Annals of Emergency Medicine
Volume 51, Issue 5 , Pages 580-582, May 2008

Miller AH, Nazeer S, Pepe P, et al Acutely Decompensated Heart Failure in a County Emergency Department: A Double Blind Randomized Controlled Comparison of Nesiritide Versus Placebo Treatment

  • Tyler W. Barrett, MD

      Affiliations

    • Vanderbilt University Medical Center, Nashville, TN
    • ,
  • David L. Schriger, MD, MPH

      Affiliations

    • University of California, Los Angeles, Los Angeles, CA

Article Outline

Editor's Capsule Summary 

What is already known on this topic

Nesiritide was widely advocated as a useful therapy for heart failure patients until safety concerns were raised.

What question this study addressed

Whether an 8-hour infusion of nesiritide results in symptomatic improvement or decreased readmission rates for patients with heart failure compared with placebo.

What this study adds to our knowledge

There was no benefit to an 8-hour infusion of nesiritide in this randomized trial.

How this might change clinical practice

Nesiritide should not be used in the emergency department until it is proven to have value.

 

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Discussion Points 


1.In 2002, the Journal of the American Medical Association (JAMA) published an article from the Vasodilatation in the Management of Acute CHF (VMAC) Investigators that reported that nesiritide improves hemodynamic function and self-reported global clinical status more effectively than intravenous nitroglycerin or placebo.1 This article was chosen by the American Board of Emergency Medicine's Lifelong Learning and Self Assessment (LLSA) for the 2005 Reading List. However, a meta-analysis of 3 trials published 3 years later in JAMA concluded that nesiritide may be associated with an increased risk of death after treatment for acutely decompensated congestive heart failure.2 This article was chosen for the 2007 LLSA Reading List.

1. A. Conduct a brief review of medical literature, tracing the history of nesiritide from its Food and Drug Administration (FDA) approval in 2001 to the current knowledge of risk and benefits of this drug. According to these published trials, what is your opinion on whether nesiritide should be included in the emergency department (ED) treatment of acutely decompensated congestive heart failure? B. According to your review for question 1A, now consider what information was known about the drug when Miller et al began their study in February 2004 and when they submitted the article for publication in July 2007. How might the studies critical of nesiritide and published between 2004 and 2007 have affected this article's discussion points? C. Hauptman et al3 published an article in 2006, showing that use of nesiritide decreased from 17% to 6% of patients admitted with heart failure between March and December 2005 after publication of 2 articles citing increased mortality and worsening renal function in March and April 2005. What factors might have contributed to this significant decrease in use? Has the use of nesiritide rebounded in the United States, or were these studies the “nail in the coffin” for the drug? What resources might a physician use to research the prescribing rates of medications in the United States?

2. A. Define “confounding.” Be sure to develop both a technical definition and a general understanding of what the term means. Draw a basic causal diagram that includes a treatment, an exposure, and a confounder (see Greenland et al4 and Glymour and Greenland5 for some help with this). Define Hume's counterfactual definition of causation and explain how it relates to medical research. B. Using the causal diagram you drew in question 2a, explain how a randomized trial, in theory, can eliminate confounding. What conditions are necessary to maximize the likelihood that randomization achieves this goal? Name some of the events that can happen during a clinical randomized trial that might undo the effects of randomization and produce a confounded result. C. How do we know whether a randomized trial is confounded? Researchers often present a table that compares characteristics of the subjects in different arms of the study. Is a statistical comparison of these characteristics helpful? Why or why not? What are some pitfalls in trying to determine whether a study is confounded? What are some solutions? Discuss Table 1 from the Miller et al article in light of the above. Do you think the study could be confounded? How?

3.Intravenous nitroglycerin is frequently used in the ED treatment of patients with acutely decompensated heart failure. The Heart Failure Society of America 2006 Comprehensive Heart Failure Practice guideline states that “in the absence of symptomatic hypotension, intravenous nitroglycerin, nitroprusside, or nesiritide may be considered as an addition to diuretic therapy for rapid improvement of congestive symptoms in patients admitted with acutely decompensated congestive heart failure.”6 A. Miller et al excluded patients who had new-onset congestive heart failure and those actively receiving nitroglycerin in the ED. Why might the authors have chosen to exclude these patients? B. Many of the original clinical trials compared nesiritide to placebo and not intravenous nitroglycerin. Why might the manufacturer of a new study drug choose to compare their treatment to placebo instead of a commonly used therapy such as nitroglycerin? Does the FDA require pharmaceutical companies to test new treatments against currently accepted treatments or is a trial showing a benefit over placebo sufficient? C. The VMAC trial compared nesiritide to both placebo and nitroglycerin and reported improved hemodynamic function. Critics of this study contend that the dose of nitroglycerin used was lower than standard doses used in the clinical treatment of acutely decompensated congestive heart failure.7, 8 According to your review of the medical literature, write a brief report for your hospital's pharmacy and therapeutics committee, comparing the benefits and drawbacks of nesiritide and intravenous nitroglycerin in the treatment of patients presenting to the ED with acutely decompensated congestive heart failure.

4. A. What is the trial registration? Why is it important? This trial was registered. Find the registration page online. Is the trial registration information adequate? When was the trial registered? Are there any potential problems? What else would you like to see? B. What is the Consolidated Standards of Reporting Trials (CONSORT) statement (see http://consort-statement.org)? Discuss the importance of items 6 through 11 in the CONSORT checklist (study outcomes, sample size, randomization generation, allocation concealment, randomization implementation, blinding, or masking). What are the pros and cons of reporting guidelines such as CONSORT, Quality of Reporting of Meta-Analysis (QUOROM) and Standards for Reporting of Diagnostic Accuracy (STAR-D)? C. Discuss to what extent this study successfully addressed items 6 to 11 in CONSORT and how any shortcomings might bias this study.

