Irbesartan Flops for Heart Failure in I-PRESERVE


NEW ORLEANS — Heart failure patients with preserved systolic function did not benefit from treatment with an angiotensin II receptor blocker, according to results of the I-PRESERVE trial, the world's largest placebo-controlled trial of an ARB.

“Disappointingly, for this large group of patients—almost half the patients with heart failure—there remains no specific evidence-based therapy,” concluded Dr. Barry M. Massie, who presented the results of the Irbesartan in Heart Failure with Preserved Systolic Function (I-PRESERVE) trial at the annual scientific sessions of the American Heart Association.

Although no pharmacologic therapy has been shown to be effective in improving outcomes in this type of heart failure, inhibitors of the renin-angiotensin-aldosterone system have been of interest because that system is involved in many of the processes associated with this syndrome, such as hypertension, left ventricular hypertrophy, myocardial fibrosis, and vascular dysfunction. Previous studies have hinted at benefits from ARBs and from ACE inhibitors, but statistically significant improvements have not been established, said Dr. Massie, professor of medicine at the University of California, San Francisco and chief of cardiology at the San Francisco Veterans Affairs Medical Center.

I-PRESERVE included 4,128 patients with class II-IV heart failure and a left ventricular ejection fraction of at least 45%. The population was similar to that seen in prior epidemiologic studies in several important ways. The patients were mostly women, were elderly (median age 72 years), and about 9 of 10 had a history of hypertension. The average left ventricular ejection fraction was 59%.

Patients were randomized to either irbesartan up to 300 mg daily or usual care (placebo). The primary end point was a composite of all-cause death, hospitalization for heart failure, myocardial infarction, unstable angina, arrhythmia, and stroke.

After a mean follow-up of approximately 4 years, the primary outcome rates were nearly identical, occurring in 36% (742 of 2,067) of the irbesartan patients and 37% (763 of 2,061) of the placebo group. Similarly, there were no significant differences in the major secondary end points of cardiovascular death and death or hospitalization due to heart failure, or in any of the eight prespecified subgroups, Dr. Massie reported.

“Irbesartan was unsuccessful in achieving its primary or secondary outcomes,” Dr. Massie announced. The results are consistent with two previous trials in patients with heart failure and preserved ejection fraction that did not show a positive treatment effect with either candesartan or perindopril, he added.

Dr. Massie acknowledged that this was a “very well treated population,” with most patients receiving diuretics and many receiving other medications. “After randomization, there was an intensification of all these therapies,” he observed, explaining that this can confound outcomes.

“For this field to move forward, we need a better understanding of the mechanisms underlying this syndrome, and we need to find potential targets above and beyond those used for low ejection fraction patients. We need to do something. This affects more than 2 million individuals in the United States alone.”

Dr. Margaret M. Redfield, professor of medicine at the Mayo Clinic, Rochester, Minn., called I-PRESERVE, “a very important trial, if only for the fact that ARBs and ACE inhibitors are already widely used for the treatment of heart failure with preserved ejection fraction, even though no randomized trial has shown a benefit. Two huge registries have shown that 60% are treated with these agents despite the lack of evidence.”

In this form of heart failure, she said there is little evidence that activation of the renin-angiotensin system is associated with disease progression, unlike in patients with reduced ejection fractions. “This may be why the trial was negative,” she speculated.

She also observed that patients in I-PRESERVE were largely similar to those in observational studies, but that they had fairly normal hemoglobin levels and renal function, “which is uncommon in the elderly with heart failure,” she pointed out. “Few had concentric hypertrophy, though some had concentric remodeling, and very few had advanced diastolic dysfunction or high filling pressures. So, this was a relatively healthy cohort and not as reflective of this syndrome as we would have hoped.”

The study was funded by Bristol-Myers Squibb Co. and Sanofi-Aventis. The results were simultaneously published online in the New England Journal of Medicine (doi:10.1056/NEJMoa08005450).

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