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MARKETWATCH

The Rise And Fall Of Natrecor For Congestive Heart Failure: Implications For Drug Policy

Abstract

 
Recent revelations of unexpected side effects of widely prescribed medications have raised questions about several aspects of U.S. drug policy, from initial Food and Drug Administration (FDA) approval to promotion by manufacturers and prescribing by physicians. One prominent example is nesiritide (Natrecor), a treatment for congestive heart failure. We use it as a case study to assess how FDA standards for drug approval, marketing practices by drug manufacturers, and physicians’ prescribing choices can shape the risk-benefit relationship of new drugs. Based on the nesiritide experience, we suggest several ways to improve policies for drug approval, postmarketing surveillance, and drug utilization.

Recently, however, questions have been raised about the drug’s safety and clinical usefulness. Reassessments of the trial data, much of which had been submitted to the FDA, found higher rates of kidney impairment and mortality in nesiritide-treated patients. In April 2005, almost four years after the drug’s approval, the FDA ordered the manufacturer to add more information about the risk of death to its package insert and sent a warning letter about kidney impairment to physicians. The manufacturer, Scios, organized a panel of expert cardiologists to examine the drug’s safety. In June 2005, the panel recommended that "the use of nesiritide should be strictly limited to patients presenting to the hospital with acutely decompensated congestive heart failure who have dyspnea at rest" and suggested that Scios undertake clinical trials to better assess the benefits and risks of the drug.² One leading cardiologist suggested that sales should be suspended because the "minimum criteria for safety and efficacy" were not being met.³

As the medical community struggles with controversies surrounding cardiovascular risks of cyclooxygenase-2 (COX-2) inhibitors such as rofecoxib (Vioxx) and suicidal behavior precipitated by some antidepressants in adolescents, the nesiritide case raises important questions about policies for drug approval and postmarketing surveillance, as well as the marketing, promotion, and reimbursement of newly approved therapeutic agents.

Premarketing Clinical Trials

Top Premarketing Clinical Trials Aggressive Promotion And... Policy Implications For New... NOTES

 
Randomized clinical trials designed and conducted by a drug’s manufacturer form the basis for FDA approval. However, such trials might overestimate the benefits of a drug and provide too little information on its risks. The initial studies of nesiritide illustrate both of these issues.

Overestimation of benefits. Drug efficacy is often determined from intermediate measures, or "surrogate endpoints," rather than final clinical outcomes.⁴ In one early study, nesiritide decreased several hemodynamic measures, such as pulmonary capillary wedge pressure.⁵ However, the authors concluded that nesiritide could be a first-line therapy for patients with symptomatic CHF without assessing more practical outcomes such as length of hospital stay, functional capacity, or mortality. In the Prospective Randomized Evaluation of Cardiac Ectopy with Dobutamine or Nesiritide Therapy (PRECEDENT) trial, investigators compared nesiritide to dobutamine, a relevant alternative therapy, and found that both improved CHF symptoms. Patients treated with dobutamine had more ventricular premature beats, but this was not accompanied by an increase in adverse events.⁶ The authors concluded that nesiritide might be a safer short-term treatment for patients with decompensated heart failure.

Limited information. In the case of heart failure, some surrogate endpoints, such as pulmonary capillary wedge pressure, can predict the severity of disease; other studies of nesiritide did use clinical endpoints such as self-reported dyspnea.⁷ Although the results based on surrogate endpoints were encouraging, they gave little indication of how nesiritide would perform in the actual long-term management of this chronic illness. In addition, preapproval studies often test drugs in atypical situations. For example, patient exclusion criteria in several nesiritide studies prevented its evaluation in the context of important coexisting conditions, such as kidney impairment or diastolic dysfunction. One trial excluded potential subjects taking commonly used medications including angiotensin-converting enzyme (ACE) inhibitors, nitrates, beta-blockers, or calcium channel blockers.⁸ Finally, trials comparing nesiritide to a placebo can also be unhelpful in evaluating the effect of the drug in patients with symptomatic heart failure. Such patients would normally receive active medical therapy with diuretics or inotropes, so infusing an inert placebo is certain not to improve their hemodynamic or symptomatic measurements. Such trial design strategies might have helped overestimate the benefits of nesiritide.

