EDITORIAL COMMENT
Is it Time to Expand the Use of Cardiac Resynchronization Therapy to Patients With Mildly Symptomatic Heart Failure?*
Derek V. Exner, MD, MPH*
Libin Cardiovascular Institute of Alberta, University of Calgary, Calgary, Alberta, Canada
* Reprint requests and correspondence: Dr. Derek V. Exner, 3330 Hospital Drive Northwest, Room G208, Calgary, Alberta T2N 4N1, Canada (Email: exner{at}ucalgary.ca).
Key Words: cardiac resynchronization therapy • heart failure • mortality • randomized trial • remodeling • subgroup
Cardiac resynchronization therapy (CRT) is central to the management of patients with highly symptomatic systolic heart failure and delayed ventricular conduction. Improved survival and reduced rates of hospital stay for heart failure with CRT versus standard medical therapy have been documented in prior trials (1). Thus, CRT combined with a pacemaker or implantable cardioverter-defibrillator (CRT-D) is now routinely recommended for patients with New York Heart Association (NYHA) functional class III or IV limitation, a QRS duration  120 ms, and left ventricular (LV) ejection fraction  0.35 despite optimal pharmacologic therapy (2–4).
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Rationale for CRT earlier in heart failure
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Cardiac resynchronization therapy has favorable hemodynamic, energetic, anatomic, and basic cellular effects in advanced heart failure (5–8). Thus, it is both plausible and attractive that early intervention with CRT in heart failure might delay or prevent disease progression. Yet, although CRT is central to the management of patients with highly symptomatic systolic heart failure, its role in patients with mildly symptomatic heart failure is less certain (1).
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LV reverse remodeling and clinical outcome
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It has been shown that favorable LV reverse remodeling is associated with improved long-term clinical outcomes with CRT (9). However, it is important to recognize that LV reverse remodeling is not a perfect surrogate for clinically important long-term outcomes. For example, the relationship between the degree of LV reverse remodeling and a long-term survival benefit from CRT is far from clear when patients with an ischemic versus nonischemic etiology of heart failure are considered (Table 1) (10–16). For example, in both the MIRACLE (Multicenter InSync Randomized Clinical Evaluation) (10,11) and the CARE HF (CArdiac REsynchronisation in Heart Failure study) (15,16) studies patients with an ischemic etiology of heart failure had less LV reverse remodeling than those with a nonischemic etiology. Yet, the survival benefit from CRT was equivalent in patients with ischemic and nonischemic heart failure. Furthermore, despite the fact that patients with ischemic heart failure typically have less LV reverse remodeling with CRT than patients with nonischemic heart failure (Table 1), the survival benefit with CRT tended to be greater in patients with an ischemic versus nonischemic etiology of heart failure in the COMPANION (Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure) trial (14). Thus, although favorable LV remodeling is desirable with CRT, it does not provide the complete answer with respect to the long-term clinical benefit from CRT.
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Table 1 Key Randomized Trials Assessing the Efficacy of CRT: Ischemic Versus Nonischemic Etiology of Heart Failure
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CRT in patients with mild heart failure symptoms
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Until recently, few studies evaluated the efficacy of CRT in patients with mild heart failure (NYHA functional class I or II). These initial studies suggested that CRT had only a minor effect on preventing heart failure hospital stay and was not associated with a significant effect on mortality (1). Table 2
summarizes completed and ongoing trials evaluating the efficacy of CRT in patients with mildly symptomatic heart failure. The CONTAK CD (Guidant Corporation, St. Paul, Minnesota) study represents the earliest of these (12). In that trial, patients with mostly NYHA functional class III or IV limitation underwent CRT-D implantation. During the post-implant period, before randomization, patients had more intensive medical therapy for their heart failure. This resulted in a substantial number of patients having improved NYHA functional class at the time of randomization to active CRT (CRT ON) or usual care (CRT OFF). The CRT did not significantly alter the primary end point of CONTAK CD, progression of heart failure. However, greater LV reverse remodeling was observed with CRT versus control, both in patients with advanced NYHA functional class limitation and those with mildly symptomatic heart failure. The MIRACLE ICD II (Multicenter InSync ICD Randomized Clinical Evaluation II) study (17) included only patients with NYHA functional class II symptoms. The primary efficacy end point for MIRACLE ICD II, change in peak oxygen uptake from baseline to 6 months, was not significantly altered with CRT. However, CRT did favorably alter the secondary outcomes of LV reverse remodeling and clinical response. These early studies were followed by the much larger REVERSE (Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction) trial (18). The REVERSE trial included 610 patients with mostly NYHA functional class II limitation. The primary end point of the REVERSE trial, the percent of patients who worsened, was not significantly different in the CRT ON versus CRT OFF group over 12 months of follow-up. However, CRT was associated with a significant reduction in the pre-specified secondary end point left ventricular end-systolic volume index (LVESVi). The reduction in LVESVi was particularly prominent in patients with a nonischemic etiology of heart failure, those with larger LV end systolic volumes, and patients with wider QRS values (152 ms) at baseline. The time to first heart failure hospital stay was delayed to a greater extent in patients randomized to CRT ON versus CRT OFF (p = 0.03). The mixed results from the REVERSE study indicate that, although CRT might slow the progression of heart failure, as measured by changes in LV remodeling, its impact on clinical outcomes over the near term seem modest. Thus, larger and longer-term studies are required to better define the role of CRT in less symptomatic patients.
