doi: 10.1161/CIRCULATIONAHA.106.664060
(Circulation. 2006;114:2692-2698.)
© 2006 American Heart Association, Inc.
Controversies in Cardiovascular Medicine |
Cardiac Resynchronization Therapy Is Important for All Patients With Congestive Heart Failure and Ventricular Dyssynchrony
From the Department Internal Medicine, Division of Cardiovascular Medicine, the Department of Physiology and Cell Biology, and the Davis Heart and Lung Research Institute, Ohio State University, Columbus.
Correspondence to William T. Abraham, MD, Ohio State University Heart Center, Division of Cardiovascular Medicine, 473 W 12th Ave, Room 110P DHLRI, Columbus, OH 43210–1252. E-mail William.Abraham{at}osumc.edu
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Introduction |
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 Top Introduction The Rationale for CRTRandomized Controlled Trials of...Who Should Receive CRT?Limitations of CRTUnanswered Questions in CRTConclusionsReferences |
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More than 4000 patients have been evaluated in randomized controlled trials of cardiac resynchronization therapy (CRT). These studies have demonstrated that CRT with or without an implantable cardioverter-defibrillator (ICD) consistently improves quality of life, functional status, exercise capacity, and cardiac structure and function and reduces morbidity and mortality in heart failure patients with ventricular dyssynchrony. The magnitude of benefit seen with CRT is comparable to or exceeds that seen with evidence-based drug therapies for heart failure but occurs in patients who are already receiving such medications. Thus, CRT has been added to the list of evidence-based therapies that make heart failure patients feel better and live longer (the Table). Consequently, a strong ethical mandate exists for the use of CRT in heart failure. This mandate is reflected in our current practice guidelines for the management of chronic heart failure, which state that all eligible patients should receive CRT unless contraindicated.1,2 End of debate! CRT should be a routine part of any evidence-based treatment regimen for heart failure.
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Of course, things are never quite so simple, so let us take a look at the evidence supporting this clinical mandate for CRT and address patient selection, some of the limitations of CRT, and some of the unanswered questions about the use of CRT in heart failure. None of this discussion will lessen the role of CRT in the treatment of heart failure; rather, it will guide the selection of appropriate patients and speculate on the future application of CRT to an even broader group of heart failure patients.
Response by Greenberg and Mehra p 2698
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The Rationale for CRT |
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TopIntroductionThe Rationale for CRTRandomized Controlled Trials of...Who Should Receive CRT?Limitations of CRTUnanswered Questions in CRTConclusionsReferences |
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Approximately one third of patients with systolic heart failure exhibit ventricular dyssynchrony, defined as a QRS duration >120 ms on the surface ECG.3,4 Ventricular dyssynchrony produces suboptimal ventricular filling, a reduction in left ventricular contractility, prolonged duration of mitral regurgitation, and paradoxical septal wall motion, which conspire to further reduce the ability of the failing heart to eject blood.5–8 The adverse consequences of ventricular dyssynchrony have been reviewed in detail previously.9,10 Importantly, ventricular dyssynchrony has been associated with increased morbidity and mortality in heart failure patients.11–14 Thus, in the mid 1990s, applying pacing therapies to overcome ventricular dyssynchrony began to be explored. CRT, or atrial-synchronized biventricular pacing, emerged as the most promising approach for the treatment of ventricular dyssynchrony.
The first application of CRT was performed by Cazeau et al,15 who used 4-chamber pacing in a middle-aged man with New York Heart Association (NYHA) class IV heart failure and a prolonged QRS duration. Standard transvenous pacing leads were placed in the right atrium and right ventricle. The left atrium was paced by a lead placed in the coronary sinus; the left ventricle was paced by an epicardial lead located on the left ventricular free wall. After 6 weeks of pacing, the patient’s clinical status improved markedly, with a weight loss of 17 kg and the disappearance of peripheral edema. His functional class improved to NYHA class II.
Such favorable case experiences led to small studies evaluating the short-term effects of CRT on systemic hemodynamics and echocardiographic measures of cardiac performance. These studies demonstrated that CRT could reverse the deleterious hemodynamic and echocardiographic effects of ventricular dyssynchrony.7,16 These short-term hemodynamic investigations of CRT led to long-term observational (uncontrolled) trials of CRT that showed consistent, sustained improvements in exercise tolerance, quality of life, NYHA functional class, and cardiac performance.17–25 Of course, the definitive proof supporting a role for CRT in heart failure management awaited the completion of subsequent large-scale, randomized, single- and double-blind, controlled clinical trials.
