Vascular Endothelial Effects of Sacubitril/Valsartan in Heart Failure With Reduced Ejection Fraction: Randomized Controlled Trial

Background: The mechanism of how sacubitril/valsartan improves outcomes in heart failure with reduced ejection fraction (HFrEF) is still incompletely understood.

Objectives: The aim of this trial was to delineate the effects of sacubitril/valsartan on endothelial function, retinal microvascular function, and arterial stiffness in HFrEF.

Methods: This double-blind controlled trial randomized 79 stable HFrEF patients with NYHA class II-IV on guideline-recommended therapy (mean age: 59.4 ± 12 years, left ventricular ejection fraction: 30% ± 7%) to sacubitril/valsartan or valsartan alone for 3 months. The primary endpoint was flow-mediated vasodilation (FMD). Secondary outcomes included flicker-induced dilatation of retinal arterioles and venules (FIDv), retinal arteriovenous ratio, and surrogate markers of arterial stiffness (pulse wave velocity and augmentation index).

Results: The primary outcome FMD did not significantly differ between sacubitril/valsartan and valsartan alone (FMD 6.6% ± 3.9% vs 6.7% ± 2.8%; ANCOVA coefficient adjusted for baseline values 0.36, 95% CI: -0.78 to 1.51, P = 0.53). The secondary outcomes flicker-induced dilatation of retinal arterioles, arteriovenous ratio, pulse wave velocity, and augmentation index showed no significant differences. FIDv was lower after sacubitril/valsartan versus valsartan alone (FIDv 2.4% ± 1.3% vs 3.1% ± 2.1%; ANCOVA coefficient -0.7, 95% CI: -1.4 to -0.02, P = 0.04). Systolic blood pressure was lower after sacubitril/valsartan versus valsartan alone (ANCOVA coefficient -6.5 mm Hg, 95% CI: -12.7 to -0.3 mm Hg, P = 0.04). There were numerically fewer serious adverse events with sacubitril/valsartan versus valsartan alone.

Conclusions: In this randomized double-blind clinical trial addressing mechanisms, sacubitril/valsartan lowered blood pressure and flicker-induced dilatation of retinal venules in patients with symptomatic HFrEF but did not improve endothelial function, retinal microvascular function, or arterial stiffness compared to valsartan monotherapy. (Differential Vascular and Endocrine Effects of Valsartan/​Sacubitril in Heart Failure With Reduced Ejection Fraction [VASCEND]; NCT03168568).