ARB ineffective in HF with preserved ejection fraction

November 12, 2008

New Orleans-The use of irbesartan for heart failure with preserved ejection fraction (HFPEF) failed to improve outcomes compared to placebo, says Barry Massie, MD, investigator for the Irbesartan in Heart Failure with Preserved EF (I-PRESERVE) trial. These results are consistent with two previous trials (CHARM PRESERVED, PEP-CHF) that failed to show a positive effect with an angiotensin-receptor blocker (ARB) for these patients, explains Dr. Massie, University of California, San Francisco.

New Orleans-The use of irbesartan for heart failure with preserved ejection fraction (HFPEF) failed to improve outcomes compared to placebo, says Barry Massie, MD, (pictured) investigator for the Irbesartan in Heart Failure with Preserved EF (I-PRESERVE) trial. These results are consistent with two previous trials (CHARM PRESERVED, PEP-CHF) that failed to show a positive effect with an angiotensin-receptor blocker (ARB) for these patients, explains Dr. Massie, University of California, San Francisco.

“Angiotenisn-converting enzyme inhibitors (ACEI) and ARBS are commonly used to treat this condition even though there are no randomized clinical trials to justify it,” says Margaret Redfield, MD, Mayo Clinic, Rochester, MN. The three trials taken together clearly indicate that diuretic treatment produces better results in this large patient population. “It’s becoming increasingly apparent that the pathophysiology of this condition is not as simple as we thought. The pathophysiology of aging may need to be considered when developing new treatments,” Dr. Redfield suggests.

Approximately half of heart failure patients have a preserved EF of 45 percent or greater and the number is growing as the population ages. This type of heart failure is most prevalent among the elderly, especially women, and hypertension is the most common underlying condition, Dr. Massie says. In the United States, HFPEF causes approximately 500,000 heart failure hospitalizations and 25,000 deaths annually.

I-PRESERVE included 4,128 HFPEF patients, who were at least age 60, and who currently had symptoms. All patients had undergone hospitalization related to heart failure within 6 months of trial entry. New York Heart Association Class III and IV patients were required to have suffered from chest congestion and documented left ventricular hypertrophy, as well as either left bundle branch block or left atrial enlargement. Patients were excluded if they had a prior EF < 40 percent, acute coronary syndrome or stroke within 3 months, hypertrophic or restrictive cardiomyopathy, pericardial or valvular disease, cor pulmonale, systolic blood pressure greater than 160 mm Hg or less than 100 mm Hg, or any other conditions that could limit life expectancy.

The participants were randomized to receive a starting dose of 75 mg irbesartan daily, which was titrated upward to 300 mg, or placebo. The mean dose achieved was 275 mg daily. The patients were followed every 4 months until 1,440 primary endpoints occurred. The primary endpoint was a composite of all-cause mortality and hospitalizations for heart failure, MI, stroke, and arrhythmia. Secondary endpoints included heart failure hospitalization, Minnesota Quality of Life score; death, MI or stroke; and CV death.

There was no significant difference between placebo and irbesartan treatment in the primary endpoint during follow up. Furthermore, there was no difference in secondary endpoints between the two groups. “In fact, the majority of hospitalizations were for worsening heart failure,” Dr. Massie points out.

“For this large group of patients there is no specific evidence-based therapy,” Dr. Massie says. Dr. Redfield adds that a better understanding of the underlying mechanisms of HFPEF is needed in order to move toward better therapies, but she acknowledges that progress may be difficult. “There is a lack of a clinically relevant animal model for HFPEF,” she notes.