Electromechanical Associations
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《新英格兰医药杂志》
The left ventricle strives valiantly with each cardiac cycle to maximize contractility and provide protection against lethal ventricular arrhythmias. Heart failure can make this coordination difficult. Heart-rhythm and heart-failure specialists are increasingly working together to restore nature's performance and lifesaving features to the failing left ventricle. Our jobs are becoming progressively more entwined as we evaluate treatments involving pacemakers and implantable cardioverter–defibrillators (ICDs) in an effort to improve the quality of life and reduce the risk of complications and death among patients with left ventricular systolic dysfunction.
Several factors contribute to this new collaboration. First, heart-rhythm specialists acknowledge the dramatic effect heart-failure specialists have had using contemporary, evidence-based medical regimens to improve left ventricular function and reduce the risks of death from arrhythmia and from any cause among patients with heart failure. However, even heart-failure specialists admit that a further benefit from drugs that antagonize neurohormonal pathways is unlikely to be achieved. Trials of new agents, such as endothelin antagonists, vasopeptidase inhibitors, and soluble tumor necrosis factor receptors, have not shown an incremental survival benefit.1,2,3
Second, heart-failure specialists recognize that at least half their patients die suddenly. They also acknowledge that ICD therapy in patients with healed myocardial infarction and left ventricular dysfunction decreases overall mortality.4 Third, both heart-rhythm and heart-failure specialists agree that patients with heart failure with left bundle-branch block have a mechanical disadvantage during systole that results from abnormal activation of the left ventricle. In these patients, the septum contracts before the lateral left ventricular wall is activated, and the lateral wall contracts during relaxation of the septum. The mechanical dysfunction increases left ventricular volume, reduces contractility, and worsens mitral regurgitation.5 The ability to place a pacemaker lead through the coronary sinus to a lateral cardiac vein in order to pace the lateral left ventricular wall and the right ventricular apex simultaneously has introduced a new treatment of heart failure and united the heart-failure and electrophysiology communities to evaluate cardiac-resynchronization therapy.
Given the progress in improving cardiac function and reducing the risks of death from arrhythmia and from any cause among patients with heart failure through the use of evidence-based medical management, physicians have been anxious to learn whether ICD therapy, cardiac-resynchronization therapy, or both provide additional benefits in patients with ischemic or nonischemic cardiomyopathy. In this issue of the Journal, two groups of investigators report the results of trials that evaluated the effect of these two approaches in patients with medically well-managed heart failure from diverse causes.6,7
The Defibrillators in Non-Ischemic Cardiomyopathy Treatment Evaluation (DEFINITE) investigators enrolled 458 patients with nonischemic dilated cardiomyopathy who had nonsustained ventricular tachycardia or frequent ventricular ectopy, were in New York Heart Association (NYHA) class I, II, or III, and had an ejection fraction of less than 36 percent.6 The patients were randomly assigned to receive standard oral medical therapy with or without an ICD. Both groups received excellent background medical therapy for heart failure and were followed for a mean (±SD) of 29±14 months. Remarkably, the annual mortality rate in the medical-treatment group was only 7 percent. Receipt of an ICD reduced the risk of the primary end point of death from any cause by 35 percent (P=0.08) and significantly reduced the risk of death from arrhythmia by 80 percent (P=0.006).
The DEFINITE study is the third prospective evaluation of the effect of prophylactic ICD therapy in high-risk patients with nonischemic cardiomyopathy.8,9 Surprisingly, none have demonstrated that ICD therapy significantly reduces the risk of death from any cause. This shortcoming in the DEFINITE study is attributable to the greater-than-anticipated reduction in mortality afforded by the use of aggressive medical regimens pioneered by heart-failure specialists. The trend toward further reduction in mortality is particularly impressive, given the lower-than-expected annual mortality rate in the medical-therapy group. Judging from results made available so far from the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT),10 which enrolled a larger number of patients with heart failure, further evidence of the positive effect of the use of ICDs in patients with nonischemic or ischemic cardiomyopathy is close at hand. Accordingly, the DEFINITE study is not the definitive word on this topic.
The Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) investigators examined morbidity and mortality outcomes in patients who had ischemic or nonischemic cardiomyopathy, an ejection fraction of no more than 35 percent, NYHA class III or IV symptoms, and a QRS interval of at least 120 msec.7 The patients were randomly assigned in a 1:2:2 ratio to receive optimal medical therapy alone, optimal medical therapy and cardiac-resynchronization therapy, or optimal medical therapy, cardiac-resynchronization therapy, and an ICD. Most patients had NYHA class III symptoms. The primary end point was death from or hospitalization for any cause.
