Cardiac Resynchronization in Mild Heart Failure Patients

Abstract & commentary

By John P. DiMarco, MD, PhD, Professor of Medicine, Division of Cardiology, University of Virginia, Charlottesville. Dr. DiMarco is a consultant for Novartis, and does research for Medtronic and Guidant.

Source: Linde C, et al. 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.

The resynchronization reverses remodeling in Systolic Left Ventricular Dysfunction (REVERSE) trial tested the hypothesis that cardiac resynchronization therapy (CRT) would benefits patients with New York Heart Association (NYHA) functional class I and II heart failure and a prolonged QRS duration. Patients were eligible for inclusion if they were currently in NYHA class I or II with prior heart failure symptoms, on optimal medical therapy for at least three months. All patients were in sinus rhythm, had a QRS duration > 120 m/sec, a left ventricular ejection fraction (LVEF) < 40%, and a left ventricular end-diastolic dimension > 55 mm. Patients with recent (within three months) class III or IV symptoms were excluded.

Baseline evaluations included a quality-of-life assessment, a six-minute walk test, and 2-D Doppler flow echocardiography. All patients received a CRT device, either a defibrillator (CRT-D) or pacemaker (CRT-P). After successful implantation, patients were randomly assigned in a 2:1 ratio to CRT-ON or CRT-OFF for 12 months. Patients were seen at 1, 3, 6, and 12 months. Study examinations for endpoints were performed by heart failure staff blinded to treatment assignment. Device follow-up was carried out by unblinded electrophysiology staff. Clinical events were adjudicated by an endpoint committee blinded to treatment assignment. The primary endpoint of the study was a composite heart failure evaluation that classified patients as worsened, improved, or unchanged. Since class I patients (asymptomatic at baseline) could not improve, the percentage of patients worsened was the primary efficacy comparison. Secondary endpoints included changes in left ventricular end-systolic volume index (LVESVI), six-minute walk distance, heart failure hospitalizations, and mortality.

A total of 642 patients were enrolled, and underwent, attempted implant of a CRT device. Successful implants were achieved in 621 patients (97%). Eleven patients were excluded, leaving a final group of 610 subjects, 419 programmed CRT-ON and 191 programmed CRT-OFF. Mean values for important clinical parameters were similar between the two groups: age 62 years; 79% male; 82% class II; 53% ischemic heart disease; QRS duration 154 m/sec; six-minute walk distance of 388 m; LVEF 26%. CRT-D devices were used in 84% of the patients. At one year, 16% of the patients in the CRT-ON group manifested worsened heart failure compared to 16% in the CRT-OFF group (p = 0.10). Subgroup analysis suggested benefits among those with lower LVEFs, wider QRS durations, and non-ischemic cardiomyopathy. Only 12 deaths occurred during the study; three in the CRT-OFF group and nine in the CRT-ON group. Paired LVESVI data, available in 80% of the participants, showed a change of -18.4 ± 29.5 mL/m2 with CRT-ON vs -1.3 ± 23.4 mL/m2 with CRT-OFF. The reduction in LVESVI was noted to be greater among the patients with a non-ischemic cardiomyopathy. LVEF also improved with CRT. There were no significant improvements in six-minute walk distances or quality-of-life scores. Among patients with a CRT-D device, there was a favorable trend toward fewer episodes of ventricular arrhythmias. Although there were 222 total hospitalizations in the study group, only 32 hospitalizations were judged to be heart failurerelated; 17 in the CRT-ON group and 15 in the CRT-OFF group. Time-to-first heart failure hospitalization was significantly prolonged by active CRT.

Since all patients in both study groups received a left ventricular lead, complications were reported for the entire group. Implant complications were noted in 4% of the patients, but some of these may have been unrelated to the LV lead implant. However, after the initial procedure, there were 41 LV lead dislodgements and 14 cases of diaphragmatic stimulation that required intervention.

Linde et al concluded that CRT improved measures of left ventricular function in patients with asymptomatic or mildly symptomatic heart failure and a prolonged QRS duration. They note that although heart failure-related hospitalizations were reduced, quality-of-life scores, exercise capacity, and the percentage with worsened heart failure did not change significantly during the course of the study.

Commentary

Although there are some positive aspects in the results of the REVERSE trial, the overall conclusion should be that preemptive intervention with CRT in patients with no or mild symptoms of heart failure must await further data. In REVERSE, all patients received a left ventricular lead. Thus, all were subject to the 16% lead- or system-related complication rate observed in the study. If reoperations and additional hospital days were included only for the CRT-ON group, then any clinical benefit associated with CRT would presumably be negated or reversed. Eliminating complications likely to be solely due to the LV lead from group comparisons, certainly biases results in favor of CRT. It is understandable that Linde et al anticipated that they might show benefit with CRT and could, therefore, offer CRT later to the control group without the need for a second procedure. However, if this approach is taken, complications related solely to CRT should count only against the active therapy group.

Another limitation of REVERSE is its relatively short follow-up duration. In asymptomatic or mildly symptomatic patients with heart failure, it is likely that clinical benefits associated with LV remodeling will begin to accrue only with prolonged therapy. Linde et al have clearly shown CRT results in favorable LV remodeling, and a longer study may have shown benefit. Fortunately, the European investigators in REVERSE are continuing the trial and plan at least a two year follow-up report. We should get a better estimate of the value of preemptive CRT when those data become available. Another study currently underway, MADIT-CRT, is a larger trial enrolling similar patients using single chamber ICDs vs CRT-D devices. In MADIT-CRT, the primary endpoint is a composite of mortality and heart failure hospitalization, and all patients will be followed for at least two years. Since complications of CRT will only be seen in the active therapy group, MADIT-CRT should provide more definitive data about the value of early intervention in these patients.