An individual patient meta-analysis of five randomized trials assessing the effects of cardiac resynchronization therapy on morbidity and mortality in patients with symptomatic heart failure

Abstract

AimsCardiac resynchronization therapy (CRT) with or without a defibrillator reduces morbidity and mortality in selected patients with heart failure (HF) but response can be variable. We sought to identify pre-implantation variables that predict the response to CRT in a meta-analysis using individual patient-data.Methods and resultsAn individual patient meta-analysis of five randomized trials, funded by Medtronic, comparing CRT either with no active device or with a defibrillator was conducted, including the following baseline variables: age, sex, New York Heart Association class, aetiology, QRS morphology, QRS duration, left ventricular ejection fraction (LVEF), and systolic blood pressure. Outcomes were all-cause mortality and first hospitalization for HF or death. Of 3782 patients in sinus rhythm, median (inter-quartile range) age was 66 (58–73) years, QRS duration was 160 (146–176) ms, LVEF was 24 (20–28)%, and 78% had left bundle branch block. A multivariable model suggested that only QRS duration predicted the magnitude of the effect of CRT on outcomes. Further analysis produced estimated hazard ratios for the effect of CRT on all-cause mortality and on the composite of first hospitalization for HF or death that suggested increasing benefit with increasing QRS duration, the 95% confidence bounds excluding 1.0 at ∼140 ms for each endpoint, suggesting a high probability of substantial benefit from CRT when QRS duration exceeds this value.ConclusionQRS duration is a powerful predictor of the effects of CRT on morbidity and mortality in patients with symptomatic HF and left ventricular systolic dysfunction who are in sinus rhythm. QRS morphology did not provide additional information about clinical response.ClinicalTrials.gov numbersNCT00170300, NCT00271154, NCT00251251.

Rationale and design of the AdaptResponse trial: a prospective randomized study of cardiac resynchronization therapy with preferential adaptive left ventricular‐only pacing

“…A total of 1100 patients experiencing a primary endpoint will generate 90% statistical power to demonstrate a significant reduction in the incidence of the primary endpoint, accounting for three equally spaced interim analyses (α = 0.05) and assuming a true intent‐to‐treat hazard ratio (HR) of 0.82 for ‘AdaptivCRT’ compared with ‘Conventional CRT’. With randomization of 3000 patients enrolled over 3 years and followed for 2.5 years, 1100 events are expected when the true control arm event‐free rate is 75% at 2 years (which is consistent with results from MADIT‐CRT,26 REVERSE,27 RAFT,28 Cleland's CRT meta‐analysis,29 and the adaptive CRT study18, 19). …”

QRS duration versus morphology and survival after cardiac resynchronization therapy

“…In contrast, patients with non‐LBBB morphology allocated to the CRT arm showed a clinical benefit only when the QRS duration was 160 ms or longer (HR 0.52, 95% CI 0.29–0.96; P  = 0.033) 5. In addition, an individual patient meta‐analysis on data from 3872 patients randomized in five clinical trials showed that patients with LBBB morphology exhibited larger benefit from CRT than patients with non‐LBBB morphology, although the difference was not statistically significant 23. Importantly, QRS duration was significantly associated with reductions in all‐cause mortality and the rates of the composite endpoint, particularly when QRS duration exceeded 140 ms 23.…”

“…The aforementioned separate analyses showing that QRS duration and morphology are important determinants of clinical benefits of CRT have led to the investigation of the interaction between QRS duration and morphology and its effects on CRT outcomes 5, 10, 23, 24. The sub‐analysis of the RAFT trial (after excluding patients with ventricular pacing and permanent atrial fibrillation) showed that regardless the QRS duration, patients with LBBB morphology who were randomized to CRT with defibrillator function showed a reduction in the rates of the primary outcome (composite endpoint of all‐cause mortality and heart failure hospitalization) (HR 0.640; 95% CI 0.524–0.781; P  < 0.001) 5.…”

“…In addition, an individual patient meta‐analysis on data from 3872 patients randomized in five clinical trials showed that patients with LBBB morphology exhibited larger benefit from CRT than patients with non‐LBBB morphology, although the difference was not statistically significant 23. Importantly, QRS duration was significantly associated with reductions in all‐cause mortality and the rates of the composite endpoint, particularly when QRS duration exceeded 140 ms 23. Based on this evidence, current guidelines have modified the recommendations and consider CRT a class I indication for heart failure patients with LBBB morphology (regardless the QRS duration) and class IIa for patients with non‐LBBB and QRS duration ≥150 ms and IIb for non‐LBBB and QRS duration between 120–150 ms 13.…”

Predictors of response to cardiac resynchronization therapy: A prospective cohort study

“…22---24 However, in a recent meta-analysis including five randomized trials, QRS duration was a powerful predictor of CRT effectiveness. 25 Moreover, a sub-analysis of the MADIT-CRT trial associated longer QRS (>150 ms) with benefits of CRT in LV function, morbidity and mortality. 7 The REVERSE study confirmed the importance of QRS duration and LBBB pattern in CRT outcomes.…”