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ALLHAT continues to stir clinical controversy.

NEW YORK -- ALLHAT, the trial that was supposed to end the bickering about drug choice in hypertension, has fallen far short of that goal, according to reports presented at the annual meeting of the American Society of Hypertension.

For example, ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) investigators reported that patients randomized to diuretics were more likely to develop new-onset diabetes than those on either a calcium channel blocker or ACE inhibitor.

But this increase in diabetes did not translate into higher risk of cardiovascular events after 4 years of follow-up, said Dr. Joshua Barzilay of Emory University, Atlanta.

In the 42,418-patient trial, researchers compared four types of antihypertensive drugs: the [alpha]-blocker doxazosin, the diuretic chlorthalidone, the ACE-inhibitor lisinopril, and the calcium channel blocker amlodipine. The doxazosin treatment arm was discontinued early when it was found to be less effective than chlorthalidone in reducing heart failure.

After 2 years, 9.3% of the patients assigned to chlorthalidone had a fasting glucose level of at least 126 mg/dL, the study definition of diabetes mellitus, compared with 6.4% of those on amlodipine and 5.9% of those on lisinopril, Dr. Barzilay said. After 4 years, the incidence of diabetes mellitus was 11.6% in those on chlorthalidone, 9.8% in those on amlodipine, and 8.1% in those on lisinopril.

Dr. Franz Messerli of the Ochsner Clinic Foundation in New Orleans took issue with the interpretation of the new-onset diabetes findings. "ALLHAT says these metabolic abnormalities did not translate into excess morbidity or mortality. Of course they didn't. It takes years to develop a stroke or heart attack because of new-on-set diabetes," he told this newspaper.

Dr. Michael Weber, professor of medicine at the State University of New York Downstate College of Medicine, Brooklyn, is a long-time critic of ALLHAT. Speaking at the meeting, he pointed out that the primary end point of ALLHAT--fatal coronary heart disease and nonfatal MI--showed no differences between the chlorthalidone, amlodipine, and lisinopril arms. All claims that chlorthalidone was better than the other two rested solely on secondary end points, he said. Therefore, no drug--not even chlorthalidone--is superior, based on the ALLHAT evidence.

Looking at mortality, which Dr. Weber said is the most important secondary end point, ALLHAT found no difference between the lisinopril and chlorthalidone treatment groups, but mortality was 4% lower with amlodipine.

Many of ALLHAT's problems are due to faulty trial design, he said. For example, according to the trial protocol, if patients did not achieve goal pressure on a properly titrated dose of the initial study drug, the physician could add a second drug, provided that it was not a study drug.

Because the protocol prohibited the use of diuretics, ACE inhibitors, or calcium channel blockers as additive treatments, [beta]-blockers were the main drugs added. According to Dr. Weber, this clearly helped chlorthalidone, the eventual "winner," since administration of a diuretic and a [beta]-blocker provides a logical and effective blood pressure-lowering combination. Even the addition of a [beta]-blocker to a calcium channel blocker would be useful. The logical addition to an ACE inhibitor, however, is a diuretic or a calcium channel blocker, neither of which was permitted.

Another example of the design flaws is the claim that chlorthalidone reduced the rate of stroke by 15% more than lisinopril. But this is most likely explained by the greater stroke rate in black patients on lisinopril, Dr. Weber said, noting that there was a discrepancy of 4 mm Hg in systolic BP favoring chlorthalidone over lisinopril in black patients and a 40% excess stroke rate in black patients on lisinopril.

Dr. Henry R. Black, chairman of the department of preventive medicine at Rush University Medical Center, Chicago, said that the ALLHAT findings hold up well to scrutiny: Chlorthalidone was associated with a reduction in certain end points, including heart failure, stroke, and overall cardiovascular events. And diuretics "are less costly than other drugs," Dr. Black said.

But Dr. Weber claimed that this cost analysis is not accurate, noting that almost all current antihypertensive drugs are relatively inexpensive, since generic ACE inhibitors and some long-acting dihydropyridine calcium channel blockers are now available. Moreover, he contended that managing a patient on thiazide diuretics requires additional office visits for monitoring of potassium, glucose, and uric acid levels. The extra office visits--and additional lab work--add to the treatment cost.


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Title Annotation:Cardiovascular Medicine; Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial
Author:Peck, Peggy
Publication:Internal Medicine News
Geographic Code:1USA
Date:Aug 1, 2004
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