NEW ORLEANS -- In the largest trial of stage D heart failure, nesiritide (Natrecor) showed no benefit as outpatient therapy, yet there was no evidence of renal safety concerns with the drug, researchers here reported.
NEW ORLEANS, March 27 -- In the largest trial of stage D heart failure, nesiritide (Natrecor) showed no benefit as outpatient therapy, yet there was no evidence of renal safety concerns with the drug, researchers here reported.
In the 920-patient FUSION II (Follow-Up Serial Infusions of Nesiritide in Advanced Heart Failure) trial, 36.7% of the nesiritide patients versus 36.8% of placebo patients reached the primary endpoint of death or cardiorenal hospitalization (P=0.79), said Clyde Yancy, M.D., of the Baylor Heart and Vascular Institute, in Dallas. Patients had a mean ejection fraction of less than 25%.
When the categories were separated and scrutinized, Dr. Yancy found that 9.6% of the 306 placebo patients had died, compared with 9.5% of 614 nesiritide patients (P=0.98) and 33.6% of placebo patients, Dr. Yancy reported at the American College of Cardiology meeting. Also 32.9% of nesiritide patients required cardiorenal hospitalizations (P=0.95),
"Serial administration of outpatient nesiritide infusions was not shown to be significantly beneficial in the context of excellent care," Dr. Yancy said. "I think these results rule out home-based therapy with this drug."
But he added that many outpatients in clear distress he encounters could benefit from nesiritide yet they don't want to be hospitalized. At this point, he said, there is no good answer for that patient.
Dr. Yancy did, however, point out that background therapy was excellent with high compliance regarding standard, evidence-based medical and device therapy, along with an extraordinary program of precise disease management.
FUSION II followed a pilot study suggesting that serial infusions improved outcomes in a select group of patients but not in the overall population.
The study recruited 920 patients to nesiritide in a 2 mcg/kg bolus and a 0.01 mg/kg/min infusion for four to six hours or matching placebo once or twice weekly for 12 weeks. The mean age of patients was 65 and 71% were men.
The event rates in FUSION II were 33% lower than that seen in FUSION I, likely due to the excellent background therapy and medical care, Dr. Yancy said
So the take home message for clinicians was "that appropriate use of evidence-based medical and device therapy, as well as avoidance of non-evidence based therapies done in concert with highly sophisticated and rigorous follow-up, is beneficial even in advanced disease," he said.
Raymond Gibbons, M.D., of the Mayo Medical School in Rochester, Minn., who is president of the American Heart Association, agreed with this upbeat spin on FUSION II.
"What we see in this study is that following guidelines results in maximum benefit for patients," said Dr. Gibbons. But at the same time, Dr. Gibbons agreed that there is a dearth of effective therapies for heart failure.
The other positive finding from this neutral trial came from the safety data--there was no evidence of renal harm or excess mortality attributed to use of nesiritide.
Niseritide, a recombinant form of human B-type natriuretic peptide that is indicated for the treatment of acute decompensated heart failure, has had a checkered history since its approval in 2001 when it was hailed as major advance in treatment of the condition.
Post marketing studies suggested excess mortality among niseritide-treated patients, but that was initially attributed to overuse of the drug.
However, last September the Journal of the American Medical Association published a pooled analysis of three published studies that found evidence of early mortality even when the drug was properly dosed.
"I would not say flat out that nesiritide is safe, but we did not see any evidence of a renal signal in this study," Dr. Gibbons said. "So that is encouraging."
Mariell Jessup, M.D., of the University of Pennsylvania, cautioned against making safety assumptions on the basis of the FUSION II trial.
"I don't think we use these results to say the drug was safe," she said, noting that the study was not powered to confirm that statement. Dr. Jessup co-chaired the late-breaking clinical trials session at which the FUSION II findings were reported.
Dr. Yancy declared no conflicts. Dr. Gibbons said his possible conflicts of interest included work for Hawaii biotech; Consumers Union, TIMI 37A; KAI Pharmaceuticals, TaraGen, Radiant Medical, Therox Corp., Cardiovascular Clinical Studies, King Pharmaceuticals. Dr. Jessup disclosed support from Medtronic, GlaxoSmithKline, Centracor, and Acorn.