Effects of CRT on Morbidity in Symptomatic Heart Failure
Effects of CRT on Morbidity in Symptomatic Heart Failure
This individual patient data meta-analysis confirms the substantial benefits of CRT on morbidity and mortality in patients with mild, moderate, or severe symptoms of HF who have left ventricular systolic dysfunction, are in sinus rhythm, and have a prolonged QRS. After adjusting for QRS duration, LBBB morphology was not a significant predictor of the benefits of CRT. Patients with non-specific intra-ventricular conduction delay had shorter QRS duration and this may account for reports suggesting that such patients receive less benefit from CRT. Age, sex, aetiology of disease, LVEF, blood pressure, and use of beta-blockers had no important, independent influence on the effects of CRT on morbidity or mortality. Furthermore, the benefits of CRT were similar whether or not the comparator group received an ICD. The failure of most patient characteristics to predict the effect of CRT in this large individual patient meta-analysis contrasts with that from some individual randomized trials and many smaller observational studies, that variously suggest that older patients, men, those with RBBB, and patients with ischaemic heart disease benefit less than others from CRT. Individual randomized trials may lack statistical power to investigate these issues, and observational studies may be unable to untangle the treatment effect of CRT from the natural history of disease. Use of individual patient data, analysis of QRS as a continuous variable, and the ability to investigate interactions between QRS duration and QRS morphology allowed a more sophisticated and granular analysis than previous meta-analyses that used only aggregated subgroup data. A more detailed analysis of subtle differences in QRS morphology might have identified patterns that provided prognostic information in addition to QRS duration, but such information was not available. Inclusion of a larger number of patients from additional trials would have increased the power to identify or refute any additional contribution from QRS morphology.
Our analysis may inform and simplify existing guidelines about the selection of patients for CRT. Current joint guidelines from the American Heart Association and American College of Cardiology strongly recommend CRT implantation in patients with an LVEF ≤35% if the QRS duration is ≥150 ms and LBBB is present. The Heart Failure Society of America guidelines strongly recommend CRT only when both QRS is ≥150 ms and RBBB morphology is absent, with a weaker recommendation when QRS is 120–150 ms regardless of BBB morphology. The 2012 joint European Heart Rhythm Association and Heart Rhythm Society expert consensus statement also suggested that QRS duration >150 ms was associated with a more consistent response and that non-LBBB morphology was associated with a poor response or even harm. European Society of Cardiology guidelines strongly recommend CRT only when LBBB is present and QRS is ≥130 ms if in NYHA class II or ≥120 ms if in NYHA class III, with a weaker recommendation for patients who have a QRS ≥ 150 ms in the absence of LBBB, regardless of NYHA class.
Some guidelines have suggested that recommendations should be based on the characteristics of patients actually enrolled in trials rather than on the trial inclusion/exclusion criteria, which has some merit but requires large data sets to explore effects in less prevalent subgroups. Indeed, such recommendations are advocating, in effect, that guidelines should be based on subgroups within trials rather than the overall effect; most clinical trialists would caution otherwise. It may also create a dilemma if treatment effects are identified in patients who do not appear to fit the study inclusion criteria. Investigators often report a lower LVEF than measured by the central trial laboratory, perhaps reflecting a bias introduced by the threshold LVEF criterion required for study inclusion. In the current analysis, patients with an LVEF >35% measured in the core echocardiography laboratory appeared to derive similar benefit from CRT compared with patients with a lower LVEF even though the entry criteria of most trials might have been expected to exclude such patients.
The precise mechanism(s) by which CRT delivers benefit remains elusive. This analysis suggests that there is something about electrical, and presumably electro-mechanical, delay that is fundamental to the effect of CRT. QRS prolongation is associated with poorer ventricular function, but in contrast with QRS duration, no significant association between the effect of CRT and baseline LVEF was noted across the measured range. Improvement in left ventricular function in the months after CRT implantation is associated with a better prognosis. However, patients with ischaemic heart disease have substantially less improvement in ventricular function with CRT, presumably because of myocardial scar, and yet the benefits of CRT on prognosis are remarkably similar in patients with or without ischaemic heart disease. Improvement in left ventricular function after CRT implantation may indicate that the patient has more viable myocardium and therefore an intrinsically better prognosis rather than providing an overriding mechanism by which CRT delivers clinical benefit. Alternatively, patients with ischaemic heart disease may benefit in ways other than improved LVEF, such as by arrhythmia suppression. In some patients, shortened AV conduction and reduction in mitral regurgitation may be an important mechanism of CRT effect. The rise in blood pressure that occurs with successful CRT may exert secondary benefits but could again just be a marker of improved cardiac function. Cardiac resynchronization therapy could also prevent brady-arrhythmic death, although this would only be noticed in studies such as CARE-HF and COMPANION where the control group did not receive a device. There may be no single mechanism by which CRT exerts its effects and the dominant mechanism of benefit may vary from one patient to the next and over time within an individual.