Importance of study size. Similarly, a study might be too small and lack the power to evaluate the frequency and importance of adverse events. For example, the most important side effect of nesiritide in one early trial was a reduction in blood pressure, but its clinical importance was unclear, because it was reported as "often asymptomatic" and "usually did not require intervention."⁹ Early studies hinted at a decrease in kidney function in patients given nesiritide, but none enrolled enough patients to determine the magnitude of the effect. Inappropriate reliance on statistical testing can label rare adverse events "insignificant" if a study is underpowered to detect them.

FDA and manufacturer’s responses. Scios submitted nesiritide for FDA approval in 1999. Although the advisory committee issued a five-to-three recommendation for approval, the agency turned down the submission because the sample size was too small—just 500 patients in eight clinical trials. The FDA sought additional clinical data and identified concerns about early evidence of hypotension (abnormally low blood pressure) and worsening renal function.¹⁰

In response, the manufacturer organized a larger trial evaluating nesiritide against intravenous nitroglycerin. A placebo arm of the trial, carried out for the first three hours, demonstrated the efficacy of nesiritide in lowering pulmonary capillary wedge pressure and improving symptoms of dyspnea but not improving global clinical status. The active comparison of nesiritide and nitroglycerin continued for twenty-four to forty-eight hours, and nesiritide showed a modest effect in improving pulmonary pressures. But there was only minimal difference between the two agents in measures of dyspnea and global clinical status.¹¹ Additionally, there were four deaths in the nesiritide group (in 278 patients) versus only one death in the nitroglycerin group (in 216 patients). The six-month mortality rate was 25.1 percent for nesiritide versus 20.8 percent for nitroglycerin; the difference was reported as "not statistically significant," even though the study was not powered adequately to show significant differences in such adverse-event endpoints.

Resubmission and approval. Pre-approval studies enroll enough subjects to demonstrate statistical significance in therapeutic outcomes but often lack power to find significant differences in the rates of more rare adverse outcomes, including death. In this case, the study was "powered to demonstrate significant differences between nesiritide and placebo" in pulmonary capillary wedge pressure and reports of dyspnea. The problem of "nonsignificance" is compounded if authors of industry-funded studies provide inadequate information about such adverse events.¹² Although the company reported to the FDA that nesiritide patients showed a trend toward increasing renal dysfunction, many papers did not mention that outcome.

With these data in hand, Scios resubmitted nesiritide to the FDA in 2001. The advisory committee discussed some limitations of the clinical trial data. One committee member noted, "You see an increase in the number of people who go on dialysis.... You see the increase in mortality.... [Do] these little smidgens of data...suggest that the people who got Natrecor somehow in some global sense maybe did just a teeny little bit worse than the people who didn’t get it?"¹³ Despite these concerns, the FDA required no further studies designed to evaluate the concerning trends in side effects. Instead, following the committee’s endorsement, Natrecor was approved for marketing in 2001.

Aggressive Promotion And Expansion Of Nesiritide’s Indications

Top Premarketing Clinical Trials Aggressive Promotion And... Policy Implications For New... NOTES

 
Once approved, how a new drug is promoted and prescribed further shapes its risk-benefit profile.¹⁴ In the case of rofecoxib, critics charged that aggressive direct-to-consumer (DTC) advertising expanded its use so widely that millions more patients were unnecessarily exposed to its risks. Although manufacturers cannot advertise a drug for unapproved indications, there is ambiguity as to whether expanding an approved use to patients with different manifestations of the same diagnosis is considered "off-label" use. Although nesiritide was approved for patients with acutely decompensated severe heart failure, several factors caused it to be used in patients with stable or milder forms of the disease.

