EDITORIAL COMMENT
Cardiac Resynchronization for Asymptomatic or Mildly Symptomatic Heart FailureA Bridge Too Far?*
Christophe Leclercq, MD, PhD ,*,
Philippe Mabo, MD and
Jean Noel Trochu, MD, PhD
CHU Rennes, Service de Cardiologie et Maladies Vasculaires, INSERM, CIC-IT, Rennes, France
Clinique Cardiologique et des Maladies Vasculaires, l'institut du thorax, CHU de Nantes, Nantes, France
* Reprint requests and correspondence: Dr. Christophe Leclercq, Service de Cardiologie et Maladies Vasculaires, Centre Cardio-Pneumologique, Hôpital Pontchaillou, 2 rue Henri Le Guilloux, 35033 Rennes Cedex 09, France (Email: christophe.leclercq{at}chu-rennes.fr).
Key Words: cardiac resynchronization therapy • heart failure • cardiomyopathy • ventricular remodeling
After the demonstration, in controlled clinical trials, of significant morbidity and mortality benefits conferred by cardiac resynchronization therapy (CRT) in patients in New York Heart Association (NYHA) heart failure (HF) functional class III or IV despite optimal medical management, in sinus rhythm, and with a QRS duration >120 ms, the issue of whether CRT might be extended to other patient populations has been raised (1). In patients with advanced HF, mechanical dyssynchrony and a QRS <120 ms in duration, preliminary results have been disappointing, perhaps because, in this subset, CRT is ineffective, or perhaps the application of standard criteria of mechanical dyssynchrony is not appropriate (2). In patients in NYHA functional class <III, the hypothetical objectives of CRT are to slow the progression of disease and lower the mortality related to its severity. The latter was examined in the REVERSE (REsynchronization reVErses Remodeling in Systolic Left vEntricular dysfunction) trial, the results of which are presented by Linde et al. (3) in this issue of the Journal.
The REVERSE trial enrolled patients presenting with no or mild manifestations of HF (American College of Cardiology/American Heart Association stage C, NYHA functional class I or II), despite optimal drug therapy, including stable doses of an angiotensin-converting enzyme inhibitor or angiotensin I receptor blocker, and a beta-adrenergic blocker for  3 months. All patients were in sinus rhythm, with 120-ms QRS duration, a <40% left ventricular (LV) ejection fraction, and a 55-mm LV end-diastolic diameter measured by echocardiography. Among 684 enrolled patients, 610 were randomly assigned to CRT-ON (n = 419) versus CRT-OFF (control group; n = 191). The primary end point of the trial was an HF clinical composite response, which, over a 12-month follow-up, classified patients as worsened, unchanged, or improved. Because of the inclusion of asymptomatic patients, the proportion of worsened patients was used to compare the efficacy of CRT between the 2 study groups. The absolute change in left ventricular end-systolic volume index (LVESVI) between baseline and 12 months of follow-up was a secondary end point adjudicated by 2 independent core echocardiographic laboratories (3). No significant difference in the proportion of worsened patients was observed between the 2 groups, and thus the primary end point did not reach the statistical significance pre-specified in the trial protocol.
With regard to LVESVI, paired data were available in only 79% of the 610 randomly assigned patients (77% of missing data), mainly because of technically unsatisfactory baseline or follow-up echocardiograms. However, a significantly greater decrease in LVESVI was observed in the CRT-ON group than in the control group, and the decrease in LVESVI was significantly greater among patients with nonischemic than among patients with ischemic heart disease. No significant differences were observed between the 2 groups with respect to NYHA functional class, quality of life, or incidence of ventricular tachyarrhythmias. However, the time to first hospitalization for management of HF was significantly longer in the CRT-ON than in the control group (hazard ratio: 0.47; p = 0.03). Finally, the overall rates of periprocedural and post-procedural or system-related complications were 4% and 16%, respectively.
