Stanford, CA - Infusions of nesiritide (Natrecor, Scios/Johnson & Johnson) on top of standard therapy were not associated with worsening renal function in a small, randomized placebo-controlled trial of patients with acute decompensated heart failure (ADHF) whose kidneys were already compromised [1].

The findings add to other limited data suggesting that, contrary to some concerns, nesiritide doesn't hurt the kidneys in patients with ADHF. But they fall far short of proving it and do not address allegations that the drug may increase mortality in the same setting.

"Importantly, administration of nesiritide did not protect against the development of renal dysfunction, either," write the authors, Dr Ronald M Witteles (Stanford University School of Medicine, CA) and associates, in the November 6, 2007 Journal of the American College of Cardiology. The remark addresses what had been an early misconception about the drug, which is functionally a vasodilator—that it can protect against declining renal function during ADHF management.

Witteles had presented the study, called B-Type Natriuretic Peptide in Cardiorenal Decompensation Syndrome (BNP-CARDS), in preliminary form at the American College of Cardiology 2007 Scientific Sessions, as reported by heartwire at the time. Nesiritide is a manufactured version of brain-type natriuretic peptide (BNP), the endogenous form of which metabolically serves to counteract neurohormonal derangements associated with heart failure [2].

These data are provocative but not nearly definitive.

Nesiritide, one of cardiology's most controversial drugs, had been popular for the management of ADHF when questions about a possible adverse effect on renal function and survival emerged in pooled analyses of trials [3,4]. As related by heartwire over the past several years, clinicians were divided on whether the drug should be pulled from the market, and eventually nesiritide's manufacturer got behind a large randomized controlled trial aimed at resolving the issues. Called the Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND HF), the trial is in its early stages.

In BNP-CARDS, 75 patients with ADHF but with "moderate" renal impairment were randomized to receive either placebo or nesiritide, ideally as a 2-µg/kg IV bolus followed by infusion at 0.01 µg/kg per minute for 48 hours. The bolus wasn't given to 33% and 36% of the actively treated patients and controls, respectively, out of concern—as Witteles had told heartwire at the ACC sessions—that patients initially with hypotension would experience further drops in blood pressure.

The primary outcomes were as previously reported: no significant differences in the incidence of a >20% rise in serum creatinine during the first seven days, compared with baseline, or in change in serum creatinine from admission to day seven (or discharge). Nor were there significant differences in hospital length of stay, net fluid balance, IV diuretic use, incidence of treatment withdrawal due to hypotension, or the 30-day rate of death or readmission. Nesiritide-treated patients tended to have lower systolic and diastolic blood pressures throughout the infusion, compared with controls, the difference occasionally reaching significance.

"These data are provocative but not nearly definitive, due to the small sample size, single-center experience, and lack of power to detect a change in important clinical outcomes," according to an accompanying editorial by Dr Marc A Silver (University of Illinois, Oak Lawn) and Dr Clyde W Yancy (Baylor University Medical Center, Dallas, TX) that was expansive in its appraisal of contemporary ADHF management.

In the context of other research, BNP-CARDS "serves to mute, but not resolve, concerns regarding renal insufficiency related to the use of natriuretic peptides," according to Silver and Yancy. The results of several prospective studies reported since the allegations against nesiritide emerged more than two years ago, conducted in a variety of clinical settings, also showed no evidence that nesiritide hurts the kidneys and have "assuaged some of our concerns of renal harm," they write. "We must, however, continue to resolve the questions of [nesiritide] safety while also continuing to pursue the precise clinical role, ideal patient phenotype, and reasonable expectation of drug effect."