Prophylactic Implantable Cardioverter–Defibrillators after Myocardial Infarction — Not for Everyone
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《新英格兰医药杂志》
A number of clinical trials have been reported to show that the implantable cardioverter–defibrillator (ICD) prevents sudden death from cardiac causes and significantly reduces overall mortality among patients with left ventricular dysfunction in the setting of ischemic heart disease.1,2,3,4 Some of these studies included patients with other risk factors for sudden death from cardiac causes, such as nonsustained ventricular tachycardia on Holter monitoring and the induction of a sustained ventricular tachyarrhythmia during electrophysiological testing.1,3 As a consequence of these studies, the use of ICDs for the primary prevention of sudden death from cardiac causes has increased worldwide. However, ICDs are costly, and there has been much discussion about the cost-effectiveness of prophylactic ICD implantation. This has led to considerable debate as to whether all patients with clinically significant ventricular dysfunction after a myocardial infarction should receive an ICD.5
In this issue of the Journal, Hohnloser et al.6 report the results of the Defibrillator in Acute Myocardial Infarction Trial (DINAMIT). The DINAMIT investigators randomly assigned 674 patients with left ventricular dysfunction and impaired cardiac autonomic function to receive ICD therapy or optimal medical therapy 6 to 40 days after a myocardial infarction. Over a follow-up period of approximately 30 months, no significant difference in overall mortality was observed between the two treatment groups. Although the rate of death due to arrhythmia was substantially lower in the ICD group (1.5 percent per year) than in the control group (3.5 percent per year), more deaths from nonarrhythmic causes occurred in the ICD group (6.1 percent per year, vs. 3.5 percent per year in the control group). Moreover, the majority of the deaths from nonarrhythmic causes in the ICD group were cardiac in nature. The authors conclude that their study defines a limitation of prophylactic ICD therapy.
This important clinical trial identifies a group of patients with risk factors for sudden death from cardiac causes in whom ICD therapy may not provide a survival benefit. These results are in direct contrast to those of several published studies reporting that the use of an ICD, as compared with medical therapy, reduces mortality in other high-risk populations with ischemic heart disease.1,2,3,4 The characteristics of the patients in the current study differ in important ways from the characteristics of the patients with ischemic heart disease who were evaluated in other primary-prevention trials. The patients in DINAMIT were enrolled within 6 to 40 days after the index myocardial infarction, and all of them had an indicator of autonomic dysfunction — abnormal heart-rate variability, an elevated heart rate at rest, or both. In contrast, in the Multicenter Automatic Defibrillator Implantation Trials I and II (MADIT I and II)1,3 and in the Multicenter Unsustained Tachycardia Trial (MUSTT),2 the majority of patients were recruited more than one year after the index myocardial infarction, and autonomic function was not assessed. The Coronary Artery Bypass Graft (CABG) Patch Trial7 showed that a prophylactic ICD was not beneficial in patients with left ventricular dysfunction who had undergone coronary-artery bypass surgery, thus demonstrating the importance of revascularization for the prevention of sudden death. In DINAMIT, patients undergoing coronary-artery bypass grafting or a three-vessel percutaneous coronary intervention were excluded. A percutaneous coronary intervention alone was performed in only about a quarter of the study population at the time of myocardial infarction.
Why was there no survival benefit among the members of the DINAMIT population who received ICDs, if they had ventricular tachyarrhythmias that were appropriately and effectively treated with the device? One must consider the possibility that the presence of markers of autonomic dysfunction identified a patient cohort at high risk for death due to progressive heart failure. Recurrent, sustained ventricular tachyarrhythmias may be a harbinger of advancing heart failure. This would suggest that although sustained ventricular tachyarrhythmias occurred and were successfully treated, patients subsequently died of heart failure. Indeed, further analysis by the DINAMIT investigators indicates that the increased risk of death from nonarrhythmic causes was confined to patients who had received a shock from the ICD.8 The interval between shock therapy and subsequent death has not yet been reported. The CABG Patch Trial investigators also reported that ICD therapy reduced the rate of death due to arrhythmias by 45 percent but did not reduce overall mortality, because the majority of deaths (71 percent) were nonarrhythmic in nature.7 Their study also supports the concept that successful termination of a ventricular tachyarrhythmia occurring as a consequence of end-stage heart failure or an acute myocardial infarction may simply convert what would have been a sudden death to a death from pump failure, without an effect on survival. Whether cardiac-resynchronization therapy would have improved the outcome in the current study population is unknown.
