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Is there new hope for sudden cardiac death prevention early after myocardial infarction?
EDITORIAL COMMENTARY
Is there new hope for sudden cardiac death prevention early after myocardial infarction? Eric C. Stecker, MD, MPH From Cardiovascular Medicine Division, Oregon Health and Science University, Portland Oregon. The development and clinical trial evaluation of implantable cardioverter-defibrillators (ICDs) were seminal achievements in the field of clinical electrophysiology. Although ICDs are invasive and expensive, for appropriately selected patients the benefits are significant, with total costs and economic efficiencies that compare favorably to many medications.1–3 The potential patient population that could benefit from ICDs is large: 200,000 to 250,000 people in the United States alone suffer sudden cardiac death (SCD) annually.4 Despite great promise, optimism that ICDs can substantially reduce death from SCD must be tempered by several important limitations (detailed in several prior reviews4 –11). SCD is a heterogeneous problem, with preventive ICDs presumably having less impact in contexts such as ventricular arrhythmias during acute myocardial infarction (MI). A majority of patients at risk for SCD do not meet current guideline criteria for ICD implantation, but at that same time many ICDs are implanted in patients who will not utilize them. Efforts to expand ICD use to additional at-risk populations are limited by low incidence rates, and therefore require the development of new SCD risk predictors. Patients in the early post-MI setting represent a population with a high incidence of SCD not currently included in primary prevention ICD strategies.12–14 Such patients were specifically excluded from most of the landmark primary prevention trials: MADIT-I, MADIT-II, and SCD-HeFT.15–17 Although MUSTT included patients with MI as recently as 4 days prior, 83% of MIs actually occurred more than 30 days prior to study enrollment.18 In this issue of Heart Rhythm, Kumar et al19 report on a single-center, prospective cohort study of electrophysiologic study– guided ICD placement in patients with ejection fraction ⱕ40% during hospitalization for ST-elevation MI. Electrophysiologic study with programmed ventricular stimulation was performed for all patients prior to hospital discharge. By protocol, a positive electrophysiologic study Dr. Stecker has licensed biventricular pacing lead technology to Medtronic, Inc.; he does not receive ongoing royalties. Address reprint requests and correspondence: Dr. Eric C. Stecker, UHN 62, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239. E-mail address: [email protected].
(EPpos) was intended to lead to ICD placement, with 71% of patients actually receiving one; negative electrophysiologic study (EPneg) led to conventional post MI therapy, with only 6% receiving an ICD. The investigators found substantially lower risk of arrhythmic events (SCD or ICD-treated ventricular tachycardia [VT] or ventricular fibrillation [VF]) among EPneg patients compared to EPpos patients: hazard ratio 0.46 (P ⫽ .035) over mean follow-up of 49 months. At 2 years, 22% of EPpos patients had an arrhythmic event versus only 4.3% of EPneg patients (P ⬍.001). In secondary analyses, all-cause and cardiac mortalities were significantly higher in the EPpos group. Among the 29% of EPpos patients who did not receive an ICD, the risk of mortality was four times that of EPpos patients with an ICD. The mortality results reported by Kumar et al differ from two randomized trials of ICDs early after MI. Investigators in DINAMIT evaluated ICD use among patients with MI 6 to 40 days prior, ejection fraction ⱕ35%, and impaired heart rate variability on 24-hour Holter monitoring.20 There was no effect on all-cause mortality, and increases in nonarrhythmic death completely offset the reductions in arrhythmic death among ICD patients. Investigators in the IRIS trial evaluated ICD use among patients with MI 5 to 31 days prior and either ejection fraction ⱕ40% with heart rate ⬎90 bpm on presenting ECG (criterion 1) or nonsustained VT on Holter monitoring (criterion 2).21 Like DINAMIT, there was no reduction in all-cause mortality in the ICD arm of IRIS, and arrhythmic death reductions again were outweighed by nonarrhythmic death increases among ICD recipients. While they were well-done randomized trials, DINAMIT and IRIS do not represent the final, negative word on whether ICDs can reduce mortality in the early post-MI setting. Both trials evaluated ICD use among patients who had undergone risk stratification with tests that may not adequately identify patients at risk for SCD. In DINAMIT, all patients were selected based on impaired heart rate variability, which is clearly associated with increased all-cause mortality but not necessarily arrhythmic mortality (or only weakly so).9 In IRIS, 67% of patients were selected based on impaired ejection fraction with elevated resting heart rate, again not specific to arrhythmic mortality. In contrast, Kumar et al used sustained mono-
1547-5271/$ -see front matter © 2010 Heart Rhythm Society. All rights reserved.
