Effect of Empagliflozin on Blood Volume Redistribution in Patients With Chronic Heart Failure and Reduced Ejection Fraction: An Analysis from the Empire HF Randomized Clinical Trial

Abstract

Background: Stressed blood volume (SBV) is a major determinant of systemic and pulmonary venous pressures which, in turn, determine left and right ventricular fillings and regulates cardiac output via the Frank-Starling mechanism. It is not known whether inhibition of the sodium-glucose cotransporter-2 (SGLT2) favorably affects SBV. We investigated the effect of empagliflozin on estimated stressed blood volume (eSBV) in patients with heart failure andreduced ejection fraction (HFrEF) compared to placebo. Methods: This was a post-hoc analysis of an investigator-initiated, double-blinded, placebo controlled, randomized trial. Seventy patients were assigned to empagliflozin 10 mg or matching placebo once-daily for 12 weeks. Patients underwent right heart catheterization at rest and during exercise at baseline and follow-up. The outcome was change in eSBV after 12 weeks of empagliflozin treatment over the full range of exercise, determined using a recently introduced analytical approach based on invasive hemodynamic assessment. Results: Patients with HFrEF, mean age, 57 years and mean ejection fraction 27 %, with 47 patients (71%) receiving diuretics were randomized. The effect of empagliflozin on eSBV over the full range of exercise loads showed a statistically significant reduction compared with placebo (−198.4 mL, 95%CI: −317.4; −79.3, p=0.001), a 9% decrease. The decrease in eSBV by empagliflozin was significantly correlated with the decrease in PCWP ((R= ̶ 0.33, p<0.0001). The effect of empagliflozin was consistent across subgroup analysis. Conclusions: Empagliflozin treatment significantly reduced stressed blood volume compared with placebo after 12 weeks of treatment in patients with stable chronic HFrEF during sub maximal exercise. Registration: URL: https://www.clinicaltrials.gov, Unique identifier: NCT03198585