Drug reduces deaths and hospital stays in heart attack patients with heart failure

CHICAGO – A drug that blocks a heart-harming hormone can significantly reduce the risk of death and hospitalization in heart attack patients who have heart failure, with minimal side effects, a new international study released today shows.

The life-saving effect began soon after patients begin taking the drug, called eplerenone, following their heart attacks. The effect was especially strong if patients were also on other heart medications, according to the results of the randomized, double-blind, placebo-controlled study of 6,632 patients in 37 countries.

The findings are being released simultaneously today at the 52nd Annual Scientific Sessions of the American College of Cardiology, and in an early online version of the New England Journal of Medicine. They will be published in the April 3 NEJM.

The success of the drug in treating people with heart failure soon after a heart attack comes on top of its recent approval by the Food and Drug Administration to treat high blood pressure. And the study's lead author predicts that more research on the same hormone pathway could lead to further heart disease advances.

"This represents a new advance in to the treatment of heart attack and heart failure," says Bertram Pitt, M.D., the University of Michigan cardiologist who led the study. "Patients receiving eplerenone had 15 percent fewer deaths compared to the placebo group, and 13 percent fewer cardiovascular-related deaths and cardiovascular hospitalizations."

He adds, "Patients who were on optimal therapy in addition to eplerenone, including an ACE inhibitor, beta-blocker, aspirin, and statin, and who had undergone coronary reperfusion, experienced a 26 percent reduction in mortality. Additionally, there was a 21 percent overall reduction in sudden cardiac death, a major cause of mortality in heart failure patients, and 15 percent fewer hospitalizations for heart failure."

In addition to the current trial, called EPHESUS, Pitt also led a previous study called RALES that showed the efficacy of spironolactone, another drug that blocks the same hormone system, in reducing death and hospitalization from severe heart failure.

Both eplerenone and spironolactone block the effects of aldosterone, a hormone known to damage heart muscle and, in conjunction with another molecule called angiotensin II, cause blood vessel damage.

The positive clinical results from the two aldosterone-blocking drugs come with some caveats. The use of spironolactone has often led to side effects like hyperkalemia, or high and potentially dangerous levels of potassium, and impotence and breast swelling, or gynecomastia, in men.

The EPHESUS results show no increased incidence of gynecomastia or impotence in the treatment group, reflecting eplerenone's higher level of selectivity for the aldosterone hormone receptors as compared with spironolactone. However, there was an increased incidence of hyperkalemia in the patients on eplerenone, especially those whose kidneys were less able to remove creatinine from the body.

"This hormone is turning out to be more important than anyone thought," says Pitt, who predicts that combining an aldosterone-blocking drug with angiotensin II inhibitor and beta blocker drugs may eventually become a standard treatment for appropriate heart failure patients.

Pitt suggests that the success of eplerenone combined with other drugs in cutting mortality and hospitalization should raise questions about the cost-effectiveness of implanted defibrillators that are being considered for approval by the Centers for Medicare and Medicaid Services for heart failure treatment under Medicare.

Eplerenone, whose trade name is Inspra, is a product of Pharmacia Corporation. Though approved for hypertension, the product is not yet on the market. The EPHESUS study was supported by a grant from Pharmacia, and Pitt is the principal investigator of the trial and a consultant to the company.

Spironolactone, which is available from various manufacturers as a generic medication and from Pharmacia under the name Aldactone, has been used for decades against hypertension and other conditions. In 1999, Pitt led a team of researchers that published results in NEJM from the RALES trial that combined it with ACE inhibitors and other drugs.

Heart failure is the only major cardiovascular disease whose prevalence and incidence are growing; 4.9 million Americans currently have it, and 500,000 more will be diagnosed this year. Heart attacks are the second most common reason (after hypertension) for heart failure, and heart failure incidence is five times greater in people who have had a heart attack. In fact, recent increases in the heart attack survival rate due to better care means more patients are living long enough to develop heart failure.

