Resynchronizing Ventricular Contraction in Heart Failure
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《新英格兰医药杂志》
One quarter to one third of patients with congestive heart failure have some form of intraventricular conduction abnormality that is manifested as an increased QRS duration on the electrocardiogram.1,2 The most common pattern is left bundle-branch block. In patients with left bundle-branch block, electrical activation of the lateral aspect of the left ventricle can be substantially delayed in relation to that of the right ventricle and interventricular septum. Dyssynchronous electrical activation results in dyssynchronous contraction, which is mechanically inefficient. Regional myocardial workload is distributed unequally, and regional myocardial blood flow and metabolism may be altered. As a result, the left ventricular ejection fraction and cardiac output decrease, and congestive heart failure becomes more severe. A similar mechanical dyssynchrony also occurs in some patients with right bundle-branch block or nonspecific intraventricular conduction delay.3
The idea that optimal timing of left and right ventricular contraction with respect to one another might be of fundamental clinical importance arose both from evidence that intraventricular conduction abnormalities are associated with a worse prognosis in patients with congestive heart failure4 and from studies showing that conventional right ventricular pacing, which creates an artificially induced intraventricular conduction delay, actually impairs ventricular function, even in patients without congestive heart failure.5 These and similar observations led to trials of pacing techniques to synchronize ventricular contraction.
The use of cardiac pacing to coordinate the contraction of the left and right ventricles is called cardiac-resynchronization therapy6 (see Video Clips 1 and 2 of the Supplementary Appendix, available with the full text of this article at www.nejm.org). In most patients, this technique requires the simultaneous pacing of both ventricles (i.e., biventricular pacing). A right ventricular pacing lead is inserted in a standard fashion. Pacing of the left ventricle, however, is more problematic. The approach that is conventionally used involves inserting the left ventricular lead into the mouth of the coronary sinus (in the right atrium) and advancing it posteriorly around the atrioventricular valve ring, toward the left ventricle (Figure 1). The lead is then passed into a venous branch running along the free wall of the left ventricle. Echocardiography can be used to guide device programming to achieve optimal filling and forward output.
Figure 1. Biventricular Pacing for Cardiac Resynchronization Therapy.
The right atrial and right ventricular pacing leads are inserted in the standard fashion. The left ventricular pacing lead is inserted into the coronary sinus and advanced into a cardiac vein on the lateral wall of the left ventricle. Because the coronary venous anatomy is variable, the location and accessibility of a suitable vein differ from patient to patient.
Biventricular-pacemaker implantation is technically more demanding than implantation of a conventional, dual-chamber pacemaker, and complications of insertion are more frequent. The most common problem is inability to implant the left ventricular lead successfully, usually because of unfavorable coronary venous anatomy. Proximity to the left phrenic nerve, and the resulting uncomfortable diaphragmatic stimulation during pacing, limits the acceptable pacing sites in some patients. In addition, subsequent lead dislodgement occurs in as many as 10 percent of patients in whom implantation is initially successful.7 Other complications include coronary-sinus dissection and cardiac perforation. Serious sequelae of these complications are infrequent, but given the current state of the art, patients are best served if implantation is performed by an electrophysiologist with considerable experience in the technique.
Many patients who are appropriate candidates for cardiac-resynchronization therapy are also candidates for implantation of a cardioverter–defibrillator. Initially, there was the technical concern that, in a patient receiving both devices, interactions could occur, leading to unintended defibrillator firing. This issue was resolved by the development of integrated devices capable of performing both functions.
Initial randomized trials of cardiac-resynchronization therapy demonstrated improvements in ventricular function, exercise tolerance, and quality of life, as well as a reduction in the frequency of hospitalizations.8,9 The subsequent Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) trial, a larger and longer study, also evaluated the effect of cardiac-resynchronization therapy, with or without an implantable cardioverter–defibrillator, on survival.10 Mortality from all causes was significantly reduced by the combination of cardiac resynchronization and use of an implantable cardioverter–defibrillator (hazard ratio, 0.64; P=0.003); the reduction in mortality from all causes with cardiac-resynchronization therapy alone was slightly less marked and not statistically significant (hazard ratio, 0.76; P=0.059).
