Effects of Empagliflozin on Right Ventricular Free-Wall Strain in Patients with Heart Failure and Reduced Ejection Fraction

Abstract Objectives To investigate the effect of empagliflozin on right ventricular (RV) function in patients with heart failure with reduced ejection fraction (HFrEF). Background Sodium-glucose cotransporter-2 (SGLT2) inhibitors improve outcomes and reverse left ventricle (LV) remodeling in HFrEF. The impact on RV function remains uncertain. Methods The Empire HF trial was an investigator-initiated, double-blind, randomised, placebo-controlled trial of 190 participants with with a left ventricular ejection fraction (LVEF) of 40% or lower, with New York Heart Association (NYHA) Class I−III symptoms. Participants were randomized to receive either empagliflozin (at a dose of 10 mg once daily) or placebo, on top of recommended therapy for 12 weeks. The primary endpoint of this exploratory sub-study was changes in RV free wall strain (RVFWS) across the whole cohort. RVFWS was also stratified into tertiles based on baseline RVFWS. Secondary endpoints included changes in TAPSE and RV S' velocity. Results Between June 2017 and September 2019, a total of 190 patients were enrolled, of whom 160 were included in this sub-study. Baseline characteristics were balanced between the groups (mean age of 64±11 years, 86% male, mean LVEF 29±8%, 79% in NYHA class II, 83 patients (52%) had an implanted cardiac device, and tricuspid valve regurgitation was absent/trace in 136 (85%) and mild in 24 (15%)). A high proportion of the population were on optimal medical treatment for HFrEF, and device therapy remained unchanged during follow-up. The overall mean RVFWS was -16.7±6.1%, with the empagliflozin group at -16.4±6.2% and the placebo group at -16.9±5.9%. No differences were observed in RVFWS between the groups. When stratified by baseline RVFWS into tertiles, patients in the lowest tertile demonstrated a significant improvement with empagliflozin (treatment effect: -2.9% 95% CI: -5.0 to -0.3; P=0.027). This finding was independent of LVEF, plasma volume, and weight loss, and remained unchanged after additional adjustment for LV remodeling and the presence of resynchronization therapy. No significant treatment effect was observed in the middle or highest tertiles of RVFWS, nor in the overall or lowest tertiles of TAPSE or RV S’. Conclusions This exploratory substudy of the Empire HF, treatment with empagliflozin exerted no overall effect on RV function in stable HFrEF patients, but significantly improved RVFWS in patients in the lowest tertile of RVFWS after 12 weeks of treatment. Trial Registration ClinicalTrials.gov, Unique Identifier: NCT03198585