Sixty-eight percent of the patients who were assigned to medical therapy alone died or were hospitalized during follow-up. By comparison, patients who received optimal medical therapy and cardiac-resynchronization therapy had a 19 percent reduction in the risk of the primary end point (hazard ratio, 0.81; 95 percent confidence interval, 0.69 to 0.96; P=0.014), with a trend toward a significant reduction in the risk of death from any cause (hazard ratio, 0.76; 95 percent confidence interval, 0.58 to 1.01; P=0.06). Patients who received optimal medical therapy, cardiac-resynchronization therapy, and an ICD had a 20 percent reduction in the risk of the primary end point (hazard ratio, 0.80; 95 percent confidence interval, 0.68 to 0.95; P=0.01) and a 36 percent reduction in the risk of death from any cause (hazard ratio, 0.64; 95 percent confidence interval, 0.48 to 0.86, P=0.003). Although the study was not powered to evaluate end points in subgroups, the investigators found that patients with nonischemic cardiomyopathy who received cardiac-resynchronization therapy and an ICD had a 50 percent reduction in the risk of death from any cause, as compared with those treated with medical therapy.
Cardiac-resynchronization therapy reduced the combined end points of death from any cause and hospitalization for cardiovascular causes or heart failure. As demonstrated in previous trials, cardiac-resynchronization therapy resulted in early and sustained improvements in exercise performance and the quality of life.
The COMPANION study is a critical addition to the data supporting the value of cardiac-resynchronization therapy. Until now, trials evaluating this approach have been small and weighted to evaluate the quality of life, exercise performance, and cardiac remodeling. The new data on morbidity and mortality are needed confidence builders as we begin to apply these relatively expensive therapies to larger populations.
Both the DEFINITE study and the COMPANION study contribute important information regarding the favorable effect of electrical therapies in patients with left ventricular systolic dysfunction, particularly those with nonischemic cardiomyopathy. The ICD data complement accumulated knowledge regarding the benefit of ICD therapy in patients with left ventricular systolic dysfunction from coronary artery disease.4,11 Collectively, the data from both studies demonstrate that cardiac-resynchronization and ICD therapies increase performance and longevity, respectively, in patients with heart failure.
How should physicians incorporate these results into the care of patients with heart failure? According to the DEFINITE investigators, ICD therapy in patients with nonischemic cardiomyopathy should be prescribed on a case-by-case basis. The COMPANION investigators believe that their data support the implantation of cardiac-resynchronization devices in patients with appropriate indications. The choice to implant a cardiac-resynchronization device or a cardiac-resynchronization device with an ICD must be based on a discussion between the patient and the physician. It is evident, however, that important issues still need to be addressed, including improved risk stratification for better identification of patients who are likely to benefit from cardiac-resynchronization or ICD therapy (or both), the development of a less complex device that provides only the critical functions, elucidation of the reasons for the failure of cardiac-resynchronization therapy in some patients, consensus on the approach used to identify optimal sites for left ventricular pacing, and clinical studies statistically powered to evaluate end points in subgroups defined according to the NYHA class and the presence or absence of ischemic cardiomyopathy. Despite these needs, we believe the totality of the data supports the value of ICD therapy in patients with NYHA class II or III heart failure of any cause who have moderate-to-severe left ventricular systolic dysfunction. Such patients with a left bundle-branch block are also candidates for cardiac-resynchronization therapy.
Dr. Cain reports having attended a consulting meeting with Medtronic.
Source Information
From the Cardiovascular Division, Department of Medicine, Washington University School of Medicine, St. Louis.
References
Teerlink JR. Recent heart failure trials of neurohormonal modulation (OVERTURE and ENABLE): approaching the asymptote of efficacy? J Card Fail 2002;8:124-127.
Packer M, Califf RM, Konstam MA, et al. Comparison of omapatrilat and enalapril in patients with chronic heart failure: the Omapatrilat Versus Enalapril Randomized Trial of Utility in Reducing Events (OVERTURE). Circulation 2002;106:920-926.
Anker SD, Coats AJS. How to RECOVER from RENAISSANCE? The significance of the results of RECOVER, RENAISSANCE, RENEWAL and ATTACH. Int J Cardiol 2002;86:123-130.
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.
Abraham WT, Hayes DL. Cardiac resynchronization therapy for heart failure. Circulation 2003;108:2596-2603.
Kadish A, Dyer A, Daubert JP, et al. Prophylactic defibrillator implantation in patients with nonischemic dilated cardiomyopathy. N Engl J Med 2004;350:2151-2158.
Bristow MR, Saxon LA, Boehmer J, et al. Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N Engl J Med 2004;350:2140-2150.