"Briefings" and medical journal ads. When the FDA approved nesiritide, the drug’s manufacturer assembled a 180-person sales force to promote Natrecor in one-on-one sales "briefings" with cardiologists.¹⁵ Advertisements in medical journals promoted rapid hemodynamic improvement and short-term benefits in patient-reported dyspnea. They featured, in large boldface type, the advice that "the heart’s response to CHF is now a recombinant therapy," including in much smaller and lighter type the details about the limited patient populations for which nesiritide had actually been approved. The ads included the required safety information in small type, but they created the immediate impression of a new medication suited for CHF generally. Warnings that "Natrecor may cause hypotension" and "Natrecor may affect renal function in susceptible patients" appeared in small type on the bottom of the ad’s third page.¹⁶

Misleading journal articles. Because the clinical studies of nesiritide evaluated only short-term infusions in acutely ill hospitalized patients, there was little published experience with longer treatment regimens or in other patient populations. Nonetheless, some publications—many underwritten by the manufacturer—championed its use in a variety of additional clinical situations beyond those studied in the original trials.¹⁷ Nesiritide was recommended as a first-line therapy for CHF or to be started concurrently with a diuretic.¹⁸ Long-term nesiritide infusions were reported as a treatment for patients awaiting heart transplantation even if they had stable heart failure.¹⁹ Several publications promoted emergency department (ED) use of nesiritide as a first-line therapy for patients with mild heart failure.²⁰ Articles argued for both the clinical and the economic benefits of such therapy. Most astonishingly, some authors advocated intermittent nesiritide infusions for outpatients with chronic CHF.²¹ None of these uses applied to the CHF patients in whom nesiritide was originally studied and for whom it was approved.

Manufacturer’s guide for physician reimbursement. Materials distributed by the drug’s manufacturer promoted the use of Natrecor as chronic maintenance therapy and taught physicians how to submit claims to insurers for reimbursement in the outpatient setting.²² This strategy took advantage of an unusual and potentially lucrative anomaly in drug reimbursement. Medicare and most private insurers reimburse physicians generously for overseeing infusion of intravenous medications. According to Scios’s reimbursement guide, physicians could receive $172 for the first hour, $39 for each additional hour, and $408 for eight hours of observation. This did not include payment for the drug itself, which could be marked up steeply over the physician’s acquisition price.²³ Cardiologists treating stable heart failure patients with outpatient nesiritide infusions could profit far more than they would for prescribing traditional oral diuretics dispensed by pharmacies.

Continuing education materials. Continuing medical education (CME) materials sponsored by Scios helped promote nesiritide as a first-line therapy and taught, under the heading of "Outpatient Infusion," that high-risk patients "who have experienced frequent hospitalizations are treated for low cardiac output in the heart failure clinic with occasional, brief, short-term inotrope therapy and, more recently, the use of [nesiritide] as a treatment for acute decompensated heart failure."²⁴ Such language gave the impression that outpatient nesiritide therapy was accepted practice, while reports of clinical trials of this therapy were just starting to appear in the literature.²⁵

Two meta-analyses question safety. Nesiritide sales doubled each year following approval, reaching $400 million in 2004.²⁶ But at this point, additional examination of the clinical data revealed serious potential harms that might have been overlooked in individual trials. In 2005 a meta-analysis of published data and some of Scios’ FDA submissions found that treatment with nesiritide actually increased the risk of worsening renal function, judged against active comparators.²⁷ Worsening renal failure during treatment of decompensated heart failure is associated with poor outcomes.²⁸ Another meta-analysis supported earlier suspicions that nesiritide was associated with an increased risk of mortality.²⁹ Although such analyses are not conclusive, they helped force a reexamination of evidence supporting nesiritide’s use.³⁰

Little or no follow-up. In the four years after the FDA approved nesiritide, the medical community made little progress in defining its appropriate clinical role. Most of the data on the drug’s potentially serious side effects had been available since 2001. Current regulatory procedures provide for neither rigorous post-marketing surveillance to properly measure these side effects nor mandatory clinical trials to pursue them. Consequently, no one had vigorously followed up the danger signals seen in the early studies. Instead, beyond-label use by cardiologists, surgeons, ED physicians, and other internists, encouraged by advertisements, advocacy articles, and distorted reimbursement incentives, led to an explosion in the number of patients treated with nesiritide, many of whom differed greatly from those originally studied. As a result, many patients were exposed to the poorly understood and unadvertised risks of nesiritide.

