NEW ORLEANS—The angiotensin II receptor blocker irbesartan (Avapro from Bristol Myers Squibb) did not improve outcomes of heart failure patients with a preserved left ventricular ejection fraction, according to the I-PRESERVE study presented Tuesday during the late-breaking clinical trials at the 2008 American Heart Association (AHA) Scientific Sessions, which was simultaneously published in the New England Journal of Medicine.

Barry M. Massie, MD, co-principal investigator of the study and chief of the cardiology division at the San Francisco Veterans Administration Medical Center presented the findings from I-PRESERVE (Irbesartan in Heart Failure with Preserved Systolic Function), which enrolled 4,128 patients, (average age was 72, 60 percent were women) from 25 countries.

The placebo-controlled trial randomized the patients to receive either irbesartan, an angiotensin II receptor blocker (ARB) currently used to treat blood pressure, or usual care for preserved ejection fraction heart failure. Researchers then followed them for 4.5 years to assess clinical outcomes.

“Typically, the public and physicians think of heart failure as a large, poorly contracting heart that can’t pump adequate blood to the rest of the body with an ejection fraction of under 35 percent,” Massie said. “But up to half of all heart failure patients have normal or preserved ejection fractions. Their hearts pump well and are not enlarged yet these patients still have the classic heart failure symptoms of fluid retention, shortness of breath and edema or swelling.”

Earlier studies suggested that patients with preserved ejection fraction heart failure may fare better on ARBs or ACE inhibitors than on conventional treatment, but their results were not statistically significant, according to Peter E. Carson, MD, co-principal investigator and chief of the coronary care unit of Washington Veterans Administration Medical Center in Washington D.C.

In I-PRESERVE, the primary outcome—a composite of all-cause death, hospitalization for heart failure, heart attack, unstable angina, arrhythmia and stroke—occurred in 742 people in the irbesartan group and 763 in the placebo group, a difference that was not statistically significant. Two major secondary endpoints, cardiovascular death and death or hospitalization specifically due to heart failure, were also not different between the treatment and control groups. Therefore, the trial failed to reach both its primary and secondary endpoints.

However, Massie said that I-PRESERVE researchers found that the ARB was safe and well-tolerated, indicating that it could be a substitute for patients unable to tolerate other high blood pressure drugs. However, he indicated that mortality and morbidity was quite high in the trial, which is much higher than the average hypertension trial.

Yet, the “treatment of a large proportion of patients with multiple inhibitors of the renin-angiotensin-aldosterone system might have left little room for further benefit from the addition of an angiotensin-receptor blocker," the researchers wrote in the NEJM study.

Two previous clinical trials have also shown that ARBs are ineffective in heart failure patients. In the CHARM-Preserved trial, candesartan (Atacand) did not reduce cardiovascular mortality or chronic heart failure-related hospitalization. The PEP-CHF trial showed that perindopril (Acenon) plus a diuretic reduced symptoms, but not heart failure deaths.

Despite not reaching its clinical endpoint, Carson noted that the trial provides “a treasure trove of information about this patient population,” and we need to further investigate the results of the trial, to find out how else heart failure can benefit from this investigation.