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(Circulation. 2004;110:2864-2868.)
© 2004 American Heart Association, Inc.

Heart Failure

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

William T. Abraham, MD; James B. Young, MD; Angel R. León, MD; Stuart Adler, MD; Alan J. Bank, MD; Shelley A. Hall, MD; Randy Lieberman, MD; L. Bing Liem, DO; John B. O’Connell, MD; John S. Schroeder, MD; Kevin R. Wheelan, MD, on behalf of the Multicenter InSync ICD II Study Group

From the Ohio State University Heart Center, Columbus (W.T.A.); Cleveland Clinic Foundation, Cleveland, Ohio (J.B.Y.); Emory University-Crawford Long Hospital, Atlanta, Ga (A.R.L.); St Paul Heart Clinic, St Paul, Minn (A.J.B., S.A.); Baylor Heart and Vascular Hospital, Dallas, Tex (S.A.H., K.R.W.); Harper University Hospital-Wayne State University, Detroit, Mich (J.B.O., R.L.); and Stanford University, Palo Alto, Calif (L.B.L., J.S.S.).

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 abraham-1{at}medctr.osu.edu

Received February 11, 2004; de novo received June 6, 2004; accepted July 21, 2004.

	Abstract

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Background— The effects of cardiac resynchronization therapy (CRT) in patients with mildly symptomatic heart failure have not been fully elucidated.

Methods and Results— The Multicenter InSync ICD Randomized Clinical Evaluation II (MIRACLE ICD II) was a randomized, double-blind, parallel-controlled clinical trial of CRT in NYHA class II heart failure patients on optimal medical therapy with a left ventricular (LV) ejection fraction 35%, a QRS 130 ms, and a class I indication for an ICD. One hundred eighty-six patients were randomized: 101 to the control group (ICD activated, CRT off) and 85 to the CRT group (ICD activated, CRT on). End points included peak O₂, E/CO₂, NYHA class, quality of life, 6-minute walk distance, LV volumes and ejection fraction, and composite clinical response. Compared with the control group at 6 months, no significant improvement was noted in peak O₂, yet there were significant improvements in ventricular remodeling indexes, specifically LV diastolic and systolic volumes (P=0.04 and P=0.01, respectively), and LV ejection fraction (P=0.02). CRT patients showed statistically significant improvement in E/CO₂ (P=0.01), NYHA class (P=0.05), and clinical composite response (P=0.01). No significant differences were noted in 6-minute walk distance or quality of life scores.

Conclusions— In patients with mild heart failure symptoms on optimal medical therapy with a wide QRS complex and an ICD indication, CRT did not alter exercise capacity but did result in significant improvement in cardiac structure and function and composite clinical response over 6 months.

Key Words: defibrillators, implantable • exercise test • heart failure • pacing • ventricular remodeling

	Introduction

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Three large, randomized, controlled trials, the Multicenter InSync Randomized Clinical Evaluation (MIRACLE),¹ the MIRACLE ICD,² and the Contak CD trial,³ and smaller randomized and nonrandomized studies^4–8 have shown that cardiac resynchronization therapy (CRT) improves quality of life, functional status, and exercise capacity in patients with systolic heart failure and a wide QRS complex with or without an indication for an implantable cardioverter-defibrillator (ICD). These studies have also demonstrated favorable effects of CRT on measures of disease progression such as left ventricular (LV) remodeling and a variety of composite outcome measures. More recently, the Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) trial demonstrated significant improvement in outcomes with CRT or CRT-ICD.⁹ To date, nearly all of these trials have evaluated the safety and efficacy of CRT in patients with NYHA class III or IV heart failure. Only the Contak CD and MIRACLE ICD trials included NYHA class II patients.

The Contak CD trial enrolled class II patients, along with class III and IV subjects, into a single study protocol with a planned analysis that included all patients. NYHA class II patients who received CRT during the study showed a reduction in LV diameters but failed to demonstrate improvement in the composite outcome end point. The Contak CD trial was limited by the instability of patients’ NYHA classes and medical therapy at enrollment, by a major change in trial design midway through the investigation that resulted in a combination of 3- and 6-month control periods from 2 different phases of study in the data analysis, and by difficulties inherent in subgroup analysis.

In contrast to the Contak CD trial, MIRACLE ICD enrolled class II to IV patients with separate prespecified end points for class II patients. Here, we report the results of the MIRACLE ICD II study, a randomized, double-blind, parallel-controlled clinical trial designed to evaluate the safety and efficacy of CRT in patients with mildly symptomatic heart failure. Specifically, we examined whether CRT limits disease progression and improves exercise performance in patients with mild NYHA class II heart failure symptoms, a wide QRS complex, and an established indication for an ICD.