The Cardiac Resynchronization–Heart Failure (CARE-HF) trial, reported by Cleland et al. in this issue of the Journal, demonstrated that cardiac-resynchronization therapy alone prolongs survival in patients with advanced congestive heart failure.11 Study participants were patients with New York Heart Association (NYHA) class III or IV congestive heart failure and a left ventricular ejection fraction of 35 percent or less who were randomly assigned to either standard medical therapy alone or standard medical therapy plus cardiac resynchronization. Resynchronization therapy significantly reduced the incidence of the primary end point (the time to death or an unplanned hospitalization for a major cardiovascular event). In addition, however, mortality from all causes was significantly reduced, from 30 percent in the medical-therapy group to 20 percent in the cardiac-resynchronization group (hazard ratio, 0.64; P<0.002). As compared with the control group, the cardiac-resynchronization group also had significant improvements in indexes of left ventricular function, symptoms, and quality of life.
It is thus now firmly established that cardiac-resynchronization therapy not only reduces symptoms and improves objective measures of left ventricular function, but also prolongs survival in patients with moderate-to-severe congestive heart failure and ventricular dyssynchrony. These observations are consistent with the Food and Drug Administration's current approval of the use of cardiac-resynchronization therapy in patients with moderate-to-severe congestive heart failure and intraventricular conduction delay; they are also consistent with the 2002 joint guidelines of the American College of Cardiology, the American Heart Association, and the North American Society of Pacing and Electrophysiology, which endorse the use of cardiac-resynchronization therapy in patients with medically refractory, symptomatic, NYHA class III or IV disease and a QRS duration of 130 msec or greater, a left ventricular end-diastolic diameter of 55 mm or greater, and a left ventricular ejection fraction of 30 percent or less.12
Several areas of uncertainty remain. It has not been established whether cardiac-resynchronization therapy is beneficial in patients with mild congestive heart failure (NYHA class II). It is also not clear whether an increased QRS duration is the best criterion for benefit from cardiac-resynchronization therapy. Some uncontrolled studies have suggested that echocardiographic evidence of ventricular dyssynchrony, which does not always correlate precisely with electrocardiographic findings, is a more reliable determinant of efficacy.13 The benefit of cardiac resynchronization in patients with atrial fibrillation is also still under study. Finally, cardiac-resynchronization therapy does not benefit all recipients, for reasons that are not always clear; in some cases, unsuccessful lead positioning may be responsible, whereas in others, the severity of dyssynchrony before the procedure may have been overestimated.
The authors of the CARE-HF report raise an interesting question about the benefit of an implantable cardioverter–defibrillator in the setting of cardiac-resynchronization therapy. They note that the survival benefit in the COMPANION trial in the group that received cardiac-resynchronization therapy along with a cardioverter–defibrillator (hazard ratio for death, 0.64) was similar to the benefit in the CARE-HF study with cardiac resynchronization alone (hazard ratio, 0.64) and not markedly different from the benefit in COMPANION with cardiac resynchronization alone (hazard ratio, 0.76). Although implantation of a cardioverter–defibrillator might have further reduced mortality in CARE-HF, only 7 percent of the patients in the cardiac-resynchronization group died suddenly.
Cleland et al. make the provocative suggestion that "retarding the progression of cardiac dysfunction to prevent malignant arrhythmias may be a better strategy than treating malignant arrhythmias once they occur" and offer a calculation for the size and duration of the trial necessary to prove an incremental benefit with implantable cardioverter–defibrillator implantation in addition to cardiac-resynchronization therapy. This issue is worthy of discussion because implantable cardioverter–defibrillators are larger and substantially more expensive than pacemakers and because they introduce the potential for inappropriate shocks from supraventricular tachycardias or device malfunction.
However, it seems unlikely that a definitive trial comparing biventricular pacing with and without use of an implantable cardioverter–defibrillator will be performed, and it is more likely that combination-device therapy will become the preferred intervention. After all, sudden deaths accounted for 35 percent of all deaths in the cardiac-resynchronization group in CARE-HF; some, at least, of those 29 deaths would most likely have been prevented with a defibrillator.
