The influence of QRS duration and resynchronization status on the efficacy and safety of omecamtiv mecarbil in heart failure with reduced ejection fraction: the GALACTIC-HF trial
M Ruppert, B L Claggett, B Merkely, J J V Mcmurray, G M Felker, M Metra, R Diaz, F I Malik, P H Divanji, S Kupfer, S B Heitner, J R Teerlink, S D Solomon, M A PfefferAbstract
Background
Wide QRS complex is associated with worse cardiovascular outcomes in patients with heart failure and reduced ejection fraction. In GALACTIC-HF, omecamtiv mecarbil (OM), the selective cardiac myosin activator, reduced the composite endpoint of cardiovascular death or heart failure hospitalization.
Purpose
This post-hoc analysis evaluated whether QRS duration and presence of a cardiac resynchronization therapy (CRT) device modified treatment effect of OM.
Methods
GALACTIC-HF enrolled patients with symptomatic heart failure (NYHA Class II-IV), reduced ejection fraction (EF ≤ 35%) and elevated natriuretic peptides. Of the 8232 randomized patients, 1158 were treated with CRT at baseline. Of those not treated with CRT, QRS duration was available in 6913 (mean age 64±12 years; 22% woman) patients. We assessed whether QRS duration modified the effect of OM on the primary endpoint, its individual components, and all-cause mortality, as well as the effectiveness of OM in patients treated with CRT. Analyses were conducted in the overall population and in the subgroup of patients with severely reduced systolic function (EF < 30%).
Results
In patients without CRT devices, 3703 patients (53.6%) had QRS < 120 ms and 3210 (46.4%) had QRS ≥ 120ms at baseline. Patients with QRS ≥ 120ms were older, more likely to have a history of chronic kidney disease, had a worse NYHA class, worse quality of life, lower ejection fraction, lower estimated glomerular filtration rate, and higher NT-proBNP. In patients without CRT devices, prolonged QRS duration was associated with an increased risk across all outcomes (Rate of the primary outcome: 19.4 per 100 patient-years in QRS < 120 ms vs. 28.4 per 100 patient-years in QRS ≥ 120 ms). Additionally, in patients without CRT devices, the effectiveness of OM was modified by baseline QRS duration, with greater benefit observed in patients with QRS < 120 ms for all the outcomes (Figure 1), even after adjusting for multivariable treatment-covariate interactions. In the subset of patients where QRS morphology was known, this effect seemed most apparent in those with lef bundle branch block (LBBB). In contrast, in patients with a CRT device at baseline, there was a consistent benefit from OM across the full spectrum of QRS durations (Figure 1). In patients with severely reduced EF (LVEF < 30%), OM was more effective overall without clear evidence of effect modification by QRS width (Figure 2).
Conclusions
Among patients without CRT devices, OM appeared to be less effective in patients with wider QRS ≥ 120 ms, (most of whom would have been clinically eligible for CRT), and this attenuation of benefit appeared to be mitigated by the presence of a CRT device. These post-hoc findings highlight the need to account for intrinsic QRS duration and resynchronization status when selecting patients for OM.For image description, please refer to the figure legend and surrounding text.For image description, please refer to the figure legend and surrounding text.