Experts are divided over nesiritide's safety in patients with acute decompensated heart failure after two metaanalyses suggested a single dose might worsen renal function and increase mortality in the first 30 days after treatment.
Concern was strong enough to prompt Johnson & Johnson, which markets nesiritide (Natrecor), to revise its labeling for the drug the same week that the second study (the one reporting an adverse mortality effect) was published (JAMA 2005;293:1900–5). The new labeling expanded the section headed “Effect on Mortality” with the company's own metaanalysis, which included more studies than the published report and showed a less alarming trend toward increased deaths among the patients who received nesiritide.
Johnson & Johnson also began to assemble a pair of expert panels to review available data and recommend future studies.
Experts differed on what the new analyses mean, what danger nesiritide might pose, and how the drug should be used in the immediate future. Some said enough questions were raised by the new findings to warrant making nesiritide a second-line treatment, at least until additional safety data are collected. Others said nesiritide remains a valuable option for patients with acute decompensation and that the drug should stay in the front-line of therapy until clear-cut evidence of danger is found.
The one point everyone agreed on was that the studies so far had not been designed to assess nesiritide's impact on survival, and thus any decisions now must be tentative, pending future findings.
“The implications of the [JAMA] paper's conclusions are that there are limited data with which to judge the safety of nesiritide at the FDA-approved dosages, and that the data that exist suggest the possibility of increased mortality with nesiritide treatment. I concur with the recommendation [of the paper's authors] to use nitroglycerin [before using nesiritide] in appropriate patients,” said John R. Teerlink, M.D., director of the heart failure clinic at the Veterans Affairs Medical Center in San Francisco. Dr. Teerlink receives speaking fees from GlaxoSmithKline Inc., which owns the European rights to nesiritide.
“I don't agree with the conclusion regarding the use of nesiritide. The analysis was limited by a small number of patients and by studies that were not designed to look at mortality. I think there need to be mortality studies that look at nesiritide, as well as nitroglycerine, nitroprusside, milrinone, and dobutamine,” the other drugs used to treat acute decompensation, said Uri Elkayam, M.D., director of the heart failure program at the University of Southern California in Los Angeles. “None of these drugs have had their safety tested” in this clinical setting, he said in an interview. Dr. Elkayam has received research support from Johnson & Johnson and is a consultant to and speaker for the company regarding nesiritide.
The first of the metaanalyses examined the possibility of a link between worsening renal function and nesiritide treatment. Jonathan D. Sackner-Bernstein, M.D., and his associates combined the findings from five randomized, controlled, double-blind studies that tested nesiritide in patients with acute decompensated heart failure and that reported the drug's effect on renal function. A significant effect on the kidney was defined as a rise in serum creatinine of more than 0.5 mg/dL following single-dose treatment.
In this combined analysis, the 797 patients who were treated with nesiritide included 21% who had worsening renal function, compared with a 15% rate among the 472 patients who were treated with comparator drugs (a diuretic, a vasodilator, or an inotrope), a statistically significant difference (Circulation 2005;111:1487–91).
The second metaanalysis, published 3 weeks later in JAMA, combined findings from three randomized, double-blind parallel group studies. In these, mortality during 30 days of follow-up was reported, nesiritide was administered as a single infusion for at least 6 hours, and inotropic therapy was not mandated in the control group. To produce intention-to-treat data, the metaanalysis included nine patients who had been excluded from the original safety analysis of one of these three studies because they had never received nesiritide.
Of 485 patients treated with nesiritide, 7.2% died within 30 days of treatment, compared with a 4.0% mortality rate among 377 patients treated with a comparator drug. This difference did not reach statistical significance.
The authors emphasized that their finding was “hypothesis generating rather than conclusive evidence of harm.”
“The best data suggest that [nesiritide] is likely to be associated with an increased risk of death after its use, all for a modest reduction in symptoms of shortness of breath for up to 6 hours, compared to placebo,” said Dr. Sackner-Bernstein, director of heart failure and preventative research at North Shore University Hospital, Manhasset, N.Y., in an interview. Dr. Sackner-Bernstein receives grant support, honoraria, and consulting fees from GlaxoSmithKline.