Effects of Rivaroxaban on Vascular FMD in Patients With Stable Atherosclerotic Vascular Diseases

Overview

The specific mechanistic benefit of rivaroxaban versus other FXa inhibitors on atherothrombotic events remain unclear. Therefore plan to initiate a prospective, randomized study to investigate the effect of rivaroxaban and aspirin versus aspirin alone on changes of number circulating endothelial cells and endothelial function, and alteration in systemic inflammation, platelet and coagulation activation in patients with stable atherosclerotic vascular diseases. The working hypothesis of this trial is that rivaroxaban and aspirin is superior to aspirin alone improvement in the number of circulating endothelial cells and endothelial function, assessed by flow-mediated vasodilatation, and reduction in systemic inflammation, platelet and coagulation activation in patients with stable atherosclerotic vascular diseases at 3 months follow-up.

Factor Xa (FXa) and thrombin are well-known components of the coagulation cascade and other biological and pathophysiological processes that are linked to atherothrombotic as well as thromboembolic events. As a result, novel oral anticoagulants that are direct inhibitors of factor Xa (e.g., rivaroxaban) and thrombin (e.g.,dabigatran) have been developed for the prevention of thromboembolic recurrences in patients with venous thromboembolism and atrial fibrillation (AF) . Moreover, FXa inhibitors have also been investigated as an adjunct antithrombotic therapy in addition to dual antiplatelet therapy in selected patients with acute coronary syndrome. While APPRAISE-2 trial (apixaban), which was prematurely terminated because of an excess of bleeding and showed no evidence of benefit, ATLAS ACS 2 TIMI 51 trial (rivaroxaban) demonstrated a significant reduction in clinical events compared with placebo. These differences in clinical outcomes cannot be accounted by the discrepancy in the rates of bleeding, which was increased to a fairly similar extent in both trials. Moreover, recent clinical trials (COMPASS trial) in patients with stable atherosclerotic vascular diseases, either in patients with stable coronary artery disease (CAD) or peripheral artery disease (PAD), rivaroxaban plus aspirin reduced cardiovascular (CV) events but increased major bleeding compared with aspirin alone. Rivaroxaban alone did not differ from aspirin alone for CV events and increased major bleeding. Nevertheless, the specific mechanistic benefit of rivaroxaban versus other FXa inhibitors on atherothrombotic events remain unclear. During the development of atherosclerosis, vascular endothelial cells, platelets, pro-inflammatory cytokines and several serine proteases, such as thrombin, Xa and tissue factor can promote vascular inflammation and leukocyte infiltration via the activation of protease-activated receptor (PAR) signalling pathway. Indeed, FXa and thrombin mediated PAR activation contributes to the linking between coagulation and inflammatory pathways on the endothelium. In experimental studies, rivaroxaban showed a concentration-dependent positive effect on cell viability and growth of vascular endothelial cells verses controls. Furthermore, preclinical studies demonstrated that direct Xa inhibition can have anti-inflammatory and protective activities in atherosclerotic plaque development beyond anticoagulation. Here, investigators hypothesize that the vascular protective effects of rivaroxaban are mediated via increasing endothelial progenitor cells and improvement of vascular endothelial function to reduce vascular inflammation and coagulation activation in patients with stable atherosclerotic vascular diseases.