Trial: Nesiritide Safe for Acute Heart Failure
By Mitchel L. Zoler
Elsevier Global Medical News
CHICAGO - Five years of uncertainty about nesiritide's safety for treating acute decompensated heart failure came to an end, as results from a multicenter trial with over 7,000 patients showed the drug does no harm.
The results also showed that nesiritide had, on average, a marginal beneficial effect for improving patients' dyspnea, with no apparent benefit at all for reducing 30-day mortality or need for rehospitalization.
But the findings provided enough evidence to allow the drug to regain a place in the otherwise skimpy armamentarium for treating acute decompensated heart failure, a second-line agent to fall back on when more standard agents - diuretics and vasodilators - fail to give patients adequate relief, experts said. They also speculated that somewhere in the varied mix of acutely ill heart failure patients lies a patient subgroup that stands to gain significant benefit from nesiritide treatment. The problem will be how to find those patients.
"Nesiritide can now be considered a safe therapy in patients with acute heart failure," Dr. Adrian F. Hernandez said at the annual scientific sessions of the American Heart Association. Further analysis of the study findings "is likely to permit better understanding of ... patient profiles that may potentially benefit from nesiritide," added Dr. Hernandez, a cardiologist at Duke University in Durham, N.C.
"I think there will be a wide divergence of opinion on the role of this drug," said Dr. Mariell L. Jessup, professor of medicine and medical director of the Heart and Vascular Center at the University of Pennsylvania in Philadelphia. "If physicians want a drug that will fundamentally change the outcome of their patients' acute decompensated heart failure, then there is no role for nesiritide. However, if a patient is suffering and continues to be very dyspneic, there may be a role for adding nesiritide to current treatment. If the patient does not respond to the traditional drugs, diuretics and vasodilators, then physicians may very well reach for nesiritide to see if it will benefit the patient," she said in an interview.
"The question was, Is nesiritide safe? Does it increase mortality or cause renal failure? Now that we know it's safe, the focus will be on [determining which] are the right patients to get it. The study showed a small average benefit, and somewhere in there is probably a smaller population who benefits," commented Dr. Alfred Bove, a cardiologist and heart failure specialist at Temple University in Philadelphia and immediate past president of the American College of Cardiology.
The cloud that hung over nesiritide dates back to a pair of meta-analyses published by Dr. Jonathan D. Sackner-Bernstein 5 years ago (JAMA 2005;293:1900-5; Circulation 2005;111:1487-91). Those analyses suggested that nesiritide treatment of heart failure patients was linked with an excess risk of death and renal failure. The reports led to a "meteoric" drop in the drug's use, said Dr. Robert M. Califf, professor of cardiology at Duke University, who collaborated with Dr. Hernandez in running the new study. It also led the company that markets nesiritide, Scios, to form a panel of experts to review the evidence.
The panel recommended a pair of studies to test the drug's safety and efficacy. Results from the first of those studies, the Second Follow-Up Serial Infusions of Nesiritide (FUSION II), failed to find any evidence that regular infusions of nesiritide helped heart failure patients (Circ. Heart Fail. 2008;1:9-16). Dr. Hernandez's new report results from the second of those studies, designed to test nesiritide's safety and efficacy for treating acute decompensated heart failure.
The Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF) randomized 7,141 patients at 398 sites in 30 countries, including 214 centers in North America. It enrolled patients hospitalized for acute decompensated heart failure within 24 hours of when they began intravenous therapy. Patients had dyspnea at rest or with minimal activity, and either a respiratory rate of at least 20 breaths per minute or rales at more than a third of bases. Patients also needed at least one objective measure of their disease severity, such as elevated brain natriuretic peptide or a history of a left ventricular ejection fraction of less than 40% within the past year. Study exclusions included patients with hypotension at baseline and those with acute coronary syndrome.
The researchers randomized patients to receive either an intravenous bolus of 2 mcg/kg nesiritide or placebo, which was followed by a continuous intravenous infusion of nesiritide at 0.01 mcg/kg per minute or placebo for up to 7 days. Each treating physician determined the exact duration of the continuous infusion. All patients also received usual care with diuretics and a vasodilator such as intravenous nitroglycerin or nitroprusside. The patients' average age was 67, and 80% had an ejection fraction of less than 40%. Average respiratory rate was about 24 breaths/min, and average systolic blood pressure was about 124 mm Hg.
At 30 days after the start of treatment, the combined rate of all-cause death or rehospitalization for heart failure, one of the study's two primary end points, was 10.1% in the 3,511 evaluable placebo patients and 9.4% in the 3,496 evaluable patients who received nesiritide, a nonsignificant difference. The 30-day mortality was 4% in both arms of the study.
The study's second primary end point was the change in dyspnea severity at 6 and 24 hours after treatment began. At 6 hours, 15.0% of patients on nesiritide and 13.4% of patients on placebo were "markedly better"; at 24 hours, 30.4% of the nesiritide patients and 27.5% of the placebo patients were markedly better. The percentage of patients whose dyspnea was either markedly or moderately better at 6 hours was 45% with nesiritide and 42% with placebo, and at 24 hours it was 68% with nesiritide and 66% with placebo. Although these between-group differences fulfilled usual definitions of statistical significance at both time points, the study prespecified a higher standard for statistical significance that was not met.
A series of subgroup analyses failed to identify any smaller group of patients who received a significant dyspnea or mortality and rehospitalization benefit from nesiritide, except for the roughly 10% of patients who had not been on diuretic treatment when they entered the study, who did show a significant dyspnea benefit from nesiritide.
The results also showed no suggestion of an adverse renal effect from nesiritide, with no change in patients' creatinine levels or in their glomerular filtration rate through the 30 days after treatment. Patients who received nesiritide had a 7% rate of symptomatic hypotension, compared with 4% in the placebo group, a statistically significant difference.
"We run out of [treatment] options really fast for patients with acute decompensated heart failure if patients don't get better with diuretics, morphine, and vasodilators," commented Dr. Jessup. "People will use [nesiritide] when patients fail to respond" to the standard agents. "We now know it's relatively safe." But nesiritide is not a first-line drug, she said.
"The problem with acute decompensated heart failure is that it is a vast array of different patients and different pathologic entities. Some patients have normal ejection fractions, some patients have renal insufficiency, some have severe hypertension. No single treatment will work. Everyone in heart failure who you talk to says some patients really respond to nesiritide. Who are those patients, and how can we identify them? I don't know," Dr. Jessup said.
Acute heart failure patients who may benefit most from nesiritide may be those who are sicker, have a low ejection fraction, or present to the hospital sooner, but more data are needed to get a clearer patient profile, Dr. Hernandez said.
ASCEND-HF was sponsored by Scios, a Johnson & Johnson company, which markets nesiritide (Natrecor). Dr. Hernandez has received research grants from Johnson & Johnson, Dr. Califf has received research grants from Johnson & Johnson-Scios, and Dr. Jessup has received research funding from Scios.