ANNALS OF EMERGENCY MEDICINE
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2014
Systematic Review Snapshot TAKE-HOME MESSAGE Intravenous nitrate vasodilators produce similar symptom improvement in acute heart failure syndromes compared with alternative therapies, though evidence is limited. METHODS DATA SOURCES The Cochrane Central Register of Controlled Trials, EMBASE, MEDLINE, and Health Research and Development Information Network databases were searched for articles published from 1950 through July 2011, without language restrictions. Abstracts of scientific meetings, gray literature, and references of included studies were also searched. STUDY SELECTION Randomized and quasi-randomized trials of adults with acute heart failure syndromes of any severity were included if they compared intravenous nitrates with alternative therapy, including other pharmacotherapy and noninvasive positive-pressure ventilation. Two independent reviewers selected articles for inclusion, and discrepancies were resolved by discussion. The defined primary outcome was rapidity of symptom resolution; secondary outcomes included the need for mechanical ventilation, change in hemodynamic parameters, adverse events, length of stay, cost, and all-cause mortality.
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Do Intravenous Nitrates Improve Dyspnea in Acute Heart Failure Syndromes More Than Alternative Pharmacologic Interventions? EBEM Commentators
Joseph Turner, MD Jonathan Kirschner, MD Department of Emergency Medicine Indiana University School of Medicine Indianapolis, IN
Results Summary of the 4 included trials. Study
Risk of Bias
VMAC2
Low
Nelson10
Unclear
Verma11
Unclear
Beltrame12 High
N
Intervention
489 Nitroglycerin
Comparison
Outcomes
Nesiritide or placebo
No difference in symptom resolution,* hemodynamic variables,†‡ or mortality 28 Isosorbide Furosemide No difference in dinitrate hemodynamic variables† or mortality 48 Isosorbide Furosemide, No difference in dinitrate hydralazine, hemodynamic variables† or mortality or prenalterol 69 NitroglycerinþNAC Furosemideþmorphine No difference in symptom resolution,§ need for ventilation, hemodynamic variables,† or mortality
NAC, N-acetylcysteine. *Symptoms graphically reported at 3, 6, and 24 hours. † Systolic blood pressure, diastolic blood pressure, pulse rate, pulmonary artery occlusion pressure, cardiac output. ‡ Except for decreased pulmonary capillary wedge pressure. § Measured on a 0 to 3 scale at 30 minutes, 60 minutes, 3 hours, and 24 hours.
Six hundred twenty-two articles were identified in the search; 6 were reviewed in full text, and only 4 studies met the inclusion criteria. Two studies enrolled patients with acute myocardial infarction in a coronary care unit, whereas the other 2 excluded patients with acute myocardial infarction. Only 1 study
clearly described enrollment of emergency department (ED) patients.12 None of the 4 studies reported use of nonpharmacologic treatment such as noninvasive positive-pressure ventilation as alternative therapy. Study quality was considered low because of poor reporting of randomization methods and Annals of Emergency Medicine 1
Systematic Review Snapshot
DATA EXTRACTION AND BIAS ASSESSMENT Two authors independently extracted trial data on standardized forms and assessed methodology according to criteria outlined in the Cochrane handbook.1 Dichotomous outcomes were reported as odds ratios or risk ratios, and continuous outcomes were reported as standardized mean differences. Study variation was assessed for the presence of clinical heterogeneity and statistical heterogeneity (I2 statistic). Publication bias was not assessed because of the scarcity of included trials.
