to control their blood pressure, it is reasonable to infer that a diuretic be included in all multidrug regimens, if possible," the authors write. "Although diuretics already play a key role in most antihypertensive treatment recommendations, the findings of ALLHAT should be carefully evaluated by those responsible for clinical guidelines and be widely applied in patient care."

In an accompanying editorial, Lawrence J. Appel, MD, MPH, from Johns Hopkins University in Baltimore, Maryland, calls ALLHAT "one of the most important trials of antihypertensive drug therapy" with "robust, unambiguous, and generalizable" results applicable to the broad population of patients with stage 1 or 2 hypertension. He recommends updating guidelines to stress the importance of thiazide diuretics as first-line therapy, and educating physicians, healthcare professionals, and those who develop guidelines for provider networks and health maintenance organizations about ALLHAT findings and their ramifications.

"While the challenges of designing and implementing ALLHAT were daunting, the subsequent tasks of disseminating results and changing physician prescription habits may be an even greater challenge," he writes. "For decades, experts have passionately debated which class of drugs should be initial therapy for hypertension. Resolution of this issue, which has enormous clinical, public health, and economic implications, comes at a time of intense pressure to reduce health care costs while improving clinical outcomes.... There is no cost-quality tradeoff; the most effective therapy was also the least expensive."  JAMA. 2002;288(23):2981-2997, 3039-3042

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