Perspective on the News About Nesiritide

Journal Watch. 2005;4(5) 

On April 20, 2005, the FDA approved a revised package insert for Natrecor (nesiritide), which is used widely as first-line therapy in the management of acute decompensated heart failure. This insert includes pooled mortality data from randomized trials of nesiritide versus standard therapy alone.

For 30-day mortality, data from seven randomized trials (involving 1717 patients) were analyzed. The overall 30-day rates were 5.3% with nesiritide and 4.3% with control therapy — a nonsignificant difference. For 180-day mortality, data from four randomized trials (involving 1167 patients) were analyzed. The overall 180-day rates were 21.7% with nesiritide and 21.5% with control therapy — also a nonsignificant difference.

The 30-day mortality data from this insert are at odds with 30-day mortality data from a meta-analysis recently published in JAMA (Journal Watch Cardiology May 6 2005). In that analysis, the overall 30-day mortality rates — based on three randomized trials (involving 862 patients) — were 6.5% with nesiritide and 4.0% with control therapy (hazard ratio, 1.86; P =0.04). This difference dropped just below statistical significance after adjustment for treatment and study characteristics (HR, 1.80; P =0.057).

The difference between the mortality findings published in JAMA and those published in the new package insert can be explained by the former's exclusion of four trials that did not meet the JAMA authors' inclusion criteria (e.g., open-label design, differences in drug-administration protocol, etc.).

Nesiritide is now at the center of a contentious debate, although no official action has been taken beyond revision of the package insert. The package-insert analysis, which used more of the available data than did the analysis published in JAMA , did not show a harm with the drug; the two approaches are currently being compared and debated. In an interview with Journal Watch Cardiology , Dr. Robert Temple, Director of the FDA's Office of Medical Policy, said that the purpose of a revised package insert was simply to present the relevant data and that he believes the bottom line on mortality risk with nesiritide hasn't changed. In their article, the JAMA authors say their data just raise questions about nesiritide's safety as a first-line agent until "an adequately powered, controlled, randomized mortality trial comparing nesiritide with traditional diuretic and vasodilator drug therapy [is] performed."

For now, clinicians will need to weigh the value of nesiritide for individual patients, particularly compared with other options, all of which have a range of potentially dangerous side effects. Still, given that nesiritide is an expensive therapy, there is an obligation to demonstrate clear safety and effectiveness. On April 12, 2005, nesiritide's manufacturer issued a press release announcing that it will convene a panel of independent cardiology and heart-failure experts, led by Dr. Eugene Braunwald of Harvard, to assess data on the drug and to "provide guidance and counsel on the ongoing and planned clinical development program" for nesiritide.

— Harlan M. Krumholz, MD, SM

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