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A Pooled Analysis of Randomized Controlled Trials

Jonathan D. Sackner-Bernstein, MD; Marcin Kowalski, MD; Marshal Fox, MD; Keith Aaronson, MD, MS

JAMA. 2005;293:1900-1905.

Context  Nesiritide improves symptoms in patients with acutely decompensated heart failure compared with placebo and appears to be safer than dobutamine. Its short-term safety relative to standard diuretic and vasodilator therapies is less clear.

Objective  To investigate the safety of nesiritide relative to noninotrope-based control therapies, primarily consisting of diuretics or vasodilators.

Data Sources  Primary reports of completed clinical trials as of December 2004 were obtained from the US Food and Drug Administration (FDA), the study sponsor (Scios Inc), a PubMed literature search using the terms nesiritide, clinical trials, and humans, and a manual search of annual meetings of 3 heart associations.

Study Selection  Of 12 randomized controlled trials evaluating nesiritide, 3 met all inclusion criteria: randomized double-blind study of patients with acutely decompensated heart failure, therapy administered as single infusion (6 hours), inotrope not mandated as control, and reported 30-day mortality.

Data Extraction  Data were extracted from FDA and sponsor documents and corroborated with published articles when available. Thirty-day survival was assessed by meta-analysis using a fixed-effects model and time-dependent risk by Kaplan-Meier analysis with Cox proportional hazards regression modeling. Where deaths were described within a range of days after treatment, an extreme assumption was made favoring nesiritide over control therapy, an approach relevant to the time-dependent analyses.

Data Synthesis  In the 3 trials, 485 patients were randomized to nesiritide and 377 to control therapy. Death within 30 days tended to occur more often among patients randomized to nesiritide therapy (35 [7.2%] of 485 vs 15 [4.0%] of 377 patients; risk ratio from meta-analysis, 1.74; 95% confidence interval [CI], 0.97-3.12; P = .059; and hazard ratio after adjusting for study, 1.80; 95% CI, 0.98-3.31; P = .057).

Conclusions  Compared with noninotrope-based control therapy, nesiritide may be associated with an increased risk of death after treatment for acutely decompensated heart failure. The possibility of an increased risk of death should be investigated in a large-scale, adequately powered, controlled trial before routine use of nesiritide for acutely decompensated heart failure.

Author Affiliations: Clinical Scholars Program, Division of Cardiology, North Shore University Hospital, Manhasset, NY (Dr Sackner-Bernstein); Department of Medicine, St Luke’s-Roosevelt Hospital Center, New York, NY (Drs Kowalski and Fox); and Division of Cardiovascular Medicine, University of Michigan, Ann Arbor (Dr Aaronson).

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