European hypertension study favors newer treatments

Stockholm, Sweden -- On this side of the Atlantic, researchers say evidence suggests that newer, more expensive antihypertensive drug regimens are more effective than older, cheaper drugs, a finding that conflicts with the latest treatment recommendations in the United States.

The newer drug combo -- calcium channel blockers plus angiotensin-converting enzyme inhibitors -- was more effective than diuretics and beta-blockers, investigators from the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA) reported last month at the European Society of Cardiology Congress 2005. The ASCOT-BPLA results were simultaneously published online by The Lancet.

"The combination of the contemporary blood pressure lowering drugs, amlodipine and perindopril, plus effective lowering of cholesterol abolished more than half the risk of strokes and heart attacks -- the most important causes of death in millions of men and women with high blood pressure," said Dr. Bjorn Dahlof, professor of medicine at Sahlgrenska University Hospital, Goteborg, Sweden.

The ASCOT results contradict findings from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), a National Heart, Lung and Blood Institute-sponsored study that found thiazide-type diuretics to be as effective as newer agents. Based on the ALLHAT results, the Seventh Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC-7) recommended those diuretics as the first choice for managing hypertension, noting that other drugs should be added as needed.

The 19,257-patient ASCOT study is the largest-ever European hypertension trial.

Participants were recruited from 1998 to 2000, with 9,639 of them randomized to amlodipine 5 mg to 10 mg with the option to add perindopril 4 mg to 8 mg as required. The second group, 9,618, received atenolol with the option to add bendroflumethiazide. The target blood pressure was less than 140/90 mm Hg for patients without diabetes and 130/80 mm Hg for patients with diabetes.

At the end of the trial, 32% of those with diabetes and 60% of those without achieved both systolic and diastolic blood pressure goals.

The amlopidine-based therapy reduced major cardiovascular events by 16%, stroke by 23%, cardiovascular mortality by 24% and total mortality by 11%, compared with the regimen of the beta-blocker atenolol with or without bendroflumethiazide.

Moreover, there were significantly fewer new cases of diabetes, 567 versus 799, in the amlopidine arm. Dr. Dahlof said about 10% to 15% of the patients were able to maintain lowered blood pressure on monotherapy. The others all required combination treatment to keep blood pressure under control.

Study halted prematurely

ASCOT-BPLA was prematurely stopped in December 2004 when the data safety monitoring board determined there was a higher event rate in the atenolol arm. As a result, the study failed to meet its primary endpoint, which was defined as a significant reduction in nonfatal myocardial infarction and fatal coronary heart disease.

The decision to halt the trial resulted in a bias that "drives up" positive findings, said Dr. Salim Yusuf, director of cardiology at McMaster University in Hamilton, Ontario, and an ESC discussant for the paper. But, "that should not detract from the value of the findings."

Richard Devereux, MD, professor of medicine at Weill Medical College of Cornell University in New York, agreed with Dr. Dahlof. "[There] is little question that if the trial was allowed to continue for just a bit further it would have reached statistical significance and the fact that it was stopped early should not be viewed as a criticism." Dr. Devereux was not involved in the study.

But other hypertension experts were skeptical in their ASCOT appraisal, with some suggesting the findings don't reflect the benefit of a particular drug treatment, but the benefit of lowering blood pressure.

In a Lancet commentary that accompanied the study results, Dr. Jan A. Staessen and Dr. Willem H. Birkenhäger, of the University of Leuven, Belgium, pointed out that patients randomized to calcium channel blockers on average achieved systolic blood pressures 2.7 mm Hg lower than patients in the beta-blocker arm. "The 2.7 mm Hg systolic gradient is sufficient to explain the cardiovascular benefit of amlodipine with or without perindopril," they said.

But, even as naysayers suggested the ASCOT findings were being oversold, there was little doubt that the many cardiologists gathered at the ESC Congress were ready to embrace them.

The failure to meet the primary endpoint "should not take away from the good results we have seen. There is a real benefit to the treatment with the newer drugs, but the size of the benefit may not be as big. ... Some part of the difference is due to the difference in blood pressure but the rest is due to other factors," said Dr. Yusuf.

And the ASCOT results add to the ongoing debate about the real world clinical utility of the ALLHAT findings and the JNC-7 recommendations.

As critics of that diuretic-driven strategy point out, use of thiazide diuretics was associated with an increase in new onset diabetes.

By contrast, ASCOT-like treatment regimens that "combat the angiotensin system, such as ACE-inhibitors and angiotensin receptor blockers reduce the risk of developing new onset diabetes," said Dr. Devereux.

More studies, more regimens

Dr. Devereux is predicting that the assault on the JNC-7 recommendations is likely to pick up steam post-ASCOT since a number of other trials are investigating the other treatment regimens.

The largest of these, a 13,000-patient study called Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) randomized patients to fixed doses of combination medicines -- either the ACE-inhibitor benazepril combined with amlodipine (Lotrel) or benazepril combined with the diuretic hydrochlorothiazide.

That study is expected to conclude in 2008.

ACCOMPLISH is likely to provide a definitive answer to the question of whether the calcium channel blocker is better than the diuretic in controlling morbidity and mortality of patients, Dr. Devereux said.

Meanwhile, clinicians will continue to digest the results.

"We'll have reports on ASCOT at Grand Rounds and then the questions, and the e-mails and the reinterpretations will start. We'll be discussing these results for years," said Raymond Gibbons, MD, professor of medicine at the Mayo Clinic in Rochester, Minn., and president-elect of the American Heart Assn.