Cardiac Resynchronization Therapy in Patients With Heart Failure and a QRS Complex <120 ms: the LESSER-EARTH Trial

Study Questions:

What is the effect of cardiac resynchronization therapy (CRT) on exercise capacity and left ventricular (LV) reverse remodeling outcomes in patients with an LV ejection fraction (LVEF) ≤35%, symptoms of heart failure, and a QRS duration <120 ms?


The LESSER-EARTH trial was a randomized, double-blind, 12-center study that was designed to compare the effects of active versus inactive CRT in patients with severe LV dysfunction and a QRS duration <120 ms. The primary outcome consisted of submaximal exercise duration (expressed in minutes). Secondary outcomes included LVEF, LV end-systolic volume (LVESV), inter- and intraventricular delays, New York Heart Association (NYHA) functional class, quality-of-life metrics, distance covered during the 6-minute walk test, and N-terminal pro–B-type natriuretic peptide (NT-proBNP) levels. For continuous efficacy endpoints, changes from baseline to 6 and 12 months were assessed using analysis of covariance (ANCOVA) models that included terms for pacing mode (CRT on vs. off) and baseline values of response variables as covariates. Adjusted mean values for each pacing mode were provided, along with 95% confidence intervals. Chi-square tests were used for categorical efficacy endpoints such as NYHA functional class and response to CRT at 6 and 12 months.


The trial was prematurely interrupted by the Data Safety and Monitoring Board due to futility and safety concerns after 85 patients were randomized. Changes in exercise duration after 12 months were no different in patients with and without active CRT [-0.7 (-2.9, 1.5) minutes vs. +0.8 (-1.2, 2.9) minutes, p = 0.31]. Similarly, no significant differences were observed in LVESVs [-6.4 (-18.8, 5.9) ml vs. +3.1 (-9.2, 15.5) ml, p = 0.28] and EF [+3.3% (0.7%, 6.0%) vs. +2.1% (-0.5%, 4.8%), p = 0.52]. Moreover, CRT was associated with a significant reduction in the 6-minute walk distance [-11.3 (-31.7, 9.7) m vs. +25.3 (6.1, 44.5) m, p = 0.01], an increase in QRS duration [40.2 (34.2, 46.2) ms vs. 3.4 (0.6, 6.2) ms, p < 0.0001], and a nonsignificant trend towards an increase in heart failure-related hospitalizations (15 hospitalizations in five patients vs. four hospitalizations in four patients).


The authors concluded that in patients with an LVEF ≤35%, symptoms of heart failure, and a QRS duration <120 ms, CRT did not improve clinical outcomes or LV remodeling, and was associated with potential harm.


The LESSER-EARTH trial was prematurely terminated after enrolling and randomizing 159 and 85 patients, respectively, due to futility and safety concerns. While no differences were observed with regard to the primary outcome and LV size and function, CRT was associated with a significant prolongation of QRS duration, a significant reduction in the 6-minute walk distance, and a nonsignificant trend towards increased heart failure-related hospitalizations. Overall, these results provide compelling evidence to suggest that CRT can worsen or provoke dyssynchrony in patients with little or no dyssynchrony to begin with, and should be avoided.

Clinical Topics: Anticoagulation Management, Arrhythmias and Clinical EP, Heart Failure and Cardiomyopathies, Implantable Devices, Acute Heart Failure

Keywords: Natriuretic Peptides, Cardiac Pacing, Artificial, Heart Failure, Ventricular Remodeling, Peptide Fragments, Ventricular Function, Medical Futility, Confidence Intervals, New York, Cardiac Resynchronization Therapy

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