ASCEND Heart Failure Study

Overview
ASCEND was a large randomized clinical trial of patients with severe heart failure that demonstrated that intravenous nesiritide in the setting of severe heart failure is safe, but is not associated with significant benefit on symptoms, 30 day readmission or mortality. The use of nesiritide did not increase the risk of kidney dysfunction or death.

A Duke press release stated the following:

In a large clinical trial, the drug nesiritide proved to be safe but had little effect on breathing symptoms (dyspnea), and no significant effect on hospital readmission or death rates among patients with acutely decompensated heart failure, according to late-breaking clinical trial results presented at the American Heart Association’s Scientific Sessions 2010.

In the Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure Trial (ASCEND-HF), researchers randomized 7,141 patients with acute, severe heart failure to receive either continuous intravenous nesiritide or a placebo, both added to standard therapy, which includes diuretics, morphine and other medications.

Six hours after treatment, nesiritide slightly improved shortness of breath compared with placebo, with significant improvement occurring in 513 nesiritide patients (15.0 percent) and 460 placebo patients (13.4 percent). Similarly, 24 hours after treatment, more patients on nesiritide displayed markedly improved breathing function compared to placebo – 1,025 nesiritide patients (30.4 percent) compared to 935 placebo patients (27.5 percent). However, there was no significant difference in the pre-specified endpoint for dyspnea. At 30 days post-treatment, the rates of death from any cause and hospital readmission for heart failure were slightly lower with nesiritide compared to placebo. At 9.4 percent versus 10.1 percent, however, the difference in these rates was not statistically significant either.

Nesiritide is a manufactured drug derived from a naturally occurring protein known as human B-type natriuretic peptide. The drug helps to relax the blood vessels, which can improve circulation, and increase the body’s output of excess salt and water.

“Nesiritide was marketed and widely used in the U.S. because of a perception that it had a major effect on dyspnea and then largely abandoned in clinical use because of concerns that it might increase rates of death and renal failure, said Robert M. Califf, M.D., study chair and vice chancellor for clinical research at Duke University School of Medicine in Durham, N.C. “Now that we finally have a proper clinical trial we know that both perceptions were incorrect; nesiritide is safe but has only a modest effect on dyspnea. This is a major signal that we must do a better job defining the biological effects of drugs early in development and conduct adequately powered outcomes trials much earlier to give doctors and patients the necessary information to enable appropriate use of the treatment in practice.”

ASCEND-HF, a randomized double-blind trial, included participants from 400 international centers in 30 countries. Average age of patients studied was 67, 34 percent were female and 15 percent were African American. More than half (60 percent) had blockages or narrowing of the blood vessels supplying the heart. Treatment began within 24 hours of hospitalization for worsening symptoms and continued for between one to seven days. The study ran from May 2007 to September 2010; patients were followed for 30 days.

Previous studies have shown that nesiritide can relieve shortness of breath if given within three hours of the onset of worsening heart failure, but it was unclear whether this improvement persisted. Also unknown was whether nesiritide caused kidney (renal) impairment or increased the risk of death, which previous, much smaller studies have indicated. An important finding from this trial is that the drug did not increase these risks.

“I think the main message is that we need to do adequately powered studies to really understand the balance of safety and effectiveness,” said Adrian F. Hernandez, M.D., co-investigator of the trial and associate professor of medicine at Duke University School of Medicine. “Now that we’ve done an adequate trial, we know that nesiritide can be used safely, but there is no mandate to use it because of its modest effects.”

“ASCEND-HF represents an important milestone in our understanding of acute heart failure care as this is the first robust drug safety study completed in this difficult to treat patient population,” said Christopher M. O’Connor, M.D., the study’s co-principal investigator and director of the Duke Heart Center. “Given the complexities of heart failure, there is a significant need for better medications for use in treatment,” said Randall C. Starling, M.D., study co-investigator and head of the section of Heart Failure and Cardiac Transplant Medicine and vice chairman of Cardiovascular Medicine at Cleveland Clinic. “With the safety questions related to nesiritide having now been addressed, it could be an option for physicians depending on their interpretation of clinical benefit.”

The trial was led by an international executive committee which also included Paul W. Armstrong, M.D.; Kenneth Dickstein, M.D.; Daniel Gennevois, M.D.; Vic Hasselblad, Ph.D.; Michael Komajda, M.D.; Barry Massie, M.D.; John J.V. McMurray, M.D.; Markku Nieminen, M.D.; Jean L. Rouleau, M.D.; and Karl Swedburg, M. D. ASCEND-HF was coordinated by the Duke Clinical Research Institute led by Craig J. Reist, Ph.D. Author disclosures are on the abstract.

Johnson & Johnson funded the study.