Another possible explanation is that the temporal proximity to the index myocardial infarction influenced the outcomes in DINAMIT. Current medical therapy with beta-blockers, angiotensin-converting–enzyme inhibitors, and aldosterone blockers prevents or at least delays the adverse ventricular remodeling that occurs after myocardial infarction and that contributes to the electrophysiological mechanisms of sudden death from cardiac causes. Thus, the benefits of ICD implantation for the prevention of sudden death may be delayed for months to years after a myocardial infarction. A retrospective analysis performed by the MADIT II investigators supports the finding that patients do not benefit from ICD therapy early after myocardial infarction.9 In MADIT II, the mean time from the most recent myocardial infarction to enrollment was 6.5 years. Patients with a remote myocardial infarction (one that had occurred at least 18 months previously) benefited greatly from the ICD, whereas those with a more recent myocardial infarction (less than 18 months previously) did not.
Coronary-artery revascularization may also have played a role in the outcomes in DINAMIT. During the course of the study, a greater proportion of patients in the control group than in the ICD group underwent revascularization procedures (about 15 percent vs. 10 percent).
Can these results be extrapolated to patients who have markers of autonomic dysfunction late after myocardial infarction? The survival curves in the DINAMIT study population do not appear to change over the follow-up period (about 30 months), suggesting that ICD therapy did not have a substantial late benefit. No information is provided about changes in the markers of autonomic function over time in the study population. One might speculate that persistent abnormalities in autonomic function or the development of such abnormalities late after myocardial infarction bode a poor prognosis. Further studies will be required to determine whether patients with impaired cardiac autonomic function late after myocardial infarction also do not obtain a survival benefit from ICD therapy.
To date, the most common variable used for risk stratification in trials of prophylactic ICD therapy has been the presence or absence of depressed left ventricular function. However, not all patients with left ventricular dysfunction have sustained ventricular tachyarrhythmias after prophylactic ICD implantation. In a study conducted by my colleagues and me, only 50 percent of patients with indications for ICD therapy according to MADIT II received treatment for ventricular tachyarrhythmias within three years after implantation of the device, as compared with 74 percent of patients with a prior myocardial infarction who received an ICD for the secondary prevention of sudden death.10 The results of DINAMIT indicate that among patients who have severe ventricular dysfunction early after myocardial infarction, not all of those with ventricular tachyarrhythmias after ICD implantation will have a survival benefit from ICD therapy.
The measures of autonomic dysfunction used by the DINAMIT investigators are inexpensive and available by means of current Holter technology. Thus, these tools can be readily used in clinical practice to identify patients who are unlikely to benefit from prophylactic implantation of an ICD. The more difficult challenge confronting us will be to develop better risk-stratification techniques — techniques that will enable us to identify the patients at high risk for sudden death who are most likely to benefit from prophylactic use of an ICD. Such an approach will make the use of ICD therapy more cost-effective.
On the basis of the current results of DINAMIT and the previous results of the CABG Patch Trial, routine implantation of an ICD cannot be recommended for all patients with left ventricular dysfunction after myocardial infarction. Therapy needs to be individualized according to the patient's risk of sudden cardiac death and the competing risk of death from other causes.
Dr. Gillis is a Medical Scientist of the Alberta Heritage Foundation for Medical Research.
Dr. Gillis reports having served on a physician advisory panel of Medtronic and having received lecture fees from Medtronic and Guidant.
Source Information
From the Libin Cardiovascular Institute of Alberta, Department of Cardiovascular Sciences, University of Calgary, and Calgary Health Region, Calgary, Alta., Canada.
References
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. N Engl J Med 1996;335:1933-1940.
Buxton AE, Lee KL, Fisher JD, Josephson ME, Prystowsky EN, Hafley G. A randomized study of the prevention of sudden death in patients with coronary artery disease. N Engl J Med 1999;341:1882-1890.
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.
Bardy GH. SCD-HeFT: Sudden Cardiac Death in Heart Failure Trial. Presented at the Late Breaking Clinical Trials Session of the 53rd Annual Scientific Sessions of the American College of Cardiology, New Orleans, March 7–10, 2004. abstract.
Josephson M, Wellens HJ. Implantable defibrillators and sudden cardiac death. Circulation 2004;109:2685-2691.
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.
Bigger JT Jr, Whang W, Rottman JN, et al. Mechanisms of death in the CABG Patch Trial: a randomized trial of implantable cardiac defibrillator prophylaxis in patients at high risk of death after coronary artery bypass graft surgery. Circulation 1999;99:1416-1421.
Dorian P, Connolly S, Hohnloser SH. Why don't ICDs decrease all-cause mortality after MI? Insights from the DINAMIT study. Circulation 2004;110:Suppl III:III-502. abstract.
