Background: Despite secondary prevention with aspirin, patients with stable cardiovascular disease (CVD) remain at elevated long-term risk of major cardiovascular events (MACE). The COMPASS double-blind randomized clinical trial demonstrated that aspirin plus low-dose Rivaroxaban (COMPASS regime) significantly decreased the incidence of MACE by 24% compared with aspirin alone. However, the mechanisms underlying these potential synergistic/non-antithrombotic effects remain elusive. Extracellular vesicles (EVs) are crucial messengers regulating a myriad of biological/pathological processes and are highly implicated in CVD. We hypothesised that circulating EV profiles reflect the cardioprotective properties of the COMPASS regime.
Patients/methods: A cohort of stable CVD patients (n=40) who participated in the COMPASS trial and were previously randomised to receive aspirin, were prospectively recruited and assigned a revised regimen of open-label aspirin plus Rivaroxaban. Blood samples were obtained at baseline (aspirin only) and 6-months follow-up. Plasma EV concentration, size and origin were analysed by NTA and flow cytometry. EVs were enriched by ultracentrifugation for proteomic analysis.
Results: The COMPASS regime fundamentally altered small (<200nm) and large (200-1000nm) EV concentration and size, compared to aspirin alone. Crucially, levels of platelet-derived, and myeloperoxidase-positive EVs became significantly decreased at follow-up. Comparative proteomic characterisation further revealed a significant decrease in highly pro-inflammatory protein expression at follow-up.
Conclusions: The observed changes in EV subpopulations, together with the differential protein expression profiles, suggest amelioration of an underlying pro-inflammatory and pro-thrombotic state upon dual therapy, which may be of clinical relevance towards understanding the fundamental mechanism underlying the reported superior cardiovascular outcomes associated with this antithrombotic regimen.
Keywords: Aspirin; Cardiovascular Disease; Extracellular Vesicles; Proteomics; Rivaroxaban.
Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.