Annals of Emergency Medicine
Volume 51, Issue 5 , Pages 583-584, May 2008

Can We Improve How We Treat Patients With Heart Failure in the Emergency Department?

  • Deborah B. Diercks, MD

      Affiliations

    • Corresponding Author InformationAddress for correspondence: Deborah B. Diercks, MD, Division of Emergency Medicine, University of California, Davis Medical Center, Suite 2100 PSSB, 2315 Stockton Boulevard, Sacramento, CA 95817; 916-734-4052, fax 916-734-7950

Department of Emergency Medicine, University of California, Davis Medical Center, Sacramento, CA.

published online 17 March 2008.

Article Outline

 

SEE RELATED ARTICLE, P. 571

[Ann Emerg Med. 2008;51:583-584]

In this issue of Annals of Emergency Medicine, Miller et al1 present an interesting article comparing standard therapy to nesiritide in the treatment of patients with acute decompensated heart failure. Randomizing patients in the emergency department (ED) to receive 8 hours of standard therapy or 8 hours of nesiritide, the authors concluded that there was no difference in the outcome of return to the ED or hospitalization at 30 days. Although substantial methodologic issues limit the conclusions of this article, the attempt to determine optimal treatment of patients within the ED is admirable.

It has been well documented that patients presenting to the ED with heart failure have a high rate of hospitalization, morbidity, and recidivism.2 Despite these facts, the treatment of patients with decompensated heart failure in the ED has not significantly changed during the last few decades. Recent trials of new pharmacologic agents for the treatment of patients with decompensated heart failure have not translated to changes in acute ED management and have not been evaluated in the ED setting.3, 4, 5, 6, 7

Review of the methodology used in large clinical trials evaluating pharmacologic therapy reveals that the majority of these trials enroll subjects up to 24 hours after hospital presentation.3, 4, 5, 6, 7, 8 It had been reported that ED treatment can result in reduction of heart failure symptoms in approximately 70% of patients.9 Intuitively, this raises the concern that these clinical trials may be prone to selection bias. Subjects enrolled may meet enrollment criteria because of disease severity and therefore are expected to have a high rate of morbidity. Alternatively, trials may be limited by the anticipated amount of improvement in symptoms because patients enrolled may have received many hours of treatment before enrollment and probably have improved since that time. Studying an investigational agent in only those inpatients with persistent symptoms may make it difficult to show a clinically relevant effect. Failure to design trials to enroll subjects in an ED timeframe has been contributed to concerns about feasibility of recruitment in the ED.

Miller et al1 successfully enrolled 104 subjects in this study. The study, however, identifies issues pertinent to trials evaluating ED subjects with heart failure. Miller et al1 defined standard of care as diuretic use only. Lack of clear management guidelines for the treatment of patients with decompensated heart failure results in institutional variation in the standard of care. Current guidelines from the Heart Failure Society of America recommend the use of diuretics as a first-line agent in patients with congestion. The use of adjunctive therapy with nitroglycerin, nesiritide, or nitroprusside was recommended for subjects with persistent congestion after initial diuretic therapy.10 This trial evaluated nesiritide in addition to standard therapy compared with standard therapy alone and showed no difference in the primary outcome measure. The current recommendations suggest that nesiritide be used only in selected patients.10 The use of a vasodilator may not be indicated in the patient population evaluated by Miller et al.1 It is therefore understandable that a difference in outcome was not identified. Unfortunately, the investigator's conclusion may be a function more of enrolling a relatively well group of patients with heart failure, rather than the efficacy of the pharmacologic agent evaluated.

Inclusion criteria in this trial were also unique to ED-based studies. The investigators enrolled subjects according to a nonvalidated questionnaire of dyspnea, respiratory rate, and evidence of volume overload. Because congestive heart failure is a chronic disease, it is possible that subjects have some degree of dyspnea, tachypnea, or evidence of volume overload at baseline. It is therefore difficult to determine the magnitude of the relative change in symptoms that prompted ED presentation.11 The entry criteria used in this trial may not stratify subjects sufficiently to identify those who would benefit from acute therapy beyond a diuretic. Using more specific definitions of congestion, along with a less conservative threshold for a marker of ventricular dysfunction (natriuretic peptide), may have resulted in less potential misclassification. This study enrolled subjects irrespective of their ejection fraction, which may affect efficacy and safety endpoints and needs to be considered when studies are designed. To optimize clinical trials performed in the ED, validated measures of dyspnea and appropriate entry criteria need to be established.

