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Risk of Death Associated With Nesiritide in Patients With Acutely Decompensated Heart Failure
To the Editor: A pooled analysis of all randomized clinical trials assessing nesiritide in patients with acutely decompensated heart failure found a nonstatistically significant association between use of nesiritide and increased risk of death within 30 days.1 The analysis included the Nesiritide Study Group Efficacy Trial (NSGET),2 the Vasodilation in the Management of Acute Congestive Heart Failure (VMAC) study,3 and the Prospective Randomized Outcomes Study of Acutely Decompensated Congestive Heart Failure Treated Initially in Outpatients With Natrecor (PROACTION).4 Scios Inc subsequently identified 2 additional deaths within 30 days of treatment in PROACTION, both in patients randomized to nesiritide.5 We repeated the original analysis and included these 2 deaths. We also performed an analysis limited to the VMAC study and PROACTION, the trials that used the currently recommended starting dose of nesiritide.
Methods
Crude risk of death at 30 days was compared by calculating a risk ratio with a 95% confidence interval (CI). Meta-analysis was performed to determine the risk of death after evaluating for interstudy heterogeneity by the Breslow-Day test. Because there was no evidence of heterogeneity (P = .36 for all 3 studies; P = .16 for the VMAC study and PROACTION), fixed-effects models were developed using the Mantel-Haenszel method. When the date of death could not be ascertained from the available data, assumptions were made to favor nesiritide by assigning the date of death to the latest possible date in the nesiritide group or to the earliest possible date in the control group. Because the follow-up time within the 30-day period at which the 2 newly identified deaths occurred was not reported, these 2 deaths were assigned to the final day of follow-up, day 30.
Unadjusted and adjusted hazard ratios were calculated using univariable and multivariable Cox proportional hazards regression modeling; multivariable modeling used a backward elimination method with P values of less than .10 for elimination. To investigate the potential effect of the use of a pulmonary artery catheter and dobutamine on survival, multivariable analysis evaluating treatment, pulmonary artery catheter use, dobutamine use, and all first-order statistical interactions were performed for the VMAC study. Only treatment was significantly associated with survival. To account for the possibility of a differential effect on therapy in the individual studies, a model including studies, treatment, and study x treatment interactions was evaluated. As the interactions were not significant, the final model included only treatment and study as independent variables. Statistics were calculated using SAS version 8.2 (SAS Institute Inc, Cary, NC).
Results
In the 3 studies combined, 485 patients were randomized to nesiritide and 377 to control therapy; analysis restricted to the VMAC study and PROACTION included 400 patients randomized to nesiritide and 335 to control therapy. Eleven (2%) of the patients randomized to nesiritide and 2 (0.5%) patients randomized to control therapy were lost to follow-up within 30 days. For all 3 studies combined, the crude mortality rate at 30 days was 7.6% for the nesiritide groups and 4.0% for the control groups. For the combined VMAC and PROACTION studies, the mortality rate was 7.8% for the nesiritide groups and 3.9% for the control groups (Table). Inclusion of the 2 additional deaths slightly increased the hazard ratios and decreased the corresponding P values to less than .05. The relative risk for death within 30 days for the fixed-effects model adjusted for study was 1.86 (95% CI, 1.05-3.27; P = .03) for all 3 studies. The corresponding hazard ratio using a proportional hazards model adjusted for study was 1.93 (95% CI, 1.06-3.52; P = .03). Restricting analysis to the VAMC study and PROACTION, nesiritide use was still associated with a significant increase in the risk of death within 30 days in both the fixed-effects model (relative risk, 1.93; 95% CI, 1.05-3.54; P = .04) and multivariable Cox model (hazard ratio, 2.00; 95% CI, 1.05-3.83; P = .04), adjusted for study.
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Table. Mortality Within 30 Days of Treatment Associated With Nesiritide or Control Therapy
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Comment
We believe that this revised analysis represents the most accurate estimate of the mortality risk associated with nesiritide use in acutely decompensated heart failure. It suggests an association between nesiritide and increased risk of death within 30 days of its use, even at the recommended starting dose.
There are limitations that must be considered in interpreting these results. The primary studies were not designed to definitively determine whether nesiritide is associated with risk of death. They did not collect complete information on the use of additional medications or procedures through follow-up. Unmeasured confounders may have contributed to the differences between nesiritide and control therapies. However, all 3 of these studies did prospectively plan to monitor for the risk of death subsequent to the administration of study medication.
Greater certainty about this risk can only come from a double-blind, placebo-controlled, randomized clinical trial adequately powered to assess mortality in patients with acutely decompensated heart failure receiving optimal background therapy. However, current data support reserving clinical use of nesiritide in acutely decompensated heart failure to situations in which diuretics and nitrates have proven inadequate.
Author Contributions: Dr Sackner-Bernstein had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Aaronson, Sackner-Bernstein.
Acquisition of data: Aaronson, Sackner-Bernstein.
Analysis and interpretation of data: Aaronson, Sackner-Bernstein.
Drafting of the manuscript: Aaronson, Sackner-Bernstein.
Critical revision of the manuscript for important intellectual content: Aaronson, Sackner-Bernstein.
Statistical expertise: Aaronson.
Administrative, technical, or material support: Aaronson, Sackner-Bernstein.
Study supervision: Aaronson, Sackner-Bernstein.
Financial Disclosures: Dr Sackner-Bernstein reported being a full-time employee of Clinilabs Inc, a privately held clinical trials organization focused on performance of clinical trials and related services for pharmaceutical and medical device companies; and owning stock in Johnson & Johnson in custodial accounts with 2 of his children. Dr Aaronson reported no disclosures.
Keith D. Aaronson, MD, MS
University of Michigan
Ann Arbor
Jonathan Sackner-Bernstein, MD
jonathansb{at}yahoo.com
Clinilabs Inc
New York, NY
1. Sackner-Bernstein JD, Kowalski M, Fox M, Aaronson K. Short-term risk of death after treatment with nesiritide for decompensated heart failure: a pooled analysis of randomized controlled trials. JAMA. 2005;293:1900-1905.
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2. Colucci WS, Elkayam U, Horton DP, et al, Nesiritide Study Group. Intravenous nesiritide, a natriuretic peptide, in the treatment of decompensated congestive heart failure [published corrections appear in N Engl J Med. 2000;343:1504 and N Engl J Med. 2000;343:896]. N Engl J Med. 2000;343:246-253.
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3. Publication Committee for the VMAC Investigators (Vasodilatation in the Management of Acute CHF). Intravenous nesiritide vs nitroglycerin for treatment of decompensated congestive heart failure: a randomized controlled trial [published correction appears in JAMA. 2002;288:577]. JAMA. 2002;287:1531-1540.
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4. Peacock WF IV, Holland R, Gyarmathy R, et al. Observation unit treatment of heart failure with nesiritide: results from the PROACTION trial. J Emerg Med. 2005;29:243-252.
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5. Scios submits interim report to FDA on Natrecor (nesiritide) [press release]. Fremont, Calif: Scios Inc; January 3, 2006.
JAMA. 2006;296:1465-1466.
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