It is noteworthy that 95% of patients included in the REVERSE trial received an angiotensin-converting enzyme inhibitor or an angiotensin I receptor blocker, and a beta-adrenergic blocker for 3 months, and that 60% received 50% of the target dose, and 30% the full target dose of beta-adrenergic blocker. By comparison with the most recent HF trials and actual clinical practice, the pharmacological management in the REVERSE trial was optimal (4,5). The quality of drug therapy might explain, at least partially, the considerably lower 1-year mortality rate observed in both groups of the REVERSE trial than the 5.3% rate in the active arm of the MERIT-HF (Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure) study (6).
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Is CRT Ineffective in Asymptomatic or Mildly Symptomatic Patients, and Will it Never Be Indicated in This Population?
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The REVERSE trial may be viewed as a "negative" trial because of the primary end point outcome. Among several potential explanations for these results, the first might be that CRT is not effective in this population, though this conclusion is probably premature. Second, the pre-specified analysis plan considered only changes in the proportion of worsened patients (i.e., that unchanged or improved statuses indicated the absence of disease progression). This is not how an HF composite score is usually analyzed (7). Typically, the analysis compares the proportion of unchanged, worsened, or improved patients without combining criteria, in which case the difference would have significantly favored CRT-ON, since it was associated with 54% of improved patients versus 40% in the control group. However, the REVERSE trial was not powered for this kind of analysis. A third explanation might be that the treatment effect requires a prolonged observation period, and that the HF clinical composite did not detect a benefit at 1 year. Previous studies limited to 6-month follow-ups have failed to show a clinical improvement conferred by CRT in patients in NYHA HF functional class II (8,9). It would, therefore, not be surprising that a 1-year trial of CRT including asymptomatic patients was too short to demonstrate its efficacy, and that the primary end point and the duration of follow-up were both lacking, particularly in view of the low clinical event rate observed in the REVERSE trial. An additional 1-year of follow-up has been planned for the European cohort of the REVERSE trial, the results of which are expected in early 2009.
As previously found in the MIRACLE (Multicenter InSync Randomized Clinical Evaluation) and CARE-HF (Cardiac Resynchronization Heart Failure) trials, LV reverse remodeling is a major therapeutic effect of CRT, which increases over time (10,11). The CONTAK-CD and MIRACLE ICD (Multicenter InSync Implantable Cardioversion Defibrillation Randomized Clinical Evaluation) II trials have suggested similar benefits in patients with less advanced HF (8,9). The strong association between reverse ventricular remodeling and clinical outcomes in trials of pharmaceuticals supports the inclusion of measures of ventricular volumes in the assessment of new treatments of HF (12). Moreover, in CRT system recipients, LV remodeling has been correlated with longer survival by contrast to improvements in clinical status (13). In the REVERSE trial, in addition to optimal treatment, CRT caused an impressive amount of reverse LV remodeling, of greater magnitude among patients with nonischemic heart disease, as previously shown. The European population followed over 24 months should provide valuable information regarding the temporal evolution of the reverse remodeling process that occurs during CRT. While the observations made with respect to time to first hospitalization for management of HF were largely encouraging, the REVERSE trial was not powered to measure morbidity and mortality rates, unlike the ongoing RAFT (Resynchronization/defibrillation for Ambulatory heart Failure Trial) and MADIT CRT (Multicenter Automatic Defibrillator Implantation Trial–Cardiac Resynchronization Therapy) studies (14,15).
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Safety Issues
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CRT is an invasive treatment requiring the implantation of leads and a pulse generator. The 97% implantation success rate observed in the REVERSE trial is higher than in previous studies (1). However, all medical centers participating in the trial had a long experience with, and a high yearly rate of CRT system implantations, suggesting these procedures should be limited to referral centers of excellence. Furthermore, the rate of LV lead dislodgement requiring reoperation in the REVERSE trial was 8% at 1 year and, as mentioned by the authors, the rates of complications should be definitively reascertained at 5 years (3). This is mandatory to objectively measure the risk/benefit ratio, particularly in a population with mild HF.