There is as yet no cure for heart failure, but advances in medications over the last 15 years, and better understanding of the molecular and physiological factors underlying the condition, have meant that many patients can live longer and better after diagnosis. However, more recent results from clinical trials of several once-promising therapies have not panned out.

Those recent failures have made the success of aldosterone blockers that much more important, Pitt explains, and encouraged further basic research on the hormone system. The results of the RALES spironolactone trial showed a 30 percent reduction in deaths and a 35 percent reduction in hospitalizations among patients with severe heart failure. Since that time, spironolactone has become part of the treatment regimen for many heart failure patients.

Eplerenone's effect on death and hospitalization rates was more moderate across the board, but these differences may be attributable to several factors, including the greater use of beta-blockers and a higher base-line left ventricular ejection fraction in the current study.

The study's main endpoints were time to death from any cause, and time to either death or hospitalization for cardiovascular causes. Patients were followed for a mean of 16 months, starting during the hospitalization for their initial heart attack. They were monitored regularly.

To qualify for EPHESUS, patients had to have had a heart attack within 3 to 14 days before enrolling in the study, and had to have a left-ventricle ejection fraction (pumping ability) of less than 40 percent of normal. Those who did not have diabetes had to have signs of heart failure such as abnormal heart and lung sounds.

Patients in the study received optimum therapy, which could have included ACE inhibitors, aspirin, angiotensin-receptor blockers, diuretics, beta-blockers and coronary reperfusion. Patients in the treatment arm were started on 25 milligrams of eplerenone, and after one month the doses were increased to a maximum of 50 mg; the mean dose was 43 mg.

The mean age of patients at baseline was 64 years, and they were on average randomized to treatment or placebo 7.3 days after their heart attack. About a third had diabetes, 60 percent had hypertension, and only 14 percent had a prior diagnosis of heart failure.

The results show that the number of treated patients needed to save one life in a year is 50, and the number needed to prevent a cardiovascular-related death or hospitalization in a year is 33.

Patients who had the worst ejection fractions, less than 30 percent, had the largest reduction in sudden cardiac death -- 37 percent. These same patients are considered by some to be prime candidates for implanted defibrillators because of their extremely high risk for instantly lethal events known collectively as sudden cardiac death. But eplerenone greatly reduced this risk.

This finding, Pitt says, means that physicians will need to closely monitor potassium levels in patients who take eplerenone once it comes on the market -- just as they should be doing with patients taking spironolactone -- and adjust doses or diuretic usage accordingly. Some patients with kidney problems or low creatinine clearance may not be able to take eplerenone.

Interestingly, eplerenone seems to have prevented hypokalemia -- dangerously low potassium -- in some patients. The risk of hypokalemia in the placebo group was more than twice as high as the risk of serious hyperkalemia, and the treatment group had a far lower hypokalemia rate.

As eplerenone becomes available, physicians will need to balance costs, side effects and contraindications to find the best way to use aldosterone blockers in heart failure patients, predicts Pitt, who is professor of internal medicine at U-M Medical School.

And, since the EPHESUS study population was heavily Caucasian (90 percent) and male (71 percent) due to the heavily European and Latin American populations from which participants were drawn, follow up studies in special populations will be needed to show whether eplerenone has comparable effects.

Overall, he says, eplerenone, like its cousin spironolactone, will be a major addition to the arsenal of medications that physicians can use to help patients with heart failure. "Treatment has gotten better over the years, but mortality is still high," Pitt concludes. "This is one more step toward reducing mortality and hospitalization. And it opens up tremendous opportunities in the next decade to attack this hormone system through blockade or synthesis inhibition."

In addition to Pitt, the lead authors of the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) are: Willem Remme, M.D.; Faiez Zannad, M.D.; James Neaton, Ph.D.; Felipe Martinez, M.D.; Barbara Ronicker, M.D.; Richard Bittman, Ph.D.; Steve Hurley, B.S.; Jay Kleiman, M.D.; and Marjorie Gatlin, M.D. The study was conducted at 674 centers in 37 countries, including the U-M Cardiovascular Center, where John Nicklas, M.D. was the local principle investigator.