B?nsch D, Antz M, Boczor S, et al. Primary prevention of sudden cardiac death in idiopathic dilated cardiomyopathy: the Cardiomyopathy Trial (CAT). Circulation 2002;105:1453-1458.
Strickberger SA, Hummel JD, Bartlett TG, et al. Amiodarone versus implantable cardioverter-defibrillator: randomized trial in patients with nonischemic dilated cardiomyopathy and asymptomatic nonsustained ventricular tachycardia -- AMIOVIRT. J Am Coll Cardiol 2003;41:1707-1712.
Bardy G. SCD-HeFT: the 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.
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.(Joseph G. Rogers, M.D., a)
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Second, heart-failure specialists recognize that at least half their patients die suddenly. They also acknowledge that ICD therapy in patients with healed myocardial infarction and left ventricular dysfunction decreases overall mortality.4 Third, both heart-rhythm and heart-failure specialists agree that patients with heart failure with left bundle-branch block have a mechanical disadvantage during systole that results from abnormal activation of the left ventricle. In these patients, the septum contracts before the lateral left ventricular wall is activated, and the lateral wall contracts during relaxation of the septum. The mechanical dysfunction increases left ventricular volume, reduces contractility, and worsens mitral regurgitation.5 The ability to place a pacemaker lead through the coronary sinus to a lateral cardiac vein in order to pace the lateral left ventricular wall and the right ventricular apex simultaneously has introduced a new treatment of heart failure and united the heart-failure and electrophysiology communities to evaluate cardiac-resynchronization therapy.
Given the progress in improving cardiac function and reducing the risks of death from arrhythmia and from any cause among patients with heart failure through the use of evidence-based medical management, physicians have been anxious to learn whether ICD therapy, cardiac-resynchronization therapy, or both provide additional benefits in patients with ischemic or nonischemic cardiomyopathy. In this issue of the Journal, two groups of investigators report the results of trials that evaluated the effect of these two approaches in patients with medically well-managed heart failure from diverse causes.6,7
The Defibrillators in Non-Ischemic Cardiomyopathy Treatment Evaluation (DEFINITE) investigators enrolled 458 patients with nonischemic dilated cardiomyopathy who had nonsustained ventricular tachycardia or frequent ventricular ectopy, were in New York Heart Association (NYHA) class I, II, or III, and had an ejection fraction of less than 36 percent.6 The patients were randomly assigned to receive standard oral medical therapy with or without an ICD. Both groups received excellent background medical therapy for heart failure and were followed for a mean (±SD) of 29±14 months. Remarkably, the annual mortality rate in the medical-treatment group was only 7 percent. Receipt of an ICD reduced the risk of the primary end point of death from any cause by 35 percent (P=0.08) and significantly reduced the risk of death from arrhythmia by 80 percent (P=0.006).
The DEFINITE study is the third prospective evaluation of the effect of prophylactic ICD therapy in high-risk patients with nonischemic cardiomyopathy.8,9 Surprisingly, none have demonstrated that ICD therapy significantly reduces the risk of death from any cause. This shortcoming in the DEFINITE study is attributable to the greater-than-anticipated reduction in mortality afforded by the use of aggressive medical regimens pioneered by heart-failure specialists. The trend toward further reduction in mortality is particularly impressive, given the lower-than-expected annual mortality rate in the medical-therapy group. Judging from results made available so far from the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT),10 which enrolled a larger number of patients with heart failure, further evidence of the positive effect of the use of ICDs in patients with nonischemic or ischemic cardiomyopathy is close at hand. Accordingly, the DEFINITE study is not the definitive word on this topic.
The Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) investigators examined morbidity and mortality outcomes in patients who had ischemic or nonischemic cardiomyopathy, an ejection fraction of no more than 35 percent, NYHA class III or IV symptoms, and a QRS interval of at least 120 msec.7 The patients were randomly assigned in a 1:2:2 ratio to receive optimal medical therapy alone, optimal medical therapy and cardiac-resynchronization therapy, or optimal medical therapy, cardiac-resynchronization therapy, and an ICD. Most patients had NYHA class III symptoms. The primary end point was death from or hospitalization for any cause.
Sixty-eight percent of the patients who were assigned to medical therapy alone died or were hospitalized during follow-up. By comparison, patients who received optimal medical therapy and cardiac-resynchronization therapy had a 19 percent reduction in the risk of the primary end point (hazard ratio, 0.81; 95 percent confidence interval, 0.69 to 0.96; P=0.014), with a trend toward a significant reduction in the risk of death from any cause (hazard ratio, 0.76; 95 percent confidence interval, 0.58 to 1.01; P=0.06). Patients who received optimal medical therapy, cardiac-resynchronization therapy, and an ICD had a 20 percent reduction in the risk of the primary end point (hazard ratio, 0.80; 95 percent confidence interval, 0.68 to 0.95; P=0.01) and a 36 percent reduction in the risk of death from any cause (hazard ratio, 0.64; 95 percent confidence interval, 0.48 to 0.86, P=0.003). Although the study was not powered to evaluate end points in subgroups, the investigators found that patients with nonischemic cardiomyopathy who received cardiac-resynchronization therapy and an ICD had a 50 percent reduction in the risk of death from any cause, as compared with those treated with medical therapy.