a lack of blinding in one study. Only 1 study commented on volume status of the patients and simply reported that most patients had “clinical evidence of volume overload.”2 Compared with alternative interventions, including furosemide and nesiritide, outcomes with intravenous nitrates did not significantly differ with respect to resolution of dyspnea, global clinical status, cardiac output, need for ventilation, or mortality. Nesiritide did appear to decrease pulmonary capillary wedge pressure compared with nitroglycerin in one study.2 Intravenous nitroglycerin was associated with more adverse events compared with placebo at 3 hours in one study, mainly because of headache.2
Commentary Acute heart failure syndrome is a frequent ED presentation associated with high mortality and health care costs.3-5 It can take many forms, with differences in levels of volume overload, cardiac dysfunction, and vascular tone.5,6 Often patients in the ED present with increased systemic vascular resistance and afterload, leading to acute decompensation of an already dysfunctional heart.7 As a result, clinical guidelines for managing acute 2 Annals of Emergency Medicine
heart failure exacerbations frequently recommend use of vasodilators such as nitroglycerin and isosorbide dinitrate, which may have beneficial effects on both preload and afterload.3,7-9 In actual practice, use of these medications is inconsistent.8 This systematic review sought to assess the efficacy of intravenous nitrate therapy compared with alternative therapies in acute heart failure syndrome. Despite a rigorous search, only 4 primary studies were included. Overall, the quality of evidence obtained was low and the generalizability limited. Two of the studies enrolled patients in the critical care unit and included only male patients who had heart failure after an acute myocardial infarction.10,11 These 2 studies were small, were judged to be at uncertain risk of bias, and may be only indirectly applicable to the ED setting. Only 2 studies reported symptom resolution with respect to time.2,12 One of these studies first reported this measurement at 3 hours after the start of treatment and therefore may not have adequately reported the rapid symptom resolution that would be of interest to emergency physicians.2 In addition, the only study considered to be at low risk for bias did not provide sufficient data about patients’ perception of dyspnea and did not report on the need for mechanical ventilation.2 Furthermore, the mean presenting systolic blood pressure for patients in this study was 121 mm Hg, with only 22% of patients having a systolic blood pressure of 140 mm Hg. This suggests that the patients in this study did not have the increased systemic vascular resistance often observed in acute heart failure syndrome and may have been less likely to benefit from nitrate vasodilators.7 Finally, none of the studies reported incidence of renal failure, which is an important consideration in the pharmacologic treatment of heart failure patients. In summary, the results of this systematic review offer no evidence to alter the
standard use of nitrates in the ED setting. The review did not find that intravenous nitrate vasodilators produce clinically important benefits compared with alternative therapies. However, the included studies had many limitations. More important, only 1 study addressed the question of whether nitrate therapy is beneficial compared with placebo and did not report sufficient data on clinically important outcomes.2 Currently, guidelines recommend the use of nitrates in patients with acute heart failure syndrome and associated dyspnea3; this review does not contradict those guidelines. Editor’s Note: This is a clinical synopsis, a regular feature of the Annals’ Systematic Review Snapshot (SRS) series. The source for this systematic review snapshot is: Wakai A, McCabe A, Kidney R, et al. Nitrates for acute heart failure syndromes. Cochrane Database Syst Rev. 2013;(8): CD005151. http://dx.doi.org/10.1002/ 14651858.CD005151.pub2. 1. Higgins JPT, Green S (eds). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. Cochrane Collaboration; 2011. Available at: www.cochranehandbook.org. Accessed July 8, 2014. 2. 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. 3. Silvers SM, Howell JM, Kosowsky JM, et al; American College of Emergency Physicians. Clinical policy: critical issues in the evaluation and management of adult patients presenting to the emergency department with acute heart failure syndromes. Ann Emerg Med. 2007;49:627-669. 4. McMurray JJ, Adamopoulos S, Anker SD, et al; ESC Committee for Practice Guidelines. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2012;33:1787-1847. 5. Yancy CW, Jessup M, Bozkurt B, et al; American College of Cardiology Foundation;
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Systematic Review Snapshot American Heart Association Task Force on Practice Guidelines. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013;62: e147-e239. 6. Gheorghiade M, Zannad F, Sopko G, et al; International Working Group on Acute Heart Failure Syndromes. Acute heart failure syndromes: current state and framework for future research. Circulation. 2005;112:3958-3968. 7. Cotter G, Moshkovitz Y, Kaluski E, et al. The role of cardiac power and systemic vascular resistance in the pathophysiology and diagnosis of patients with acute congestive
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heart failure. Eur J Heart Fail. 2003;5:443-451. 8. Crane SD. Epidemiology, treatment and outcome of acidotic, acute, cardiogenic pulmonary oedema presenting to an emergency department. Eur J Emerg Med. 2002;9:320-324. 9. Cotter G, Metzkor E, Kaluski E, et al. Randomised trial of high-dose isosorbide dinitrate plus low-dose furosemide versus high-dose furosemide plus low-dose isosorbide dinitrate in severe pulmonary oedema. Lancet. 1998;351:389-393. 10. Nelson GI, Silke B, Ahuja RC, et al. Haemodynamic advantages of isosorbide dinitrate over frusemide in acute heartfailure following myocardial infarction. Lancet. 1983;1:730-733.
11. Verma SP, Silke B, Hussain M, et al. First-line treatment of left ventricular failure complicating acute myocardial infarction: a randomised evaluation of immediate effects of diuretic, venodilator, arteriodilator, and positive inotropic drugs on left ventricular function. J Cardiovasc Pharmacol. 1987;10:38-46. 12. Beltrame JF, Zeitz CJ, Unger SA, et al. Nitrate therapy is an alternative to furosemide/ morphine therapy in the management of acute cardiogenic pulmonary edema. J Card Fail. 1998;4:271-279.
Michael Brown, MD, MSc, Alan Jones, MD, and David Newman, MD, serve as editors of the SRS series.