This analysis was conducted using common, relatively simple variables that were available from all five trials. It does not preclude the possibility that other markers of cardiac dyssynchrony are superior to QRS duration in predicting benefit from CRT. However, the reduced effect of CRT in patients with QRS duration <140 ms implies either that the individual benefit is small in such patients or that only a few patients respond or that substantial benefit in some patients is negated by harm in others. Whether measures of ventricular dyssynchrony by imaging are able to identify a patient who is more likely to benefit, and if so which measure, remains controversial. A randomized controlled trial enrolling patients with QRS < 130 ms is addressing this question (enrolment recently stopped); results will be presented at the European Society of Cardiology Congress in 2013.
An important limitation of this analysis was the lack of access to individual patient data from two large trials that were funded by Boston Scientific Incorporated. The COMPANION trial would have added a further 1520 patients (308 assigned to the control group), predominantly with NYHA class III or IV HF, a further 313 deaths, and at least 594 events of death or first HF hospitalization. The MADIT-CRT trials would have added a further 1555 patients (618 assigned to the control group) with NYHA class II HF and up to a further 127 deaths and 372 events of death or first hospitalization. This compares with 662 deaths and 1082 events of death or first hospitalization in the current analysis. Review of aggregate data from these two trials reinforces our findings about the relationship of QRS duration and the benefits of CRT and the relationship between QRS morphology and QRS duration. In both COMPANION and MADIT-CRT, longer QRS duration was associated with greater benefit. In a univariate analysis of MADIT-CRT, despite substantial reductions in cardiac volumes and improvement in LVEF, a trend towards an increase in mortality was observed with CRT amongst patients who did not have LBBB. However, there were few deaths in MADIT-CRT amongst such patients, especially in the small number randomized to the control group. This will have increased the risk of a chance finding of an adverse effect of CRT in patients without LBBB. Our univariate analysis also showed less benefit with respect to the composite of mortality or HF hospitalization in patients without LBBB. However, after adjusting for QRS duration, outcomes were similar whether or not LBBB was present. QRS morphology might play a role in predicting the effect of CRT, but QRS duration appears consistently stronger. Individual patient data-sets that include larger representation of subjects with RBBB or non-specific intra-ventricular conduction delay are required to explore how QRS duration and QRS morphology interact with the effects of CRT on morbidity and mortality.
Care should be taken in extrapolating data gathered from patients selected to participate in clinical trials to the wider population of patients with HF who might be considered for CRT. However, the heterogeneity of the studies, in terms of symptom severity, background therapy, and whether the intervention was CRT or CRT-D, may be seen as a strength rather than a limitation of the analysis as these differences did not appear to influence the benefits of CRT. Trials with longer durations of follow-up will have accumulated more events and had a greater influence on the results. Although an absolute benefit of CRT on the composite outcome of first hospitalization for HF or death appeared within 6 months, the absolute benefit for mortality was not obvious until 12–18 months. Short-term trials will have contributed little to this part of the analysis.
In practical terms, this analysis suggests that the chances of a patient benefiting from CRT diminish when QRS is <140 ms. If the choice is between CRT or no device, then renewed efforts at medical management are justified rather than preferring device implantation. If the choice is between CRT-D and ICD, then a lower decision threshold of 130 ms may be justified as the patient is already going to have a procedure; there is evidence of benefit in patients with QRS 130–140 ms and QRS duration increases over time. Implanting a CRT-D system initially may prevent the need for a later upgrade with its attendant risk of complications.
In conclusion, this individual patient meta-analysis confirms the benefits of CRT on morbidity and mortality in patients with mild, moderate, or severe symptoms of HF who have moderate or severe left ventricular systolic dysfunction and who are in sinus rhythm with a QRS duration >140 ms. The clinical benefits of CRT in patients with QRS durations between 120 and 140 ms are, on average, smaller and/or less certain. After adjusting for QRS duration, in this analysis, QRS morphology was not a determinant of the clinical response to CRT. Future analyses of these data will investigate whether QRS duration or other variables can predict which patients obtain symptomatic benefits from CRT.