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Randomized Controlled Trials of CRT |
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TopIntroductionThe Rationale for CRTRandomized Controlled Trials of...Who Should Receive CRT?Limitations of CRTUnanswered Questions in CRTConclusionsReferences |
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As noted, a series of randomized controlled trials have evaluated the safety and efficacy of CRT in heart failure patients. Collectively, these trials have studied virtually all the clinically meaningful end points that are routinely evaluated in clinical trials of heart failure, including end points that measure quality of life, functional status, exercise capacity, morbidity, and mortality. The beneficial effects of CRT on such end points have been striking. Moreover, these trials have provided convincing evidence that CRT produces reverse remodeling of the failing heart. That is, CRT makes the failing heart smaller and stronger, an effect that is generally associated with improved survival in heart failure clinical trials. Thus, it is not surprising that CRT prolongs life just like angiotensin-converting enzyme inhibitors and ß-blockers do.
Although more than a dozen randomized controlled trials have contributed to our knowledge of CRT in heart failure, 6 studies have been most influential in establishing CRT as a routine therapy for heart failure. These 6 trials are the Multisite Stimulation in Cardiomyopathy (MUSTIC) studies,26,27 the Multicenter InSync Randomized Clinical Evaluation (MIRACLE),28,29 MIRACLE ICD,30 the CONTAK CD trial,31 the Cardiac Resynchronization in Heart Failure (CARE HF) trial,32,33 and the Comparison of Medical Therapy, Pacing and Defibrillation in Heart Failure (COMPANION) trial.34,35
MUSTIC was designed to evaluate the safety and efficacy of CRT in patients with advanced heart failure, ventricular dyssynchrony, and either normal sinus rhythm26 or atrial fibrillation.27 The unique contribution of MUSTIC to the evolution of CRT is that it represents the first randomized (single-) blinded trial of CRT for heart failure. The normal sinus rhythm arm involved 58 randomized patients with NYHA class III heart failure, normal sinus rhythm, and a QRS duration of 
150 ms. All patients were implanted with a CRT device, and after a run-in period, patients were randomized in a single-blind fashion to either active pacing or no pacing. After 12 weeks, patients were crossed over and remained in the alternate study assignment for 12 weeks. After this second 12-week period, the device was programmed to the patient’s preferred mode of therapy. The atrial fibrillation arm involved fewer patients (37 completers) with atrial fibrillation and a slow ventricular rate, either spontaneously or from radiofrequency ablation. A VVIR biventricular pacemaker and leads for each ventricle were implanted, and the randomization procedure described above was applied, but biventricular VVIR pacing was compared with single-site right ventricular VVIR pacing rather than no pacing in this group of patients with atrial fibrillation.
The primary end points for MUSTIC were exercise tolerance assessed by measurement of peak 
O2 or the 6-minute hall walk test and quality of life determined with the Minnesota Living With Heart Failure questionnaire. In the normal sinus rhythm arm of MUSTIC, the mean distance walked in 6 minutes was 23% greater with CRT than during the inactive pacing phase (P<0.001). Significant improvement also was seen in quality of life and NYHA functional class ranking. There were fewer hospitalizations during active resynchronization therapy, an effect that was surprisingly significant given the small number of patients enrolled. The atrial fibrillation group demonstrated similar improvements, although the magnitude of benefit was slightly less.
MIRACLE was the first prospective, randomized, double-blind, parallel-controlled clinical trial designed to evaluate the risks and benefits of CRT.28,29 Four hundred fifty-three patients with moderate to severe symptoms of heart failure associated with a left ventricular ejection fraction 
35% and a QRS duration of 130 ms were randomized (double blind) to CRT (n=228) or to a control group (n=225) for 6 months while conventional therapy for heart failure was maintained.29 Primary end points were NYHA class, quality-of-life score (using the Minnesota Living with Heart Failure questionnaire), and 6-minute hall walk distance.
