Regarding manuscript: “Resuscitation Outcomes Consortium–Amiodarone, Lidocaine, or Placebo study: Rationale and methodology behind out-of-hospital cardiac arrest antiarrhythmic drug trial” Response: We appreciate the inquiry by Dr Iannone in which he correctly observes that there is evidence of a short-term outcome benefit (admission alive to hospital) from the use of certain antiarrhythmic drugs in cardiac arrest. [1,2] Indeed, such surrogate measures of resuscitation outcome such as return of spontaneous circulation or survival to hospital admission are helpful starting points for assessing the merits of an antiarrhythmic drug. But they are at best only starting points. These short-term measures have not as yet distinguished treatments that truly save lives from those that may only forestall death or lead to poor neurologic outcome. For example, despite the apparent short-term benefit from amiodarone as compared with placebo or with lidocaine on hospital admission rates after cardiac arrest in the ARREST i and ALIVE ii trials, respectively, neither trial had sufficient statistical power to detect a difference in survival to hospital discharge between treatment groups, and no such differences were observed. Accordingly, some have interpreted the “success” of treatment in these trials to merely mean that more patients were brought to the hospital and subsequently died there—perhaps changing the location of death but not its eventuality. An even more telling example is the marked discordance that was recently reported between the higher rates of return of spontaneous circulation among recipients of epinephrine during cardiac arrest (versus nonrecipients) and yet their comparatively lower rates of survival and neurologic recovery. [3] These findings raise precisely the opposite ethical concern to that expressed in the inquiry. That is, is it ethical to deploy interventions that improve short-term (surrogate) outcomes but do not result in better survival and may only lead to an added health care burden, cost, grief, and suffering for families? Dr Iannone also correctly observes that the Declaration of Helsinki does not exclude the use of placebo or no treatment, where no proven therapeutic method exists for a given condition [4]. This is indeed the case with regard to the use of antiarrhythmic drugs in cardiac arrest. As stated in the 2010 European Resuscitation Council Guidelines for Resuscitation and also iterated in the International Consensus on Cardiopulmonary Resuscitation and 2010 American Heart Association Guidelines, “there is no evidence that giving any antiarrhythmic drug therapy routinely during human cardiac arrest increases survival to hospital discharge [5–7].” Accordingly, in the European Resuscitation Council Guidelines, antiarrhythmic drugs are weakly recommended strictly based on
expert consensus, whereas in American Heart Association Guidelines, they are classified as a treatment “consideration (class IIb),” rather than a requirement. At the present time, use of amiodarone, lidocaine, both, or neither during resuscitation is highly variable across prehospital emergency medical services in North America, indicating that there is no universal agreement about the “drug of choice,” if any, during cardiac arrest [8]. In addition, a recent randomized prehospital trial of resuscitation from cardiac arrest with and without standard medications found no significant difference in survival outcome between “drug-treated” and “untreated” groups, lending further support to the existence of clinical equipoise on this important question [9]. The value of performing placebo-controlled trials in such circumstances is attested by past investigations which, for example, addressed the benefit of treating premature ventricular complexes with antiarrhythmic drugs after myocardial infarction [10], the use of estrogen therapy for primary prevention of cardiovascular disease [11], vitamin supplements for secondary prevention of cardiovascular disease [12], and even surgical procedures such as ligation of internal mammary arteries for refractory angina. [13] In challenging the effectiveness of these once widely accepted therapies, such trials (some of which were also accused of lacking clinical stewardship at the time of their conduct) taught us the valuable lesson that placebo in some cases may actually prove to be superior to “accepted” treatment. The ALPS is specifically designed and statistically powered to evaluate the effectiveness of amiodarone as compared with placebo, lidocaine as compared with placebo, and amiodarone as compared with lidocaine in shock-refractory cardiac arrest, as measured by actual lives saved, with a secondary emphasis on survival with favorable neurologic function [14]. The trial has been scientifically and ethically vetted at multiple levels, is conducted with close scrutiny of the quality of cardiopulmonary resuscitation and accompanying interventions, and performed in accordance with all regulations pertaining to exception from informed consent including advance community consultation, approval by institutional review boards in all localities where it is being conducted, notification of all enrolled subjects and/or their family, and ongoing oversight by an independent data safety and monitoring board. The ALPS affords the unique opportunity to definitively establish the worth of antiarrhythmic drugs in shock-refractory cardiac arrest, inform future clinical practice, and promote the ultimate goal of resuscitation, which is saving more functionally intact lives. We therefore thank Dr Iannone for his thoughtful inquiry and for giving us the opportunity to highlight the importance of conducting large clinical trials with clinically meaningful end points in the field of emergency cardiac care. Am Heart J 2014;168:e19-e20. 0002-8703 http://dx.doi.org/10.1016/j.ahj.2014.07.014
e20 Kudenchuk et al
Peter J. Kudenchuk, MD Department of Medicine, Division of Cardiology University of Washington, Seattle, WA Public Health Seattle & King County, Seattle WA E-mail: [email protected] Siobhan P. Brown, PhD Department of Biostatistics, Clinical Trial Center University of Washington, Seattle, WA Mohamud Daya, MD Department of Emergency Medicine Oregon Health Science University, Portland, OR Laurie J. Morrison, MSc, MD RESCU, Keenan Research Centre, St. Michaels Hospital Division of Emergency Medicine, Department of Medicine University of Toronto, Toronto, Ontario Judy Powell, BSN Department of Biostatistics, Clinical Trial Center University of Washington, Seattle, WA Brian Leroux, PhD Department of Biostatistics, Clinical Trial Center University of Washington, Seattle, WA Paul Dorian, MD Department of Medicine, Division of Cardiology St Michael’s Hospital, University of Toronto Toronto, Ontario, Canada
References 1. Kudenchuk PJ, Cobb LA, Copass MK, et al. Amiodarone for resuscitation after out-of-hospital cardiac arrest due to ventricular fibrillation. N Engl J Med 1999;341:871-8.
