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CONTEMPORARY REVIEW ASSOCIATE EDITOR: D. GEORGE WYSE Cardiac resynchronization therapy in congestive heart failure: Ready for prime time? Antonis S. Manolis, MD From the A Department of Cardiology, Evagelismos
CONTEMPORARY REVIEW ASSOCIATE EDITOR: D. GEORGE WYSE Cardiac resynchronization therapy in congestive heart failure: Ready for prime time? Antonis S. Manolis, MD From the A Department of Cardiology, Evagelismos General Hospital of Athens, Athens, Greece. OBJECTIVES/BACKGROUND The aim of this article is to critically review the data accumulated to date on the application of cardiac resynchronization therapy (CRT) via biventricular pacing techniques to manage patients with advanced heart failure. The data from studies evaluating the effects of long-term right ventricular (RV) pacing are also briefly reviewed. METHODS MEDLINE and selective journal searches of English-language reports and a search of references of relevant papers were conducted. RESULTS Cardiac dyssynchrony as reflected by a prolonged QRS complex, often in the form of left bundle branch block, is encountered in about 30% of patients with moderate-to-advanced heart failure. Among these patients, 10% to 15% are candidates for CRT via biventricular pacing. Accumulated evidence from randomized controlled studies over the last few years has indicated a significant hemodynamic and clinical improvement conferred by CRT to class III or IV heart failure patients with idiopathic or ischemic dilated cardiomyopathy having a low left ventricular ejection fraction ( 35%) and a wide QRS complex ( ms). Newer data suggest a significant reduction in overall mortality and heart failure hospitalization, particularly when CRT is combined with automatic defibrillator backup. Technical advances with percutaneous methods accessing the tributaries of the cardiac veins have raised the success rate of implantation of left ventricular leads to 90%. Further confirmation from ongoing trials is awaited, and more data from cost-effectiveness studies are needed before CRT is considered for prime time therapy in the heart failure population. If the data confirm a survival benefit from CRT, use of this electrical therapy at earlier stages of heart failure might be contemplated. New evidence from recent studies suggests a deleterious effect of the long-standing practice of producing an iatrogenic left bundle branch block by conventional RV apical pacing in patients receiving permanent pacemakers. Thus, having already become poignantly aware of the harmful effects of spontaneous left bundle branch block, this emerging new evidence about RV apical pacing would dictate a change of attitude and direct our attention to alternate sites of pacing, such as the left ventricle and/or the RV outflow tract, if not for all patients then at least for those with left ventricular dysfunction. CONCLUSIONS CRT offers hemodynamic and clinical improvement to patients with moderate-toadvanced heart failure, and it might significantly prolong survival in selected patients, particularly if devices with defibrillation backup are used. Further confirmatory data from randomized mortality trials are needed, and issues of cost efficacy must be resolved before this vital therapeutic alternative is ready for prime time therapy of heart failure patients. KEYWORDS Cardiac resynchronization; Biventricular pacing; Heart failure; Left ventricular pacing; Left bundle branch block; Cardiac dyssynchrony; Cardiomyopathy; Implantable cardioverter defibrillator 2004 Heart Rhythm Society. All rights reserved. The prevalence of congestive heart failure has increased significantly over the last few decades. According to epidemiologic studies, an estimated 4 to 5 million people in the United States have heart failure (50% men), and the number Address reprint requests and correspondence: Dr. Antonis S. Manolis, 41 Kourempana Street, Agios Dimitrios , Athens, Greece. address: (Received January 30, 2004; accepted March 18, 2004.) rises to 22.5 million worldwide. An additional 2 million patients are reported each year. The prevalence of the disease is age dependent. In the years 1988 to 1991, the prevalence was estimated to be about 10% in the age group 70 years. Mortality of heart failure is dependent on its clinical severity; for advanced cases, mortality reaches 30% to 50% by 5 years. Cost estimates bring the health care cost for heart failure hospitalization, medications, and follow-up to $20 to $40 billion annually. 1, /$ -see front matter 2004 Heart Rhythm Society. All rights reserved. Heart Rhythm (2004) 3, doi: /j.hrthm 356 Heart Rhythm, Vol 1, No 3, September 2004 Clinical improvement trials Figure 1 Coronary sinus angiography (left) can visually guide insertion of the left ventricular (LV) lead into a suitable vein tributary. This is best facilitated with insertion via the central lumen of the lead of a steerable angioplasty guidewire (middle), which can make it possible to advance the lead into a midcavitary position (right). Also shown are the other two leads in place: the right ventricular (RV) lead in the right ventricular apex and the right atrial (RA) lead in the right atrial appendage. Over the last decade, considerable progress has been made in the management of heart failure with the use of angiotensin-converting enzyme inhibitors (or angiotensin antagonists), aldosterone antagonists, and, more recently, new beta-blocking agents with vasodilating properties. 