Effects of CRT on Morbidity in Symptomatic Heart Failure
Effects of CRT on Morbidity in Symptomatic Heart Failure
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.
ClinicalTrials.gov numbers NCT00170300, NCT00271154, NCT00251251.
Despite the successes of pharmacological therapy for heart failure (HF), many patients remain symptomatic, many relapse after a period of control, the underlying disease often progresses and morbidity and mortality still remain high. For some patients, symptoms and/or prognosis can be improved by implanted devices. Cardiac defibrillators (ICD) are designed to treat malignant ventricular tachyarrhythmias and are highly effective in preventing sudden arrhythmic death. Cardiac resynchronization therapy (CRT) has a broader range of therapeutic benefits in appropriately selected patients, including improvements in cardiac function symptoms and quality of life and reductions in HF-related hospitalizations and death. Devices with both CRT and ICD functions (CRT-D) are often implanted and have been shown to be superior to an ICD alone in improving outcome.
Clinical trials are designed to show the average effect of an intervention in the population enrolled and usually lack the power to assess effects within subgroups. However, from a patient and clinician perspective, estimating risks and benefits on an individual basis is paramount. Clearly, CRT will sometimes fail to improve cardiac function, symptoms, or prognosis. This has spawned many observational studies attempting to identify predictors of success or failure, usually based on surrogate outcomes. These may be unable to untangle the therapeutic response to CRT from the natural history of the underlying disease. Ideally, analyses to predict benefit or lack thereof should be done on data from randomized trials. Several meta-analyses using aggregate data from trials of CRT have been reported but these are limited by variable reporting of subgroup data and cannot reliably investigate potential interactions between variables, for example QRS duration and morphology, conferred by access to individual patient data. Accordingly, we undertook an individual patient meta-analysis on data from five landmark randomized clinical trials of CRT.
Abstract and Introduction
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.
ClinicalTrials.gov numbers NCT00170300, NCT00271154, NCT00251251.
Introduction
Despite the successes of pharmacological therapy for heart failure (HF), many patients remain symptomatic, many relapse after a period of control, the underlying disease often progresses and morbidity and mortality still remain high. For some patients, symptoms and/or prognosis can be improved by implanted devices. Cardiac defibrillators (ICD) are designed to treat malignant ventricular tachyarrhythmias and are highly effective in preventing sudden arrhythmic death. Cardiac resynchronization therapy (CRT) has a broader range of therapeutic benefits in appropriately selected patients, including improvements in cardiac function symptoms and quality of life and reductions in HF-related hospitalizations and death. Devices with both CRT and ICD functions (CRT-D) are often implanted and have been shown to be superior to an ICD alone in improving outcome.
Clinical trials are designed to show the average effect of an intervention in the population enrolled and usually lack the power to assess effects within subgroups. However, from a patient and clinician perspective, estimating risks and benefits on an individual basis is paramount. Clearly, CRT will sometimes fail to improve cardiac function, symptoms, or prognosis. This has spawned many observational studies attempting to identify predictors of success or failure, usually based on surrogate outcomes. These may be unable to untangle the therapeutic response to CRT from the natural history of the underlying disease. Ideally, analyses to predict benefit or lack thereof should be done on data from randomized trials. Several meta-analyses using aggregate data from trials of CRT have been reported but these are limited by variable reporting of subgroup data and cannot reliably investigate potential interactions between variables, for example QRS duration and morphology, conferred by access to individual patient data. Accordingly, we undertook an individual patient meta-analysis on data from five landmark randomized clinical trials of CRT.