American Heart Journal September 2014
2. Dorian P, Cass D, Schwartz B, et al. Amiodarone as compared with lidocaine for shock-resistant ventricular fibrillation. N Engl J Med 2002;346:884-90. 3. Hagihara A, Hasegawa M, Abe T, et al. Prehospital epinephrine use and survival among patients with out-of-hospital cardiac arrest. JAMA 2012;307:1161-8. 4. Lewis JA, Jonsson B, Kreutz G, et al. Placebo-controlled trials and the Declaration of Helsinki. Lancet 2002;359:1337-40. 5. Nolan JP, Soar J, Zideman DA, et al. European Resuscitation Council Guidelines for Resuscitation 2010. Resuscitation 2010;81:1219-76. 6. Nolan JP, Hazinski MF, Billi JE, et al. 2010 international consensus on cardiopulmonary resuscitation and emergency cardiovascular care science with treatment recommendations. Resuscitation 2010;81S: e1-25. 7. Neumar RW, Otto CW, Link MS, et al. Part 8: adult advanced cardiovascular life support: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2010;122(Suppl 3):S729-67. 8. Glover BM, Brown SP, Morrison L, et al. Wide variability in drug use in out of hospital cardiac arrest: a report from the resuscitation outcomes consortium. Resuscitation 2012;83:1324-30. 9. Olasveengen TM, Sunde K, Brunborg C, et al. Intravenous drug administration during out-of-hospital cardiac arrest: a randomized trial. JAMA 2009;302:2222-9. 10. Echt DS, Liebson PR, Mitchell LB, et al. Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial. N Engl J Med 1991;324:781-8. 11. Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women’s Health Initiative randomized controlled trial. JAMA 2002;288:321-33. 12. Yusuf S, Dagenais G, Pogue J, et al. Vitamin E supplementation and cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 2000;342: 154-60. 13. Cobb LA, Thomas GI, Dillard DH, et al. An evaluation of internal mammary-artery ligation by a double-blind technic. N Engl J Med 1959;260:1115-8. 14. Kudenchuk PJ, Brown SP, Daya M, et al. Resuscitation Outcomes Consortium- Amiodarone, Lidocaine or Placebo study (ROC-ALPS): rationale and methodology behind out of hospital cardiac arrest antiarrhythmic drug trial. Am Heart J 2014;167:653-9.
