NEJM: Should nesiritide be prescribed for HF at all?
While nesiritide (Natrecor, Johnson & Johnson) is approved by the FDA to treat dyspnea in acute heart failure (HF) patients, there is still an ongoing debate as to whether or not the human B-type natriuretic peptide is safe for the HF population. However, authors of the ASCEND-HF trial published in the July 7 issue of the New England Journal of Medicine concluded that they cannot recommend the drug’s use in the majority of acute HF patients due to its association with hypotension.

The results of the ASCEND-HF (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure) trial first presented at last year's meeting of the American Heart Association (AHA), showed that 30 days post-treatment, the death rates from any cause and hospital readmission for HF were slightly lower with nesiritide compared with placebo.

Christopher O’Connor, MD, of Duke University Medical Center in Durham, N.C., and his ASCEND-HF colleagues concluded that "the use of nesiritide in patients with acute decompensated heart failure neither increased nor decreased the incidence of death or rehospitalization for heart failure at 30 days." They wrote that "nesiritide thus cannot be recommended in the broad population of patients with acute decompensated heart failure represented by the study population in this trial."

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

The ASCEND-HF trial was undertaken after results from several small studies showed that the nesiritide could worsen renal function and increase death.

During the AHA meeting, Clyde W. Yancy, medical director at Baylor Heart and Vascular Institute in Dallas (at the time), said that based on the trial's results, practitioners will need to evaluate whether the drug's benefits are worth prescribing the drug to decompensated HF patients. "These will be highly individualized decisions," he noted.

In an accompanying NEJM editorial, Eric J. Topol, MD, of the Scripps Translational Science Institute in La Jolla, Calif., wrote that while nesiritide is approved to relieve patients from dyspnea, the 7,141-patient ASCEND-HF study showed no significant reduction of self-reported dyspnea at six and 24 hours after treatment and failed to show a lack of efficacy for the clinical endpoint.

In fact, Topol noted that O'Connor and colleagues failed to identify any patient population who would benefit from the drug.

Topol offered that the FDA’s 2001 approval--based on the VMAC (Vasodilatation in the Management of Acute Congestive Heart Failure) trial that compared nesiritide with placebo or intravenous nitroglycerin--led to marketing of the drug beyond the drug's indications. Topol said that the drug’s approval cultivated the use of “outpatient ‘tune-up’ clinics where patients with chronic heart failure would come for weekly intravenous injections of nesiritide--an off-label and nonvalidated approach.”

The VMAC trial showed an improvement of self-reported dyspnea at three hours after drug administration; however, Topol noted that nearly two-thirds of these patients did not receive diuretics and that the dose of nitroglycerin was not appropriately titrated.

Topol added that “it has taken a full decade to learn the truth about nesiritide’s lack of efficacy in acute HF.

“With regulatory approval of nesiritide on the basis of self-reported dyspnea and pulmonary-capillary wedge pressure, these end points can now be added to the list of surrogate end points that do not necessarily predict clinical efficacy,” Topol wrote. He added that far too often physicians learn that a drug's effects on surrogate endpoints may not be representative of clinical outcomes (i.e., high-density lipoprotein and low-density lipoprotein cholesterol levels with lipid-modifying agents).

He offered that a clinical trial that offered definitive results could alleviate any questions physicians may have on how to treat patients with the drug.

Topol offered that within the 10-year period of “fuzziness,” where how to treat patients with nesiritide was unknown, more than $1 billion was spent on nesiritide purchases. Additionally, he noted that at that time there was still clear cut uncertainty as to whether the drug caused renal dysfunction or increased mortality.

“The FDA, without a prospective plan or capability to force the sponsor to perform a fitting trial after approval, unwittingly created a monster,” Topol said. He added that physicians who prescribed nesiritide were doing so without proper evidence. However, Topol said that the manufacturer was the prime culprit due to the fact that it promoted the drug’s use but did so without compelling trial results.

Tropol said that ideally, the ASCEND-HF trial would have been conducted prior to the drug’s approval; however, he noted that “in the interest of promoting innovation for unmet medical needs, it may sometimes be appropriate to grant conditional approval on the basis of convincing evidence from small, Phase III, randomized trials, such as the recent example of a trial of a drug for cystic fibrosis.”

Additionally, Tropol concluded that “the nesiritide case study should provide the impetus for manufacturers to believe in their drug and want to learn as much and as quickly as possible rather than getting away with a de minimis approach.”