CHF drug trials are highlight of ACC 2000

Omapatrilat looks promising

The results of two separate late-breaking CHF-related clinical trials presented at the American College of Cardiology’s 2000 meeting held in March in Anaheim, CA, found no benefit in either of the drugs studied. But a third presentation comparing the investigational drug omapatrilat with lisinopril found that the new drug appears to be more effective in preventing death or hospitalization in CHF patients.

PRAISE-2 (Prospective Randomized Amlodipine Survival Evaluation), presented by Milton Packer, MD, of Columbia University College of Physicians and Surgeons in New York City, did not confirm the survival benefit of the calcium channel blocker amlodipine seen in nonischemic cardiomyopathy in the PRAISE-1 trial.

Packer said in his presentation that there was one significant benefit from PRAISE-2, and that was to emphasize the need for replication, even when the results of a trial define a mortality benefit and are associated with low P values.

David Roffman, PharmD, BCPS, associate professor in the University of Maryland School of Pharmacy in Baltimore, agrees with Packer that there is an important lesson to be learned from the trial. "PRAISE-1 basically gave some hint that nonischemic cardiomyopathies might benefit from calcium channel blockers," Roffman explains to CHF Disease Management.

"What often happens is that people implement that kind of data in their clinical practice before the definitive trial, like PRAISE-2, has the chance to be done. I think that’s an important lesson for people not to run with the results of preliminary data until the definitive data are in. The PRAISE-2 trial demonstrates that really nicely."

PRAISE-2 was conducted as a follow-up to test a hypothesis generated by PRAISE-1 that amlodipine could prolong life in patients with nonischemic cardiomyopathy. In PRAISE-1, all-cause mortality was reduced by 46%. PRAISE-2 enrolled 1,652 patients by January and found that there were no significant differences in all-cause mortality between the two arms of the study (31.7% in placebo and 33.7% with amlodipine).

The combined results of PRAISE-1 and PRAISE-2 show that long-term treatment with amlodipine is neither beneficial nor harmful in patients with severe chronic heart failure, Packer said in his presentation. The favorable survival benefit of amlodipine seen in PRAISE-1 was most likely due to chance, he said.

OPTIME-CHF, a study presented by Mihai Gheorghiade, MD, of Northwestern University in Evanston, IL, found that an infusion of intravenous milrinone had few beneficial effects in hospitalized patients with CHF. Milrinone did not cut hospital days or mortality, and the results showed milrinone should not be incorporated as routine therapy for all patients admitted with CHF.

OPTIME-CHF (The Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure) was designed to look for a new indication for milrinone by examining the role of the drug in patients hospitalized with CHF who would not normally receive this therapy.

A total of 951 patients were randomized within 48 hours of admission to intravenous milrinone. Patients had to have ejection fraction of less than 40%, chronic heart failure, no myocardial infarction, no significant hypertension or hypotension, and no need, in the opinion of the investigator, for milrinone therapy. But at 60 days, there was no significant difference in hospital days or mortality (35% event rate) between the placebo and milrinone groups.

"In effect, the study is not changing current practice," Gheorghiade explains. "The importance of this study is that it is the first large trial that is placebo-controlled and randomized to be conducted in this patient population.

"Although we have 1.5 million admissions for heart failure per year in the United States, there have been no studies to address this population. It’s really interesting how there are so many studies for acute MI, one after another, but none for heart failure. I hope many more studies will come on how to manage, how to develop a strategy in patients admitted with exacerbation of their heart failure," he says.

Mike Cuffe, MD, an OPTIME researcher from Duke University in Durham, NC, says a lot of people were very optimistic that the trial, the largest ever done with milrinone, would show a reduced length of stay.

"There’s enormous pressure in health care right now to find strategies to improve outcomes and simultaneously reduce length of stay and cut costs," Cuffe says. "We were pleasantly surprised that the drug appeared safe but disappointed that it didn’t appear to have efficacy in this broader population."

A third study1 to come out of the annual meeting that has implications for CHF treatment is one on the investigational drug omapatrilat, a member of a new class of cardiovascular medications called vasopeptidase inhibitors.

These drugs simultaneously inhibit two key enzymes that regulate heart function and blood pressure — neutral endopeptidase and angiotensin-converting enzyme.

A combined analysis of two Phase II studies comparing omapatrilat with the ACE inhibitor lisinopril found that the new drug was more effective in preventing death or hospitalization in the 1,242 participating CHF patients.

The relative risk of the combined endpoint of death or hospitalization was 78% with omapatrilat and 95% with lisinopril. Both drugs were well-tolerated.

"Omapatrilat is the first and most clinically advanced vasopeptidase inhibitor," says John Kostis, MD, principal investigator of the study and chair of the department of medicine at the University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School in New Brunswick, NJ. "The major implication of these trials is that this new agent may be better than the gold standard for heart failure treatment, the ACE inhibitor."

Other studies are ongoing to compare omapatrilat with enalapril and to evaluate the drug’s efficacy in treating patients with isolated systolic hypertension. The drug is under priority review at the U.S. Food and Drug Administration. Princeton, NJ-based Bristol Myers-Squibb, which is marketing omapatrilat under the name Vanlev, expects a decision by June 20.

Reference

1. Kostis JB, et al. Beneficial effects of vasopeptidase inhibition on mortality and morbidity in heart failure: evidence from the omapatrilat heart failure program. J Am Coll Cardiol 2000; 35:240.