	Methods

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Patients
Patients were eligible for enrollment if they had mildly symptomatic (NYHA class II) chronic heart failure, an LV ejection fraction (LVEF) 35%, an LV end diastolic dimension 55 mm, a QRS interval 130 ms, and an indication for an ICD. Patients received all appropriate treatments for heart failure, which included a diuretic, an ACE inhibitor, or an angiotensin receptor blocker and usually digitalis and a ß-blocker. Doses of these background medications were stable for 1 month, except for doses of the ß-blocker, which were stable for 3 months. Patients were excluded from the study for a variety of medical reasons,² including having an indication for or contraindication to cardiac pacing. The investigational review board of each participating institution approved the study protocol, and all patients provided written informed consent.

Study Protocol
Within 7 days before device implantation, eligible patients underwent the following baseline assessments: NYHA class; 6-minute hall walk test; quality of life evaluation with the Minnesota Living With Heart Failure Questionnaire; 2D Doppler echocardiography, which included measurement of LVEF, internal LV diastolic dimensions, end-systolic and end-diastolic volumes, and degree of mitral regurgitation; plasma neurohormone concentrations (epinephrine, norepinephrine, brain natriuretic peptide, big endothelin, and dopamine); and QRS interval by 12-lead ECG. After this initial evaluation, study participants underwent an attempt at implantation of a combined cardiac resynchronization/ICD device (model 7272 InSync ICD, Medtronic, Inc), along with 3 pacing leads: a standard right atrial pacing lead, a standard right ventricular pacing/defibrillation lead, and 1 of several LV transvenous leads positioned in a distal cardiac vein via the coronary sinus.

Before randomization, patients underwent a baseline treadmill cardiopulmonary exercise test that used a modified Naughton protocol¹⁰ to measure exercise capacity. Patients were then randomly assigned, in permuted groups for each center, to either optimal medical treatment with active CRT and active ICD therapy (CRT group) or optimal medical treatment and active ICD therapy only (control group). Neither the patients nor the physicians treating them for heart failure and performing the study evaluations were aware of the treatment assignment. At each site, an electrophysiologist unblinded to treatment opened a sealed envelope at the time of randomization, programmed the device, and performed all tests that could reveal the identity of the assigned mode. For the CRT group patients, the device was programmed to a mode that paced both ventricles simultaneously after atrial sensed events at rates of 130 bpm. Atrial pacing occurred only for sinus rates of 35 bpm. For control patients, the device was programmed to inhibit atrial or ventricular pacing unless the intrinsic rate was <35 bpm.

At 1, 3, and 6 months, patients returned for full interrogation of the CRT-ICD system, reassessment of quality of life and 6-minute hall walk distance, estimation of NYHA functional class, and monitoring of background drug regimen. Echocardiogram, metabolic exercise testing, and plasma neurohormone measurements were repeated at the 6-month visit, after which the blinded phase of the study was completed and CRT was activated in patients initially randomized to the control group. During the metabolic exercise tests, minute oxygen consumption (O₂), minute carbon dioxide production (CO₂), and minute ventilation (E) were measured with a breath-by-breath respiratory gas analyzer to determine peak oxygen consumption (peak O₂) and the ventilatory response to exercise (E/CO₂). Peak O₂ was established to be the oxygen consumption at peak exercise when the respiratory gas exchange ratio (CO₂/O₂) was >1.0. Cardiopulmonary gas exchange analysis was done at a core laboratory with personnel blinded to CRT activation status. Likewise, standard protocols were used to perform echocardiograms and to collect plasma neurohormones. Independent core laboratories, blinded to patient study assignment, interpreted the data.

Data Analysis
The primary efficacy end point for the MIRACLE ICD II study was the change in peak O₂ from baseline to 6 months. Secondary outcome measures were E/CO₂, NYHA class, quality of life, 6-minute hall walk distance, LV volumes and LVEF, and a composite clinical response that assigned all randomized patients to 1 of 3 response groups: worsened, improved, or unchanged.¹¹

SAS software (SAS Institute) was used to generate the random allocation sequence. The method of randomization was not disclosed to participating centers and was accomplished in blocked groups of 4 for each center to ensure balance of CRT and control assignments at each participating institution. Randomization occurred after a successful implant.

All end points were analyzed according to the intention-to-treat principle. For continuous variables, including NYHA class, changes from baseline to the 6-month visit in the control group compared with the CRT group were compared through the use of the Wilcoxon rank-sum test. For categorical end points, differences in the distribution of responses to treatment at 6 months were compared by Fisher’s exact test, except for inappropriately detected ventricular tachycardia/ventricular fibrillation episodes for which generalized estimating equation methods were used. For reporting of adverse events, a complication was defined as a sign, symptom, illness, or other medical event that was resolved invasively or that resulted in the death of or serious injury to a patient. Termination of a significant device function was also considered a complication. A clinical events review committee reviewed and classified adverse events without knowledge of the randomization assignment.

