CHICAGO--Despite previous safety questions, the embattled nesiritide can now be considered a safe therapy in patients with acute decompensated heart failure (HF), based on the late-breaking ASCEND-HF trial presented today at the American Heart Association (AHA) Scientific Sessions. However, nesiritide had little effect on dyspnea, and no significant effect on hospital readmission or death rates in this same patient population.

As a discussant of the ASCEND-HF trial at the conference, Eugene Braunwald, MD, from Harvard Medical School, explained the history of nesiritide (Natrecor, Johnson & Johnson), a manufactured drug derived from the naturally occurring protein, human B-type natriuretic peptide. In the first few years after the drug’s approval in 2001, it was widely used as a vasodilator and for patients with acute decompensated HF, and also widely used off-label in the outpatient setting for severe heart failure.

In 2005, two meta-analyses were published that questioned the safety of the drug: one assessed survivability (JAMA 2005;293:1900-1905), and the other assessed the potential side effect of worsening renal functions (Circ 2005;111:1487-1491). Subsequently, J&J asked Braunwald to chair an independent panel to design a clinical trial to definitively answer the question of nesiritide’s safety and efficacy, which resulted in the formation of ASCEND-HF.

“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 ASCEND-HF Committee Chair Robert M. Califf, MD, who presented the results on behalf of primary investigator Adrian F. Hernandez, MD, and the other researchers at this morning’s press conference.

Slideshow | Acute Study of Clinical Affectiveness of Nesiritide in Decompensated Heart Failure

Adrian F. Hernandez MD on behalf of the ASCEND-HF Committees, Investigators and Study Coordinators

The trial had co-primary endpoints to assess whether nesiritide versus placebo, in addition to standard care, provides:

• Reduction in rate of HF re-hospitalization or all-cause mortality through day 30; and
• Significant improvement in self-assessed dyspnea at six or 24 hours using 7-point Likert scale.

Specifically, the safety endpoints were all-cause mortality, renal function (25 percent in eGFR at any time from study drug initiation through day 30) and hypotension (as reported by investigator as symptomatic or asymptomatic).

In the double-blind placebo trial, more than 800 investigators and coordinators enrolled 7,141 patients in 30 countries (mean age, 68 years, 34 percent female).

Six hours after treatment, nesiritide slightly improved shortness of breath compared with placebo, with significant improvement occurring in 13.4 percent of nesiritide patients and 15 percent in the placebo arm. Similarly, 24 hours after treatment, more patients on nesiritide displayed markedly improved breathing function compared with placebo—30.4 percent versus 27.5 percent. However, there was no significant difference in the pre-specified endpoint of dyspnea.

At 30 days post-treatment, the death rates from any cause and hospital readmission for HF were slightly lower with nesiritide compared with placebo. Yet, at 9.4 percent versus 10.1 percent, the difference in these rates was not statistically significant either.

Based on these findings, the researchers concluded that “nesiritide can be used safely, but there is no mandate to use it because of its modest effects.”

Also, Braunwald pointed to the other study commissioned by the independent panel to address off-label usage, FUSION II, which found that nesiritide should not be given as an intermittent outpatient infusion (Circ Heart Fail 2008;1:9-16).

Based on these results, “practitioners will have to evaluate whether the very modest benefit with nesiritide provides enough value to prescribe the drug to decompensated HF patients. These will be highly individualized decisions,” said Clyde W. Yancy, medical director at Baylor Heart and Vascular Institute in Dallas, who commented on the trial.