A protocol for DUAL pathway inhibition (low-dose rivaroxaban and aspirin) as compared to aspirin only to improve endothelial function in peripheral artery disease

Background: Peripheral artery disease (PAD) patients are at high risk of major adverse cardiovascular events and major adverse limb events. Recent trials demonstrate that rivaroxaban, a factor Xa inhibitor, in addition to single antiplatelet therapy results in lower mortality. A potential explanation is that Factor Xa improves endothelial function through crosstalk between coagulation and inflammatory pathways, subsequently attenuating the occurrence of major adverse cardiovascular and major adverse limb events. In this study, we hypothesize that combined treatment of low-dose rivaroxaban and acetylsalicylic acid improves endothelial function in PAD patients. Methods: DUAL-PAD is a multicenter, two-arm, phase IV clinical trial. Two cohorts of patients with symptomatic lower extremity PAD are enrolled: a:) moderate PAD (intermittent claudication), b) severe PAD (critical limb ischemia). Participants are treated with acetylsalicylic acid for a 1-month run-in period, followed by 3-months of dual pathway inhibition with acetylsalicylic acid and low-dose rivaroxaban. The primary outcome is the change in proportion of patients with endothelial dysfunction, measured as carotid artery vasoconstriction upon sympathetic stimulation. The secondary endpoint is the change in level of endothelial dysfunction, as reflected by plasma endothelin-1 levels. Discussion: the aim of the study is to examine if dual pathway inhibition improves endothelial function in patients with moderate or severe PAD. Trial registration: This study is registered at ClinicalTrials.gov on January 6, 2020 (URL https://clinicaltrials.gov/ct2/show/NCT04218656?term=NCT04218656&draw=2&rank=1).