A Clinical-Trial Cautionary Tale: Nesiritide ASCEND-HF

July 07, 2011

July 6, 2011 (Boston, Massachusetts) — The IV drug nesiritide (Natrecor, Scios/Johnson & Johnson) isn't especially better than standard treatment for patients with acute decompensated heart failure (ADHF), nor does it seem to hurt the kidneys or increase mortality, suggests a >7000-patient trial now published in the July 7, 2011 issue of the New England Journal of Medicine [1].

The issue contains the peer-reviewed version of the Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF), which was presented in November at the American Heart Association 2010 Scientific Sessions and covered by heartwire . The published data are essentially the same.

"In this trial, the use of nesiritide in patients with ADHF neither increased nor decreased the incidence of death or rehospitalization for heart failure at 30 days. Self-reported dyspnea at six and 24 hours was marginally improved when nesiritide was added to conventional therapy, but this finding did not meet prespecified criteria for statistical significance," write the authors, led by Dr Christopher M O'Connor (Duke Clinical Research Center, Durham, NC).

They go on to say that the drug, a commercial version of a native natriuretic peptide, "cannot be recommended" in patients like those in the trial.

Once widely used in ADHF for what seemed like a sometimes-dramatic effect on dyspnea, nesiritide quickly fell off in popularity following publication of two controversial meta-analyses suggesting the drug might worsen renal function and 30-day mortality, as long covered by heartwire . Viewpoints clashed over the methodologies of the two studies, the balance of nesiritide benefit vs harm, and other issues, leading to calls for a prospective, randomized trial to settle the issue.

The resulting ASCEND-HF trial suggests that neither belief about the drug--good effects on dyspnea vs bad effects on mortality and renal function--were true, observe O'Connor et al, arguing that should serve as a lesson.

"The development of nesiritide poses fundamental questions about the manner in which therapies are developed and assessed," they write. "Because nesiritide was not studied in a major outcome trial early in its life cycle, both patients and physicians lacked an appropriate understanding of the proper role of the drug in practice." Also evident is that analyses (like the two meta-analyses that triggered the debate) covering comparatively few adverse events "yield unreliable estimates of the balance of benefits and risks."

An editorial accompanying the current publication elaborates more strongly on the same point [2]. From nesiritide's approval by the FDA--based on the short-term surrogate end point of relief of dyspnea--to the publication of ASCEND-HF, "it has taken a full decade to learn the truth about nesiritide’s lack of efficacy in acute heart failure," writes Dr Eric J Topol (Scripps Translational Science Institute).

"In this time frame of 10 years of fuzziness and ambiguity regarding whether or how to use nesiritide, there was also legitimate uncertainty regarding the potential side effect of renal dysfunction and an increased mortality, simply because such a limited number of patients had been evaluated in controlled trials. Along the way, well more than $1 billion was wasted on purchasing the drug."

The FDA, he argues, "should be provided the full regulatory authority to require definitive trials and withdraw a drug if the sponsor does not promptly conduct a far-reaching clinical-end-point trial for a new molecular entity. Ideally, this trial would have been performed before approval."

Topol's editorial represents a coda to a 2005 perspective he published in the same journal, in which he warned, "Until a trial definitively proves that this drug reduces the risk of death or repeated hospitalization for heart failure, there will be questions about the appropriateness of the drug's use or even commercial availability." Questioning whether nesiritide should be on the market, Topol wrote, "In my view, nesiritide has not yet met the minimal criteria for safety and efficacy."

ASCEND-HF randomized 7141 patients hospitalized with ADHF to receive either nesiritide or placebo for 24 hours to seven days on top of standard care, which could include other vasoactive drugs.

The hazard ratio for death from any cause or hospitalization for heart failure, the primary clinical end point, for nesiritide vs placebo was 0.93 (95% CI 0.80–1.08).

Clinical Outcomes and Self-Assessed Changed in Dyspnea at Six and 24 Hours in ASCEND-HF

End point Placebo, n=3511 (%) Nesiritide, n=3496 (%) pa
30-d all-cause death or HF rehospitalizationb 10.1 9.4 0.31
Self-assessed dyspnea at 6 h (moderately or markedly improved)b 42.1 44.5 0.03
Self-assessed dyspnea at 24 h (moderately or markedly improved) 66.1 68.2 0.007

a. For clinical end points, significance defined as <0.045; for dyspnea change, significance defined as p<0.005 at both six and 24 hours or <0.0025 at either six or 24 hours.

b. Co–primary end points

A subgroup analysis by demographics, what drugs were given at randomization, LVEF, blood pressure, renal function, and comorbidities didn't show any kind of patient that benefited significantly from nesiritide for the primary clinical end point.

On the occasion of the preliminary ASCEND-HF presentation in November, as related by heartwire , Dr Robert Califf (Duke Clinical Research Institute), chair of the trial's executive committee, said, "We constantly put drugs on the market without doing the right outcome trials. If this outcome trial had been done earlier, clinicians and patients would have had a much better idea of the potentially very limited role of this treatment, but they also would have known that it was not harmful."

ASCEND-HF was sponsored by Scios/Johnson & Johnson. O'Connor discloses receiving research funding, ASCEND-HF-related travel reimbursement, and fees for participating in "review activities such as data monitoring boards, statistical analysis, end-point committees, and the like" from Johnson & Johnson, all on behalf of his institution; and receiving payments for himself and his institution for consulting for Merck, Medtronic, GE Healthcare, Amgen, Medpace, Roche, Actelion, Johnson & Johnson, Novella Clinical, and Trevena. Califf discloses receiving grants, travel reimbursement, fees for participating in "review activities such as data monitoring boards, statistical analysis, end-point committees, and the like," payment for manuscript writing or reviewing on behalf of ASCEND-HF, and receiving consultancy fees from Amylin, Bristol-Myers Squibb, Boehringer Ingelheim, Daiichi Sankyo, GlaxoSmithKline, Kowa, and Medtronic. Topol, who is editor in chief of theheart.org , had nothing to disclose for his editorial.