Compared with the control group, patients randomized to CRT demonstrated a significant improvement in all 3 primary end points: the quality-of-life score (–18.0 versus –9.0 points; P=0.001), 6-minute walk distance (39 versus 10 m; P=0.005), and NYHA functional class ranking (–1.0 versus 0.0 class; P<0.001).29 Moreover, treadmill exercise time (81 versus 19 seconds; P=0.001), peak O2 (1.1 versus 0.1 mL · kg–1 · min–1; P<0.01), and left ventricular ejection fraction (4.6% versus –0.2%; P<0.001), as well as other measures of ventricular structure and function, were significantly improved. Patients randomized to CRT demonstrated a highly significant improvement in a composite clinical heart failure response end point compared with control subjects, suggesting an overall improvement in heart failure clinical status. In addition, 
50% fewer patients in the CRT group required hospitalization or intravenous medications for worsening heart failure (both P<0.05). The major limitation of the therapy was the unsuccessful implantation of the device in 8% of patients. In August 2001, the results of this trial led the US Food and Drug Administration to approve the InSync system, the first approved CRT system in America, ushering in the device era for the treatment of heart failure.
The MIRACLE ICD study was designed to be almost identical to the MIRACLE trial. MIRACLE ICD was a prospective, multicenter, randomized, double-blind, parallel-controlled clinical trial designed to assess the safety and efficacy of a combined CRT-ICD system in patients with NYHA class III or IV heart failure, ventricular dyssynchrony, and an indication for an ICD. Three hundred sixty-nine patients were randomized, 182 to the control arm (ICD activate, CRT inactive) and 187 to the active CRT group (ICD activate, CRT active).30 Primary end points were the same as those evaluated in the MIRACLE trial; measures of ICD function also were assessed.
Like MIRACLE, the MIRACLE-ICD trial demonstrated the efficacy of CRT although in a slightly different group of heart failure patients (ie, those with secondary prevention indications for an ICD). At 6 months, patients assigned to active CRT had a greater improvement in median quality-of-life score (–17.5 versus –11.0; P=0.02) and functional class (–1 versus 0; P=0.007) than control subjects; however, there was no change in the distance walked in 6 minutes (55 versus 53 m; P=0.36) between groups.30 This latter observation may simply be a fluke; virtually all other controlled trials of CRT have demonstrated improvements in the 6-minute hall walk distance, and MIRACLE ICD demonstrated a significant improvement in peak oxygen consumption (1.1 versus 0.1 mL · kg–1 · min–1; P=0.04) and an increase in treadmill exercise time (56 versus 11 seconds; P=0.0006), confirming the benefit of CRT on exercise capacity. The CRT-ICD device used in this study was approved by the US Food and Drug Administration for use in NYHA class III and IV systolic heart failure patients with ventricular dyssynchrony and an ICD indication in June 2002, further establishing a place for CRT in the routine management of heart failure.
The CONTAK CD trial enrolled 581 symptomatic heart failure patients with ventricular dyssynchrony and malignant ventricular tachyarrhythmias who were also candidates for an ICD.31 After unsuccessful implantation attempts and withdrawals, 490 patients were available for analysis. Although the study did not meet its primary end point of a reduction in disease progression, defined by a composite end point of heart failure hospitalization, all-cause mortality, and ventricular arrhythmia requiring defibrillator therapies, the trends were in a direction favoring improved outcomes with CRT. However, the CONTAK CD trial confirmed the benefits of CRT seen in other randomized controlled trials and led the US Food and Drug Administration to approve yet another CRT device for use in the treatment of heart failure in May 2002.
Thus, these trials demonstrated that CRT improved multiple functional measures of heart failure clinical status and established CRT as an approved therapy for heart failure. However, debate ensued on the advisability of implanting expensive devices associated with modest but real implant- and device-related adverse events only to improve so-called soft end points such as quality of life and NYHA class ranking. The unequivocal mandate for the use of CRT would subsequently come from the large-scale morbidity and mortality studies, namely COMPANION and CARE HF.
