Debate continues over best drug for hypertension

Conflicting results from two clinical trials seeking to determine the best treatment for hypertension have left some clinicians scratching their heads.

The long-awaited and surprising results of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) published in the Journal of the American Medical Association last December concluded that diuretics are the best initial choice for treating hypertension, beating out both ACE inhibitors and calcium-channel blockers. But before health professionals could even consider these new findings, results from the Second Australian National Blood Pressure study (ANBP-2) were published in the New England Journal of Medicine, identifying ACE inhibitors as the superior choice. The ensuing controversy has sparked debate between trial investigators and hypertension specialists challenging the design and results of both studies.

The hypertension portion of the 33,357-patient ALLHAT trial reported chlorthalidone more effective than both lisinopril and amlodipine at lowering systemic blood pressure and, compared with lisinopril, reducing the incidence of overall stroke by 15% with a 40% lower risk of stroke in African-Americans. It also reported chlorthalidone superior at decreasing risk of heart failure and hospitalization. However, results showed no difference between the agents in preventing the primary outcomes of fatal coronary heart disease and nonfatal myocardial infarction. Despite the ALLHAT authors' claim that the results proved thiazide diuretics should be used as a first-line agent when treating all hypertensive patients, many were skeptical.

"I don't believe it's true across the board," said Judy Cheng, Pharm.D., BCPS, associate professor of pharmacy practice, Long Island University and clinical pharmacy specialist in cardiology at Mount Sinai Medical Center, New York. "The ALLHAT investigators are certainly implying that diuretics should be the preferred choice, given the results of the trial and economic issues, but we must look at the comorbid conditions of patients as well," she said. Although chlorthalidone may be a reasonable first choice in otherwise healthy patients, those with diabetes, for example, respond better to an ACE inhibitor, she maintained.

Critics of ALLHAT were somewhat reassured when the results of ANBP-2, a large, open-label study following 6,083 hypertensive patients, were published in February. This time the ACE inhibitor surpassed the diuretic, with fewer cardiovascular events or death, particularly among men. These opposing results initiated almost immediate comparison between the two trials.

"Approximately 40% of patients in ALLHAT were under age 65, and everyone in ANBP-2 was over that age," Cheng said. Regarding race, approximately 35% in ALLHAT were African-American, and 95% in ANBP-2 were white—an important consideration, given that Blacks are known to respond better to diuretics than to ACE inhibitors. Another critical point is the difference in specific medications. The ALLHAT trial used chlorthalidone and lisinopril, while ANBP-2 used hydrochlorothiazide and enalapril. "Whether all thiazide diuretics and all ACE inhibitors are the same has yet to be debated," she said.

There were also relatively fewer patients at baseline with other cardiovascular risk factors in ANBP-2, said Cheng. Of ALLHAT patients, 52% had a history of atherosclerotic cardiovascular disease and 36% had diabetes, compared with only 8% and 7%, respectively, in ANBP-2 with coronary artery disease or diabetes. Other experts question the high number of crossovers within the treatment groups, e.g., only 67.5% of the chlorthalidone group in ALLHAT actually received the drug alone, with the remainder having lisinopril or amlodipine either added to their regimen or substituted for chlorthalidone.

Do we really need to declare a winner—a best initial drug for hypertension? "Absolutely not," responded Cheng. The patient's concurrent diseases, economic situation, and even genetic factors all need to be taken into account before choosing the best agent. "If I had a patient with a previous history of heart attack and diabetes, I'd want to start him or her on a beta-blocker and an ACE inhibitor, no matter what ALLHAT and ANBP-2 had concluded. We cannot abandon all the previous studies showing the beneficial effects of beta-blockers and ACE inhibitors in preventing another heart attack and reducing all-cause mortality," she said.

"There are often other conditions present in hypertensive patients, where ACE inhibitors and beta- blockers continue to play a major role in the treatment regimen," agreed Wendy Gattis, Pharm.D., department of cardiology at Duke University Medical Center. She believes diuretics will continue to be a component in a multiple drug regimen that includes agents having shown clinical benefits for other comorbidities.

Heidi Belden, Pharm.D.

The author is a clinical writer based in Plymouth, Mass.