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