COMPANION was a multicenter, prospective, randomized, controlled clinical trial designed to compare drug therapy alone with drug therapy combined with CRT in patients with NYHA class III or IV heart failure, ventricular dyssynchrony, and no indication for a standard pacemaker or ICD device.34,35 The trial was begun in 2000 and terminated early at the unanimous recommendation of an independent data and safety monitoring committee on November 21, 2002, because of marked efficacy. That is, independent assessment of the risks and benefits of CRT so overwhelmingly supported the use of the therapy that it was deemed unethical to continue patients in the control arm of the study. The study was terminated, and control patients were offered treatment with a CRT device.
In COMPANION, 1520 patients were randomized into 1 of 3 treatment groups in a 1:2:2 allocation.35 Group 1 (308 patients) received optimal medical care only; group 2 (617 patients) received optimal medical care and the Guidant CONTAK TR (biventricular pacemaker); group 3 (595 patients) received optimal medical care and the CONTAK CD (combined CRT-ICD device). The primary end point of the COMPANION trial was a composite of all-cause mortality and all-cause hospitalization, measured as time to first event, beginning from time of randomization. Other measures of morbidity and mortality were assessed as secondary end points. Compared with optimal medical therapy alone, the combined end point of mortality or heart failure hospitalization was reduced by 35% for patients receiving CRT and 40% for patients receiving CRT-ICD (both P<0.001). For the mortality end point alone, CRT patients had a 24% risk reduction (P=0.060) and CRT-ICD patients experienced a risk reduction of 36% (P<0.003) compared with optimal medical therapy. Thus, COMPANION showed for the first time the impact of CRT with or without an ICD in reducing morbidity and mortality in heart failure patients. Although CRT combined with an ICD had a greater impact on mortality alone compared with CRT without an ICD, the 2 forms of CRT devices reduced combined measures of morbidity and mortality to a similar extent. However, COMPANION was not prospectively designed nor adequately powered to compare CRT without an ICD with medical therapy alone. Thus, the CARE HF trial that followed COMPANION uniquely evaluated the effect of CRT without a defibrillator on morbidity and mortality in an adequately powered comparison to optimal medical therapy.
The CARE HF trial was designed to evaluate the effects of CRT without an ICD on morbidity and mortality in patients with NYHA class III or IV heart failure and ventricular dyssynchrony.32,33 Eight hundred nineteen patients with systolic heart failure and ventricular dyssynchrony, defined as a QRS duration 150 ms or a QRS duration between 120 and 150 ms with echocardiographic evidence of dyssynchrony, were enrolled in this randomized, unblinded, controlled trial and followed up for an average of 29.4 months.33 Four hundred four patients were assigned to receive optimal medical therapy alone; 409 patients were randomized to optimal medical therapy plus CRT. The risk of death from any cause or unplanned hospitalization for a major cardiac event, the primary end point analyzed as time to first event, was significantly reduced by 37% in the treatment group compared with control subjects (hazard ratio, 0.63; 95% CI, 0.51 to 0.77; P<0.001). In the CRT group, 82 patients (20%) died during follow-up compared with 120 patients (30%) in the medical group, yielding a significant 36% reduction in all-cause mortality with CRT (hazard ratio, 0.64; 95% CI, 0.48 to 0.85; P<0.002; the Figure). CRT also significantly reduced the risk of unplanned hospitalization for a major cardiac event by 39%, all-cause mortality plus heart failure hospitalization by 46%, and heart failure hospitalization by 52%.