doi:10.1016/j.hrthm.2010.08.012
Stecker
Editorial Commentary
morphic VT during programmed ventricular stimulation to define high-risk groups. Programmed ventricular stimulation had been clearly predictive of arrhythmic death in the chronic MI settings of MADIT-I and MUSTT.15,22 The results of the study by Kumar et al are intriguing because they raise the potential for expanded SCD prevention in a new patient population with a high incidence rate. Nonetheless, several important limitations prevent clinical adoption of this approach at this time. 1. The higher rates of arrhythmic events in the EPpos group may be an artifact of measurement bias (different arrhythmia detection methods were used between the EPpos and EPneg groups). EPpos patients were much more likely to experience ICD-detected VT/VF because 71% of patients in the EPpos group had ICDs compared to only 6% of the EPneg group, with no other forms of rhythm monitoring used. It is well accepted that ICD-detected ventricular arrhythmias may be nonsustained and thus overestimate true SCD rates.23 2. ICDs cannot be inferred as reducing mortality in the present study because of its observational rather than randomized design and lack of statistical controlling for known predictors of mortality. 3. It is unclear how many patients in the study by Kumar et al would have qualified for (and been protected by) standard primary prevention ICD use during the follow-up period. Three fourths of the events in the EPpos group occurred more than 40 days after MI. Normally the degree of measurement bias in the present study would have cast significant doubt and potentially invalidated the results. Although this remains a serious concern, reexamination of the data from the study by Kumar et al with the assumption that ICD-detected VT/VF rates overestimated SCD rates yields interesting hypothetical results. Assuming a 2⫻ ICD overestimation of SCD rates, the 2-year event rate and statistical significance for EPpos versus EPneg groups hypothetically would be 16.4% and 4.8%, respectively (P ⫽ .003 by Fisher exact test). Assuming a 3⫻ overestimate, the rates would be 11.8% and 4.3%, respectively (P ⫽ .028). Kumar et al have raised the possibility of using a programmed ventricular stimulation– guided ICD strategy to expand SCD prevention into part of the large population of at-risk patients who currently are not eligible for ICD-based prevention.24 Although this approach is not yet ready for clinical application, its potential implications are important and warrant evaluation in a randomized clinical trial.
1599
References 1. Mark DB, Nelson CL, Anstrom KJ, et al. Cost-effectiveness of defibrillator therapy or amiodarone in chronic stable heart failure: results from the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT). Circulation 2006;114:135– 142. 2. Zwanziger J, Hall WJ, Dick AW, et al. The cost effectiveness of implantable cardioverter-defibrillators: results from the Multicenter Automatic Defibrillator Implantation Trial (MADIT)-II. J Am Coll Cardiol 2006;47:2310 –2318. 3. Camm J, Klein H, Nisam S. The cost of implantable defibrillators: perceptions and reality. Eur Heart J 2007;28:392–397. 4. Chugh SS, Reinier K, Teodorescu C, et al. Epidemiology of sudden cardiac death: clinical and research implications. Prog Cardiovasc Dis 2008;51:213– 228. 5. Myerburg RJ, Kessler KM, Castellanos A. Sudden cardiac death. Structure, function, and time-dependence of risk. Circulation 1992;85:I2–10. 6. Huikuri HV, Castellanos A, Myerburg RJ. Sudden death due to cardiac arrhythmias. N Engl J Med 2001;345:1473–1482. 7. Myerburg RJ. Implantable cardioverter-defibrillators after myocardial infarction. N Engl J Med 2008;359:2245–2253. 8. Zipes DP, Wellens HJ. Sudden cardiac death. Circulation 1998;98:2334 –2351. 9. Buxton AE. Risk stratification for sudden death in patients with coronary artery disease. Heart Rhythm 2009;6:836 – 847. 10. Buxton AE, Lee KL, Hafley GE, et al. Limitations of ejection fraction for prediction of sudden death risk in patients with coronary artery disease: lessons from the MUSTT study. J Am Coll Cardiol 2007;50:1150 –1157. 11. Chugh SS. Early identification of risk factors for sudden cardiac death. Nat Rev 2010;7:318 –326. 12. Solomon SD, Zelenkofske S, McMurray JJ, et al. Sudden death in patients with myocardial infarction and left ventricular dysfunction, heart failure, or both. N Engl J Med 2005;352:2581–2588. 13. Adabag AS, Therneau TM, Gersh BJ, Weston SA, Roger VL. Sudden death after myocardial infarction. JAMA 2008;300:2022–2029. 