In addition, it is noteworthy that the beneficial effect of cardiac-resynchronization therapy on mortality is gradual and probably due to the effects of reverse ventricular remodeling, whereas the benefits of defibrillator therapy are immediate. This difference is suggested by detailed examination of the survival curves in the COMPANION trial: the curves for pharmacologic therapy alone and for cardiac-resynchronization therapy do not begin to diverge until about eight months, whereas the curve for cardiac resynchronization plus implantation of a cardioverter–defibrillator begins to diverge much earlier. Waiting for the protective effect of cardiac-resynchronization therapy to "kick in," rather than implanting a cardioverter–defibrillator at the outset, will probably not be a very attractive option for most patients. The data from CARE-HF do provide support for the implantation of a pacing device alone in those patients in NYHA class IV who do not desire an implantable cardioverter–defibrillator but who do desire a treatment to improve their quality of life without the risk of painful shocks from a cardioverter–defibrillator.
The issue of cost-effectiveness is not addressed in CARE-HF, but modeling studies suggest that cost-effectiveness is highly dependent on the patient population selected.14 As with studies of implantable cardioverter–defibrillators, trials demonstrating a benefit with cardiac-resynchronization therapy have led to the establishment in the United States of carefully crafted criteria for reimbursement from the Centers for Medicare and Medicaid Services. These criteria tend to become the de facto criteria for use of the device and are therefore the target of intense scrutiny by electrophysiologists, device manufacturers, and government accountants. In an era of resource limitation, it is the payer who ultimately decides how an expensive therapy will be used clinically. Careful clinical trials such as CARE-HF are physicians' best guarantee that such decisions will be made on the basis of sound data.
References
Shamim W, Francis DP, Yousufuddin M, et al. Intraventricular conduction delay: a prognostic marker in chronic heart failure. Int J Cardiol 1999;70:171-178.
Farwell D, Patel NR, Hall A, Ralph S, Sulke AN. How many people with heart failure are appropriate for biventricular resynchronization? Eur Heart J 2000;21:1246-1250.
Fantoni C, Kawabata M, Massaro R, et al. Right and left ventricular activation sequence in patients with heart failure and right bundle branch block: a detailed analysis using three-dimensional non-fluoroscopic electroanatomic mapping systems. J Cardiovasc Physiol 2005;16:112-9.
Baldasseroni S, Opasich C, Gorini M, et al. Left bundle-branch block is associated with increased 1-year sudden and total mortality rate in 5517 outpatients with congestive heart failure: a report from the Italian network on congestive heart failure. Am Heart J 2002;143:398-405.
Sweeney MO, Hellkamp AS, Ellenbogen KA, et al. Adverse effect of ventricular pacing on heart failure and atrial fibrillation among patients with normal baseline QRS duration in a clinical trial of pacemaker therapy for sinus node dysfunction. Circulation 2003;107:2932-2937.
Leclercq C, Kass DA. Retiming the failing heart: principles and current clinical status of cardiac resynchronization. J Am Coll Cardiol 2002;39:194-201.
McAlister FA, Ezekowitz JA, Wiebe N, et al. Systematic review: cardiac resynchronization in patients with symptomatic heart failure. Ann Intern Med 2004;141:381-390.
Cazeau S, Leclercq C, Lavergne T, et al. Effects of multisite biventricular pacing in patients with heart failure and intraventricular conduction delay. N Engl J Med 2001;344:873-880.
Abraham WT, Fisher WG, Smith AL, et al. Cardiac resynchronization in chronic heart failure. N Engl J Med 2002;346:1845-1853.
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.
Cleland JGF, Daubert J-C, Erdmann E, et al. The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med 2005;352:1539-1549.
Gregoratos G, Abrams J, Epstein AE, et al. ACC/AHA/NASPE 2002 guideline update for implantation of cardiac pacemakers and antiarrhythmia devices: summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/NASPE Committee to Update the 1998 Pacemaker Guidelines). Circulation 2002;106:2145-2161.
