Nesiritide — Not Verified
http://www.100md.com
《新英格兰医药杂志》
To the Editor: In his Perspective article, Topol (July 14 issue)1 discusses current clinical practice with respect to nesiritide. According to the Food, Drug, and Cosmetic Act, drug approval can be withdrawn when "new evidence of clinical experience, not contained in such application or not available to the Secretary until after such application was approved, or tests by new methods, or tests by methods not deemed reasonably applicable when such application was approved, evaluated together with the evidence available to the Secretary when the application was approved, shows that such drug is not shown to be safe for use under the conditions of use upon the basis of which the application was approved (emphasis added)."2 Both of the Food and Drug Administration (FDA) reviews, in 19993 and 2001,4 omitted mortality analyses such as the one we recently published,5 and the results of PROACTION (the Prospective Randomized Outcomes Study of Acutely Decompensated Congestive Heart Failure Treated Initially as Outpatients with Nesiritide) were not available at the time of those reviews. Both fulfill the definition of new evidence, according to the FDA in its recent decision to withdraw enrofloxacin.6 Moreover, the FDA decision letter in the enrofloxacin case makes it clear that if there is "a reasonable basis from which serious questions may be inferred about the ultimate safety of . . . the drug's sponsor has the burden of persuasion on the ultimate question of whether is shown to be safe."6
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@yahoo.com
Keith D. Aaronson, M.D.
University of Michigan
Ann Arbor, MI 48109
References
Topol EJ. Nesiritide -- not verified. N Engl J Med 2005;353:113-116.
Federal Food, Drug, and Cosmetic Act, tit. 21, ch. 9, subch. V, pt. A, 355e. (Accessed September 15, 2005, at http://frwebgate.access.gpo.gov/cgi-bin/getdoc.cgi?dbname=browse_usc&docid=Cite:+21USC355.)
Throckmorton DC. 3749b2_02_01-FDA-combined medical & statistical review. 1999. (Accessed September 15, 2005, at http://www.fda.gov/cder/audiences/acspage/cardiovascularmeetings1.htm.)
Karkowsky AM. 3749b2_02_02-FDA-medical review. NDA 20-920. 2001. (Accessed September 15, 2005, at http://www.fda.gov/cder/audiences/acspage/cardiovascularmeetings1.htm.)
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.
Crawford LM. Withdrawal of approval of the new animal drug application for enrofloxacin in poultry: final decision of the commissioner. Docket no. 2000N-1571. 2005. (Accessed September 15, 2005, at http://www.fda.gov/oc/antimicrobial/baytril.html.)
To the Editor: Scios disagrees with Topol's perspective on nesiritide for the treatment of acute decompensated heart failure. His conclusion depends on numerous inaccuracies relating to the Vasodilatation in the Management of Acute Congestive Heart Failure (VMAC) trial. In the VMAC trial, 81 percent (not 30 percent) of patients received diuretics before enrollment. The lack of prescribed dose titration of nitroglycerin was criticized, but regulatory requirements dictate dosing as labeled in pivotal trials. Also, a balanced assessment of the safety of nesiritide should have included the recent large observational study on vasoactive drugs in acute decompensated heart failure.1
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
Abraham WT, Adams KF, Fonarow GC, et al. In-hospital mortality in patients with acute decompensated heart failure requiring intravenous vasoactive medications: an analysis from the Acute De-compensated Heart Failure National Registry (ADHERE). J Am Coll Cardiol 2005;46:57-64.
Felker G, Benza RL, Chandler AB, et al. Heart failure etiology and response to milrinone in decompensated heart failure: results from the OPTIME-CHF study. J Am Coll Cardiol 2003;41:997-1003.
Elkayam U, Akhter MW, Singh H, Khan S, Usman A. Comparison of effects on left ventricular filling pressure of intravenous nesiritide and high-dose nitroglycerin in patients with decompensated heart failure. Am J Cardiol 2004;93:237-240.
To the Editor: Topol's Perspective article touches on a pharmaceutical manufacturer's invitation to practitioners to earn money from office-administered medication and the evident overuse of the medication in question — in this case, of a medication of little benefit.
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. Topol replies: The medical community is indebted to Drs. Sackner-Bernstein and Aaronson, who published the pooled analyses of randomized, placebo-controlled trials of nesiritide that demonstrate an 80 percent increase in mortality1 and a 50 percent increase in renal dysfunction.2 Beyond the serious questions about nesiritide safety, there have been no trials to demonstrate clinically meaningful efficacy. This would require a reduction of death or repeated hospitalization for heart failure at 30 days, and such a trial has not been initiated, despite the drug having been approved more than 4 years ago. Clearly, the minimal criteria for safety and efficacy have not been fulfilled, and I agree that drug withdrawal, until such time validation is assured, is a reasonable proposition.