14. Epstein AE, Dimarco JP, Ellenbogen KA, et al. ACC/AHA/HRS 2008 guidelines for device-based therapy of cardiac rhythm abnormalities: executive summary. Heart Rhythm 2008;5:934 –955. 15. Moss AJ, Hall WJ, Cannom DS, et al. Improved survival with an implanted defibrillator in patients with coronary disease at high risk for ventricular arrhythmia. Multicenter Automatic Defibrillator Implantation Trial Investigators. N Engl J Med 1996;335:1933–1940. 16. Moss AJ, Zareba W, Hall WJ, et al. Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. N Engl J Med 2002;346:877– 883. 17. Bardy GH, Lee KL, Mark DB, et al. Amiodarone or an implantable cardioverterdefibrillator for congestive heart failure. N Engl J Med 2005;352:225–237. 18. Buxton AE, Lee KL, Fisher JD, et al. A randomized study of the prevention of sudden death in patients with coronary artery disease. Multicenter Unsustained Tachycardia Trial Investigators. N Engl J Med 1999;341:1882–1890. 19. Kumar S, Sivagangabalan G, Zaman S, et al. Electrophysiology-guided defibrillator implantation early after ST-elevation myocardial infarction. Heart Rhythm 2010;7:1589 –1597. 20. Hohnloser SH, Kuck KH, Dorian P, et al. Prophylactic use of an implantable cardioverter-defibrillator after acute myocardial infarction. N Engl J Med 2004; 351:2481–2488. 21. Steinbeck G, Andresen D, Seidl K, et al. Defibrillator implantation early after myocardial infarction. N Engl J Med 2009;361:1427–1436. 22. Buxton AE, Lee KL, Hafley GE, et al. Relation of ejection fraction and inducible ventricular tachycardia to mode of death in patients with coronary artery disease: an analysis of patients enrolled in the multicenter unsustained tachycardia trial. Circulation 2002;106:2466 –2472. 23. Ellenbogen KA, Levine JH, Berger RD, et al. Are implantable cardioverter defibrillator shocks a surrogate for sudden cardiac death in patients with nonischemic cardiomyopathy? Circulation 2006;113:776 –782. 24. Stecker EC, Vickers C, Waltz J, et al. Population-based analysis of sudden cardiac death with and without left ventricular systolic dysfunction: two-year findings from the Oregon Sudden Unexpected Death Study. J Am Coll Cardiol 2006;47:1161–1166.
Is there new hope for sudden cardiac death prevention early after myocardial infarction? Eric C. Stecker, MD, MPH From Cardiovascular Medicine Division, Oregon Health and Science University, Portland Oregon. The development and clinical trial evaluation of implantable cardioverter-defibrillators (ICDs) were seminal achievements in the field of clinical electrophysiology. Although ICDs are invasive and expensive, for appropriately selected patients the benefits are significant, with total costs and economic efficiencies that compare favorably to many medications.1–3 The potential patient population that could benefit from ICDs is large: 200,000 to 250,000 people in the United States alone suffer sudden cardiac death (SCD) annually.4 Despite great promise, optimism that ICDs can substantially reduce death from SCD must be tempered by several important limitations (detailed in several prior reviews4 –11). SCD is a heterogeneous problem, with preventive ICDs presumably having less impact in contexts such as ventricular arrhythmias during acute myocardial infarction (MI). A majority of patients at risk for SCD do not meet current guideline criteria for ICD implantation, but at that same time many ICDs are implanted in patients who will not utilize them. Efforts to expand ICD use to additional at-risk populations are limited by low incidence rates, and therefore require the development of new SCD risk predictors. Patients in the early post-MI setting represent a population with a high incidence of SCD not currently included in primary prevention ICD strategies.12–14 Such patients were specifically excluded from most of the landmark primary prevention trials: MADIT-I, MADIT-II, and SCD-HeFT.15–17 Although MUSTT included patients with MI as recently as 4 days prior, 83% of MIs actually occurred more than 30 days prior to study enrollment.18 In this issue of Heart Rhythm, Kumar et al19 report on a single-center, prospective cohort study of electrophysiologic study– guided ICD placement in patients with ejection fraction ⱕ40% during hospitalization for ST-elevation MI. Electrophysiologic study with programmed ventricular stimulation was performed for all patients prior to hospital discharge. By protocol, a positive electrophysiologic study Dr. Stecker has licensed biventricular pacing lead technology to Medtronic, Inc.; he does not receive ongoing royalties. Address reprint requests and correspondence: Dr. Eric C. Stecker, UHN 62, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239. E-mail address: [email protected].