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Results in the REVERSE European cohort
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The sub-analysis of European data from the REVERSE trial by Daubert et al. (19) in this issue of the Journal provides important additional insights into the role of CRT in patients with mild symptoms of heart failure. Their analysis included the 262 patients who received CRT devices in Europe. As in the main REVERSE study, European participants were required to have a QRS width 120 ms and LV ejection fraction of 0.40. Participants were randomly assigned in a 2:1 manner to active therapy (CRT ON, n = 180) or control (CRT OFF, n = 82). European patients were followed for 24 months, twice the duration of the North American cohort. Over 24 months, 19% of the CRT ON versus 34% of the CRT OFF patients worsened (p = 0.01). Furthermore, LVESVi decreased by a mean of 27.5 ± 31.8 ml/m2 in the CRT ON versus only 2.7 ± 25.8 ml/m2 in the CRT OFF group (p < 0.0001). The time to first heart failure hospital stay or death was also significantly delayed with CRT ON versus CRT OFF (p = 0.003). Thus, these results provide additional data to support the use of CRT in delaying heart failure progression.
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The REVERSE European cohort data in perspective
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Although the data from Daubert et al. (19) are interesting, they should not be considered definitive. First, it is important to recognize that few patients were truly asymptomatic and the results are mostly applicable to patients with mildly symptomatic heart failure. Furthermore, as with any subanalysis, there is the distinct possibility of overestimating or underestimating the true effect size by chance alone. This is particularly relevant, given that only 13 deaths were observed in the entire European cohort.
As acknowledged by the authors, important differences in demographic characteristics were apparent between the European and North American patients. Furthermore, these might in part explain the apparent differences in CRT efficacy in this subanalysis. European patients were less likely to have an ischemic etiology of heart failure, had longer average QRS durations, and less comorbid illness as compared with the non-European participants in the REVERSE study. Thus, the author's conclusion, "these observations suggest that CRT prevents the progression of disease in patients with asymptomatic or mildly symptomatic LV dysfunction," is generally reasonable. However, it is important to acknowledge that additional evidence is required before more wide-scale use of CRT in patients with mildly symptomatic heart failure.
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Ongoing and recently completed trials
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Two large trials will provide important additional evidence of the efficacy of CRT in a broader group of patients with mildly symptomatic heart failure. The MADIT CRT (Multi-center Automatic Defibrillator Implantation with Cardiac Resynchronization Therapy) study compared usual implantable cardioverter-defibrillator therapy with CRT-D in 1,820 subjects in sinus rhythm with LV ejection fraction values 0.30, QRS durations 130 ms, and mild heart failure. This trial demonstrated a 29% reduction in the risk of the combined end point of death or heart failure events (p = 0.003) (20). This outcome was purely driven by a reduction in heart failure events. The proportion of these events that were actual hospitalizations for heart failure is unclear. Further, the average 6-min walk test distance of 361 ± 108 m suggests that many of these patients would have been categorized as NYHA functional class III in past trials, based on a walk distance of <450 m (10). Nonetheless, clear improvements in LV mechanical indexes and corresponding reductions in heart failure events were demonstrated in MADIT-CRT. The RAFT (Resynchronization/Defibrillation in Advanced Heart Failure Trial) is another large ongoing study comparing implantable cardioverter-defibrillator therapy with CRT-D among 1,800 subjects in sinus rhythm or with atrial fibrillation, LV ejection fractions 0.30, QRS durations 120 ms, and mostly mildly symptomatic heart failure (21). The REVERSE study and other trials will provide clearer answers as to the role of CRT in patients with mildly symptomatic heart failure. Given the growing evidence for CRT as a means to delay heart failure progression, it is tempting to recommend it beyond present guidelines (2–4). However, it is premature to recommend CRT as a routine intervention to patients with asymptomatic LV dysfunction or those with mildly symptomatic heart failure today.
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Footnotes
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Dr. Exner is a Scholar of the Alberta Heritage Foundation for Medical Research; and he has received honoraria and research support from Medtronic and St. Jude Medical, honoraria from Boston Scientific, and research support from Sorin/ELA.
* Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. 