For primary and secondary efficacy variables, a value of P<0.05 was considered statistically significant. All probability values were calculated from 2-sided tests. In an analysis that was not prespecified, potential clinically relevant covariates were analyzed by ANOVA with random assignment as independent variables. Investigators had full access to all data and performed analyses without restrictions or limitations from the sponsor.

	Results

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Through July 1, 2002, 222 patients were enrolled in the study. Of those, 210 patients underwent an implant attempt, with 191 patients (91%) successfully implanted. Of the 191 patients successfully implanted, 1 patient died and 4 patients had LV lead dislodgements that were not corrected. The remaining 186 implanted patients were randomized (control group, n=101; CRT group, n=85); their baseline characteristics are summarized in Table 1. There were no statistically significant differences noted between the 2 groups. A total of 98 control and 82 CRT patients completed the study through the 6-month follow-up visit (2 patients died and 1 missed the 6-month follow-up visit in each group). Five control patients (5%) crossed over to CRT before 6 months. Biventricular pacing was activated early because of bradycardia in 3 patients, center error in 1 patient, and pacemaker dependency after AV node ablation for atrial flutter in 1 patient. In the CRT group, 2 patients (2%) crossed over from active biventricular pacing to no pacing before the end of the randomized phase. Biventricular pacing was deactivated because of LV lead dislodgement in 1 patient and diaphragmatic stimulation in biventricular and right ventricular pacing modes in the other patient. On an intention-to-treat principle, results were assessed on the basis of the original treatment assignment.

View this table: [in this window] [in a new window]   TABLE 1. Baseline Characteristics of MIRACLE ICD II Study Groups*

Effect on Primary and Secondary Efficacy End Points
Table 2 summarizes the primary and secondary efficacy end-point results of the MIRACLE ICD II study. At 6 months, patients receiving CRT had improved exercise time, 6-minute walk distance, and peak O₂, but these results were not statistically different compared with the control group (P=0.56, P=0.59, and P=0.87, respectively). E/CO₂ also improved in CRT patients, and the difference was statistically significant compared with placebo (P=0.01).

View this table: [in this window] [in a new window]   TABLE 2. Efficacy End-Point Analysis Between Baseline and 6 Months

Echocardiographic assessment showed statistically significant reductions in LV end-diastolic and end-systolic volumes (P=0.04 and P=0.01, respectively) and improvement in LVEF (P=0.02) in patients receiving CRT (Figure 1). NYHA class also improved in patients receiving CRT (P=0.05). Composite clinical response of the CRT group showed a clear improvement (P=0.01) over the control group, with 58% of the CRT patients improving compared with 36% of the control patients (Figure 2). Between-group differences in changes in quality of life scores, QRS duration, and plasma neurohormone levels did not achieve statistical significance.

View larger version (27K): [in this window] [in a new window]   Figure 1. Change in LV volumes and LVEF after 6 months of CRT or no pacing.

View larger version (39K): [in this window] [in a new window]   Figure 2. Effect of CRT on composite clinical response at 6 months.

Effect on Arrhythmic Events and Survival
During the 6-month follow-up period, 26 patients (26%) in the control group and 19 patients (22%) in the CRT group experienced 1 appropriately detected, spontaneous episode of ventricular tachycardia or ventricular fibrillation (P=0.61). Of the spontaneous and treated episodes, records for 71 episodes in the control group and 48 episodes in the CRT group were available in device memory. Five episodes (7%) were not successfully terminated within the interval determined by device criteria in the control group; however, all 5 events were terminated after redetection but before additional therapies could be delivered. The device terminated all 48 episodes in the CRT group. There was no statistically significant difference in the percentage of inappropriately detected ventricular tachycardia/ventricular fibrillation treated (P=0.21) or shocked (P=0.78) episodes between the control and CRT groups.

Two patients in the control group and 2 patients in the CRT group died during the 6-month follow-up period. Of the 2 control patients who died, 1 died of cardiac arrest 15 days after implant, and the other died of myocardial infarction with cardiogenic shock 151 days after implant. Both CRT patients died of a cardiac arrest, one 22 days after implant and the other 35 days after implant.

Complications
Among the 210 patients undergoing a CRT-ICD implant attempt, 46 patients (22%) experienced a total of 56 complications from the time of implant to hospital discharge. Of these 56 complications, 19 (34%) were related to the placement of the LV lead, including 3 coronary sinus dissections, 3 cardiac perforations, and 5 lead dislodgements. Twenty-three patients failed their initial implant attempt; 4 eventually went on to receive a CRT-ICD system. From hospital discharge to the end of the 6-month randomization period, 66 (35%) of the 191 patients with successful CRT-ICD implants experienced 109 complications; 19 (17%) were related to the LV lead, including 11 lead dislodgements, 1 cardiac perforation, 3 diaphragmatic muscle stimulation, and 4 elevated pacing thresholds.

