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Our recent pooled analyses included all three randomized, double-blind, controlled clinical trials of nesiritide in patients with acute decompensated heart failure who had dyspnea at rest or on minimal exertion — the current FDA indication — and estimated that the risk of death within 30 days was 74 to 86 percent higher after the use of nesiritide than after the use of control medication, with P values ranging from 0.04 to 0.06 among the analyses.5 Although these analyses do not provide proof, by providing a reasonable basis for concern about the safety of nesiritide, Scios (the developer and marketer of nesiritide) shares the same burden of proof that was faced by the sponsor of enrofloxacin: the need to demonstrate that the drug is safe in the intended population.
Although controlled trials demonstrate that nesiritide reduces symptoms of dyspnea and lowers pulmonary-capillary wedge pressure, no clinical trial has demonstrated that nesiritide is safe in patients with acute decompensated heart failure who have dyspnea at rest or on minimal exertion. To be consistent with federal regulations addressing the basis for drug withdrawal,2 the FDA can and should withdraw approval for the marketing of nesiritide. At a minimum, an advisory panel to the FDA should address these issues in a public forum.
Jonathan Sackner-Bernstein, M.D.
12 Southlawn Ave.
Dobbs Ferry, NY 10522
jonathansb{at}yahoo.com
Keith D. Aaronson, M.D.
University of Michigan
Ann Arbor, MI 48109
References
355e. (Accessed September 15, 2005, at http://frwebgate.access.gpo.gov/cgi-bin/getdoc.cgi?dbname=browse_usc&docid=Cite:+21USC355.)
No medicine for acute decompensated heart failure has ever been found to offer a survival benefit in controlled trials. Medications other than nesiritide are used off label, improve only surrogate end points, have significant toxic effects,1,2 or are associated with tachyphylaxis.3
With its current and planned research activities and the Acute Decompensated Heart Failure National Registry, Scios, the developer and marketer of nesiritide (Natrecor), is committed to evidence-based medicine. Nesiritide is the only treatment for acute decompensated heart failure that has been proved in controlled clinical trials to provide a clinical benefit — improvement of dyspnea, which is not a surrogate end point. Safe and effective when used as labeled, nesiritide continues to be an important therapy for acute decompensated heart failure.
George Schreiner, M.D.
Scios
Fremont, CA 94555
References
In rheumatology, we have a situation in which the manufacturer of infliximab (Remicade) provided information to enable physicians to earn money by office infusions of this drug, which is effective for rheumatoid arthritis but not more effective than two other drugs that may be injected at home by patients and from which the physician derives no income. The current president of the American College of Rheumatology and at least one past president encourage this as a way to offset poor reimbursement for patient care. Medicare policy is also skewed toward the use of the infusions by paying for them and the drug used and by denying payment for home use of the alternative drugs. It has also come to my attention that the infusions are being given to patients who do not have the recognized indications.
Paul A. April, M.D.
St. Francis Hospital
Tulsa, OK 74136
Dr. Schreiner raises several points, each of which can be readily addressed. In the FDA advisory committee review in May 2001, the VMAC trial was discussed in depth. An expert panelist was concerned about withholding diuretic therapy in the trial and pointed out that "only 30 percent of the Natrecor patients got an intravenous diuretic within 6 hours before they began these [study drug] infusions." The principal investigator of the trial responded, "You hit right smack dab on an incredibly important thing."3 The trial was not blinded for half the patients in the trial who had a pulmonary artery catheter in place. Nitroglycerin was essentially not titrated, with a mean dose of only 29 µg per minute in noncatheterized patients and 42 µg per minute in catheterized patients.4 Nevertheless, the significant excess in length of hospital stay with nesiritide as compared with nitroglycerin (10.0 vs. 8.1 days, P=0.008) was not reported even in the primary article.5
Observational studies are not an adequate or appropriate substitute for randomized trials. Furosemide, nitroglycerin, and nitroprusside are standard, inexpensive medications that have been used in this setting for decades and that have not been associated with an excess risk of death or kidney damage. Furthermore, the short half-life of nitroglycerin is more protective against clinically significant hypotension, which is yet another untoward effect of nesiritide. The statement that "Scios is committed to evidence-based medicine" is not in agreement with its failure to conduct a definitive randomized trial or its promotion of outpatient infusion "tune-up" centers across the country, for which there are no data to justify.
Dr. April raises awareness about the problems of reimbursement to physicians for administration of infliximab. Both the situation with this medication and the situation with nesiritide serve as examples of what may occur when there is alignment of financial incentives for manufacturers and physicians.
Eric J. Topol, M.D.
Cleveland Clinic
Cleveland, OH 44195
References
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Related Letters:
Treatment for Rheumatic Disorders
Tindall E. A., Fox D. A.
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Full Text |
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N Engl J Med 2006;
354:1322-1323, Mar 23, 2006.
Correspondence
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