Annals of Emergency Medicine 3
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2014
Systematic Review Snapshot TAKE-HOME MESSAGE Intravenous nitrate vasodilators produce similar symptom improvement in acute heart failure syndromes compared with alternative therapies, though evidence is limited. METHODS DATA SOURCES The Cochrane Central Register of Controlled Trials, EMBASE, MEDLINE, and Health Research and Development Information Network databases were searched for articles published from 1950 through July 2011, without language restrictions. Abstracts of scientific meetings, gray literature, and references of included studies were also searched. STUDY SELECTION Randomized and quasi-randomized trials of adults with acute heart failure syndromes of any severity were included if they compared intravenous nitrates with alternative therapy, including other pharmacotherapy and noninvasive positive-pressure ventilation. Two independent reviewers selected articles for inclusion, and discrepancies were resolved by discussion. The defined primary outcome was rapidity of symptom resolution; secondary outcomes included the need for mechanical ventilation, change in hemodynamic parameters, adverse events, length of stay, cost, and all-cause mortality.
Volume
-,
no.
-
:
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2014
Do Intravenous Nitrates Improve Dyspnea in Acute Heart Failure Syndromes More Than Alternative Pharmacologic Interventions? EBEM Commentators
Joseph Turner, MD Jonathan Kirschner, MD Department of Emergency Medicine Indiana University School of Medicine Indianapolis, IN
Results Summary of the 4 included trials. Study
Risk of Bias
VMAC2
Low
Nelson10
Unclear
Verma11
Unclear
Beltrame12 High
N
Intervention
489 Nitroglycerin
Comparison
Outcomes
Nesiritide or placebo
No difference in symptom resolution,* hemodynamic variables,†‡ or mortality 28 Isosorbide Furosemide No difference in dinitrate hemodynamic variables† or mortality 48 Isosorbide Furosemide, No difference in dinitrate hydralazine, hemodynamic variables† or mortality or prenalterol 69 NitroglycerinþNAC Furosemideþmorphine No difference in symptom resolution,§ need for ventilation, hemodynamic variables,† or mortality
NAC, N-acetylcysteine. *Symptoms graphically reported at 3, 6, and 24 hours. † Systolic blood pressure, diastolic blood pressure, pulse rate, pulmonary artery occlusion pressure, cardiac output. ‡ Except for decreased pulmonary capillary wedge pressure. § Measured on a 0 to 3 scale at 30 minutes, 60 minutes, 3 hours, and 24 hours.
Six hundred twenty-two articles were identified in the search; 6 were reviewed in full text, and only 4 studies met the inclusion criteria. Two studies enrolled patients with acute myocardial infarction in a coronary care unit, whereas the other 2 excluded patients with acute myocardial infarction. Only 1 study
clearly described enrollment of emergency department (ED) patients.12 None of the 4 studies reported use of nonpharmacologic treatment such as noninvasive positive-pressure ventilation as alternative therapy. Study quality was considered low because of poor reporting of randomization methods and Annals of Emergency Medicine 1
Systematic Review Snapshot
DATA EXTRACTION AND BIAS ASSESSMENT Two authors independently extracted trial data on standardized forms and assessed methodology according to criteria outlined in the Cochrane handbook.1 Dichotomous outcomes were reported as odds ratios or risk ratios, and continuous outcomes were reported as standardized mean differences. Study variation was assessed for the presence of clinical heterogeneity and statistical heterogeneity (I2 statistic). Publication bias was not assessed because of the scarcity of included trials.