(EPpos) was intended to lead to ICD placement, with 71% of patients actually receiving one; negative electrophysiologic study (EPneg) led to conventional post MI therapy, with only 6% receiving an ICD. The investigators found substantially lower risk of arrhythmic events (SCD or ICD-treated ventricular tachycardia [VT] or ventricular fibrillation [VF]) among EPneg patients compared to EPpos patients: hazard ratio 0.46 (P ⫽ .035) over mean follow-up of 49 months. At 2 years, 22% of EPpos patients had an arrhythmic event versus only 4.3% of EPneg patients (P ⬍.001). In secondary analyses, all-cause and cardiac mortalities were significantly higher in the EPpos group. Among the 29% of EPpos patients who did not receive an ICD, the risk of mortality was four times that of EPpos patients with an ICD. The mortality results reported by Kumar et al differ from two randomized trials of ICDs early after MI. Investigators in DINAMIT evaluated ICD use among patients with MI 6 to 40 days prior, ejection fraction ⱕ35%, and impaired heart rate variability on 24-hour Holter monitoring.20 There was no effect on all-cause mortality, and increases in nonarrhythmic death completely offset the reductions in arrhythmic death among ICD patients. Investigators in the IRIS trial evaluated ICD use among patients with MI 5 to 31 days prior and either ejection fraction ⱕ40% with heart rate ⬎90 bpm on presenting ECG (criterion 1) or nonsustained VT on Holter monitoring (criterion 2).21 Like DINAMIT, there was no reduction in all-cause mortality in the ICD arm of IRIS, and arrhythmic death reductions again were outweighed by nonarrhythmic death increases among ICD recipients. While they were well-done randomized trials, DINAMIT and IRIS do not represent the final, negative word on whether ICDs can reduce mortality in the early post-MI setting. Both trials evaluated ICD use among patients who had undergone risk stratification with tests that may not adequately identify patients at risk for SCD. In DINAMIT, all patients were selected based on impaired heart rate variability, which is clearly associated with increased all-cause mortality but not necessarily arrhythmic mortality (or only weakly so).9 In IRIS, 67% of patients were selected based on impaired ejection fraction with elevated resting heart rate, again not specific to arrhythmic mortality. In contrast, Kumar et al used sustained mono-
1547-5271/$ -see front matter © 2010 Heart Rhythm Society. All rights reserved.
doi:10.1016/j.hrthm.2010.08.012
Stecker
Editorial Commentary
morphic VT during programmed ventricular stimulation to define high-risk groups. Programmed ventricular stimulation had been clearly predictive of arrhythmic death in the chronic MI settings of MADIT-I and MUSTT.15,22 The results of the study by Kumar et al are intriguing because they raise the potential for expanded SCD prevention in a new patient population with a high incidence rate. Nonetheless, several important limitations prevent clinical adoption of this approach at this time. 1. The higher rates of arrhythmic events in the EPpos group may be an artifact of measurement bias (different arrhythmia detection methods were used between the EPpos and EPneg groups). EPpos patients were much more likely to experience ICD-detected VT/VF because 71% of patients in the EPpos group had ICDs compared to only 6% of the EPneg group, with no other forms of rhythm monitoring used. It is well accepted that ICD-detected ventricular arrhythmias may be nonsustained and thus overestimate true SCD rates.23 2. ICDs cannot be inferred as reducing mortality in the present study because of its observational rather than randomized design and lack of statistical controlling for known predictors of mortality. 3. It is unclear how many patients in the study by Kumar et al would have qualified for (and been protected by) standard primary prevention ICD use during the follow-up period. Three fourths of the events in the EPpos group occurred more than 40 days after MI. Normally the degree of measurement bias in the present study would have cast significant doubt and potentially invalidated the results. Although this remains a serious concern, reexamination of the data from the study by Kumar et al with the assumption that ICD-detected VT/VF rates overestimated SCD rates yields interesting hypothetical results. Assuming a 2⫻ ICD overestimation of SCD rates, the 2-year event rate and statistical significance for EPpos versus EPneg groups hypothetically would be 16.4% and 4.8%, respectively (P ⫽ .003 by Fisher exact test). Assuming a 3⫻ overestimate, the rates would be 11.8% and 4.3%, respectively (P ⫽ .028). Kumar et al have raised the possibility of using a programmed ventricular stimulation– guided ICD strategy to expand SCD prevention into part of the large population of at-risk patients who currently are not eligible for ICD-based prevention.24 Although this approach is not yet ready for clinical application, its potential implications are important and warrant evaluation in a randomized clinical trial.
