Special to BioWorld Today
A study of nearly 4,000 congestive heart failure patients showed the use of the Astra AB's beta blocker Toprol-XL improved survival by 35 percent.
The study, begun in February 1997, was stopped nearly two years early because of the significantly beneficial effects seen during an interim analysis by an independent safety monitoring committee. Preliminary results were disclosed yesterday in Dallas at the annual scientific sessions of the American Heart Association.
Separately, Intercardia Inc., which has been in Phase III trials with its beta blocker Bextra since 1995, said Wednesday that a safety and monitoring board recommended continuing its Beta-blocker Evaluation of Survival Trial, or BEST. The status of that trial will be reviewed in three months at the board's next meeting.
Bextra was being developed in collaboration with Astra Merck Inc. until restructuring led to the merger of that group with Sweden-based Astra's subsidiary, Astra USA Inc., into a new entity called Astra Pharmaceuticals LP. Astra had to drop development of either Bextra (bucindolol HCl) or Toprol (metoprolol) for heart failure because of a non-compete clause, and terminated the collaboration with Intercardia in September.
The Toprol-XL study was called Merit-HF, or Metoprolol Randomized Intervention Trial in Heart Failure. It included patients in 14 countries with moderate to severe heart failure who received either Toprol or placebo. Presentation of complete results is expected in March at the American College of Cardiology meeting, said Gary Bruell, senior manager, public affairs, at Wayne, N.J.-based Astra Pharmaceuticals.
"These studies continue to indicate wonderful results of beta blockers in reducing deaths in heart failure," Bruell told BioWorld Today. "There are some nuances between the beta blockers. Physicians are finding these nuances as more studies are being done. The important thing is it confirms what we've seen in other trials: a profound reduction in mortality."
Bruell said superiority of one over another cannot be established without head-to-head trials. One beta blocker, SmithKline Beecham's Coreg (carvedilol), already is indicated for heart failure.
Toprol is approved in the U.S. for treating hypertension and angina. Bruell said the full Merit-HF trial results could warrant Astra seeking that additional indication.
Astra had no knowledge of the Merit-HF or BEST results when it chose Toprol over Bextra, Bruell said.
Bennett Love, vice president of corporate planning and communications at Research Triangle Park, N.C.-based Intercardia, agreed the Toprol results add evidence that beta blockers have a place in treating heart failure. He also said the results will improve information available in the marketplace and among physicians about that class of drug.
"There's the real possibility we will compete with [Astra] in the marketplace," Love told BioWorld Today. "We have to be pleased another trial has shown the benefits of using beta blockers in treating heart failure."
Love said the Bextra monitoring committee is looking for specific requirements related to statistical significance before stopping the study. "But beyond that," he said, "there are judgment issues which they would look at, such as patient subgroups. Even if overall statistical significance was achieved, the board may feel it appropriate to continue the trial as they look at subgroup analysis. We imagine different beta blockers are more appropriate for different subgroups."
Different beta blockers have different vasodilating properties and target different receptors, he said.
The BEST trial has enrolled about 2,600 patients at 90 centers in the U.S. and Canada. Enrollment is scheduled to end Dec. 31. The trial includes an 18-month follow-up period.
Love said Astra was able to run its trial more quickly than Intercardia because it had more than twice as many sites and enrolled patients much faster. The BEST study is being conducted by the Department of Veterans Affairs and the National Institutes of Health.
The American Heart Association said up to 4.7 million people in the U.S. suffer from heart failure and 400,000 new cases are diagnosed each year.
In other news from the AHA meeting yesterday:
o Celgene Corp., of Warren, N.J., said that several SelCIDS (selective cytokine inhibitory drugs) being developed by the company effectively suppress production of tumor necrosis factor-alpha (TNF-alpha), an inflammatory protein linked to congestive heart failure. SelCIDS are potent, small-molecule inhibitors of TNF-alpha.
o The 825-patient PREVENT trial showed those taking New York-based Pfizer Inc.'s calcium channel blocker Norvasc (amlodipine besylate) had 31 percent fewer cardiovascular events than those taking placebo. The primary endpoint was angiographic analysis of coronary arteries. Norvasc patients had a significant reduction in plaque buildup in the carotid artery.
o The Randomized Aldactone Evaluation Study, or RALES, sponsored by G.D. Searle & Co., of Skokie, Ill., showed the addition of Aldactone (spironolactone), an aldosterone antagonist, to standard regimens, including ACE inhibitors, reduced mortality 27 percent in patients with severe heart failure. n