a lack of blinding in one study. Only 1 study commented on volume status of the patients and simply reported that most patients had “clinical evidence of volume overload.”2 Compared with alternative interventions, including furosemide and nesiritide, outcomes with intravenous nitrates did not significantly differ with respect to resolution of dyspnea, global clinical status, cardiac output, need for ventilation, or mortality. Nesiritide did appear to decrease pulmonary capillary wedge pressure compared with nitroglycerin in one study.2 Intravenous nitroglycerin was associated with more adverse events compared with placebo at 3 hours in one study, mainly because of headache.2
Commentary Acute heart failure syndrome is a frequent ED presentation associated with high mortality and health care costs.3-5 It can take many forms, with differences in levels of volume overload, cardiac dysfunction, and vascular tone.5,6 Often patients in the ED present with increased systemic vascular resistance and afterload, leading to acute decompensation of an already dysfunctional heart.7 As a result, clinical guidelines for managing acute 2 Annals of Emergency Medicine
heart failure exacerbations frequently recommend use of vasodilators such as nitroglycerin and isosorbide dinitrate, which may have beneficial effects on both preload and afterload.3,7-9 In actual practice, use of these medications is inconsistent.8 This systematic review sought to assess the efficacy of intravenous nitrate therapy compared with alternative therapies in acute heart failure syndrome. Despite a rigorous search, only 4 primary studies were included. Overall, the quality of evidence obtained was low and the generalizability limited. Two of the studies enrolled patients in the critical care unit and included only male patients who had heart failure after an acute myocardial infarction.10,11 These 2 studies were small, were judged to be at uncertain risk of bias, and may be only indirectly applicable to the ED setting. Only 2 studies reported symptom resolution with respect to time.2,12 One of these studies first reported this measurement at 3 hours after the start of treatment and therefore may not have adequately reported the rapid symptom resolution that would be of interest to emergency physicians.2 In addition, the only study considered to be at low risk for bias did not provide sufficient data about patients’ perception of dyspnea and did not report on the need for mechanical ventilation.2 Furthermore, the mean presenting systolic blood pressure for patients in this study was 121 mm Hg, with only 22% of patients having a systolic blood pressure of 140 mm Hg. This suggests that the patients in this study did not have the increased systemic vascular resistance often observed in acute heart failure syndrome and may have been less likely to benefit from nitrate vasodilators.7 Finally, none of the studies reported incidence of renal failure, which is an important consideration in the pharmacologic treatment of heart failure patients. In summary, the results of this systematic review offer no evidence to alter the
standard use of nitrates in the ED setting. The review did not find that intravenous nitrate vasodilators produce clinically important benefits compared with alternative therapies. However, the included studies had many limitations. More important, only 1 study addressed the question of whether nitrate therapy is beneficial compared with placebo and did not report sufficient data on clinically important outcomes.2 Currently, guidelines recommend the use of nitrates in patients with acute heart failure syndrome and associated dyspnea3; this review does not contradict those guidelines. Editor’s Note: This is a clinical synopsis, a regular feature of the Annals’ Systematic Review Snapshot (SRS) series. The source for this systematic review snapshot is: Wakai A, McCabe A, Kidney R, et al. Nitrates for acute heart failure syndromes. Cochrane Database Syst Rev. 2013;(8): CD005151. http://dx.doi.org/10.1002/ 14651858.CD005151.pub2. 1. Higgins JPT, Green S (eds). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. Cochrane Collaboration; 2011. Available at: www.cochranehandbook.org. Accessed July 8, 2014. 2. 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. 3. Silvers SM, Howell JM, Kosowsky JM, et al; American College of Emergency Physicians. Clinical policy: critical issues in the evaluation and management of adult patients presenting to the emergency department with acute heart failure syndromes. Ann Emerg Med. 2007;49:627-669. 4. McMurray JJ, Adamopoulos S, Anker SD, et al; ESC Committee for Practice Guidelines. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2012;33:1787-1847. 5. Yancy CW, Jessup M, Bozkurt B, et al; American College of Cardiology Foundation;
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no.
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:
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2014
Systematic Review Snapshot American Heart Association Task Force on Practice Guidelines. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013;62: e147-e239. 6. Gheorghiade M, Zannad F, Sopko G, et al; International Working Group on Acute Heart Failure Syndromes. Acute heart failure syndromes: current state and framework for future research. Circulation. 2005;112:3958-3968. 7. Cotter G, Moshkovitz Y, Kaluski E, et al. The role of cardiac power and systemic vascular resistance in the pathophysiology and diagnosis of patients with acute congestive
Volume
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:
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2014
heart failure. Eur J Heart Fail. 2003;5:443-451. 8. Crane SD. Epidemiology, treatment and outcome of acidotic, acute, cardiogenic pulmonary oedema presenting to an emergency department. Eur J Emerg Med. 2002;9:320-324. 9. Cotter G, Metzkor E, Kaluski E, et al. Randomised trial of high-dose isosorbide dinitrate plus low-dose furosemide versus high-dose furosemide plus low-dose isosorbide dinitrate in severe pulmonary oedema. Lancet. 1998;351:389-393. 10. Nelson GI, Silke B, Ahuja RC, et al. Haemodynamic advantages of isosorbide dinitrate over frusemide in acute heartfailure following myocardial infarction. Lancet. 1983;1:730-733.
11. Verma SP, Silke B, Hussain M, et al. First-line treatment of left ventricular failure complicating acute myocardial infarction: a randomised evaluation of immediate effects of diuretic, venodilator, arteriodilator, and positive inotropic drugs on left ventricular function. J Cardiovasc Pharmacol. 1987;10:38-46. 12. Beltrame JF, Zeitz CJ, Unger SA, et al. Nitrate therapy is an alternative to furosemide/ morphine therapy in the management of acute cardiogenic pulmonary edema. J Card Fail. 1998;4:271-279.
Michael Brown, MD, MSc, Alan Jones, MD, and David Newman, MD, serve as editors of the SRS series.
Annals of Emergency Medicine 3
