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

John G Cleland, William T Abraham, Cecilia Linde, Michael R Gold, James B Young, J Claude Daubert, Lou Sherfesee, George A Wells, Anthony S L Tang, John G Cleland, William T Abraham, Cecilia Linde, Michael R Gold, James B Young, J Claude Daubert, Lou Sherfesee, George A Wells, Anthony S L Tang

Abstract

Aims: Cardiac 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 results: An 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.

Conclusion: QRS 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.

Clinicaltrialsgov numbers: NCT00170300, NCT00271154, NCT00251251.

Keywords: Cardiac resynchronization therapy; Heart failure; Morbidity; Mortality.

Figures

Figure 1
Figure 1
CONSORT flow diagram showing reasons for excluding patients from analysis.
Figure 2
Figure 2
Overall effect of cardiac resynchronization therapy vs. control on all-cause mortality (A) and on death or heart failure hospitalization (B).
Figure 3
Figure 3
Models showing hazard ratios (Y-axis and solid black line) and their 95% confidence intervals (dotted lines) for the effects of cardiac resynchronization therapy vs. control with QRS plotted on the X-axis. (A) The relationship between the effect of cardiac resynchronization therapy on all-cause mortality and QRS. (B) The corresponding relationship for heart failure hospitalization or death. The intersection of the 95% confidence interval and the line indicating a hazard ratio of 1.0 (no effect) indicates the QRS duration above which there is a high certainty of response.
Figure 4
Figure 4
Forest plot for univariate frailty models evaluating the effect of cardiac resynchronization therapy in pre-specified subgroups on all-cause mortality.
Figure 5
Figure 5
Forest plot for univariate frailty models evaluating the effect of cardiac resynchronization therapy in other pre-specified subgroups on death or heart failure hospitalization. Figures show hazard ratio and 95% confidence intervals.

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