5. A. In your opinion, what are the most important conclusions from this article? How might the limitations mentioned by the authors affect your decision whether to change your clinical practice with regard to the treatment of patients with acutely decompensated congestive heart failure in your ED? B. Nesiritide is a recombinant form of the natural human peptide, hBNP. Studies have demonstrated that patients with acutely decompensated congestive heart failure often already have increased BNP levels in the blood.9, 10 If these patients already have increased levels of BNP circulating in their blood, how does nesiritide improve the treatment of acutely decompensated congestive heart failure? C. What additional information or data analyses would you like the authors to provide for you to change your clinical practice?

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References 

  1. Publication Committee for VMAC Investigators. Intravenous nesiritide vs nitroglycerin for treatment of decompensated congestive heart failure: a randomized controlled trial. JAMA. 2002;287:1531–1540
  2. Sackner-Bernstein JD, Kowalski M, Fox M, et al. 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
  3. Hauptman PJ, Schnitzler MA, Swindle J, et al. Use of nesiritide before and after publications suggesting drug-related risks in patients with acute decompensated heart failure. JAMA. 2006;296:1877–1884
  4. Greenland S, Pearl J, Robins JM. Causal diagrams for epidemiologic research. Epidemiology. 1999;10:37–48
  5. Glymour MM, Greenland S. Causal diagrams. In:  Rothman KJ,  Greenland S,  Lash TL editor. Modern Epidemiology. 3rd ed.. Philadelphia, PA: Lippincott; 2008;
  6. Heart Failure Society of America. HFSA 2006 Comprehensive Heart Failure Practice Guideline. J Card Fail. 2006;12:e1–e2
  7. Topol EJ. Nesiritide—not verified. N Engl J Med. 2005;353:113–116
  8. Collins SP, Hinckley WR, Storrow AB. Critical review and recommendations for nesiritide use in the emergency department. J Emerg Med. 2005;29:317–329
  9. Dao Q, Krishnaswamy P, Kazanegra R, et al. Utility of B-type natriuretic peptide in the diagnosis of congestive heart failure in an urgent-care setting. J Am Coll Cardiol. 2001;37:379–385
  10. Maisel AS, Krishnaswamy P, Nowak RM, et al. Rapid measurement of B-type natriuretic peptide in the emergency diagnosis of heart failure. N Engl J Med. 2002;347:161–167

 SEE RELATED ARTICLE, P. 571.

 Editor's Note: You are reading the third installment of Annals of Emergency Medicine Journal Club. This bimonthly feature seeks to improve the critical appraisal skills of emergency physicians and other interested readers through a guided critique of actual Annals of Emergency Medicine articles. Each Journal Club will pose questions that encourage readers, be they clinicians, academics, residents, or medical students, to critically appraise the literature. Answers to this Journal Club will be published in the October issue.During a 2- to 3-year cycle, we plan to ask questions that cover the main topics in research methodology and critical appraisal of the literature. To do this we will select articles that use a variety of study designs and analytic techniques. These may or may not be the most clinically important articles in a specific issue, but they are articles that serve the mission of covering the clinical epidemiology curriculum.Journal Club entries will be published in 2 phases. In the first phase, a list of questions about the article will be published in the issue in which the article appears. Questions are rated “novice,” () “intermediate,” () and “advanced” () so that individuals planning a journal club can assign the right question to the right student. The “novice” rating does not imply that a novice should be able to spontaneously answer the question. “Novice” means we expect that someone with little background should be able to do a bit of reading, formulate an answer, and teach the material to others. Intermediate and advanced questions also will likely require some reading and research, and that reading will be sufficiently difficult that some background in clinical epidemiology will be helpful in understanding the reading and concepts.The second phase of each journal club consists of the publication of suggested answers. This will be done 5 months after the publication of the questions. However, residency directors can have immediate access to the answers for the purpose of guiding the journal club. US residency directors can access the answers through the Council of Emergency Medicine Residency Directors Share Point Web site. International residency directors can gain access to the answers by going to http://www.emergencymedicine.ucla.edu/annalsjc/ and following the directions. Thus, if an actual journal club is conducted within 5 months of the publication of the questions, no one will have access to the published answers except the residency director. The purpose of delaying the publication of the answers is to promote discussion and critical review of the literature by both residents and medical students and discourage regurgitation of the published answers.It is our hope that the Journal Club will broaden Annals of Emergency Medicine's appeal to residents and medical students. We are interested in receiving feedback about this feature. Please e-mail journalclub@acep.org with your comments.This is the first journal club in our series that considers a randomized controlled trial (RCT). For that reason, we include some basic questions about this fundamental study design. We will cover other topics about RCTs in future installments. Those planning a journal club should note that although 1a is a novice question, it requires a substantial amount of work to answer. This task could be divided among several participants.

PII: S0196-0644(08)00600-8

doi:10.1016/j.annemergmed.2008.03.008

Refers to article:

  • Journal Club questions Acutely Decompensated Heart Failure in a County Emergency Department: A Double-Blind Randomized Controlled Comparison of Nesiritide Versus Placebo Treatment , 28 February 2008

    Adam H. Miller, Shameem Nazeer, Paul Pepe, Barbi Estes, April Gorman, Clyde W. Yancy
    Annals of Emergency Medicine May 2008 (Vol. 51, Issue 5, Pages 571-578)

Annals of Emergency Medicine
Volume 51, Issue 5 , Pages 580-582, May 2008

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