Cardiac-resynchronization therapy reduced the combined end points of death from any cause and hospitalization for cardiovascular causes or heart failure. As demonstrated in previous trials, cardiac-resynchronization therapy resulted in early and sustained improvements in exercise performance and the quality of life.
The COMPANION study is a critical addition to the data supporting the value of cardiac-resynchronization therapy. Until now, trials evaluating this approach have been small and weighted to evaluate the quality of life, exercise performance, and cardiac remodeling. The new data on morbidity and mortality are needed confidence builders as we begin to apply these relatively expensive therapies to larger populations.
Both the DEFINITE study and the COMPANION study contribute important information regarding the favorable effect of electrical therapies in patients with left ventricular systolic dysfunction, particularly those with nonischemic cardiomyopathy. The ICD data complement accumulated knowledge regarding the benefit of ICD therapy in patients with left ventricular systolic dysfunction from coronary artery disease.4,11 Collectively, the data from both studies demonstrate that cardiac-resynchronization and ICD therapies increase performance and longevity, respectively, in patients with heart failure.
How should physicians incorporate these results into the care of patients with heart failure? According to the DEFINITE investigators, ICD therapy in patients with nonischemic cardiomyopathy should be prescribed on a case-by-case basis. The COMPANION investigators believe that their data support the implantation of cardiac-resynchronization devices in patients with appropriate indications. The choice to implant a cardiac-resynchronization device or a cardiac-resynchronization device with an ICD must be based on a discussion between the patient and the physician. It is evident, however, that important issues still need to be addressed, including improved risk stratification for better identification of patients who are likely to benefit from cardiac-resynchronization or ICD therapy (or both), the development of a less complex device that provides only the critical functions, elucidation of the reasons for the failure of cardiac-resynchronization therapy in some patients, consensus on the approach used to identify optimal sites for left ventricular pacing, and clinical studies statistically powered to evaluate end points in subgroups defined according to the NYHA class and the presence or absence of ischemic cardiomyopathy. Despite these needs, we believe the totality of the data supports the value of ICD therapy in patients with NYHA class II or III heart failure of any cause who have moderate-to-severe left ventricular systolic dysfunction. Such patients with a left bundle-branch block are also candidates for cardiac-resynchronization therapy.
Dr. Cain reports having attended a consulting meeting with Medtronic.
Source Information
From the Cardiovascular Division, Department of Medicine, Washington University School of Medicine, St. Louis.
References
Teerlink JR. Recent heart failure trials of neurohormonal modulation (OVERTURE and ENABLE): approaching the asymptote of efficacy? J Card Fail 2002;8:124-127.
Packer M, Califf RM, Konstam MA, et al. Comparison of omapatrilat and enalapril in patients with chronic heart failure: the Omapatrilat Versus Enalapril Randomized Trial of Utility in Reducing Events (OVERTURE). Circulation 2002;106:920-926.
Anker SD, Coats AJS. How to RECOVER from RENAISSANCE? The significance of the results of RECOVER, RENAISSANCE, RENEWAL and ATTACH. Int J Cardiol 2002;86:123-130.
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.
Abraham WT, Hayes DL. Cardiac resynchronization therapy for heart failure. Circulation 2003;108:2596-2603.
Kadish A, Dyer A, Daubert JP, et al. Prophylactic defibrillator implantation in patients with nonischemic dilated cardiomyopathy. N Engl J Med 2004;350:2151-2158.
Bristow MR, Saxon LA, Boehmer J, et al. Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N Engl J Med 2004;350:2140-2150.
B?nsch D, Antz M, Boczor S, et al. Primary prevention of sudden cardiac death in idiopathic dilated cardiomyopathy: the Cardiomyopathy Trial (CAT). Circulation 2002;105:1453-1458.
Strickberger SA, Hummel JD, Bartlett TG, et al. Amiodarone versus implantable cardioverter-defibrillator: randomized trial in patients with nonischemic dilated cardiomyopathy and asymptomatic nonsustained ventricular tachycardia -- AMIOVIRT. J Am Coll Cardiol 2003;41:1707-1712.
Bardy G. SCD-HeFT: the 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.
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.(Joseph G. Rogers, M.D., a)