Bax JJ, Ansalone G, Breithardt OA, et al. Echocardiographic evaluation of cardiac resynchronization therapy: ready for routine clinical use? A critical appraisal. J Am Coll Cardiol 2004;44:1-9.
Nichol G, Kaul P, Huszti E, Bridges JF. Cost-effectiveness of cardiac resynchronization therapy in patients with symptomatic heart failure. Ann Intern Med 2004;141:343-351.(John A. Jarcho, M.D.)
The idea that optimal timing of left and right ventricular contraction with respect to one another might be of fundamental clinical importance arose both from evidence that intraventricular conduction abnormalities are associated with a worse prognosis in patients with congestive heart failure4 and from studies showing that conventional right ventricular pacing, which creates an artificially induced intraventricular conduction delay, actually impairs ventricular function, even in patients without congestive heart failure.5 These and similar observations led to trials of pacing techniques to synchronize ventricular contraction.
The use of cardiac pacing to coordinate the contraction of the left and right ventricles is called cardiac-resynchronization therapy6 (see Video Clips 1 and 2 of the Supplementary Appendix, available with the full text of this article at www.nejm.org). In most patients, this technique requires the simultaneous pacing of both ventricles (i.e., biventricular pacing). A right ventricular pacing lead is inserted in a standard fashion. Pacing of the left ventricle, however, is more problematic. The approach that is conventionally used involves inserting the left ventricular lead into the mouth of the coronary sinus (in the right atrium) and advancing it posteriorly around the atrioventricular valve ring, toward the left ventricle (Figure 1). The lead is then passed into a venous branch running along the free wall of the left ventricle. Echocardiography can be used to guide device programming to achieve optimal filling and forward output.
Figure 1. Biventricular Pacing for Cardiac Resynchronization Therapy.
The right atrial and right ventricular pacing leads are inserted in the standard fashion. The left ventricular pacing lead is inserted into the coronary sinus and advanced into a cardiac vein on the lateral wall of the left ventricle. Because the coronary venous anatomy is variable, the location and accessibility of a suitable vein differ from patient to patient.
Biventricular-pacemaker implantation is technically more demanding than implantation of a conventional, dual-chamber pacemaker, and complications of insertion are more frequent. The most common problem is inability to implant the left ventricular lead successfully, usually because of unfavorable coronary venous anatomy. Proximity to the left phrenic nerve, and the resulting uncomfortable diaphragmatic stimulation during pacing, limits the acceptable pacing sites in some patients. In addition, subsequent lead dislodgement occurs in as many as 10 percent of patients in whom implantation is initially successful.7 Other complications include coronary-sinus dissection and cardiac perforation. Serious sequelae of these complications are infrequent, but given the current state of the art, patients are best served if implantation is performed by an electrophysiologist with considerable experience in the technique.
Many patients who are appropriate candidates for cardiac-resynchronization therapy are also candidates for implantation of a cardioverter–defibrillator. Initially, there was the technical concern that, in a patient receiving both devices, interactions could occur, leading to unintended defibrillator firing. This issue was resolved by the development of integrated devices capable of performing both functions.
Initial randomized trials of cardiac-resynchronization therapy demonstrated improvements in ventricular function, exercise tolerance, and quality of life, as well as a reduction in the frequency of hospitalizations.8,9 The subsequent Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) trial, a larger and longer study, also evaluated the effect of cardiac-resynchronization therapy, with or without an implantable cardioverter–defibrillator, on survival.10 Mortality from all causes was significantly reduced by the combination of cardiac resynchronization and use of an implantable cardioverter–defibrillator (hazard ratio, 0.64; P=0.003); the reduction in mortality from all causes with cardiac-resynchronization therapy alone was slightly less marked and not statistically significant (hazard ratio, 0.76; P=0.059).
