Nesiritide of No Benefit in Acute Decompensated Heart Failure

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Ten Years to Uncover the Truth

"It has taken a full decade to learn the truth about nesiritide’s lack of efficacy in acute heart failure," said Dr. Eric J. Topol.

"Along the way, well more than $1 billion was wasted on purchasing the drug," he wrote.

The FDA "unwittingly created a monster" because it had no plan or capability to perform an adequate clinical trial after the drug was approved. And physicians, "who prescribed nesiritide without definitive knowledge of efficacy or safety, particularly for off-label use such as for ‘tune-up clinics,’ were treating patients without an adequate evidence base," Dr. Topol said.

But the chief culprit was the manufacturer, Scios, "because it widely promoted nesiritide in the early years after its approval but was unwilling to appropriate the resources to design and execute a compelling trial."

Dr. Topol is with the Scripps Translational Science Institute, La Jolla, Calif. He reported no financial conflicts of interest. These remarks were taken from his editorial comment accompanying Dr. O’Connor’s report (N. Engl. J. Med. 2011;365:81-2).



Nesiritide has no effect on 30-day mortality or rehospitalization rates in patients with acute decompensated heart failure, according to results of the ASCEND-HF trial reported in the July 7 issue of the New England Journal of Medicine.

In a large 3-year international clinical trial called by an independent panel "to answer the question of whether nesiritide is effective and safe," the drug also failed to improve self-reported dyspnea at 6 hours or 24 hours. It did not worsen renal function, but it nearly doubled the rates of both symptomatic and asymptomatic hypotension.

"Nesiritide thus cannot be recommended in the broad population of patients with acute decompensated heart failure represented by the study population in this trial," wrote Dr. Christopher M. O’Connor of Duke Clinical Research Institute, Durham, N.C., and his associates in the Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF) trial.

Nesiritide, a recombinant B-type natriuretic peptide with vasodilatory action, was approved in 2001 for use in patients with acute heart failure, based on separate small studies showing that it reduced pulmonary-capillary wedge pressure and eased dyspnea within 3 hours of administration. Later meta-analyses of these and other small trials, however, indicated that the drug worsened renal function and nearly doubled early mortality.

"In hindsight, nesiritide was approved and swiftly adopted in the United States because of its perceived large benefit in relieving dyspnea and congestion, and then its used markedly decreased because of published meta-analyses reporting a detrimental effect on survival and renal function. Our study showed that neither belief was accurate," Dr. O’Connor and his colleagues noted.

ASCEND-HF involved 7,141 patients treated at 398 medical centers around the world. All the participants received standard therapies including diuretics, morphine, and vasoactive medications. Half also received intravenous nesiritide and half received a placebo for up to 7 days.

The two coprimary end points were change in self-reported dyspnea at 6 and 24 hours and rehospitalization for heart failure or death from any cause within 30 days. There was a slight numerical advantage with nesiritide over placebo for dyspnea (44.5% vs. 42.1%, P = .03), but it did not reach the prespecified level for statistical significance. The rates of the second end point were 9.4% with nesiritide and 10.1% with placebo, another nonsignificant difference.

The two study groups also showed no significant differences in self-reported patient well-being, rehospitalization for cardiovascular causes, death from cardiovascular causes, total days alive and out of the hospital at 1 month, rates of persistent or worsening HF, or death from any cause at 1 month. Rates of renal impairment also were comparable between the two groups, regardless of baseline renal insufficiency, the investigators noted (N. Engl. J. Med. 2011;365:32-43).

Significantly more patients who received nesiritide had an episode of asymptomatic (21.4%) or symptomatic (7.2%) hypotension, compared with patients who received placebo (12.4% and 4.0%, respectively).

"The development of nesiritide poses fundamental questions about the manner in which therapies are developed and assessed. 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.

"Our findings underscore the fact that systematic overviews with small numbers of events can yield unreliable estimates of the balance of benefits and risks, and interpretation of the data is confounded by these imprecise estimates," Dr. O’Connor and his colleagues wrote.

The results also "highlight the urgent need for rigorously designed trials with adequate power to provide reliable estimates that can replace incomplete or inadequate evidence as a basis for therapeutic decisions," they added. The ASCEND-HF results were presented at the annual scientific sessions of the American Heart Association in November 2010.

ASCEND-HF was sponsored by Scios, a Johnson & Johnson company, which markets nesiritide (Natrecor). The investigators reported ties to numerous industry sources. Dr. O’Connor has received consulting fees from Medtronic, Forest, Amgen, Medpace, Roche, and Actelion. Two of the authors are employees of Johnson & Johnson.

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