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 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
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.
Sackner-Bernstein JD, Skopicki HA, Aaronson KD. Risk of worsening renal function with nesiritide in patients with acutely decompensated heart failure. Circulation 2005;111:1487-1491.
Food and Drug Administration Cardiovascular and Renal Drugs Advisory Committee, 92nd meeting, May 25, 2001. (Accessed September 15, 2005, at http://www.fda.gov/ohrms/dockets/ac/01/transcripts/3749t2.rtf.)
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. JAMA 2002;287:1531-1540.
Teerlink JR, Massie BM. Nesiritide and worsening of renal function: the emperor's new clothes? Circulation 2005;111:1459-1461.
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@yahoo.com
Keith D. Aaronson, M.D.
University of Michigan
Ann Arbor, MI 48109
References
Topol EJ. Nesiritide -- not verified. N Engl J Med 2005;353:113-116.
Federal Food, Drug, and Cosmetic Act, tit. 21, ch. 9, subch. V, pt. A, 355e. (Accessed September 15, 2005, at http://frwebgate.access.gpo.gov/cgi-bin/getdoc.cgi?dbname=browse_usc&docid=Cite:+21USC355.)
Throckmorton DC. 3749b2_02_01-FDA-combined medical & statistical review. 1999. (Accessed September 15, 2005, at http://www.fda.gov/cder/audiences/acspage/cardiovascularmeetings1.htm.)
Karkowsky AM. 3749b2_02_02-FDA-medical review. NDA 20-920. 2001. (Accessed September 15, 2005, at http://www.fda.gov/cder/audiences/acspage/cardiovascularmeetings1.htm.)
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.
Crawford LM. Withdrawal of approval of the new animal drug application for enrofloxacin in poultry: final decision of the commissioner. Docket no. 2000N-1571. 2005. (Accessed September 15, 2005, at http://www.fda.gov/oc/antimicrobial/baytril.html.)
To the Editor: Scios disagrees with Topol's perspective on nesiritide for the treatment of acute decompensated heart failure. His conclusion depends on numerous inaccuracies relating to the Vasodilatation in the Management of Acute Congestive Heart Failure (VMAC) trial. In the VMAC trial, 81 percent (not 30 percent) of patients received diuretics before enrollment. The lack of prescribed dose titration of nitroglycerin was criticized, but regulatory requirements dictate dosing as labeled in pivotal trials. Also, a balanced assessment of the safety of nesiritide should have included the recent large observational study on vasoactive drugs in acute decompensated heart failure.1
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
Abraham WT, Adams KF, Fonarow GC, et al. In-hospital mortality in patients with acute decompensated heart failure requiring intravenous vasoactive medications: an analysis from the Acute De-compensated Heart Failure National Registry (ADHERE). J Am Coll Cardiol 2005;46:57-64.
Felker G, Benza RL, Chandler AB, et al. Heart failure etiology and response to milrinone in decompensated heart failure: results from the OPTIME-CHF study. J Am Coll Cardiol 2003;41:997-1003.
Elkayam U, Akhter MW, Singh H, Khan S, Usman A. Comparison of effects on left ventricular filling pressure of intravenous nesiritide and high-dose nitroglycerin in patients with decompensated heart failure. Am J Cardiol 2004;93:237-240.
To the Editor: Topol's Perspective article touches on a pharmaceutical manufacturer's invitation to practitioners to earn money from office-administered medication and the evident overuse of the medication in question — in this case, of a medication of little benefit.
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. Topol replies: The medical community is indebted to Drs. Sackner-Bernstein and Aaronson, who published the pooled analyses of randomized, placebo-controlled trials of nesiritide that demonstrate an 80 percent increase in mortality1 and a 50 percent increase in renal dysfunction.2 Beyond the serious questions about nesiritide safety, there have been no trials to demonstrate clinically meaningful efficacy. This would require a reduction of death or repeated hospitalization for heart failure at 30 days, and such a trial has not been initiated, despite the drug having been approved more than 4 years ago. Clearly, the minimal criteria for safety and efficacy have not been fulfilled, and I agree that drug withdrawal, until such time validation is assured, is a reasonable proposition.
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 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
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.
Sackner-Bernstein JD, Skopicki HA, Aaronson KD. Risk of worsening renal function with nesiritide in patients with acutely decompensated heart failure. Circulation 2005;111:1487-1491.
Food and Drug Administration Cardiovascular and Renal Drugs Advisory Committee, 92nd meeting, May 25, 2001. (Accessed September 15, 2005, at http://www.fda.gov/ohrms/dockets/ac/01/transcripts/3749t2.rtf.)
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. JAMA 2002;287:1531-1540.
Teerlink JR, Massie BM. Nesiritide and worsening of renal function: the emperor's new clothes? Circulation 2005;111:1459-1461.