New Orleans, LA - Until a large, randomized controlled trial that's still in the works sheds a brighter light on the question, concerns that nesiritide may be renotoxic or life-threatening when used in patients with acute decompensated heart failure (ADHF) are based on hindsight observations from separate, often very different studies [1,2]. With prospectively gained insights in short supply, a small randomized, placebo-controlled trial suggested that the drug neither worsens nor improves kidney function in an especially high-risk population that presented with ADHF and moderate to severe renal insufficiency [3].

Dr Ronald M Witteles

Although it randomized only 75 patients, "the results of our study don't show even a hint of a trend, positive or negative, on renal function," Dr Ronald M Witteles (Stanford University, CA) told heartwire. "So the likelihood of [our] missing a large adverse renal effect from this treatment is small."

As the first ADHF trial to prospectively evaluate the drug's effects on renal function, Witteles said, finding "no indication of benefit or harm," it should "alleviate some concerns" about the use of nesiritide. He presented the findings here at the American College of Cardiology 2007 Scientific Sessions.

The patients, required at randomization to have a glomerular filtration rate (GFR) of 15 to 60 mL/min, received either nesiritide as a 0.01-µg/kg/min infusion for 48 hours or matching placebo. Patients also received an initial 2-µg/kg bolus at the treating physicians' discretion; more often than not, the bolus was omitted as a caution in patients with preexisting hypotension, which occurred in about 35% of patients in each group, Witteles said.

The mean admission serum creatinine was about the same in both groups, 1.82 and 1.86 mg/dL for nesiritide recipients and controls, respectively. Also comparable were the admission GFR and systolic blood pressure.

Safety and acute efficacy end points, nesiritide in ADHF with renal dysfunction

End point	Nesiritide, n=39	Placebo, n=36
>20% increase in SCr anytime during 1st hospital week* (%)	23	25
Change in SCr from admission to discharge or hospital day 7* (mg/dL)	-0.05	+0.05
Weight loss during infusion (kg)	2.19	1.58
Total IV furosemide dose while on infusion (mg)	124.5	106.7
Infusion stopped due to hypotension (%)	13	6
Dialysis performed (%)	0	3

There were no significant differences in either primary end point, prevention of worsened renal function (defined as >20% increase in serum creatinine compared with admission) and change in serum creatinine from admission to discharge or the seventh hospital day, whichever came first, Witteles reported. Nor were there differences in a range of secondary end points, including weight loss, furosemide intake, hypotension prompting withdrawal of the continuous infusion, and hospital length of stay.

Thirty-day mortality and rate of death or rehospitalization were statistically similar, although there were "small trends favoring placebo," Witteles said. But he noted the trial was underpowered to show any such differences authoritatively.

Clinical end points, nesiritide in ADHF with renal dysfunction

End point	Nesiritide, n=39 (%)	Placebo, n=36 (%)
Admission to coronary care unit	10	8
Mortality at 30 days	10	6
Death or rehospitalization at 30 days	33	25

Dr Barry M Massie

The findings "should make people more comfortable" about using nesiritide in ADHF, agreed Dr Barry M Massie (University of California and Veterans Affairs Medical Center, San Francisco), who wasn't involved in the trial. Any evidence for nesiritide's kidney effects should be kept in perspective, he observed for heartwire: in the previous trials that led to concerns that the drug may be renotoxic, serum creatinine levels were seen to be increased often later than one week after the nesiritide infusion, inconsistently, and in presumably sicker patients who had subsequently come back to the hospital. The current study's results may be more reliable, according to Massie. "Common sense tells me, if a drug is going to affect renal function, you should see it by seven days."

He also said the findings dispute the idea that nesiritide protects the kidneys when given with diuretics, which had been the drug's reputation and a key reason for its previous popularity in ADHF. "My concern all along was that there was no evidence that it improved renal function, and yet physicians believed it."

Scios funded the current study, which Witteles said, nonetheless, was "investigator-initiated." Massie is a member of the steering committee for the Scios-backed FUSION-2 and ASCEND-HF trials and reports having consulted for Scios. Coauthor Dr Donald Schreiber (Stanford University) reports being on the speakers' bureau for Sanofi-Aventis and Schering and receiving research support from Abbott Point of Care, Scios, and AstraZeneca. Coauthor Dr Michael Fowler (Stanford University) reports receiving consulting fees or honoraria from AstraZeneca, Scios, Medtronic, Merck, and GlaxoSmithKline and research support from Scios.