Policy Implications For New Drug Approval And Marketing

Top Premarketing Clinical Trials Aggressive Promotion And... Policy Implications For New... NOTES

 
Nesiritide’s path during the past decade illustrates a number of problems in U.S. policy concerning premarketing trials, FDA criteria for approval, manufacturers’ promotion, physicians’ use, and payers’ reimbursement. Each lesson has been seen before in controversies surrounding other medications. But nesiritide is unusual in that its brief history illustrates problems in each of these domains, demonstrating how flaws at each level can contribute to the risky overexpansion of use of an understudied medication. Its story also reveals ways in which the drug approval and postapproval evaluation processes can be improved.

Preapproval studies. The FDA often accepts clinical trial designs that rely on surrogate endpoints (such as decrease in pulmonary capillary wedge pressure) in determining whether or not to approve a drug for marketing. These can be valid measures of a drug’s eventual clinical usefulness, but sometimes they are not. This policy allows for speedy trial results and more rapid movement of products to market, a key concern for manufacturers because of the looming expiration of patent protection. But such trials can also poorly predict how a product will affect patients. For example, the occurrence of premature ventricular contractions (PVCs) in survivors of myocardial infarction (MI) is associated with an increased risk of sudden death. Early trials of the antiarrhythmic medications flecainide and encainide suppressed such PVCs, generating enthusiasm for their use following MI. However, when a large randomized trial compared these drugs to placebo, patients treated with the active drug had a much higher death rate; the trial had to be discontinued early for ethical reasons.³¹ If the FDA continues to allow surrogate endpoints to be used as the sole basis for approval of some new drugs, those endpoints must be validated as having links to real clinical outcomes.

Postmarketing surveillance. Proper assessment of the risks of medications requires a vigorous postmarketing surveillance mechanism. Yet after a drug is approved, there is no organized postmarketing surveillance system in place. Although the FDA can suggest that a manufacturer perform postmarketing studies, it has little authority to require the completion of these studies. In the rofecoxib case, for example, early randomized clinical studies showed increased cardiovascular risk over traditional nonsteroidal anti-inflammatory drugs (NSAIDs), but the manufacturer did not pursue targeted investigation of that side effect after approval.³² The drug was removed from the market only when the problem surfaced again in other, unrelated trials. When drugs are approved, drug manufacturers often make "commitments" to the FDA that they will address unresolved safety questions. However, a 2005 FDA report found that in its active file of such commitments, more than 70 percent of the studies had not even been initiated.³³

Comparison with European process. Despite preliminary reservations at the FDA advisory committee meeting about nesiritide’s safety, approval of the drug was not delayed a second time in 2001. Yet faced with similar data, the European Medicines Evaluation Agency (EMEA) did not authorize nesiritide, awaiting longer-term data on renal side effects and mortality and a large randomized study. That study was never completed.³⁴ Critics have charged that a pro-industry FDA culture favored drug approval more eagerly than its European counterparts.³⁵ One factor that might contribute to this culture is the Prescription Drug User Fee Act (PDUFA), which has allowed industry sources to direct funding to the FDA to help speed new drug approval.³⁶

Ways to improve postmarketing surveillance. To solve deficits in postmarketing surveillance, the FDA’s regulatory authority could be expanded in two ways. The agency could be allowed to require postmarketing studies as a condition of marketing authorization and authorized to suspend sales if preset milestones in the evaluation are not met. As data emerge, the FDA could also require a re-approval process based on those data.³⁷ These efforts would better inform physicians about ongoing concerns and allow the FDA to serve not just as a gatekeeper for drugs entering the market but also as a sustained regulatory oversight authority for all drugs.