Wilber DJ, Zareba W, Hall WJ, et al. Time dependence of mortality risk and defibrillator benefit after myocardial infarction. Circulation 2004;109:1082-1084.
Gillis AM, Sheldon RS, Exner DV, et al. Sustained ventricular tachyarrhythmias following ICD implantation — lower event rates in patients receiving ICD for primary prophylaxis of sudden death. Heart Rhythm 2004;1:Suppl 1:S43. abstract(Anne M. Gillis, M.D.)
In this issue of the Journal, Hohnloser et al.6 report the results of the Defibrillator in Acute Myocardial Infarction Trial (DINAMIT). The DINAMIT investigators randomly assigned 674 patients with left ventricular dysfunction and impaired cardiac autonomic function to receive ICD therapy or optimal medical therapy 6 to 40 days after a myocardial infarction. Over a follow-up period of approximately 30 months, no significant difference in overall mortality was observed between the two treatment groups. Although the rate of death due to arrhythmia was substantially lower in the ICD group (1.5 percent per year) than in the control group (3.5 percent per year), more deaths from nonarrhythmic causes occurred in the ICD group (6.1 percent per year, vs. 3.5 percent per year in the control group). Moreover, the majority of the deaths from nonarrhythmic causes in the ICD group were cardiac in nature. The authors conclude that their study defines a limitation of prophylactic ICD therapy.
This important clinical trial identifies a group of patients with risk factors for sudden death from cardiac causes in whom ICD therapy may not provide a survival benefit. These results are in direct contrast to those of several published studies reporting that the use of an ICD, as compared with medical therapy, reduces mortality in other high-risk populations with ischemic heart disease.1,2,3,4 The characteristics of the patients in the current study differ in important ways from the characteristics of the patients with ischemic heart disease who were evaluated in other primary-prevention trials. The patients in DINAMIT were enrolled within 6 to 40 days after the index myocardial infarction, and all of them had an indicator of autonomic dysfunction — abnormal heart-rate variability, an elevated heart rate at rest, or both. In contrast, in the Multicenter Automatic Defibrillator Implantation Trials I and II (MADIT I and II)1,3 and in the Multicenter Unsustained Tachycardia Trial (MUSTT),2 the majority of patients were recruited more than one year after the index myocardial infarction, and autonomic function was not assessed. The Coronary Artery Bypass Graft (CABG) Patch Trial7 showed that a prophylactic ICD was not beneficial in patients with left ventricular dysfunction who had undergone coronary-artery bypass surgery, thus demonstrating the importance of revascularization for the prevention of sudden death. In DINAMIT, patients undergoing coronary-artery bypass grafting or a three-vessel percutaneous coronary intervention were excluded. A percutaneous coronary intervention alone was performed in only about a quarter of the study population at the time of myocardial infarction.
Why was there no survival benefit among the members of the DINAMIT population who received ICDs, if they had ventricular tachyarrhythmias that were appropriately and effectively treated with the device? One must consider the possibility that the presence of markers of autonomic dysfunction identified a patient cohort at high risk for death due to progressive heart failure. Recurrent, sustained ventricular tachyarrhythmias may be a harbinger of advancing heart failure. This would suggest that although sustained ventricular tachyarrhythmias occurred and were successfully treated, patients subsequently died of heart failure. Indeed, further analysis by the DINAMIT investigators indicates that the increased risk of death from nonarrhythmic causes was confined to patients who had received a shock from the ICD.8 The interval between shock therapy and subsequent death has not yet been reported. The CABG Patch Trial investigators also reported that ICD therapy reduced the rate of death due to arrhythmias by 45 percent but did not reduce overall mortality, because the majority of deaths (71 percent) were nonarrhythmic in nature.7 Their study also supports the concept that successful termination of a ventricular tachyarrhythmia occurring as a consequence of end-stage heart failure or an acute myocardial infarction may simply convert what would have been a sudden death to a death from pump failure, without an effect on survival. Whether cardiac-resynchronization therapy would have improved the outcome in the current study population is unknown.
Another possible explanation is that the temporal proximity to the index myocardial infarction influenced the outcomes in DINAMIT. Current medical therapy with beta-blockers, angiotensin-converting–enzyme inhibitors, and aldosterone blockers prevents or at least delays the adverse ventricular remodeling that occurs after myocardial infarction and that contributes to the electrophysiological mechanisms of sudden death from cardiac causes. Thus, the benefits of ICD implantation for the prevention of sudden death may be delayed for months to years after a myocardial infarction. A retrospective analysis performed by the MADIT II investigators supports the finding that patients do not benefit from ICD therapy early after myocardial infarction.9 In MADIT II, the mean time from the most recent myocardial infarction to enrollment was 6.5 years. Patients with a remote myocardial infarction (one that had occurred at least 18 months previously) benefited greatly from the ICD, whereas those with a more recent myocardial infarction (less than 18 months previously) did not.