Discussion
This individual patient data meta-analysis confirms the substantial benefits of CRT on morbidity and mortality in patients with mild, moderate, or severe symptoms of HF who have left ventricular systolic dysfunction, are in sinus rhythm, and have a prolonged QRS. After adjusting for QRS duration, LBBB morphology was not a significant predictor of the benefits of CRT. Patients with non-specific intra-ventricular conduction delay had shorter QRS duration and this may account for reports suggesting that such patients receive less benefit from CRT. Age, sex, aetiology of disease, LVEF, blood pressure, and use of beta-blockers had no important, independent influence on the effects of CRT on morbidity or mortality. Furthermore, the benefits of CRT were similar whether or not the comparator group received an ICD. The failure of most patient characteristics to predict the effect of CRT in this large individual patient meta-analysis contrasts with that from some individual randomized trials and many smaller observational studies, that variously suggest that older patients, men, those with RBBB, and patients with ischaemic heart disease benefit less than others from CRT. Individual randomized trials may lack statistical power to investigate these issues, and observational studies may be unable to untangle the treatment effect of CRT from the natural history of disease. Use of individual patient data, analysis of QRS as a continuous variable, and the ability to investigate interactions between QRS duration and QRS morphology allowed a more sophisticated and granular analysis than previous meta-analyses that used only aggregated subgroup data. A more detailed analysis of subtle differences in QRS morphology might have identified patterns that provided prognostic information in addition to QRS duration, but such information was not available. Inclusion of a larger number of patients from additional trials would have increased the power to identify or refute any additional contribution from QRS morphology.
Our analysis may inform and simplify existing guidelines about the selection of patients for CRT. Current joint guidelines from the American Heart Association and American College of Cardiology strongly recommend CRT implantation in patients with an LVEF ≤35% if the QRS duration is ≥150 ms and LBBB is present. The Heart Failure Society of America guidelines strongly recommend CRT only when both QRS is ≥150 ms and RBBB morphology is absent, with a weaker recommendation when QRS is 120–150 ms regardless of BBB morphology. The 2012 joint European Heart Rhythm Association and Heart Rhythm Society expert consensus statement also suggested that QRS duration >150 ms was associated with a more consistent response and that non-LBBB morphology was associated with a poor response or even harm. European Society of Cardiology guidelines strongly recommend CRT only when LBBB is present and QRS is ≥130 ms if in NYHA class II or ≥120 ms if in NYHA class III, with a weaker recommendation for patients who have a QRS ≥ 150 ms in the absence of LBBB, regardless of NYHA class.
Some guidelines have suggested that recommendations should be based on the characteristics of patients actually enrolled in trials rather than on the trial inclusion/exclusion criteria, which has some merit but requires large data sets to explore effects in less prevalent subgroups. Indeed, such recommendations are advocating, in effect, that guidelines should be based on subgroups within trials rather than the overall effect; most clinical trialists would caution otherwise. It may also create a dilemma if treatment effects are identified in patients who do not appear to fit the study inclusion criteria. Investigators often report a lower LVEF than measured by the central trial laboratory, perhaps reflecting a bias introduced by the threshold LVEF criterion required for study inclusion. In the current analysis, patients with an LVEF >35% measured in the core echocardiography laboratory appeared to derive similar benefit from CRT compared with patients with a lower LVEF even though the entry criteria of most trials might have been expected to exclude such patients.
The precise mechanism(s) by which CRT delivers benefit remains elusive. This analysis suggests that there is something about electrical, and presumably electro-mechanical, delay that is fundamental to the effect of CRT. QRS prolongation is associated with poorer ventricular function, but in contrast with QRS duration, no significant association between the effect of CRT and baseline LVEF was noted across the measured range. Improvement in left ventricular function in the months after CRT implantation is associated with a better prognosis. However, patients with ischaemic heart disease have substantially less improvement in ventricular function with CRT, presumably because of myocardial scar, and yet the benefits of CRT on prognosis are remarkably similar in patients with or without ischaemic heart disease. Improvement in left ventricular function after CRT implantation may indicate that the patient has more viable myocardium and therefore an intrinsically better prognosis rather than providing an overriding mechanism by which CRT delivers clinical benefit. Alternatively, patients with ischaemic heart disease may benefit in ways other than improved LVEF, such as by arrhythmia suppression. In some patients, shortened AV conduction and reduction in mitral regurgitation may be an important mechanism of CRT effect. The rise in blood pressure that occurs with successful CRT may exert secondary benefits but could again just be a marker of improved cardiac function. Cardiac resynchronization therapy could also prevent brady-arrhythmic death, although this would only be noticed in studies such as CARE-HF and COMPANION where the control group did not receive a device. There may be no single mechanism by which CRT exerts its effects and the dominant mechanism of benefit may vary from one patient to the next and over time within an individual.
