Endothelin (ET) is involved in the etiopathogenesis of peripheral arterial disease (PAD). We hypothesized that ET antagonism might improve the endothelial function, inflammatory status, and symptoms in PAD. This pilot randomized clinical trial was designed to determine the clinical efficacy, pleiotropic effects, and safety of dual ET-receptor antagonist bosentan in Hispanic patients with PAD presenting intermittent claudication. The Bosentan Population-Based Randomized Trial for Clinical and Endothelial Function Assessment on Endothelin Antagonism Therapy was a 12-month, randomized, controlled, parallel-group, double-blind, proof-of-concept pilot study evaluating the effect of bosentan on absolute claudication distance (primary efficacy end point), flow-mediated arterial dilation, and C-reactive protein levels (primary pleiotropic end points) in patients with PAD with Rutherford category 1 to 2 of recent diagnosis. Secondary end points included ankle-brachial index, subjective claudication distance, and safety. Of the 629 screened subjects, 56 patients were randomized 1:1 to receive bosentan for 12 weeks (n = 27) or placebo (n = 29). Six months after the initiation, a significant treatment effect in flow-mediated arterial dilation of 2.43 ± 0.3% (95% CI 1.75 to 3.12; p = 0.001), absolute claudication distance of 283 ± 23 m (95% CI 202 to 366; p = 0.01), ankle-brachial index of 0.16 ± 0.03 (95% CI 0.09 to 0.23; p = 0.001), and a decrease in C-reactive protein levels of -2.0 ± 0.5 mg/L (95% CI -2.8 to -1.1; p = 0.02) were observed in the bosentan-treated group compared to the control group. No severe adverse effects were found in the bosentan group. In conclusion, in Hispanic patients with intermittent claudication, bosentan was well tolerated and improved endothelial function and claudication distance as well as inflammatory and hemodynamic states.
Trial registration: ClinicalTrials.gov NCT01738542 NCT25102012.
Copyright © 2016 Elsevier Inc. All rights reserved.