	Discussion

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The results of the present study demonstrate that CRT significantly improves cardiac structure and function and a composite clinical response measure over a 6-month period of follow-up in optimally treated patients with mildly symptomatic NYHA class II heart failure, a wide QRS complex, and an ICD indication. CRT did not alter exercise capacity, but this finding is not surprising in patients whose exercise capacity was neither moderately nor severely impaired at baseline. This observation is consistent with another study demonstrating that heart failure patients with relatively preserved exercise capacity at baseline receive only minor improvement in exercise capacity during CRT.¹²

It is noteworthy that, despite having mild heart failure symptoms, patients in this study already showed signs of significant adverse cardiac remodeling. The degree of remodeling was comparable to that seen in the NYHA class III and IV patients at baseline in the MIRACLE and MIRACLE ICD studies. In these 2 studies, significant reverse remodeling and improvement in LVEF were seen in NYHA class III and IV patients receiving CRT.^1,2,13 In the present study, CRT produced significant improvement in LV systolic and diastolic volumes and LVEF, indicating that CRT promotes reverse remodeling even in patients with less symptomatic heart failure. These effects did not translate into improved exercise capacity, however. As noted earlier, this finding is not completely unexpected because patients with mildly symptomatic heart failure typically have better-preserved exercise tolerance than those with advanced heart failure. Furthermore, follow-up was limited to 6 months, which might have been too short a period to detect exercise improvement in mild heart failure patients. Nevertheless, the beneficial impact of CRT on parameters that characterize adverse cardiac remodeling is interesting and important and should be put into perspective.

Patients receiving CRT also showed significant improvement in their ventilatory response to exercise (ie, E/CO₂). Several studies have shown that an abnormally high E/CO₂ is an important independent predictor of adverse outcomes in patients with heart failure, including those whose exercise tolerance is relatively well preserved.^14–16 Thus, the improved E/CO₂ seen in patients receiving CRT suggests that CRT may have a favorable effect on the prognosis of patients with mildly symptomatic heart failure.

A key finding in this clinical trial was the significant increase in LVEF seen after 6 months of CRT. This increase occurred primarily because of a reduction in end-systolic volume in CRT patients compared with that of the control subjects. Improved heart volumes suggest that CRT can have a positive effect on the detrimental pathophysiology of heart failure.

Several small, uncontrolled studies have suggested that CRT may also prevent ventricular arrhythmias.^17–19 In the present study, the number of patients experiencing ventricular arrhythmias was similar in both treatment groups. The 6-month duration of the study, however, may have been too short to demonstrate the full effect of CRT on the occurrence of ventricular arrhythmias, especially when one considers that significantly longer follow-up has often been required to show the benefits of antiarrhythmic agents in drug trials. This study did demonstrate, however, that the detection and successful treatment of ventricular arrhythmias by an ICD were unaffected by the presence of CRT.

In summary, CRT appears to offer important benefits to optimally medically managed, mildly symptomatic NYHA class II heart failure patients with ventricular dyssynchrony and an indication for an ICD. Taken together, the improvement seen in LV volumes, LVEF, E/CO₂, and composite clinical response in the CRT group suggests that CRT acts to limit disease progression even in patients with mild heart failure symptoms. However, these observations must be confirmed by future randomized controlled trials of mildly symptomatic heart failure patients before the indication for resynchronization therapy is extended to this population. Whether other variables such as exercise capacity, quality of life, and arrhythmia prevention might also improve given a longer treatment period requires further research.

	Acknowledgments

 
This study was supported by Medtronic, Inc, Minneapolis, Minn. We wish to acknowledge the efforts of the MIRACLE ICD II Study Group. The sites, investigators, and coordinators participating in the MIRACLE ICD II trial are identical to those contributing to the MIRACLE ICD study and are listed elsewhere.²

Disclosure

Dr William Abraham is a consultant and investigator for and has received honoraria for speaking engagements for Medtronic. Dr James Young is a consultant and investigator for Medtronic and Guidant. Dr Alan Bank is a consultant and investigator for and has received honoraria for speaking engagements for Medtronic. Dr Randy Lieberman is a consultant for Medtronic, St Jude Medical, Guidant, and GlaxoSmithKline and an investigator for and shareholder in Medtronic; he has received honoraria for speaking engagements for GlaxoSmithKline. Dr Bing Liem has received honoraria for speaking engagements for Medtronic. Dr John Schroeder is an investigator for Medtronic.

	References

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