This analysis was conducted using common, relatively simple variables that were available from all five trials. It does not preclude the possibility that other markers of cardiac dyssynchrony are superior to QRS duration in predicting benefit from CRT. However, the reduced effect of CRT in patients with QRS duration <140 ms implies either that the individual benefit is small in such patients or that only a few patients respond or that substantial benefit in some patients is negated by harm in others. Whether measures of ventricular dyssynchrony by imaging are able to identify a patient who is more likely to benefit, and if so which measure, remains controversial. A randomized controlled trial enrolling patients with QRS < 130 ms is addressing this question (enrolment recently stopped); results will be presented at the European Society of Cardiology Congress in 2013.
An important limitation of this analysis was the lack of access to individual patient data from two large trials that were funded by Boston Scientific Incorporated. The COMPANION trial would have added a further 1520 patients (308 assigned to the control group), predominantly with NYHA class III or IV HF, a further 313 deaths, and at least 594 events of death or first HF hospitalization. The MADIT-CRT trials would have added a further 1555 patients (618 assigned to the control group) with NYHA class II HF and up to a further 127 deaths and 372 events of death or first hospitalization. This compares with 662 deaths and 1082 events of death or first hospitalization in the current analysis. Review of aggregate data from these two trials reinforces our findings about the relationship of QRS duration and the benefits of CRT and the relationship between QRS morphology and QRS duration. In both COMPANION and MADIT-CRT, longer QRS duration was associated with greater benefit. In a univariate analysis of MADIT-CRT, despite substantial reductions in cardiac volumes and improvement in LVEF, a trend towards an increase in mortality was observed with CRT amongst patients who did not have LBBB. However, there were few deaths in MADIT-CRT amongst such patients, especially in the small number randomized to the control group. This will have increased the risk of a chance finding of an adverse effect of CRT in patients without LBBB. Our univariate analysis also showed less benefit with respect to the composite of mortality or HF hospitalization in patients without LBBB. However, after adjusting for QRS duration, outcomes were similar whether or not LBBB was present. QRS morphology might play a role in predicting the effect of CRT, but QRS duration appears consistently stronger. Individual patient data-sets that include larger representation of subjects with RBBB or non-specific intra-ventricular conduction delay are required to explore how QRS duration and QRS morphology interact with the effects of CRT on morbidity and mortality.
Care should be taken in extrapolating data gathered from patients selected to participate in clinical trials to the wider population of patients with HF who might be considered for CRT. However, the heterogeneity of the studies, in terms of symptom severity, background therapy, and whether the intervention was CRT or CRT-D, may be seen as a strength rather than a limitation of the analysis as these differences did not appear to influence the benefits of CRT. Trials with longer durations of follow-up will have accumulated more events and had a greater influence on the results. Although an absolute benefit of CRT on the composite outcome of first hospitalization for HF or death appeared within 6 months, the absolute benefit for mortality was not obvious until 12–18 months. Short-term trials will have contributed little to this part of the analysis.
In practical terms, this analysis suggests that the chances of a patient benefiting from CRT diminish when QRS is <140 ms. If the choice is between CRT or no device, then renewed efforts at medical management are justified rather than preferring device implantation. If the choice is between CRT-D and ICD, then a lower decision threshold of 130 ms may be justified as the patient is already going to have a procedure; there is evidence of benefit in patients with QRS 130–140 ms and QRS duration increases over time. Implanting a CRT-D system initially may prevent the need for a later upgrade with its attendant risk of complications.
In conclusion, this individual patient meta-analysis confirms the benefits of CRT on morbidity and mortality in patients with mild, moderate, or severe symptoms of HF who have moderate or severe left ventricular systolic dysfunction and who are in sinus rhythm with a QRS duration >140 ms. The clinical benefits of CRT in patients with QRS durations between 120 and 140 ms are, on average, smaller and/or less certain. After adjusting for QRS duration, in this analysis, QRS morphology was not a determinant of the clinical response to CRT. Future analyses of these data will investigate whether QRS duration or other variables can predict which patients obtain symptomatic benefits from CRT.
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