Analysis of data from FDA, manufacturer prompts call for new nesiritide study
ANN ARBOR, Mich. -- A drug that helps heart failure patients survive a crisis may actually increase their risk of dying in the first month after they leave the hospital, according to a new study that will be published April 20 in the Journal of the American Medical Association.
In fact, the analysis shows, patients treated with the intravenous drug nesiritide were 80 percent more likely to die in the next month than patients who received traditional drugs for acute heart failure symptoms, such as diuretics and vasodilators. The study analyzed clinical trial data obtained from the manufacturer of the drug, which is marketed as Natrecor, and from the U.S. Food & Drug Administration. All the clinical trials were conducted by the manufacturer, Scios, a unit of Johnson & Johnson.
The study's authors, from North Shore University Hospital in New York and the University of Michigan Cardiovascular Center, also published findings in March showing that nesiritide is associated with a much higher risk of kidney dysfunction.
"When we reported that nesiritide is linked to worsening kidney function, some physicians did not seem convinced that concern was warranted," says Jonathan Sackner-Bernstein, M.D., the study's principal investigator and director of clinical research at the Heart Failure and Cardiomyopathy Center at North Shore University Hospital in Manhasset, NY. He notes that a Scios spokesperson was quoted in the press saying that the kidney effect was already "well-known" and "dose related", and "not associated with worse outcomes."
But, Sackner-Bernstein adds, "This new meta-analysis estimating the risk of death to be increased by 80 percent serves as a compelling argument for a randomized, controlled clinical trial to be performed, to define the risks associated with nesiritide prior to its widespread use. To date, the company has not initiated any trial that will address these concerns about the link between nesiritide therapy and the risk of worsening kidney failure or higher risk of death reported in this analysis."
The new finding was made using data from three carefully designed clinical trials involving 862 heart failure patients who required urgent treatment for acute decompensation, or sudden worsening of symptoms. The 485 randomly assigned to receive nesiritide had a higher risk of death than the 377 randomized to traditional non-inotropic drugs. The size of the risk was much larger than a prior FDA estimate.
The authors acknowledge that their study can't give definitive proof of harm, but note that these are the only data that evaluate the safety of nesiritide in randomized, double-blind controlled trials.
"All the other data available are from sources that are less rigorous and less reliable. Therefore, clinical decisions need to rest on the understanding that these, the best data available, suggest that nesiritide is likely to be associated with important risk," says Sackner-Bernstein.
Co-investigator Keith Aaronson, M.D., associate professor of cardiovascular medicine at the U-M Medical School and medical director of the U-M heart transplant program, notes that the increased mortality risk was seen even when the researchers focused on data from the two clinical trials that used the starting dose of nesiritide that is now recommended to physicians.
Aaronson hopes the new finding will give physicians better perspective on the risks of nesiritide, which is perceived as being more effective and safer than dobutamine, an inotropic (heart strength-enhancing) drug that carries a substantial risk of increased mortality.
The analysis of all three clinical trials, he says, suggests that the safety of nesiritide may have been over-estimated -- especially compared with diuretics and vasodilators, which are also much less expensive. "Doctors should remember that there's no data showing that nesiritide is any better at calming acute symptoms than diuretics and vasodilators," Aaronson says.
"When the FDA approved nesiritide, they acknowledged that it could be associated with a 50 percent increased risk of death," he adds. "But it seems the FDA believed that physicians could judge how to balance the risks and benefits for individual patients. Our meta-analysis demonstrates that the risk may be even higher. In view of the relatively modest symptomatic benefit this drug provides, a death risk of this size should take precedence in a physician's treatment decision."
With that in mind, he says, the first choice for treatment should be diuretics, which aren't perfect but which are effective and cost pennies in comparison with hundreds of dollars for nesiritide. And he questions the intermittent outpatient use of nesiritide, which is covered by Medicare in several states. That approach infuses patients with the drug up to three times a week, to ease ongoing non-acute symptoms.
"Although the outpatient use of nesiritide is now being explored in a Scios-funded trial, we're concerned the study will not be large enough to allow for risks to be seen if they are present," says Aaronson.
In addition, nesiritide is currently being used in patients who have had open-heart surgery, but this too is likely to be a misguided approach, the authors say. "Very few patients require a vasodilator after open-heart surgery, but kidney dysfunction is a major concern post-operatively," Sackner-Bernstein says. "In addition to this mortality risk in patients with acutely decompensated heart failure, the meta-analysis we reported last month contradicted the perception that nesiritide protects the kidneys. Between these two analyses, and in the absence of a randomized controlled clinical trial, it's hard to see any rationale for the use of nesiritide in patients post-operatively."
The new analysis used data from the NSGET, VMAC and PROACTION trials. Nine other studies were not included because they were not randomized, double-blind trials, meaning that their results could be biased. The team pored over FDA and company data, looking closely at the risk of death within 30 days of treatment. They controlled for concurrent dobutamine use in the VMAC study.
The authors noted the statement released on April 12 by Scios, stating that the company will convene an expert panel headed by Eugene Braunwald, M.D., to evaluate the risks of nesiritide.
"We certainly welcome the forthcoming outside expert review and trust they will conclude, as we have, that there is a pressing need for a prospective, randomized clinical trial that is large enough to accurately assess kidney and mortality risks from nesiritide," says Sackner-Bernstein. "We regret that a kidney safety review was not undertaken sooner, as those data were available to them since 2001. With the disclosure of increased risk of death associated with nesiritide use in the current issue of JAMA, based on data available to Scios since 2002, the data support the need for further action."
Acutely decompensated heart failure results in nearly one million hospitalizations annually, and is the most common reason for hospitalization among people over age 65. Nearly 10 percent of such patients receive nesiritide. More than 4.9 million Americans have heart failure, a gradual worsening of heart function that often begins after a heart attack weakens the heart muscle.
Hospitalizations for acutely decompensated heart failure cost Medicare $3.6 billion in 1999. Typically, patients are hospitalized with organ congestion, an indicator that there is excess fluid present. Symptoms can include severe shortness of breath, especially with activity or when lying down. The cornerstone of therapy is the use of diuretics.
In addition to Sackner-Bernstein and Aaronson, the study's authors are Marcin Kowalski, M.D., and Marshal Fox, M.D., of St. Luke's-Roosevelt Hospital Center.
Source: Eurekalert & othersLast reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
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