The Cardiac Resynchronization–Heart Failure (CARE-HF) trial, reported by Cleland et al. in this issue of the Journal, demonstrated that cardiac-resynchronization therapy alone prolongs survival in patients with advanced congestive heart failure.11 Study participants were patients with New York Heart Association (NYHA) class III or IV congestive heart failure and a left ventricular ejection fraction of 35 percent or less who were randomly assigned to either standard medical therapy alone or standard medical therapy plus cardiac resynchronization. Resynchronization therapy significantly reduced the incidence of the primary end point (the time to death or an unplanned hospitalization for a major cardiovascular event). In addition, however, mortality from all causes was significantly reduced, from 30 percent in the medical-therapy group to 20 percent in the cardiac-resynchronization group (hazard ratio, 0.64; P<0.002). As compared with the control group, the cardiac-resynchronization group also had significant improvements in indexes of left ventricular function, symptoms, and quality of life.
It is thus now firmly established that cardiac-resynchronization therapy not only reduces symptoms and improves objective measures of left ventricular function, but also prolongs survival in patients with moderate-to-severe congestive heart failure and ventricular dyssynchrony. These observations are consistent with the Food and Drug Administration's current approval of the use of cardiac-resynchronization therapy in patients with moderate-to-severe congestive heart failure and intraventricular conduction delay; they are also consistent with the 2002 joint guidelines of the American College of Cardiology, the American Heart Association, and the North American Society of Pacing and Electrophysiology, which endorse the use of cardiac-resynchronization therapy in patients with medically refractory, symptomatic, NYHA class III or IV disease and a QRS duration of 130 msec or greater, a left ventricular end-diastolic diameter of 55 mm or greater, and a left ventricular ejection fraction of 30 percent or less.12
Several areas of uncertainty remain. It has not been established whether cardiac-resynchronization therapy is beneficial in patients with mild congestive heart failure (NYHA class II). It is also not clear whether an increased QRS duration is the best criterion for benefit from cardiac-resynchronization therapy. Some uncontrolled studies have suggested that echocardiographic evidence of ventricular dyssynchrony, which does not always correlate precisely with electrocardiographic findings, is a more reliable determinant of efficacy.13 The benefit of cardiac resynchronization in patients with atrial fibrillation is also still under study. Finally, cardiac-resynchronization therapy does not benefit all recipients, for reasons that are not always clear; in some cases, unsuccessful lead positioning may be responsible, whereas in others, the severity of dyssynchrony before the procedure may have been overestimated.
The authors of the CARE-HF report raise an interesting question about the benefit of an implantable cardioverter–defibrillator in the setting of cardiac-resynchronization therapy. They note that the survival benefit in the COMPANION trial in the group that received cardiac-resynchronization therapy along with a cardioverter–defibrillator (hazard ratio for death, 0.64) was similar to the benefit in the CARE-HF study with cardiac resynchronization alone (hazard ratio, 0.64) and not markedly different from the benefit in COMPANION with cardiac resynchronization alone (hazard ratio, 0.76). Although implantation of a cardioverter–defibrillator might have further reduced mortality in CARE-HF, only 7 percent of the patients in the cardiac-resynchronization group died suddenly.
Cleland et al. make the provocative suggestion that "retarding the progression of cardiac dysfunction to prevent malignant arrhythmias may be a better strategy than treating malignant arrhythmias once they occur" and offer a calculation for the size and duration of the trial necessary to prove an incremental benefit with implantable cardioverter–defibrillator implantation in addition to cardiac-resynchronization therapy. This issue is worthy of discussion because implantable cardioverter–defibrillators are larger and substantially more expensive than pacemakers and because they introduce the potential for inappropriate shocks from supraventricular tachycardias or device malfunction.
However, it seems unlikely that a definitive trial comparing biventricular pacing with and without use of an implantable cardioverter–defibrillator will be performed, and it is more likely that combination-device therapy will become the preferred intervention. After all, sudden deaths accounted for 35 percent of all deaths in the cardiac-resynchronization group in CARE-HF; some, at least, of those 29 deaths would most likely have been prevented with a defibrillator.
