"Exploratory" study suggests nesiritide protects kidneys during cardiac surgery

February 05, 2007

Washington, DC - Perioperative infusion of nesiritide (Natrecor, Scios/Johnson & Johnson) apparently blunted the adverse renal effects of pump-supported coronary bypass surgery in patients with systolic heart failure, including those who went into the procedure with impaired kidney function, in a small randomized study published in the Journal of the American College of Cardiology[1].

In the Nesiritide Administered Peri-Anesthesia in Patients Undergoing Cardiac Surgery (NAPA) study, nesiritide—compared with placebo—was associated with smaller rises in serum creatinine and decreases in glomerular filtration rate (GFR) and greater urine output. In addition, there were suggestions of shorter hospital stay and possibly better survival over six months related to active therapy, report Dr Robert M Mentzer Jr (Wayne State University, Detroit, MI) and colleagues. The report appeared online December 8, 2006 and is scheduled for the journal's February 13, 2007 issue.

"There is still much to learn regarding how best to use this promising agent," writes Dr Israel Belenkie (University of Calgary, AB) in an accompanying editorial[2], referring in part to the current controversy over whether nesiritide's symptomatic benefits in acute decompensated HF come at the expense of kidney function and survival. "The NAPA trial provides encouraging results in one subgroup of patients who might benefit from the use of nesiritide, but more comprehensive data are required before promoting routine use in this population."

The major results of the "exploratory" study, as the authors refer to it, had been previously reported by heart wire based on presentations at several conferences, most recently the Heart Failure Society of America 2006 Scientific Meeting.

Conducted at 54 US centers, NAPA had randomized 303 patients in NYHA functional class 2-4 and an LVEF <40% who were undergoing CABG supported by cardiopulmonary bypass to receive perioperative placebo or nesiritide at 0.01 µg/kg per minute for 24 to 96 hours. A total of 272 patients ultimately received their assigned agent and underwent cardiopulmonary-bypass-supported CABG.

The nesiritide-related attenuations in peak serum creatinine and GFR responses to surgery were significant whether or not baseline serum creatinine levels exceeded 1.2 mg/dL but were more pronounced when concentrations were above that threshold, according to the authors.

Mean changes* in SCr and GFR by treatment group and baseline renal function

End point Nesiritide Placebo p
Peak SCr increase (mg/dL)      
All evaluable patients 0.15 (n=133) 0.34 (n=133) <0.001
Baseline SCr <1.2 mg/dL 0.19 (n=104) 0.30 (n=100) 0.027
Baseline SCr >1.2 mg/dL 0.02 (n=29) 0.48 (n=33) 0.001
Maximum decrease in GFR
(mL/min per 1.73 m 2 )
     
All evaluable patients -10.2 (n=133) -17.8 (n=133) 0.001
Subjects with baseline SCr <1.2 mg/dL -13.1 (n=104) -20.6 (n=100) 0.010
Subjects with baseline SCr >1.2 mg/dL -0.4 (n=29) -8.9 (n=33) 0.003
*Through discharge or hospital day 14, whichever came first
SCr=serum creatinine
GFR=glomerular filtration rate

Urine output during the first 24 hours after surgery was 2926 mL in the nesiritide group and 2350 mL among controls (p<0.001). Patients who received the active drug also were discharged earlier (9.1 hospitalization days vs 11.5, p=0.043) and might have lived longer (180-day mortality, 6.6% vs 14.7%, p=0.046). There were no other safety differences, nor were there differences in postoperative use of IV diuretics, vasodilators, or vasopressor and inotropic agents.

"The most likely explanation for the salutary effects of nesiritide administration on patient outcomes in the NAPA trial seems to be prevention or attenuation of postoperative renal dysfunction," speculate Mentzer et al.

"The effects of nesiritide on renal function were clear; however, translation of those results to clinical outcomes remains to be demonstrated," Belenkie writes. Also, 180-day mortality was not a prespecified end point, was added late in the course of the trial, and couldn't be determined for many of the patients, he observes. The resulting shortfall in data "precludes acceptance of the mortality difference with confidence despite the statistical significance of the results."

NAPA was sponsored by Scios, a division of Johnson & Johnson, from which M entzer and coauthor Dr Robert N Sladen (Columbia University, New York, NY) have received honoraria; for which Mentzer and coauthors Dr Mehmet C Oz (Columbia University) and Dr Nicholas G Smedira (Cleveland Clinic, OH) have been consultants/advisory board members; from which Sladen and coauthors Dr John M Luber (Franciscan Health System, Tacoma, WA) and Dr Robert F Hebeler (Baylor University, Dallas, TX) have received grant/research support, and for which Hebeler was a speakers' bureau participant. Belenkie reports having been an adviser to and applied for grant support to Ortho-Biotech, the Johnson & Johnson subsidiary responsible for nesiritide in Canada.

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