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

Abstract

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/m2) 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.

Keywords: adult cardiology; cardiomyopathy; heart failure; pacing & electrophysiology; statistics & research methods.

Conflict of interest statement

Competing interests: The SMART-AV trial was sponsored by Boston Scientific Corporation. Two co-authors are the Boston Scientific Corporation employees. Boston Scientific had role in the design of this study and had no any role during its execution, analyses, interpretation of the data, or decision to submit results.

© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1

Flowchart of study cohort development. AV, atrioventricular; CRT, cardiac resynchronisation therapy; LVESVI, left ventricular end-systolic volume index.

Figure 2

Proportion of men and women among composite CRT responders and non-responders for all participants, and for subgroups of composite CRT non-responders. CRT, cardiac resynchronisation therapy; HF, heart failure.

Figure 3

Relative odds of the composite cardiac resynchronisation therapy (CRT) response for women compared with men, by logistic regression (LR), and augmented-inverse-probability-weighted (AIPW) average treatment effect (ATE) estimator in models 1–3. The forest plot shows the relative OR or ATE OR with a 95% CI for women compared with men, with OR/ATE=1 for men. Black lines correspond to 95% CI bounds. Model 1 was conditioned for body mass index and body surface area. Model 2 was conditioned on 33 covariates, and model 3 was conditioned on confounders only.

Figure 4

Direct acyclic graph. The average treatment effect is interpreted as the population risk difference in 6 month CRT response for women compared with men. ACEI, angiotensin-converting enzyme inhibitor; ARB angiotensin receptor blocker; AV, atrioventricular; BP, blood pressure; BMI body mass index; BSA, body surface area; COPD, chronic obstructive pulmonary disease; CRT, cardiac resynchronisation therapy; eGFR, estimated glomerular filtration rate; HF, heart failure; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association; BBB, bundle branch block; DS, disease; Hx, history; HTN, hypertension.

Figure 5

An overlap plot for the estimated densities of the probabilities of being male (score=0) or female (score=1), conditioned for covariates included in augmented-inverse-probability-weighted (AIPW) models 1–3.