Bendroflumethiazide

Initiating an antihypertensive therapeutic strategy with the calcium antagonist amlodipine is superior to starting treatment with the beta blocker atenolol in preventing cardiovascular events, Peter S. Sever, MD, said.

He presented the results of a clinical trial, ASCOT (Anglo-Scandinavian Cardiac Outcomes Trial), which was stopped prematurely on the advice of the trial's Data Safety Monitoring Board because of the magnitude of difference in the incidence of clinical events between the two treatment regimens.

"The future place of beta blockers as first-line treatment in hypertension should be re-evaluated," said Dr. Sever, professor of clinical pharmacology, Imperial College, London. Certain patients, such as those with prior MI or symptomatic coronary heart disease (CHD), would remain candidates for beta blocker therapy as first-line treatment of hypertension, he added.

In ASCOT, 19,257 patients age 40 to 79 with hypertension who were free of CHD were randomized to receive therapy starting with amlodipine, with or without the ACE inhibitor perindopril, or the beta blocker atenolol, with or without the diuretic bendroflumethiazide. The target blood pressure was <140/90 mm Hg (<130/80 mm Hg for patients with diabetes).

The trial was stopped after an average follow-up of 5.5 years, at which time the composite endpoint of nonfatal MI or fatal CHD occurred in 10% fewer patients randomized to amlodipine/perindopril compared with atenolol/ bendroflumethiazide, which did not reach statistical significance (p=0.12).

"If the trial had gone along to the planned number of events...that relative reduction might have become significant," Dr. Sever said. The study was powered to achieve significance with 1,150 events but was terminated after 869 events.

Amlodipine/perindopril was associated with significant relative reductions in all-cause mortality (14%; p<0.001), stroke (23%; p<0.001), cardiovascular death (24%; p<0.001), cardiovascular events and procedures (16%; p<0.001), and total coronary events (14%; p=0.005).

The significant reduction in mortality was a surprise, he said, given the small sample size. "It's certainly a finding we would not have predicted because the trial wasn't powered for all-cause mortality," he said.

As expected, the beta blocker/diuretic regimen was associated with a 32% excess in the development of new diabetes.

The differences in event rates between the two arms should not be attributed to the initial drugs, Dr. Sever said. "The trial was designed to look at a treatment strategy rather than an individual drug because we recognize that most people with high blood pressure require at least two drugs to achieve target pressures."

Richard Devereux, MD, agrees. Dr. Devereux, professor of medicine, Weill Medical College of Cornell University, New York, noted the high use of diuretic in the beta blocker arm (67%) and perindopril in the amlodipine arm (63%) as evidence that the effects cannot "solely be attributed to the initial drug in either arm."

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