3 Newer pacing techniques have emerged as a vital therapeutic alternative for patients who remain refractory to optimal medical therapy and prior to utilization of inotropes, mechanical support, or heart transplantation with its inherent problems and limited number of donors. 4 7 Beyond conventional pacing therapies that treat bradycardia, manage chronotropic incompetence, and provide atrioventricular (AV) synchronization, the coordination of ventricular contraction (ventricular resynchronization) has emerged as an important and most promising pacing technique. 7 Patients with intraventricular conduction delay, most evident in the presence of left bundle branch block, have significant intraventricular discoordination from delayed lateral wall contraction, which is excessively preloaded due to redistribution of regional wall stress 8 and leads to dire hemodynamic consequences such as reduced stroke volume and cardiac output. If this also is associated with AV asynchrony limiting ventricular filling, then the hemodynamic problem is accentuated. Major hemodynamic benefit is derived from restoring AV and ventricular synchrony in such patients using AV biventricular pacing techniques (Figures 1 and 2). The prevalence of ventricular dyssynchrony, defined as an abnormality in electromechanical coupling occurring in conjunction with interventricular conduction block or prolonged QRS duration with measured QRS width 120 ms, ranges from 27% to 53%. 7,9 Thus, a significant number of patients may be candidates for cardiac resynchronization therapy (CRT) (Table 1), even if only those patients refractory to optimal medical therapy, estimated to be around 10% to 15% of heart failure patients, are considered. 10 In a recent study of 5,517 patients with congestive heart failure, the subgroup (25%) with left bundle branch block (n 1,391) had a hazard ratio of 1.7 for total mortality and 1.6 for sudden death compared to patients without left bundle branch block. 11 Studies such as PATH-CHF (n 42), CONTAK CD (n 490), InSync (n 103), InSync ICD (n 554), MUSTIC (n 131; 67 patients in sinus rhythm and 64 patients with atrial fibrillation), and, more recently, MIRACLE (n 433) and MIRACLE ICD (n 369) all have convincingly shown that CRT provides significant hemodynamic benefits and symptomatic improvement over 3 to 6 months in patients with moderate-to-severe heart failure 5,6,12 15 (Table 2). The characteristics of these patients were as follows: New York Heart Association (NYHA) class III to IV, mean age 63 to 67 years, dilated (31% 63%) or ischemic (37% 69%) cardiomyopathy, mostly left bundle branch block (54% 87%), QRS duration 120 ms, PR interval 150 ms, and mean left ventricular ejection fraction 21% 24%. Electrical (CRT) therapy led to improved functional capacity (increase in 6-minute walk distance and peak VO 2 ), improved quality of life, symptom relief (improvement by at least one functional NYHA class), reduction in hospitalization rates, reduced mitral regurgitation, and positive trends toward improvement of left ventricular ejection fraction. The long-term results of these studies were reported recently and indicate that the short-term improvement noted at 3 to 6 months is maintained over 1-year follow-up. In the MUSTIC study, the following findings at 12 months compared with baseline were noted in all patients in sinus rhythm and in 88% of patients with atrial fibrillation who Figure 2 Very wide QRS complex resulting from right ventricular apical pacing (top) is significantly shortened with biventricular pacing (bottom) in a patient with complete heart block and severe dilated cardiomyopathy. The patient had a single-chamber ventricular pacemaker that produced total cardiac dyssynchrony with AV asynchrony and ventricular dyssynchrony (iatrogenic left bundle branch block). This was remedied by upgrading the ventricular pacemaker to an AV biventricular pacing system. Manolis Cardiac Resynchronization Therapy 357 Table 1 ACC/AHA/NASPE guidelines for cardiac resynchronization therapy in patients with congestive heart failure (class IIA/level of evidence: A)* Medically refractory advanced heart failure (NYHA class III/IV) Idiopathic dilated or ischemic cardiomyopathy with LVEDD 5.5 cm LVEF 35% QRS complex duration 130 ms *Patients who also have malignant ventricular arrhythmias or belong to defined high-risk patients (e.g., MADIT I or II patients) and therefore have an indication for an implantable cardioverter defibrillator (ICD) would be candidates for combined cardiac resynchronization therapy and ICD therapy. LVEDD left ventricular end-diastolic dimension; LVEF left