Postmarketing promotion. Manufacturers cannot promote off-label use of medications for different diagnoses. When this was done for gabapentin (Neurontin), initially approved for epilepsy treatment but promoted for chronic pain, the manufacturer paid a $430 million penalty. But public promotion of medications in general may help stimulate beyond-label use and overtreatment of patients by physicians. Dexfenfluramine (Redux) was tested in morbidly obese patients but was used for cosmetic purposes in many patients with more normal weights, resulting in pulmonary hypertension and cardiac valve disease.

With nesiritide, the expansion of use occurred as physicians (and possibly the manufacturer) encouraged treating not only acutely ill CHF patients but also outpatients with stable disease and hospitalized patients awaiting cardiac transplantation. "Indication expansion" is a major problem in prescription drug use. In this setting, the original FDA evaluation becomes essentially meaningless because the drug’s risks and benefits were not assessed in this novel context. The FDA advisory committee evaluating nesiritide discussed a number of concerns about its safety, and at least one member voted to approve the drug despite the trend to increased mortality, specifically because "this is a short-term use drug."³⁸ If the committee had anticipated how nesiritide would be used in a much wider manner, they might have requested more preapproval studies or stricter warnings to physicians.

Physicians’ role and liability. Physicians must better understand the context in which approval recommendations are made and should not allow lucrative reimbursement encouragements to drive their prescribing. In 2001, TAP Pharmaceuticals pled guilty to charges that it provided free samples of leuproide (Lupron) to physicians and encouraged them to bill Medicare for the drug; a number of physicians faced fraud charges as well.³⁹ Such charges have not arisen in this case, although the Justice Department is evaluating Scios’ promotion of nesiritide’s use. Government and other payers should also better assess justifications for off-label medication use before making their payment determinations. Medicare reimbursed for outpatient use of nesiritide until December 2005, when it restricted coverage to patients with "acutely decompensated" heart failure—the sole original indication for which the FDA approved the drug.⁴⁰

Dangers of "overly enthusiastic" marketing practices. If "indication expansion" were considered akin to off-label promotion, manufacturers might be less likely to encourage use of products for purposes for which data do not exist. Prohibiting manufacturers from sponsoring educational programs promoting these uses could help curtail such abuses. If the marketplace does not constrain such practices (and it has not), expansion of the FDA’s authority might be necessary to contain overly enthusiastic marketing practices that include advertising, sponsored advocacy pieces in the literature, and promotion-oriented "continuing education." Reforming the FDA’s approval process would have to be done in a way that would not stifle innovation; there need not be a trade-off between adequate efficacy and safety assessment of drugs and making new therapies available to patients in a timely manner.⁴¹

ULTIMATELY, NESIRITIDE might not represent a failed drug like rofecoxib. It might eventually prove useful in treating severe CHF in selected patients, such as those with a history of serious arrhythmias, or those with elevated pulmonary vasculature resistance awaiting heart transplant.⁴² Conclusions about nesiritide’s place in physicians’ armamentarium will require investment in appropriate prospective clinical trials, as recommended by the recent expert panel review, as well as careful pharmacoepidemiological follow-up. For future potentially revolutionary drugs, four years should not have to pass before the health care system can engage in an evidence-based discussion of a medication’s actual risks and benefits.

Editor's Notes

 
The authors are all affiliated with Harvard Medical School and Brigham and Women’s Hospital in Boston, Massachusetts. Aaron Kesselheim (akesselheim{at}partners.org) is an attorney and a fellow in medicine in the Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine; Michael Fischer is an instructor in medicine there; and Jerry Avorn is a professor of medicine and chief of the division.

The authors thank Charles A. Morris for his research work and insights in the early stages of this project.

