Seattle, WA - Perioperative infusion of nesiritide (Natrecor, Scios/Johnson & Johnson) was associated with reductions in mortality over six months among patients with chronic heart failure who had undergone CABG surgery in a placebo-controlled study designed primarily to assess the treatment's safety [1]. Nesiritide used in this fashion—the drug is currently labeled to relieve dyspnea associated with acute decompensated HF—also appeared to protect the kidneys during the procedure and to cut the risk of respiratory failure as a surgical complication.

The six-month outcomes from the Nesiritide Administered Peri-Anesthesia in Patients Undergoing Cardiac Surgery (NAPA) study were reported here today at the Heart Failure Society of America (HFSA) 2006 Scientific Meeting. The trial's previously reported 30-day findings had suggested that perioperative nesiritide may reduce the risk of kidney damage typically associated with cardiac surgery supported by cardiopulmonary bypass (CPB).

The results of NAPA add a further wrinkle to a continuing controversy over nesiritide's safety and effectiveness in the treatment of patients with heart failure. As extensively covered by heartwire, allegations that the drug might be renotoxic and have an adverse effect on 30-day survival [2,3] in patients with acute decompensated HF had led some in the cardiology community to question whether the drug should be available and others to defend its use while urging further study of the issue. The preliminary NAPA findings point to nesiritide's potential in other clinical settings as well as an expanded need to explore the drug's safety.

The 54-center NAPA study had randomized 303 patients in NYHA functional class 2-4 with an LVEF <40% who underwent CPB-supported CABG to receive or not receive perioperative nesiritide at 0.01 µg/kg per minute for 24 to 96 hours. The infusion was started at the induction of anesthesia. Surgery consisted of CABG alone in about two thirds of each group; most of the remaining patients also had mitral-valve replacement or repair.

Perioperative hemodynamics had precluded nesiritide administration in some patients and a few others had surgery without CPB, leaving 279 patients for inclusion in the safety analysis, reported Dr John M Luber Jr (Franciscan Health System Research Center, Tacoma, WA) at the HFSA sessions.

In the 30-day outcomes analysis of NAPA previously reported by heartwire, perioperative nesiritide had been associated with improvements in kidney function, as gauged by urine output and changes in serum creatinine and glomerular filtration rate, and a significantly reduced postoperative hospital length of stay. The drug's apparently protective effects on the kidneys seemed most pronounced among patients who had initially showed some degree of renal functional impairment.

Although nesiritide had demonstrated no significant effect on survival at 30 days, it was associated with a marginally significant 56% decrease in mortality in a post hoc analysis of 180-day outcomes.

Mortality at 30 and 180 days after CABG with vs without perioperative nesiritide

Outcome	Nesiritide, n=141 (%)	Placebo, n=138 (%)	HR (95% CI)	p
30-day mortality	2.8	5.9	0.48 (0.14-1.59)	0.219
180-day mortality	6.7	14.7	0.44 (0.19-1.01)	0.046

There was no significant difference between the two groups in the rate of adverse events, including hypotension, pleural effusion, ventricular arrhythmias, or acute renal failure. Patients who had received nesiritide, however, showed a significantly decreased rate of respiratory failure as well as a possible reduction, short of significance, in the rate of postoperative atrial fibrillation.

Adverse events* associated with CABG with vs without perioperative nesiritide

Outcome	Nesiritide (%)	Placebo (%)	p
Atrial fibrillation	21.3	31.9	0.057
Respiratory failure	2.1	11.6	0.002

Cardiopulmonary bypass support is associated with intense neurohormonal activation and an increased risk of renal dysfunction in patients undergoing CABG, Luber observed in an interview with heartwire. The renoprotective effects of nesiritide, he said, probably have less to do with afterload reduction associated with peripheral vasodilation than with attenuation of neurohormonal activation.

"Blockage of the neurohormonal milieu changes endothelial activation and probably interferes with the soft-plaque rupture that produces perioperative myocardial infarction and maybe stroke, and I think nesiritide may do just that," Luber speculated. "We know that it can't be just afterload reduction because we've been afterload-reducing patients for 35 years and doing a pretty effective job of it."

Luber said that a much larger, more statistically powerful NAPA-2 trial is in the works to explore the potential of nesiritide in protecting renal function and improving clinical outcomes in different forms of cardiac surgery.

The NAPA trial was sponsored by Scios, a division of Johnson & Johnson.