Discussion
In the present study we provide several important insights on predictors for VTA outcomes in CRT-D patients with non-LBBB, in whom data on the potential benefit of the device are limited and conflicting. First, we identified 4 simple baseline clinical factors (BUN>25mg/dl, EF<20%, prior NSVT, and female gender) that were associated with increased risk for VTA in CRT-D patients with non-LBBB. Second, we have shown that among patients without any of the identified RF, treatment with CRT-D was associated with a significant reduction in the risk of arrhythmic events compared with ICD-only therapy, including any VTA, VTA/death, and appropriate defibrillator shocks. In contrast, among patients with at least one RF, treatment with CRT-D was associated with a possible proarrhytmic effect, wherein the risk of any VTA, VTA/death, and appropriate defibrillator shocks, was significantly higher among patients implanted with a CRT-D device compared with those treated only with an ICD. These findings suggest that combined assessment of simple baseline clinical parameters can be used to distinguish CRT-D candidates without LBBB who may benefit from biventricular pacing compared with those in whom CRT-D may be possibly be associated with a harmful proarrhythmic effect.
In a meta-analysis of the five landmark randomized controlled trials evaluating CRT in the HF population, with a total of 1766 patients with non-LBBB QRS morphology at baseline, the use of CRT was not associated with a significant reduction in mortality or HF hospitalizations.15 Moreover, among non-LBBB patients the use of CRT-D was suggested to be harmful and possibly associated with increased all-cause mortality when compared with ICD alone.8,16 The mechanism related to the observed trend in mortality increase associated with CRT-D in non-LBBB patients remains unclear. We have previously shown that in MADIT-CRT non-LBBB patients who were randomized to CRT-D therapy experienced a significant 3.6-fold (p=0.009) increased risk for recurrent VTAs compared to ICD-only patients.17 These findings may be due to a pro-arrhythmic effect of CRT among patients without LBBB leading to increased risk associated with the device in this population. These data are consistent with previous studies, including a large comprehensive meta-analysis, which reported on the pro-arrhythmic effect of CRT among non-responders to the device.10-13A potential mechanism for the pro-arrhythmic role of CRT-D in non-LBBB patients is the reversal of left ventricular activation and increased transmural dispersion of repolarization with epicardial pacing, thus allowing for the development of early after depolarizations and re-entrant circuits.12Despite the above-mentioned observations, current ESC Guidelines provide a Class II recommendation (with a or b level based on QRS duration) for CRT in non-LBBB patients.4 Based on this recommendation, approximately one quarter of CRT-D implants from 2012 to 2015 through the National Cardiovascular Data Registry for Implantable Cardioverter-Defibrillators were in patients who had a non-LBBB morphology at baseline.18