1599
References 1. Mark DB, Nelson CL, Anstrom KJ, et al. Cost-effectiveness of defibrillator therapy or amiodarone in chronic stable heart failure: results from the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT). Circulation 2006;114:135– 142. 2. Zwanziger J, Hall WJ, Dick AW, et al. The cost effectiveness of implantable cardioverter-defibrillators: results from the Multicenter Automatic Defibrillator Implantation Trial (MADIT)-II. J Am Coll Cardiol 2006;47:2310 –2318. 3. Camm J, Klein H, Nisam S. The cost of implantable defibrillators: perceptions and reality. Eur Heart J 2007;28:392–397. 4. Chugh SS, Reinier K, Teodorescu C, et al. Epidemiology of sudden cardiac death: clinical and research implications. Prog Cardiovasc Dis 2008;51:213– 228. 5. Myerburg RJ, Kessler KM, Castellanos A. Sudden cardiac death. Structure, function, and time-dependence of risk. Circulation 1992;85:I2–10. 6. Huikuri HV, Castellanos A, Myerburg RJ. Sudden death due to cardiac arrhythmias. N Engl J Med 2001;345:1473–1482. 7. Myerburg RJ. Implantable cardioverter-defibrillators after myocardial infarction. N Engl J Med 2008;359:2245–2253. 8. Zipes DP, Wellens HJ. Sudden cardiac death. Circulation 1998;98:2334 –2351. 9. Buxton AE. Risk stratification for sudden death in patients with coronary artery disease. Heart Rhythm 2009;6:836 – 847. 10. Buxton AE, Lee KL, Hafley GE, et al. Limitations of ejection fraction for prediction of sudden death risk in patients with coronary artery disease: lessons from the MUSTT study. J Am Coll Cardiol 2007;50:1150 –1157. 11. Chugh SS. Early identification of risk factors for sudden cardiac death. Nat Rev 2010;7:318 –326. 12. Solomon SD, Zelenkofske S, McMurray JJ, et al. Sudden death in patients with myocardial infarction and left ventricular dysfunction, heart failure, or both. N Engl J Med 2005;352:2581–2588. 13. Adabag AS, Therneau TM, Gersh BJ, Weston SA, Roger VL. Sudden death after myocardial infarction. JAMA 2008;300:2022–2029. 14. Epstein AE, Dimarco JP, Ellenbogen KA, et al. ACC/AHA/HRS 2008 guidelines for device-based therapy of cardiac rhythm abnormalities: executive summary. Heart Rhythm 2008;5:934 –955. 15. Moss AJ, Hall WJ, Cannom DS, et al. Improved survival with an implanted defibrillator in patients with coronary disease at high risk for ventricular arrhythmia. Multicenter Automatic Defibrillator Implantation Trial Investigators. N Engl J Med 1996;335:1933–1940. 16. Moss AJ, Zareba W, Hall WJ, et al. Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. N Engl J Med 2002;346:877– 883. 17. Bardy GH, Lee KL, Mark DB, et al. Amiodarone or an implantable cardioverterdefibrillator for congestive heart failure. N Engl J Med 2005;352:225–237. 18. Buxton AE, Lee KL, Fisher JD, et al. A randomized study of the prevention of sudden death in patients with coronary artery disease. Multicenter Unsustained Tachycardia Trial Investigators. N Engl J Med 1999;341:1882–1890. 19. Kumar S, Sivagangabalan G, Zaman S, et al. Electrophysiology-guided defibrillator implantation early after ST-elevation myocardial infarction. Heart Rhythm 2010;7:1589 –1597. 20. Hohnloser SH, Kuck KH, Dorian P, et al. Prophylactic use of an implantable cardioverter-defibrillator after acute myocardial infarction. N Engl J Med 2004; 351:2481–2488. 21. Steinbeck G, Andresen D, Seidl K, et al. Defibrillator implantation early after myocardial infarction. N Engl J Med 2009;361:1427–1436. 22. Buxton AE, Lee KL, Hafley GE, et al. Relation of ejection fraction and inducible ventricular tachycardia to mode of death in patients with coronary artery disease: an analysis of patients enrolled in the multicenter unsustained tachycardia trial. Circulation 2002;106:2466 –2472. 23. Ellenbogen KA, Levine JH, Berger RD, et al. Are implantable cardioverter defibrillator shocks a surrogate for sudden cardiac death in patients with nonischemic cardiomyopathy? Circulation 2006;113:776 –782. 24. Stecker EC, Vickers C, Waltz J, et al. Population-based analysis of sudden cardiac death with and without left ventricular systolic dysfunction: two-year findings from the Oregon Sudden Unexpected Death Study. J Am Coll Cardiol 2006;47:1161–1166.