ventricular ejection fraction; NYHA New York Heart Association (classification). were programmed to biventricular pacing: 6-minute walked distance increased by 20% (P.0001) and 17% (P.004), respectively; peak VO 2 increased by 11% and 9%, respectively; quality of life improved by 36% (P.0001) and 32% (P.002), respectively; and NYHA class improved by 25% (P.0001) and 27% (P.0001), respectively. Left ventricular ejection fraction improved by 5% and 4%, whereas mitral regurgitation decreased by 45% and 50%, respectively. In other studies using Doppler echocardiography or the newly developed tissue Doppler imaging techniques, CRT has been shown to significantly improve left ventricular function and reverse left ventricular remodeling during long-term follow-up Patients likely to benefit from CRT may be identified by tissue Doppler imaging before implantation of a biventricular pacemaker. Based on the results of these studies, the revised ACC/ AHA/NASPE 2002 guideline update for implantation of cardiac pacemakers and antiarrhythmia devices included CRT as a class IIa indication for medically refractory heart failure (class III IV), prolonged QRS ( 130 ms), left ventricular end-diastolic diameter 55 mm, and left ventricular ejection fraction 35% (Table 1). 22 This is a new development given that the earlier guidelines for heart failure therapy, published at the end of 2001, did not even mention this therapeutic modality. 23 In addition, the generic pacemaker mode code recently was modified to include multisite pacing modes. 24 Mortality trials Despite all of this progress, for a new therapeutic modality to survive and establish itself as a viable alternative, randomized studies that have total mortality, rather than symptomatic and functional improvement, as a primary endpoint are needed (Table 2). Such studies are in progress (PACMAN, CARE-HF, RAFT), 14,25 and the preliminary results of the COMPANION trial have just been published. 26 According to these data, CRT resulted in a 24% reduction in all-cause mortality over 12 months (P.06), whereas CRT plus defibrillation [implantable cardioverter defibrillator (ICD)] led to a 36% reduction in total mortality (P.003) compared to optimal medical therapy. This study recruited 1,520 high-risk patients with moderate-to-severe heart failure (NYHA class III IV, left ventricular ejection fraction 35%, LV end-diastolic diameter 6 cm),qrs complexes 120 ms, and PR intervals 150 ms, who were randomized to 1 of 3 arms in a 1:2:2 scheme. Although all patients received maximal medical therapy, one group also received CRT and another group received CRT plus defibrillation with an ICD device. The study was prematurely halted by the safety committee because it met the prespecified stopping rule on November 21, According to the Table 2 Clinical randomized trials of cardiac resynchronization therapy Trial No. of patients Mean age (yr) Mean LVEF NYHA class CAD Mean QRS (ms) LBBB Clinical Improvement Trials CONTAK CD % II IV 69% % InSync ICD % II IV 65% % MUSTIC 58* 63 23% III 37% % MIRACLE % III IV 54% % MIRACLE ICD % III IV 69% % Trial No. of patients Mean age (yr) Mean LVEF CAD Mean QRS (ms) LBBB MR2 Mortality Trials Meta-analysis 1, % 23% 37% 69% % 87% 23% COMPANION 1, % 56% % 24% *Patients in sinus rhythm (58/67 randomized). There was another group of 64 patients with atrial fibrillation who also benefited from CRT but to a lesser degree. CRT alone (P.06). MR2 was 36% when CRT was combined with ICD therapy (P.003). CAD coronary artery disease (ischemic cardiomyopathy); CRT cardiac resynchronization therapy; LBBB left bundle branch block; LVEF left ventricular ejection fraction; MR2 (all-cause) mortality rate reduction; NYHA New York Heart Association. 358 Heart Rhythm, Vol 1, No 3, September 2004 cause of heart failure, CRT with an ICD was associated with a 27% reduction in total mortality in patients with ischemic cardiomyopathy and a 50% mortality reduction in patients with nonischemic cardiomyopathy. 26 More data regarding total mortality have been provided by a recent meta-analysis of 11 reports of four randomized trials evaluating CRT in 1,634 patients. 12 According to the results of this meta-analysis, CRT reduced heart failure hospitalization by 29% and reduced death from progressive heart failure by 51% relative to controls (1.7% vs 3.5%). CRT showed a trend toward reducing all-cause mortality, being responsible for an overall 23% fewer deaths in heart failure patients. More data from ongoing randomized studies (PACMAN, CARE-HF, RAFT) evaluating the effect of CRT on total mortality will soon be available. 14 Iatrogenic dyssynchrony caused by right ventricular apical pacing and alternate sites of pacing Another important point to consider is the accumulating evidence that not only is spontaneous left bundle branch block harmful to our patients, but the iatrogenic left bundle branch block produced by right ventricular apical pacing is equally deleterious. In a study involving 24 young patients (mean age 19.5 years) in need of permanent pacing compared with 33 age- and basal surface area-matched healthy control individuals over a mean follow-up of 9.5 years, right ventricular apical pacing led to irreversible left ventricular dysfunction. 