NOTES

Top Premarketing Clinical Trials Aggressive Promotion And... Policy Implications For New... NOTES

 

1. S. Saul, "Panel Urges Limits on Use of a Heart Drug," New York Times, 15 June 2005.
2. Scios, "Panel of Cardiology Experts Provides Recommendations to Scios regarding Natrecor," Press Release, 13 June 2005, http://www.sciosinc.com/scios/pr_1118721302 (accessed 26 April 2006).
3. E.J. Topol, "Nesiritide—Not Verified," New England Journal of Medicine 353, no. 2 (2005): 113–116.[Free Full Text]
4. J. Avorn, "FDA Standards—Good Enough for Government Work?" New England Journal of Medicine 353, no. 10 (2005): 969–972.[Free Full Text]
5. R.M. Mills et al., "Sustained Hemodynamic Effects of an Infusion of Nesiritide (Human B-Type Natriuretic Peptide) in Heart Failure: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial," Journal of the American College of Cardiology 34, no. 1 (1999): 155–162.[Abstract/Free Full Text]
6. A.J. Burger et al., "Effect of Nesiritide (B-Type Natriuretic Peptide) and Dobutamine on Ventricular Arrhythmias in the Treatment of Patients with Acutely Decompensated Congestive Heart Failure: The PRECEDENT Study," American Heart Journal 144, no. 6 (2002): 1102–1108.[CrossRef][Web of Science][Medline]
7. A. Nohria et al., "Clinical Assessment Identifies Hemodynamic Profiles That Predict Outcomes in Patients Admitted with Heart Failure," Journal of the American College of Cardiology 41, no. 10 (2003): 1797–1804.[Abstract/Free Full Text]
8. Mills et al., "Sustained Hemodynamic Effects."
9. Ibid.
10. U.S. Food and Drug Administration, "United States of America, Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research, Cardiovascular and Renal Drugs Advisory Committee, Ninety-second Meeting" (transcript), 25 May 2001, http://www.fda.gov/ohrms/dockets/ac/01/transcripts/3749t2.rtf (accessed 26 April 2006).
11. Publication Committee for the VMAC Investigators, "Intravenous Nesiritide versus Nitroglycerin for Treatment of Decompensated Congestive Heart Failure: A Randomized Controlled Trial," Journal of the American Medical Association 287, no. 12 (2002): 1531–1540.[Abstract/Free Full Text]
12. S. Saul, "U.S. Not Told of Two Deaths during Study of Heart Drug," New York Times, 4 January 2006.
13. FDA, Advisory Committee transcript.
14. J. Avorn, Powerful Medicines: The Benefits, Risks, and Costs of Prescription Drugs (New York: Alfred A. Knopf, 2004).
15. T. Abate, "Late-Bloomer Scios Inc. Leads Sky-Rocketing Stocks," San Francisco Chronicle, 7 May 2001.
16. Natrecor advertisement in the Journal of the American College of Cardiology 39, no. 2 (2002): 300.
17. M.A. Silver et al., "BNP Consensus Panel 2004: A Clinical Approach for the Diagnostic, Prognostic, Screening, Treatment Monitoring, and Therapeutic Roles of Natriuretic Peptides in Cardiovascular Diseases," Congestive Heart Failure 10, no. 5, Supp. 3 (2004): 1–30.
18. V. Bhalla, S. Willis, and A.S. Maisel, "B-Type Natriuretic Peptide: The Level and the Drug—Partners in the Diagnosis of Congestive Heart Failure," Congestive Heart Failure 10, no. 1, Supp. 1 (2004): 3–27.
19. J.A. Hill et al., "Sustained Use of Nesiritide to Aid in Bridging to Heart Transplant," Clinical Cardiology 26, no. 5 (2003): 211–214.[Web of Science][Medline]
20. W.F. Peacock, "Acute Emergency Department Management of Heart Failure," Heart Failure Reviews 8, no. 4 (2003): 335–338.[CrossRef][Web of Science][Medline]