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References
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1. McAlister FA, Ezekowitz J, Hooton N, et al. Cardiac resynchronization therapy for patients with left ventricular systolic dysfunction: a systematic review JAMA 2007;297:2502-2514.[Abstract/Free Full Text]2. Epstein AE, DiMarco JP, Ellenbogen KA, et al. ACC/AHA/HRS 2008 guidelines for device-based therapy of cardiac rhythm abnormalities: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the ACC/AHA/NASPE 2002 Guideline Update for Implantation of Cardiac Pacemakers and Antiarrhythmia Devices) J Am Coll Cardiol 2008;51:e1-e62.[Free Full Text] 3. Howlett JG, McKelvie RS, Arnold JM, et al. Canadian Cardiovascular Society consensus conference guidelines on heart failure, update 2009: diagnosis and management of right-sided heart failure, myocarditis, device therapy and recent important clinical trials Can J Cardiol 2009;25:85-105.[Web of Science][Medline] 4. Dickstein K, Cohen-Solal A, Filippatos G, et al. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2008: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2008 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association of the ESC (HFA) and endorsed by the European Society of Intensive Care Medicine (ESICM). Eur Heart J 2008;29:2388-2442.[Free Full Text] 5. Leclercq C, Cazeau S, Le Breton H, et al. Acute hemodynamic effects of biventricular DDD pacing in patients with end-stage heart failure J Am Coll Cardiol 1998;32:1825-1831.[Abstract/Free Full Text] 6. Nelson GS, Berger RD, Fetics BJ, et al. Left ventricular or biventricular pacing improves cardiac function at diminished energy cost in patients with dilated cardiomyopathy and left bundle-branch block Circulation 2000;102:3053-3059.[Abstract/Free Full Text] 7. St. John Sutton MG, Plappert T, Abraham WT, et al. Effect of cardiac resynchronization therapy on left ventricular size and function in chronic heart failure Circulation 2003;107:1985-1990.[Abstract/Free Full Text] 8. Vanderheyden M, Mullens W, Delrue L, et al. Myocardial gene expression in heart failure patients treated with cardiac resynchronization therapy responders versus nonresponders J Am Coll Cardiol 2008;51:129-136.[Abstract/Free Full Text] 9. Yu CM, Bleeker GB, Fung JW, et al. Left ventricular reverse remodeling but not clinical improvement predicts long-term survival after cardiac resynchronization therapy Circulation 2005;112:1580-1586.[Abstract/Free Full Text] 10. Abraham WT, Fisher WG, Smith AL, et al. Cardiac resynchronization in chronic heart failure N Engl J Med 2002;346:1845-1853.[CrossRef][Web of Science][Medline] 11. Woo GW, Petersen-Stejskal S, Johnson JW, Conti JB, Aranda Jr. JA, Curtis AB. Ventricular reverse remodeling and 6-month outcomes in patients receiving cardiac resynchronization therapy: analysis of the MIRACLE study J Interv Card Electrophysiol 2005;12:107-113.[CrossRef][Web of Science][Medline] 12. Higgins SL, Hummel JD, Niazi IK, et al. Cardiac resynchronization therapy for the treatment of heart failure in patients with intraventricular conduction delay and malignant ventricular tachyarrhythmias J Am Coll Cardiol 2003;42:1454-1459.[Abstract/Free Full Text] 13. Young JB, Abraham WT, Smith AL, et al. Combined cardiac resynchronization and implantable cardioversion defibrillation in advanced chronic heart failure: the MIRACLE ICD trial JAMA 2003;289:2685-2694.[Abstract/Free Full Text] 14. 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.[CrossRef][Web of Science][Medline] 15. Cleland JG, Daubert JC, Erdmann E, et al. The effect of cardiac resynchronization on morbidity and mortality in heart failure N Engl J Med 2005;352:1539-1549.[CrossRef][Web of Science][Medline] 16. Wikstrom G, Blomstrom-Lundqvist C, Andren B, et al. The effects of aetiology on outcome in patients treated with cardiac resynchronization therapy in the CARE-HF trial Eur Heart J 2009;30:782-788.[Abstract/Free Full Text] 17. Abraham WT, Young JB, Leon AR, et al. Effects of cardiac resynchronization on disease progression in patients with left ventricular systolic dysfunction, an indication for an implantable cardioverter-defibrillator, and mildly symptomatic chronic heart failure Circulation 2004;110:2864-2868.[Abstract/Free Full Text] 18. Linde C, Abraham WT, Gold MR, St. John Sutton M, Ghio S, Daubert C. Randomized trial of cardiac resynchronization in mildly symptomatic heart failure patients and in asymptomatic patients with left ventricular dysfunction and previous heart failure symptoms J Am Coll Cardiol 2008;52:1834-1843.[Abstract/Free Full Text] 19. Daubert C, Gold MR, Abraham WT, et al. REVERSE Study Group Prevention of disease progression by cardiac resynchronization therapy in patients with asymptomatic or mildly symptomatic left ventricular dysfunction: insights from the European cohort of the REVERSE (Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction) trial J Am Coll Cardiol 2009;54:1837-1846.[Abstract/Free Full Text] 20. Moss AJ, Hall WJ, Cannom DS, et al. MADIT-CRT Trial Investigators Cardiac-resynchronization therapy for the prevention of heart-failure events N Engl J Med 2009 Sep 1[E-pub ahead of print]. 21. Tang T, Wells G. Resynchronization/defibrillation for ambulatory heart failure trial (RAFT) http://clinicaltrials.gov/ct2/show/NCT00251251 2009 Sep 1Accessed June 23, 2009.
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