In addition, it is noteworthy that the beneficial effect of cardiac-resynchronization therapy on mortality is gradual and probably due to the effects of reverse ventricular remodeling, whereas the benefits of defibrillator therapy are immediate. This difference is suggested by detailed examination of the survival curves in the COMPANION trial: the curves for pharmacologic therapy alone and for cardiac-resynchronization therapy do not begin to diverge until about eight months, whereas the curve for cardiac resynchronization plus implantation of a cardioverter–defibrillator begins to diverge much earlier. Waiting for the protective effect of cardiac-resynchronization therapy to "kick in," rather than implanting a cardioverter–defibrillator at the outset, will probably not be a very attractive option for most patients. The data from CARE-HF do provide support for the implantation of a pacing device alone in those patients in NYHA class IV who do not desire an implantable cardioverter–defibrillator but who do desire a treatment to improve their quality of life without the risk of painful shocks from a cardioverter–defibrillator.
The issue of cost-effectiveness is not addressed in CARE-HF, but modeling studies suggest that cost-effectiveness is highly dependent on the patient population selected.14 As with studies of implantable cardioverter–defibrillators, trials demonstrating a benefit with cardiac-resynchronization therapy have led to the establishment in the United States of carefully crafted criteria for reimbursement from the Centers for Medicare and Medicaid Services. These criteria tend to become the de facto criteria for use of the device and are therefore the target of intense scrutiny by electrophysiologists, device manufacturers, and government accountants. In an era of resource limitation, it is the payer who ultimately decides how an expensive therapy will be used clinically. Careful clinical trials such as CARE-HF are physicians' best guarantee that such decisions will be made on the basis of sound data.
References
Shamim W, Francis DP, Yousufuddin M, et al. Intraventricular conduction delay: a prognostic marker in chronic heart failure. Int J Cardiol 1999;70:171-178.
Farwell D, Patel NR, Hall A, Ralph S, Sulke AN. How many people with heart failure are appropriate for biventricular resynchronization? Eur Heart J 2000;21:1246-1250.
Fantoni C, Kawabata M, Massaro R, et al. Right and left ventricular activation sequence in patients with heart failure and right bundle branch block: a detailed analysis using three-dimensional non-fluoroscopic electroanatomic mapping systems. J Cardiovasc Physiol 2005;16:112-9.
Baldasseroni S, Opasich C, Gorini M, et al. Left bundle-branch block is associated with increased 1-year sudden and total mortality rate in 5517 outpatients with congestive heart failure: a report from the Italian network on congestive heart failure. Am Heart J 2002;143:398-405.
Sweeney MO, Hellkamp AS, Ellenbogen KA, et al. Adverse effect of ventricular pacing on heart failure and atrial fibrillation among patients with normal baseline QRS duration in a clinical trial of pacemaker therapy for sinus node dysfunction. Circulation 2003;107:2932-2937.
Leclercq C, Kass DA. Retiming the failing heart: principles and current clinical status of cardiac resynchronization. J Am Coll Cardiol 2002;39:194-201.
McAlister FA, Ezekowitz JA, Wiebe N, et al. Systematic review: cardiac resynchronization in patients with symptomatic heart failure. Ann Intern Med 2004;141:381-390.
Cazeau S, Leclercq C, Lavergne T, et al. Effects of multisite biventricular pacing in patients with heart failure and intraventricular conduction delay. N Engl J Med 2001;344:873-880.
Abraham WT, Fisher WG, Smith AL, et al. Cardiac resynchronization in chronic heart failure. N Engl J Med 2002;346:1845-1853.
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.
Cleland JGF, Daubert J-C, Erdmann E, et al. The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med 2005;352:1539-1549.
Gregoratos G, Abrams J, Epstein AE, et al. ACC/AHA/NASPE 2002 guideline update for implantation of cardiac pacemakers and antiarrhythmia devices: summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/NASPE Committee to Update the 1998 Pacemaker Guidelines). Circulation 2002;106:2145-2161.
Bax JJ, Ansalone G, Breithardt OA, et al. Echocardiographic evaluation of cardiac resynchronization therapy: ready for routine clinical use? A critical appraisal. J Am Coll Cardiol 2004;44:1-9.
Nichol G, Kaul P, Huszti E, Bridges JF. Cost-effectiveness of cardiac resynchronization therapy in patients with symptomatic heart failure. Ann Intern Med 2004;141:343-351.(John A. Jarcho, M.D.)