The outcome measure that Miller et al1 used to design the clinical trial was 30-day recidivism. One limitation the authors identified was the overestimate of this endpoint, which resulted in lack of power to detect a difference. One explanation they gave for this overestimation was the initiation of a congestive heart failure pathway contemporaneous to study commencement. For interventions initiated in the ED, appropriate outcome measures need to be defined. As evident by this study, multiple factors affect 30-day recidivism, and this may not be the optimal efficacy endpoint. Short-term endpoints such as hospital length of stay, inhospital adverse events, hemodynamic characteristics, 7-day recidivism, or patient symptoms may be alternative measures of efficacy for interventions initiated in the ED because they may be less affected by subsequent events that occur in the outpatient setting.12

Miller et al1 should be applauded for the completion of this trial. Despite the limitations identified by the investigators, the assessment of pharmaceutical agents in the ED should be commended. To assess the efficacy of current therapies or future pharmaceutic agents in the acute care setting, trials such as this must be completed. As these investigators recognized, results of clinical trials that enroll patients long after ED treatment should be replicated in the ED before general adaptation.

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References 

  1. Miller A, Nazeer S, Pepe P, et al. Acutely decompensated heart failure in a county emergency department: a double-blind randomized controlled comparison of nesiritide vs. placebo treatment. Ann Emerg Med. 2008;51:571–578
  2. Rame JE, Sheffield MA, Dries DL, et al. Outcomes after emergency department discharge with a primary diagnosis of heart failure. Am Heart J. 2001;142:714–719
  3. Cuffe MS, Califf RM, Adams KF, et al. Short-term intravenous milrinone for acute exacerbation of chronic heart failure: a randomized controlled trial. JAMA. 2002;287:1541–1547
  4. Mebazaa A, Nieminen MS, Packer M, et al. Levosimendan vs dobutamine for patients with acute decompensated heart failure: the SURVIVE Randomized Trial. JAMA. 2007;297:1883–1891
  5. O'Connor CM, Gattis WA, Adams KF, et al. Tezosentan in patients with acute heart failure and acute coronary syndromes: results of the Randomized Intravenous TeZosentan Study (RITZ-4). J Am Coll Cardiol. 2003;41:1452–1457
  6. 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
  7. Udelson JE, McGrew FA, Flores E, et al. Multicenter, randomized, double-blind, placebo-controlled study on the effect of oral tolvaptan on left ventricular dilation and function in patients with heart failure and systolic dysfunction. J Am Coll Cardiol. 2007;49:2151–2159
  8. Peacock WF, Holland R, Gyarmathy R, et al. Observation unit treatment of heart failure with nesiritide: results from the Proaction Trial. J Emerg Med. 2005;29:243–252
  9. Gheorghiade M, Konstam MA, Burnett JC, et al. Short-term clinical effects of tolvaptan, an oral vasopressin antagonist, in patients hospitalized for heart failure: the EVEREST Clinical Status Trials. JAMA. 2007;297:1332–1343
  10. Heart Failure Society of American. HFSA 2006 comprehensive heart failure practice guideline. J Card Fail. 2006;12:e1–e2
  11. Teerlink JR. Dyspnea as an end point in clinical trials of therapies for acute decompensated heart failure. Am Heart J. 2003;145(2 suppl):S26–S33
  12. Gheorghiade M, Adams KF, Gattis WA, et al. Surrogate end points in heart failure trials. Am Heart J. 2003;145(2 suppl):S67–S70

 Supervising editor: Judd E. Hollander, MD

 Funding and support: By Annals policy, all authors are required to disclose any and all commercial, financial, and other relationships in any way related to the subject of this article that might create any potential conflict of interest. See the Manuscript Submission Agreement in this issue for examples of specific conflicts covered by this statement. Dr. Diercks has served on the speakers bureau for Scios.

 Publication date: Available online March 17, 2008.

 Reprints not available from the authors.

PII: S0196-0644(08)00352-1

doi:10.1016/j.annemergmed.2008.01.321

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 583-584, May 2008

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