21. C.W. Yancy et al., "Decompensated Heart Failure: Is There a Role for the Outpatient Use of Nesiritide?" Congestive Heart Failure 10, no. 5 (2004): 230–236.
22. S. Saul, "Issues Arise as Drug’s Use Goes beyond Emergencies," New York Times, 17 May 2005.
23. Topol, "Nesiritide—Not Verified."
24. M.A. Silver, P. Cianci, and C.L. Pisano, Outpatient Management of Heart Failure: Program Development and Experience in Clinical Practice, November 2004, http://www.theheart.org/documents/satellite_programs/monograph/329067/mono_heartorg.pdf (accessed 26 April 2006).
25. C.W. Yancy et al., "Safety and Feasibility of Using Serial Infusions of Nesiritide for Heart Failure in an Outpatient Setting (from the FUSION I Trial)," American Journal of Cardiology 94, no. 5 (2004): 595–601.[CrossRef][Web of Science][Medline]
26. Saul, "Panel Urges Limits on Use of a Heart Drug."
27. J.D. Sackner-Bernstein, H.A. Skopicki, and K.D. Aaronson, "Risk of Worsening Renal Function with Nesiritide in Patients with Acutely Decompensated Heart Failure," Circulation 111, no. 12 (2005): 1487–1491.[Abstract/Free Full Text]
28. D.E. Forman et al., "Incidence, Predictors at Admission, and Impact of Worsening Renal Function among Patients Hospitalized with Heart Failure," Journal of the American College of Cardiology 43, no. 1 (2004): 61–67.[Abstract/Free Full Text]
29. J.D. Sackner-Bernstein et al., "Short-Term Risk of Death after Treatment with Nesiritide for Decompensated Heart Failure: A Pooled Analysis of Randomized Controlled Trials," Journal of the American Medical Association 293, no. 15 (2005): 1900–1905.[Abstract/Free Full Text]
30. J.R. Teerlink and B.M. Massie, "Nesiritide and Worsening of Renal Function: The Emperor’s New Clothes?" Circulation 111, no. 12 (2005): 1459–1461.[Free Full Text]
31. Cardiac Arrhythmia Suppression Trial (CAST) Investigators, "Preliminary Report: Effect of Encainide and Flecainide on Mortality in a Randomized Trial of Arrhythmia Suppression after Myocardial Infarction," New England Journal of Medicine 321, no. 6 (1989): 406–412.[Abstract]
32. C. Bombardier et al., "Comparison of Upper Gastrointestinal Toxicity of Rofecoxib and Naproxen in Patients with Rheumatoid Arthritis," New England Journal of Medicine 343, no. 21 (2000): 1520–1528.[Abstract/Free Full Text]
33. FDA, "Report on the Performance of Drug and Biologics Firms in Conducting Postmarketing Commitment Studies; Availability," Federal Register 70, no. 33 (18 February 2005): 8379–8381.
34. S. Saul, "Johnson and Johnson Faces U.S. Inquiry on Marketing of Heart Drug," New York Times, 22 July 2005.
35. D. Grady, "In a Survey, the FDA Is Accused of Hasty Approval of Drugs," New York Times, 3 December 1998.
36. W.A. Ray and C.M. Stein, "Reform of Drug Regulation—Beyond an Independent Drug-Safety Board," New England Journal of Medicine 354, no. 2 (2006): 194–201.[Free Full Text]
37. Avorn, Powerful Medicines.
38. FDA Advisory Committee transcript.
39. A. Dembner, "TAP Agrees to $150M Settlement," Boston Globe, 2 December 2004.
40. S. Saul, "Medicare Balks at Covering Johnson Heart Drug in Some Cases," New York Times, 3 December 2005.
41. J. Avorn, "Evaluating Drugs in the Post-Vioxx World: There Must Be a Better Way," Circulation 13, no. 18 (2006): 2173–2176.
42. R. Witteles, K. Matsuda, and M.B. Fowler, "B-Type Natriuretic Peptide Is Effective Therapy before Care," Annals of Internal Medicine 141, no. 11 (2004): 895.[Free Full Text]

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