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Who Should Receive CRT? |
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TopIntroductionThe Rationale for CRTRandomized Controlled Trials of...Who Should Receive CRT?Limitations of CRTUnanswered Questions in CRTConclusionsReferences |
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The 2005 American College of Cardiology/American Heart Association heart failure guidelines propose a class I indication for CRT.1 The 2006 heart failure guidelines from the Heart Failure Society of America likewise promote a strong indication for CRT.2 On the basis of the inclusion criteria of the many randomized controlled trials, patients with left ventricular ejection fractions
35%, normal sinus rhythm, and NYHA functional class III or ambulatory class IV symptoms despite recommended optimal medical therapy who have ventricular dyssynchrony should receive CRT unless contraindicated. Currently, the guidelines define ventricular dyssynchrony as a QRS duration of 120 ms. This may change in the future because echocardiography has emerged as a promising way to define ventricular dyssynchrony that may be better than the ECG. |
Limitations of CRT |
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TopIntroductionThe Rationale for CRTRandomized Controlled Trials of...Who Should Receive CRT?Limitations of CRTUnanswered Questions in CRTConclusionsReferences |
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The success rate for placement of a transvenous cardiac resynchronization system has ranged from
88% to 92% in clinical trials. Thus, some patients undergoing an implantation procedure will not receive a functioning system with this approach. In this instance, the option of surgical placement, via full thoracotomy, or a minimally invasive approach, via a left ventricular epicardial lead, may be pursued. However, as always, an appropriate preoperative assessment of risk versus benefit should be considered. Moreover, it should be noted that major clinical trials of CRT used a transvenous approach to left ventricular lead placement and excluded patients undergoing surgical epicardial lead placement. Thus, the equivalence of these 2 approaches to left ventricular lead placement is not proved but rather presumed in clinical practice. Implant-related complications are similar to those seen with standard pacemakers and defibrillators, with the additional risk of dissection or perforation of the coronary sinus. This rare event may lead to substantial morbidity and even mortality in heart failure patients. One theoretical risk raised during the early study of CRT was proarrhythmia. This concern has been addressed by the observation that CRT without a defibrillator reduces total mortality and tends to reduce the incidence of sudden cardiac death in heart failure patients.33 Moreover, serial 24-hour ambulatory ECG monitoring was used during early CRT trials and demonstrated no proarrhythmic effect.
Although most patients respond favorably to biventricular pacing, some do not respond. The nonresponder rate for CRT appears to be 25%, a rate similar to the nonresponder rate for heart failure drug therapies. Suboptimal left ventricular lead placement, suboptimal AV and VV timing, ventricular scar, heart failure disease progression, and a variety of other factors have been proposed as contributing to the nonresponder rate associated with CRT. To date, however, no prospective predictors of responsiveness to CRT have been identified from the major clinical trials, including pooled analysis of nearly 2000 patients from 3 large-scale CRT trials (unpublished observation). As mentioned below, 1 trial is underway in an attempt to identify echocardiographic predictors (including the degree of mitral regurgitation) of CRT response. Ongoing and future studies may facilitate a better understanding of the limitations of CRT and aid in better patient selection.
One identifiable cause of poor response is loss of resynchronization. A specific programming sequence should be performed in the clinic to determine capture thresholds and to document that left ventricular capture is present. Lead dislodgement or a change in capture threshold may result in the loss of left ventricular and thus biventricular pacing. It also is possible that left ventricular lead placement and pacing thresholds are fine, but resynchronization is lost for other reasons.36 Anything that frequently or consistently inhibits left ventricular stimulation can effectively inhibit CRT. If the AV interval is too long and the patient’s intrinsic PR conduction inhibits biventricular pacing, deterioration may occur. The AV interval may have been programmed appropriately, but accelerated intrinsic AV conduction could result in loss of effective biventricular pacing. This is commonly seen when atrial fibrillation occurs, resulting in a rapid ventricular response competing with biventricular pacing. Frequent premature ventricular contractions also may inhibit ventricular pacing output. Although follow-up of the device itself and battery life are similar to that seen for contemporary dual-chamber pacemakers and defibrillators and generally managed by an implanting physician, heart failure specialists, general cardiologists, and primary care providers must possess the knowledge required to recognize the aforementioned limitations of CRT and to troubleshoot them.
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Unanswered Questions in CRT |
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TopIntroductionThe Rationale for CRTRandomized Controlled Trials of...Who Should Receive CRT?Limitations of CRTUnanswered Questions in CRTConclusionsReferences |
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Although CRT is considered a proven and routine therapy in those patients who have been evaluated in randomized controlled trials to date, many unanswered questions remain. For example, does CRT improve outcomes in patients with asymptomatic (NYHA class I) or minimally symptomatic (NYHA class II) heart failure? Is CRT better than standard right-sided pacing in heart failure patients without ventricular dyssynchrony who require cardiac pacing? Is echocardiography a better way to measure ventricular dyssynchrony and to select candidates for CRT than an ECG? Do patients with narrow QRS durations and echocardiographic evidence of dyssynchrony benefit from CRT? Recent pilot data and ongoing clinical investigations promise to answer such questions.