27 Another recent study, the DAVID trial, examined the possible harmful effect of unnecessary right ventricular pacing in ICD patients. 28 Patients (n 256) with their ICD device programmed to standby VVI mode at 40 beats/min fared much better compared with those (n 250) who had the device programmed to DDDR pacing at 70 beats/min. 28 Over 1 year, the hazard ratios for the DDDR pacing group compared with the VVI group were 1.61 for heart failure hospitalization or death, 1.54 for heart failure hospitalization, and 1.61 for death. A MADIT II substudy reported during the NASPE meeting in May 2003 raised similar concerns about right ventricular apical pacing. Patients with high cumulative right ventricular pacing ( 50%) had a higher incidence of heart failure (hazard ratio 2.1) and heart failure or death (hazard ratio 1.9) compared to patients with infrequent right ventricular pacing. 29 More data on the adverse effect of right ventricular apical pacing have become available via a recent study assessing the prevalence of heart failure or left ventricular dysfunction among 307 chronically paced patients (about half of whom had dual-chamber devices). 30 Low left ventricular ejection fraction ( 40%) was detected in 94 (31%) patients, of whom 83 had symptoms of heart failure. Although the etiology of heart failure in this population may be multifactorial, a good percentage probably is pacing induced. 30 A subanalysis of the MOST trial refutes the assumption that dual-chamber pacing mitigates the adverse effects of right ventricular pacing. 31 Of 1,339 patients with sinus node dysfunction and baseline QRS 120 ms, 707 (53%) were randomly assigned to DDDR and 632 (47%) to VVIR pacing. The overall rates of heart failure hospitalization were similar (10% DDDR, 9% VVIR). Despite maintenance of AV synchrony, ventricular pacing in the DDDR mode 40% of the time conferred a 2.6-fold increased risk of heart failure hospitalization compared with less pacing among similar patients with normal baseline QRS duration. 31 In another recently published randomized trial, 177 patients (age 74 9 years) with sinus node dysfunction were randomized to 1 of 3 modes of pacing: AAIR (n 54), DDDR with short AV delay (n 60), or DDDR with long AV delay (n 63). Over years, the patients in the two DDDR groups with conventional right ventricular apical pacing had increased left atrial diameter and more common atrial fibrillation, and those with a high proportion of right ventricular pacing (DDDR pacing with short AV delay) had significantly decreased left ventricular fractional shortening compared to patients with AAIR pacing. 32 In a search for alternate sites of ventricular stimulation, a recent pooled analysis of nine studies evaluating the hemodynamic effects of right ventricular outflow tract pacing in 217 patients indicated a significant hemodynamic benefit compared with right ventricular apical pacing (odds ratio 0.34). 33 In the same direction, a recently completed, randomized multicenter study examined the feasibility of a new steerable system using novel technology that allows implantation of a very thin, active-fixation lead at alternate sites in the right atrium and right ventricular outflow tract. The success rate of implantation was 93% in 30 patients at our center, with excellent measurements obtained intraoperatively and during short-term 3-month follow-up. 34 However, a recently reported, randomized cross-over trial (ROVA), which compared right ventricular outflow tract with right ventricular apical pacing in 103 pacemaker patients with congestive heart failure and chronic atrial fibrillation, did not show any consistent improvement in quality of life after 3 months of right ventricular outflow tract pacing compared to right ventricular apex pacing. 35 Finally, experimental animal data confirm the harmful effect of right ventricular apex pacing on left ventricular function and indicate that the optimal ventricular pacing site is in the left ventricle. 36 Eligible patients and other issues for CRT application A key issue for CRT is the identification of eligible patients who are most likely to respond and receive the most benefit. QRS duration has been deemed a primary variable as a principal electrical marker of spatially dispersed mechanical activation; thus, patients with wider QRS complexes seem to have a greater mechanical response to CRT. In addition, Manolis Cardiac Resynchronization Therapy 359 the worse the ventricular dysfunction, which probably reflects the degree of dyssynchrony, the greater the response to CRT. The percentage of nonresponders varies between 18% and 32%. 6,37,38 Responders are more likely to have idiopathic dilated cardiomyopathy and no history of myocardial infarction. In contrast, prior myocardial infarction, no significant degree of mitral
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