In summary, the REVERSE trial showed, for the first time, significant reverse LV remodeling by CRT in mildly symptomatic patients who received optimal drug treatment. This is a major and encouraging observation, especially in this particular HF population. Unfortunately, and not surprisingly, the REVERSE trial did not observe a clinical improvement conferred by CRT in this HF population at 1 year, but we may reasonably expect a more positive result with the 2-year follow-up. These factors should be considered in the completion of further clinical trials. The marked progress in the medical management of HF requires the inclusion of large numbers of patients and long follow-ups to confirm the clinical benefits conferred by supplemental therapy in trials with low expected rates of adverse clinical events. Is the bridge of CRT in patients with mild HF too far? Probably yes for those who are rushed. Clinical trials, like countless valuable products, need to mature.
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Footnotes
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Dr. Leclercq is a consultant for Medtronic, Boston Scientific, St. Jude Medical, Biotronik, and Sorin, and has received research grants from Medtronic and Sorin. Dr. Mabo is a consultant for Medtronic, Boston Scientific, St. Jude Medical, Biotronik, and Sorin, and has received research grants from Medtronic and Sorin.
* 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. Vardas PE, Auricchio A, Blanc JJ, et al. European Society of Cardiology; European Heart Rhythm Association. Guidelines for cardiac pacing and cardiac resynchronization therapy: the task force for cardiac pacing and cardiac resynchronization therapy of the European Society of Cardiology. Developed in collaboration with the European Heart Rhythm Association. Eur Heart J 2007;28:2256-2295.[Free Full Text]2. Beshai JF, Grimm RA, Nagueh SF, et al. RethinQ Study Investigators Cardiac-resynchronization therapy in heart failure with narrow QRS complexes N Engl J Med 2007;357:2461-2471.[CrossRef][Web of Science][Medline] 3. Linde C, Abraham WT, Gold MR, et al. on behalf of the REVERSE (REsynchronization reVErses Remodeling in Systolic left vEntricular dysfunction) Study Group 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] 4. Kjekshus J, Apetrei E, Barrios V, et al. CORONA Group Rosuvastatin in older patients with systolic heart failure N Engl J Med 2007;357:2248-2261.[CrossRef][Medline] 5. de Groote P, Isnard R, Assyag P, et al. Is the gap between guidelines and clinical practice in heart failure treatment being filled?. Insights from the IMPACT RECO survey. Eur J Heart Fail 2007;9:1205-1211.[Abstract/Free Full Text] 6. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF) Lancet 1999;353:2001-2007.[CrossRef][Web of Science][Medline] 7. Packer M. Proposal for a new clinical end point to evaluate the efficacy of drugs and devices in the treatment of chronic heart failure J Cardiac Fail 2001;7:176-182.[CrossRef][Web of Science][Medline] 8. 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] 9. Abraham WT, Young JB, León AR, et al. Multicenter InSync ICD II Study Group 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] 10. 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] 11. Cleland JG, Daubert JC, Erdmann E, et al. Cardiac Resynchronization-Heart Failure (CARE-HF) Study Investigators 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] 12. Konstam MA. Reliability of ventricular remodeling as a surrogate for use in conjunction with clinical outcomes in heart failure Am J Cardiol 2005;96:867-871.[CrossRef][Web of Science][Medline] 13. 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] 14. Tang A. Resynchronization/defibrillation for ambulatory heart failure trialClinical trials identifier NCT00251251
http://www.clinicaltrials.gov/ct2/show/NCT00251251?term=Canada%2C+CRT& rank=6 2005Accessed August 27, 2008. 15. Moss AJ, Brown MW, Cannom DS, et al. Multicenter automatic defibrillator implantation trial-cardiac resynchronization therapy (MADIT-CRT): design and clinical protocol Ann Noninvasive Electrocardiol 2005;104(Suppl):34-43.
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