expert consensus, whereas in American Heart Association Guidelines, they are classified as a treatment “consideration (class IIb),” rather than a requirement. At the present time, use of amiodarone, lidocaine, both, or neither during resuscitation is highly variable across prehospital emergency medical services in North America, indicating that there is no universal agreement about the “drug of choice,” if any, during cardiac arrest [8]. In addition, a recent randomized prehospital trial of resuscitation from cardiac arrest with and without standard medications found no significant difference in survival outcome between “drug-treated” and “untreated” groups, lending further support to the existence of clinical equipoise on this important question [9]. The value of performing placebo-controlled trials in such circumstances is attested by past investigations which, for example, addressed the benefit of treating premature ventricular complexes with antiarrhythmic drugs after myocardial infarction [10], the use of estrogen therapy for primary prevention of cardiovascular disease [11], vitamin supplements for secondary prevention of cardiovascular disease [12], and even surgical procedures such as ligation of internal mammary arteries for refractory angina. [13] In challenging the effectiveness of these once widely accepted therapies, such trials (some of which were also accused of lacking clinical stewardship at the time of their conduct) taught us the valuable lesson that placebo in some cases may actually prove to be superior to “accepted” treatment. The ALPS is specifically designed and statistically powered to evaluate the effectiveness of amiodarone as compared with placebo, lidocaine as compared with placebo, and amiodarone as compared with lidocaine in shock-refractory cardiac arrest, as measured by actual lives saved, with a secondary emphasis on survival with favorable neurologic function [14]. The trial has been scientifically and ethically vetted at multiple levels, is conducted with close scrutiny of the quality of cardiopulmonary resuscitation and accompanying interventions, and performed in accordance with all regulations pertaining to exception from informed consent including advance community consultation, approval by institutional review boards in all localities where it is being conducted, notification of all enrolled subjects and/or their family, and ongoing oversight by an independent data safety and monitoring board. The ALPS affords the unique opportunity to definitively establish the worth of antiarrhythmic drugs in shock-refractory cardiac arrest, inform future clinical practice, and promote the ultimate goal of resuscitation, which is saving more functionally intact lives. We therefore thank Dr Iannone for his thoughtful inquiry and for giving us the opportunity to highlight the importance of conducting large clinical trials with clinically meaningful end points in the field of emergency cardiac care. Am Heart J 2014;168:e19-e20. 0002-8703 http://dx.doi.org/10.1016/j.ahj.2014.07.014
e20 Kudenchuk et al
Peter J. Kudenchuk, MD Department of Medicine, Division of Cardiology University of Washington, Seattle, WA Public Health Seattle & King County, Seattle WA E-mail: [email protected] Siobhan P. Brown, PhD Department of Biostatistics, Clinical Trial Center University of Washington, Seattle, WA Mohamud Daya, MD Department of Emergency Medicine Oregon Health Science University, Portland, OR Laurie J. Morrison, MSc, MD RESCU, Keenan Research Centre, St. Michaels Hospital Division of Emergency Medicine, Department of Medicine University of Toronto, Toronto, Ontario Judy Powell, BSN Department of Biostatistics, Clinical Trial Center University of Washington, Seattle, WA Brian Leroux, PhD Department of Biostatistics, Clinical Trial Center University of Washington, Seattle, WA Paul Dorian, MD Department of Medicine, Division of Cardiology St Michael’s Hospital, University of Toronto Toronto, Ontario, Canada
References 1. Kudenchuk PJ, Cobb LA, Copass MK, et al. Amiodarone for resuscitation after out-of-hospital cardiac arrest due to ventricular fibrillation. N Engl J Med 1999;341:871-8.
American Heart Journal September 2014
2. Dorian P, Cass D, Schwartz B, et al. Amiodarone as compared with lidocaine for shock-resistant ventricular fibrillation. N Engl J Med 2002;346:884-90. 3. Hagihara A, Hasegawa M, Abe T, et al. Prehospital epinephrine use and survival among patients with out-of-hospital cardiac arrest. JAMA 2012;307:1161-8. 4. Lewis JA, Jonsson B, Kreutz G, et al. Placebo-controlled trials and the Declaration of Helsinki. Lancet 2002;359:1337-40. 5. Nolan JP, Soar J, Zideman DA, et al. European Resuscitation Council Guidelines for Resuscitation 2010. Resuscitation 2010;81:1219-76. 6. Nolan JP, Hazinski MF, Billi JE, et al. 2010 international consensus on cardiopulmonary resuscitation and emergency cardiovascular care science with treatment recommendations. Resuscitation 2010;81S: e1-25. 7. Neumar RW, Otto CW, Link MS, et al. Part 8: adult advanced cardiovascular life support: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2010;122(Suppl 3):S729-67. 8. Glover BM, Brown SP, Morrison L, et al. Wide variability in drug use in out of hospital cardiac arrest: a report from the resuscitation outcomes consortium. Resuscitation 2012;83:1324-30. 9. Olasveengen TM, Sunde K, Brunborg C, et al. Intravenous drug administration during out-of-hospital cardiac arrest: a randomized trial. JAMA 2009;302:2222-9. 10. Echt DS, Liebson PR, Mitchell LB, et al. Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial. N Engl J Med 1991;324:781-8. 11. Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women’s Health Initiative randomized controlled trial. JAMA 2002;288:321-33. 12. Yusuf S, Dagenais G, Pogue J, et al. Vitamin E supplementation and cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 2000;342: 154-60. 13. Cobb LA, Thomas GI, Dillard DH, et al. An evaluation of internal mammary-artery ligation by a double-blind technic. N Engl J Med 1959;260:1115-8. 14. Kudenchuk PJ, Brown SP, Daya M, et al. Resuscitation Outcomes Consortium- Amiodarone, Lidocaine or Placebo study (ROC-ALPS): rationale and methodology behind out of hospital cardiac arrest antiarrhythmic drug trial. Am Heart J 2014;167:653-9.
