Safety concerns rose again for the heart failure drug nesiritide when the manufacturer, Scios, announced in early January that 2 additional patients had died in the nesiritide arm of a placebo-controlled trial with 237 patients.
The previously missed deaths, which were deemed to be accidental and unrelated to nesiritide treatment, were uncovered by Scios researchers who were working on a request from the Food and Drug Administration for an “expanded analysis” of the trial's results using an extended, 180-day follow-up of patients in the study.
Questions about the drug's safety first surfaced last March, when the published results of a metaanalysis suggested that patients with acute decompensated heart failure who were treated with nesiritide had an increased rate of worsening renal function. A second metaanalysis published last April further suggested increased mortality associated with nesiritide treatment. And last June, an expert panel of cardiologists assembled by Scios and led by Dr. Eugene Braunwald, Distinguished Hersey Professor of Medicine at Harvard Medical School, Boston, urged the company to run a new study to better define the safety and efficacy of nesiritide (Natrecor), compared with standard therapy. The panel also recommended that nesiritide use be limited to only its labeled indications and that Scios start a educational program to inform physicians about nesiritide's proper use.
The two previously missed deaths in nesiritide-treated patients were found in a study sponsored by Scios that was designed to assess the impact of nesiritide treatment on patients with acute decompensated heart failure who were treated in a hospital emergency department or observation unit. Efficacy measures included the need for hospital admission, the length of hospitalization, and the rate of rehospitalization during 30 days of follow-up. The study was done at 38 hospitals in the United States and was led by Dr. W. Franklin Peacock IV, an emergency medicine physician at the Cleveland Clinic.
When the results from the study were published last October, the report said that 5 patients of the 120 who had received nesiritide had died within 30 days of treatment, compared with 1 patient out of 117 in the placebo group, a difference that was not statistically significant (J. Emerg. Med. 2005;29:243–52).
Both Dr. Peacock and Scios downplayed the significance of the two additional deaths, which also occurred during the first 30 days after treatment. Both deaths were accidental and not linked to nesiritide treatment. One patient died from carbon monoxide poisoning, and the second was in a traffic accident, said a spokeswoman for the Cleveland Clinic on behalf of Dr. Peacock.
The two additional deaths would not have changed the study's conclusions about nesiritide's safety, the spokeswoman added.
“Mortality was not the focus of the study, and detailed information about patient mortality was not collected,” said Mark Wolfe, a spokesman for Scios.
This study “was unique in that patients were randomized in the emergency department. Therefore, I'm not entirely surprised that 30-day follow-up may not have been complete,” commented Dr. Barry Massie, professor of medicine at the University of California, San Francisco, and chief of cardiology at the San Francisco Veterans Affairs Hospital.
“The new numbers, 7 deaths in 120 nesiritide patients and 1 death in 117 placebo patients, border on statistical significance. But the numbers are small and some of the deaths are most likely unrelated to treatment. Nonetheless, this finding does raise concern,” said Dr. Massie.