Am Fam Physician. 2006 Oct 15;74(8):1279-1280.
to the editor: In the February 15, 2006, issue of American Family Physician, the STEPS department by Dr. Shatsky provides a concise review of the use of nesiritide (Natrecor) in the treatment of acute decompensated heart failure.1 The author commented on the safety of nesiritide, citing evidence from two metaanalysis reviews, but failed to mention that these reviews had serious limitations.2,3 First, the reviews included studies using higher-than-approved doses of nesiritide, which may have accounted for the higher increase in serum creatinine (an effect that is stated clearly in the full prescribing information) and also indicates that this worsening of renal function did not correlate with any increase in the rate of hemodialysis in those receiving nesiritide.2,3 Second, the authors of those reviews state that serum creatinine elevations were observed “during the inpatient portion” of the trials2,3; however, in a randomized controlled trial comparing intravenous nesiritide versus nitroglycerin for the treatment of decompensated congestive heart failure, 66 percent of serum creatinine increases occurred more than seven days after discontinuation of nesiritide.4 Third, the studies were small and not powered to show differences in mortality,2,3 and it was impossible to adjust for important baseline differences, which clearly hindered any meaningful conclusions.5
Dr. Shatsky then reviewed the effectiveness of nesiritide, citing evidence from the FUSION I study,6 and concluded that this study was not enough to recommend serial treatments in the outpatient setting. However, it should be pointed out that this study6 was designed to test the safety, tolerability, and feasibility of nesiritide serial infusion, which was demonstrated and served as the rationale for the implementation of the ongoing FUSION II study that will address the outcome of such an intervention.
Physicians should be mindful of the limitations and potential bias of meta-analyses, especially when studies combined are not powered to answer the clinical question being posed. Patients with acute heart failure deserve to receive treatments such as nesiritide that have been shown to improve hemodynamics and alleviate symptoms.
Author disclosure: Dr. Alhosaini is on the speakers bureau for Scios, Inc., which manufactures nesiritide.
1. Shatsky M. Nesiritide (Natrecor) for acute decompensated heart failure. Am Fam Physician. 2006;73:687–8.
2. 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;293:1900–5.
3. Sackner-Bernstein JD, Skopicki HA, Aaronson KD. Risk of worsening renal function with nesiritide in patients with acutely decompensated heart failure [Published correction appears in Circulation 2005;111:2274]. Circulation. 2005;111:1487–91.
4. Heywood JT. Temporal characteristics of serum creatinine elevations in patients receiving nesiritide and nitroglycerin. Poster presented at: Heart Failure Society of America; Sept. 18–21, 2005; Boca Raton, Fla.
5. Abraham WT. J Card Fail. 2005;11(6):S169. Abstract 298.
6. Yancy CW, Saltzberg MT, Berkowitz RL, Bertolet B, Vijayaraghavan K, Burnham K, et al. Safety and feasibility of using serial infusions of nesiritide for heart failure in an outpatient setting (from the FUSION I trial). Am J Cardiol. 2004;94:595–601.
in reply: I appreciate Dr. Alhosaini’s interest in the STEPS review of nesiritide (Natrecor) for the treatment of acute decompensated heart failure. The methodologic issues that Dr. Alhosaini notes affect our ability to define the risks and benefits of nesiritide.1,2 Nesiritide has only been studied in selected patient populations. The link between nesiritide and increased mortality or renal failure is not conclusive. However, we need to be mindful that these are serious potential risks in severely ill patients. Patients with acute heart failure certainly deserve a treatment that may improve their symptoms, but they also deserve to know the potential risks of the treatment.
Neither the use of nesiritide for outpatient treatment nor the use of nesiritide for patients with chronic or stable heart failure has been approved by the U.S. Food and Drug Administration (FDA).3 Also, the manufacturer has clearly stated that nesiritide is not indicated for intermittent outpatient infusion, nor is it indicated for scheduled repetitive use.2,4,5 Although the results of the ongoing FUSION II study may provide physicians with more information about the safety and effectiveness of nesiritide for outpatient serial infusions, the currently available evidence fails to support the use of nesiritide in this manner.
With the recent erosion of public trust in the prescribing of certain medications (e.g., cyclooxygenase-2 inhibitors, selective serotonin reuptake inhibitors), it is essential that health care providers neither overestimate a medication’s benefits nor underestimate its potential risks. Physicians should understand that approval recommendations from the FDA are made based on limited evidence6 and should be curious about the data on the risks and benefits of new medications. I look forward to new outcome data that will clarify the appropriate clinical use of nesiritide.
1. U.S. Food and Drug Administration. 2005 Safety Alert: Natrecor (nesiritide). Accessed July 18, 2006, at: http://www.fda.gov/medwatch/safety/2005/natrecor2_DHCP.htm.
2. Topol EJ. Nesiritide - not verified. N Engl J Med. 2005;353:113–6.
3. United States of America, Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research. Transcripts of the 92nd Meeting of the Cardiovascular and Renal Drugs Advisory Committee; May 25, 2001; Bethesda, Md. Accessed July 20, 2006, at: http://www.fda.gov/ohrms/dockets/ac/01/transcripts/3749t2.rtf.
4. Panel of cardiology experts provides recommendations to Scios regarding natrecor [press release]. Fremont, Calif: Scios, Inc.; June 13, 2005. Accessed July 18, 2006, at: http://www.sciosinc.com/scios/pr_1118721302.
5. Natrecor [fact sheet]. Accessed July 19, 2006, at: http://www.natrecor.com/natrecor/fact_sheet.
6. Kesselheim AS, Fischer MA, Avorn J. The rise and fall of Natrecor for congestive heart failure: implications for drug policy. Health Aff (Millwood). 2006;25:1095–102.
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