Response to cardiac resynchronisation therapy in men and women: a secondary analysis of the SMART-AV randomised controlled trial

Objectives There is a controversy about whether both sexes' response to cardiac resynchronisation therapy (CRT) is similar. We aimed to assess a causal effect of sex on CRT response. Design Secondary analysis of a randomised controlled trial (RCT) data. Doubly robust augmented-inverse-probability-weighted (AIPW) estimation of sex effect on CRT response. Setting The SmartDelay Determined Atrioventricular (AV) Optimisation (SMART-AV) RCT. Participants The SMART-AV RCT enrolled New York Heart Association class III-IV patients with heart failure (HF) with left ventricular ejection fraction (LVEF) ≤35% despite optimal medical therapy and QRS duration ≥120 ms, in sinus rhythm. After exclusion of those with missing outcome or covariates, 741 participants (age 66±11 years; 33% female; 78% white; LVEF 28%±9%; 58% ischaemic cardiomyopathy; 75% left bundle branch block; left ventricular end-systolic volume index (LVESVI) 65±30 mL/m 2) were included. Interventions Implanted CRT defibrillator with randomly assigned AV delay as either (1) fixed at 120 ms, or (2) echocardiography-determined, or (3) SmartDelay algorithm-programmed. Outcome A composite of freedom from death and HF hospitalisation and a >15% reduction in LVESVI at 6 month post-CRT was the endpoint. Results The primary endpoint was met by 337 patients (45.5%); 134 were women (55.6% response) and 203 were men (40.6% response); p<0.0001. After conditioning for 33 covariates that included baseline demographic, clinical, ECG, echocardiographic and biomarker characteristics, known predictors of CRT response, logistic regression showed a higher probability for composite CRT response for women versus men (OR 1.79; 95% CI 1.08 to 2.98; p<0.0001), whereas AIPW estimation showed no difference in CRT response (average treatment effect 0.88; 95% CI 0.41 to 1.89; p=0.739). After removing colliders from the model, both logistic regression (OR 1.00; 95% CI 0.69 to 1.44) and AIPW (ATE 1.06; 95% CI 0.96 to 1.16) reported similar results. Conclusions Both sexes' response to CRT is similar. Sex differences in HF substrate, treatment and comorbidities explain sex disparities in CRT outcomes. Trial registration number ClinicalTrials.gov Identifier; NCT00677014.