Coronary-artery revascularization may also have played a role in the outcomes in DINAMIT. During the course of the study, a greater proportion of patients in the control group than in the ICD group underwent revascularization procedures (about 15 percent vs. 10 percent).
Can these results be extrapolated to patients who have markers of autonomic dysfunction late after myocardial infarction? The survival curves in the DINAMIT study population do not appear to change over the follow-up period (about 30 months), suggesting that ICD therapy did not have a substantial late benefit. No information is provided about changes in the markers of autonomic function over time in the study population. One might speculate that persistent abnormalities in autonomic function or the development of such abnormalities late after myocardial infarction bode a poor prognosis. Further studies will be required to determine whether patients with impaired cardiac autonomic function late after myocardial infarction also do not obtain a survival benefit from ICD therapy.
To date, the most common variable used for risk stratification in trials of prophylactic ICD therapy has been the presence or absence of depressed left ventricular function. However, not all patients with left ventricular dysfunction have sustained ventricular tachyarrhythmias after prophylactic ICD implantation. In a study conducted by my colleagues and me, only 50 percent of patients with indications for ICD therapy according to MADIT II received treatment for ventricular tachyarrhythmias within three years after implantation of the device, as compared with 74 percent of patients with a prior myocardial infarction who received an ICD for the secondary prevention of sudden death.10 The results of DINAMIT indicate that among patients who have severe ventricular dysfunction early after myocardial infarction, not all of those with ventricular tachyarrhythmias after ICD implantation will have a survival benefit from ICD therapy.
The measures of autonomic dysfunction used by the DINAMIT investigators are inexpensive and available by means of current Holter technology. Thus, these tools can be readily used in clinical practice to identify patients who are unlikely to benefit from prophylactic implantation of an ICD. The more difficult challenge confronting us will be to develop better risk-stratification techniques — techniques that will enable us to identify the patients at high risk for sudden death who are most likely to benefit from prophylactic use of an ICD. Such an approach will make the use of ICD therapy more cost-effective.
On the basis of the current results of DINAMIT and the previous results of the CABG Patch Trial, routine implantation of an ICD cannot be recommended for all patients with left ventricular dysfunction after myocardial infarction. Therapy needs to be individualized according to the patient's risk of sudden cardiac death and the competing risk of death from other causes.
Dr. Gillis is a Medical Scientist of the Alberta Heritage Foundation for Medical Research.
Dr. Gillis reports having served on a physician advisory panel of Medtronic and having received lecture fees from Medtronic and Guidant.
Source Information
From the Libin Cardiovascular Institute of Alberta, Department of Cardiovascular Sciences, University of Calgary, and Calgary Health Region, Calgary, Alta., Canada.
References
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. N Engl J Med 1996;335:1933-1940.
Buxton AE, Lee KL, Fisher JD, Josephson ME, Prystowsky EN, Hafley G. A randomized study of the prevention of sudden death in patients with coronary artery disease. N Engl J Med 1999;341:1882-1890.
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.
Bardy GH. SCD-HeFT: Sudden Cardiac Death in Heart Failure Trial. Presented at the Late Breaking Clinical Trials Session of the 53rd Annual Scientific Sessions of the American College of Cardiology, New Orleans, March 7–10, 2004. abstract.
Josephson M, Wellens HJ. Implantable defibrillators and sudden cardiac death. Circulation 2004;109:2685-2691.
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.
Bigger JT Jr, Whang W, Rottman JN, et al. Mechanisms of death in the CABG Patch Trial: a randomized trial of implantable cardiac defibrillator prophylaxis in patients at high risk of death after coronary artery bypass graft surgery. Circulation 1999;99:1416-1421.
Dorian P, Connolly S, Hohnloser SH. Why don't ICDs decrease all-cause mortality after MI? Insights from the DINAMIT study. Circulation 2004;110:Suppl III:III-502. abstract.
Wilber DJ, Zareba W, Hall WJ, et al. Time dependence of mortality risk and defibrillator benefit after myocardial infarction. Circulation 2004;109:1082-1084.
Gillis AM, Sheldon RS, Exner DV, et al. Sustained ventricular tachyarrhythmias following ICD implantation — lower event rates in patients receiving ICD for primary prophylaxis of sudden death. Heart Rhythm 2004;1:Suppl 1:S43. abstract(Anne M. Gillis, M.D.)