Results of 1 pilot study, the MIRACLE ICD II trial, support the potential efficacy of CRT in class II heart failure.37 In this study, CRT significantly improved ventricular remodeling indexes, specifically left ventricular diastolic and systolic volumes (P=0.04 and P=0.01, respectively) and left ventricular ejection fraction (P=0.02). CRT also significantly improved E/CO2 (P=0.01), NYHA class (P=0.05), and a heart failure clinical composite response (P=0.01), suggesting the potential for improved outcomes with CRT in this patient population. The safety and efficacy of CRT in NYHA class I and II patients are being evaluated further in the REsynchronization reVErses Remodeling in Systolic left vEntricular dysfunction (REVERSE)38 and the Multicenter Automatic Defibrillator Implantation Trial with CRT (MADIT-CRT), randomized controlled trials evaluating the effects of biventricular pacing on disease progression and outcomes, respectively.
The PRedictors Of reSPonse to CrT (PROSPECT) study39 is evaluating the utility of echocardiography as a measure of ventricular dyssynchrony in 450 patients receiving CRT devices. In this regard, echocardiography has identified evidence of dyssynchrony in some patients with QRS durations <120 ms. Whether these patients benefit from CRT is currently under investigation. Moreover, the optimal pacing strategy for heart failure patients with bradycardia or heart block but no evidence of ventricular dyssynchrony remains controversial. Right ventricular pacing produces "iatrogenic" left ventricular dyssynchrony and may worsen heart failure, as demonstrated in the Dual Chamber and VVI Implantable Defibrillator (DAVID) trial.40 Ongoing studies are evaluating the effects of biventricular pacing versus right-sided pacing in narrow QRS heart failure patients with a pacemaker indication.
Finally, the comparative efficacy of left ventricular versus biventricular pacing needs to be evaluated further in large-scale clinical trials. Observations in animals, in humans studied in the short-term setting, and in smaller trials of long-term pacing in heart failure support the potential of effectiveness of left ventricular pacing without a right ventricular lead. Of course, this possibility needs to be confirmed in an adequately powered randomized controlled trial.
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Conclusions |
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TopIntroductionThe Rationale for CRTRandomized Controlled Trials of...Who Should Receive CRT?Limitations of CRTUnanswered Questions in CRTConclusionsReferences |
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The benefits of CRT are substantial and unequivocal in the group of patients studied to date. CRT represents guideline-recommended, evidence-based therapy for the treatment of chronic heart failure. As such, it should be routinely offered to all heart failure patients who meet the criteria stated above.
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Acknowledgments |
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Disclosures
Dr Abraham has received research grants from Medtronic Inc, Biotronik, and St Jude Medical and has received speakers’ honoraria/consulting fees from Medtronic Inc, St Jude Medical, and Boston Scientific (Guidant Corp).
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References |
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TopIntroductionThe Rationale for CRTRandomized Controlled Trials of...Who Should Receive CRT?Limitations of CRTUnanswered Questions in CRTConclusionsReferences |
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26. Cazeau S, Leclercq C, Lavergne T, Walker S, Varma C, Linde C, Garrigue S, Kappenberger L, Haywood GA, Santini M, Bailleul C, Daubert JC; for the Multisite Stimulation in Cardiomyopathies (MUSTIC) Study Investigators. Effects of multisite biventricular pacing in patients with heart failure and intraventricular conduction delay. N Engl J Med. 2001; 344: 873–880.
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28. Abraham WT, on behalf of the Multicenter InSync Randomized Clinical Evaluation (MIRACLE) Investigators and Coordinators. Rationale and design of a randomized clinical trial to assess the safety and efficacy of cardiac resynchronization therapy in patients with advanced heart failure: the Multicenter InSync Randomized Clinical Evaluation (MIRACLE). J Card Fail. 2000; 6: 369–380.[CrossRef][Medline] [Order article via Infotrieve]
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The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.
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  K. Swedberg, J. Cleland, M. R. Cowie, M. Nieminen, S. G. Priori, L. Tavazzi, D. J. van Veldhuisen, L. Alonso-Pulpon, J. Camm, K. Dickstein, et al. Successful treatment of heart failure with devices requires collaboration Eur J Heart Fail, December 1, 2008; 10(12): 1229 - 1235. [Abstract] [Full Text] [PDF]
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