Can Cardiac Resynchronization Therapy Use be Expanded?

Abstract & Commentary

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

Source: Thibault B, et al. Cardiac resynchronization therapy in patients with heart failure and a QRS complex <120 milliseconds: The Evaluation of Resynchronization Therapy for Heart Failure (LESSER-EARTH) Trial. Circulation 2013;127:873-881.

The Evaluation of Resynchronization Therapy for Heart Failure (LESSER-EARTH) trial tested the hypothesis that cardiac resynchronization therapy in addition to optimal medical therapy would benefit patients with severe congestive heart failure but no pacing indication and a QRS duration < 120 milliseconds (msec). Patients were recruited from 12 Canadian sites. Patients were eligible for inclusion if they had a clinical indication for an implantable cardioverter defibrillator (ICD), a left ventricular ejection fraction ≤ 35%, a QRS duration < 120 msec, and symptoms of heart failure with a 6-minute walk test distance ≤ 400 meters. Evidence for left ventricular dyssynchrony was not required. Patients with permanent atrial fibrillation, with factors other than heart failure that would limit exercise testing, and those with recent myocardial infarction or cardiac surgery were excluded. Patients with prior pacemakers or ICDs were eligible if their percentage of ventricular pacing was < 5%.

All patients underwent an attempted placement of or upgrade to a CRT-D system. They then entered a 2- to 8-week run-in period during which CRT was programmed (off) with an AV delay set ≥ 325 msec. During this run-in period, the function of the CRT system was assessed and an optimal pharmacologic regimen established. Baseline submaximal exercise and 6-minute walk tests were performed and quality-of-life questionnaires administered. Left ventricular function, geometry, and synchrony were assessed by echocardiography. These evaluations were repeated 6 and 12 months after randomization to either CRT-On or CRT-Off. The primary outcome was submaximal exercise duration. This was assessed using progressive exercise treadmill exercise with an individualized ramp protocol. The slope and speed were individually programmed. The test was terminated due to exhaustion, after 25 minutes of exercise at baseline, or after 45 minutes during follow-up testing.

The study was terminated prematurely for futility after only 159 patients were enrolled. Only 85 patients were randomized; 74 patients did not undergo randomization due to either problems with the CRT system (34), inability to perform exercise testing (5), an exercise duration > 25 minutes (11), or for miscellaneous other reasons (21). There was no difference in improvement in the duration of submaximal exercise in patients with (32.3%) and those without (37.1%) active CRT. Quality of measurements showed an improvement during the run-in phase and then showed no difference between patients with and without active CRT therapy. Assessment of left ventricular size and function showed intraventricular dyssynchrony induced by CRT that had not been present at baseline. There was no difference between the proportion of patients who had improvement in left ventricular and diastolic dimensions in the two groups. Adverse events were more common in the active CRT group. There were only two deaths during the study, both in the active CRT group, with one due to heart failure and one due to cancer. Five patients with active CRT were hospitalized 15 times for heart failure compared to four patients with inactive CRT who were hospitalized once each.

Commentary

When CRT was first introduced, there was widespread hope that electrical resynchronization would benefit a broad spectrum of patients with heart failure and left ventricular dysfunction. It was even postulated that patients with a normal baseline QRS might benefit. Over the years, we have learned that although CRT remains a very effective intervention, its benefits are seen only in selected patient groups. The greatest potential benefits are seen in those with left bundle branch block or in those who require right ventricular pacing and QRS durations > 150 msec. The benefits are less predictable in patients with a shorter QRS duration or a non-left bundle QRS pattern and, as shown here, in patients with a normal QRS, CRT is more likely to harm than to help.