Standard Treatment Ineffective for Common Type of Heart Failure

November 11, 2008
Contact: Steve Tokar (415) 221-4810

CORRECTION: As clarified in paragraphs 1, 2 and 6, the drug irbesartan is not commonly used to treat heart failure, though it is a member of a class of medications, called angiotensin receptor blockers, that is.

Irbesartan, a member of a class of medications called angiotensin receptor blockers (ARBs) that are commonly used to treat heart failure, was no more effective than placebo in treating a particular and widespread form of the condition, known as preserved ejection fraction heart failure, according to an international study led by a researcher at the San Francisco VA Medical Center (SFVAMC).

Irbesartan, itself, is not approved for use in treating heart failure, but other drugs in the ARB class are.

The finding was presented on Tuesday, Nov. 11, at the annual research meeting of the American Heart Association, in New Orleans. The study was published simultaneously in the "Online First" section of the New England Journal of Medicine.

Heart failure is a condition in which the heart is no longer able to pump a sufficient supply of blood to the rest of the body. It results from a variety of structural or functional defects in the heart.

A key measure of how efficiently the heart pumps blood is ejection fraction, which measures the proportion of blood that is pumped out of the left ventricle with each heartbeat compared with how much was in the ventricle before it contracted.

Irbesartan, which the researchers consider a representative ARB, widens constricted arteries, increasing blood flow and thus reducing pressure on the arteries. With its use, the heart does not have to work as hard to pump blood. Other agents in the ARB class have been shown to be very effective in heart failure patients with reduced ejection fractions, according to the researchers.

Over the last two decades, however, doctors have realized that about half of all patients with heart failure have a normal, or preserved, ejection fraction. They are usually older, more often are women and are more likely to have high blood pressure than those with low ejection fractions.

"These patients have classic heart failure symptoms -- fluid retention in the lungs, shortness of breath and swelling -- even though their hearts pump well and are not enlarged," says Dr. Barry M. Massie, chief of cardiology at SFVAMC and the principal investigator of the trial.

The current study examined whether the drug was effective in treating their symptoms.

"Unfortunately, ARBs and other agents studied thus far do not seem to help these patients," says Massie, who is also a professor of medicine at the University of California, San Francisco. "We need to learn more about the mechanisms underlying this form of heart failure and continue the search for effective treatments."

In the trial, called Irbesartan in Heart Failure with Preserved Systolic Function, or I-PRESERVE, 4,128 participants with heart failure and an ejection fraction of at least 45 percent were randomly assigned to receive either irbesartan or a placebo and then followed clinically for an average of 4.5 years. The mean age of participants was 72. Sixty percent were female. Participants' blood pressure was maintained at normal levels in both groups.

At the end of the study, which was conducted at 293 sites in 25 countries, irbesartan was no more likely than placebo to protect against death from any cause or from hospitalization for heart failure or other major cardiovascular events.

"We really don't understand the nature of heart failure with preserved ejection fraction," says Massie. "It's likely not a single disease or syndrome, and, so far, it has been difficult to come up with a therapy that makes a difference. This study at least tells us that ARBs are probably not the answer."

Co-authors of the study were Dr. Peter E. Carson of Georgetown University and Washington, DC Veterans Administration Medical Center; Dr. John J. McMurray of the British Heart Foundation Glasgow Cardiovascular Research Centre, United Kingdom; Dr. Michel Komajda of Universite Paris 6, France; Dr. Robert McKelvie of Hamilton Health Sciences, McMaster University, Ontario, Canada; Dr. Michael R. Zile of RHJ Department of Veterans Affairs Medical Center and Medical University of South Carolina, Charleston, S.C.; Susan Anderson, of University of Wisconsin, Madison, Wis.; Mark Donovan of Bristol-Myers Squibb; Erik Iverson of the University of Washington; Dr. Christoph Staiger of Sanofi-Aventis; and Dr. Agata Ptaszynska of Bristol-Myers Squibb.

The study was sponsored by Bristol-Myers Squibb and Sanofi-Aventis, which jointly market irbesartan under the trade names Aprovel, Karvea, and Avapro. Massie has received consulting fees from the two companies.

Some of this funding was administered through the Northern California Institute for Research and Education.

NCIRE -- the Veterans Health Research Institute -- is the largest research institute associated with a VA medical center. Its mission is to improve the health and well-being of veterans and the general public by supporting a world-class biomedical research program conducted by the UCSF faculty at SFVAMC.

SFVAMC has the largest medical research program in the national VA system, with more than 200 research scientists, all of whom are faculty members at UCSF.

UCSF is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care.

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