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Rivaroxaban, in combination with low-dose aspirin, is associated with a reduction in proinflammatory and prothrombotic circulating vesicle signatures in patients with cardiovascular disease

L. Weiss, A. O'Doherty, W. Uhrig, PB. Szklanna, M. Hong-Minh, K. Wynne, A. Blanco, J. Zivny, V. Lima Passos, B. Kevane, S. Murphy, F. Ní Áinle, M. O'Donnell, PB. Maguire

. 2025 ; 23 (2) : 531-545. [pub] 20241015

Language English Country England, Great Britain

Document type Journal Article, Randomized Controlled Trial

Persistent link   https://www.medvik.cz/link/bmc25010119

BACKGROUND: Despite secondary prevention with aspirin, patients with stable cardiovascular disease (CVD) remain at elevated long-term risk of major adverse cardiovascular events. The Cardiovascular Outcomes in People Using Anticoagulant Strategies (COMPASS) double-blind, randomized clinical trial demonstrated that aspirin plus low-dose rivaroxaban (COMPASS regime) significantly decreased the incidence of major adverse cardiovascular events by 24% compared with aspirin alone. However, the mechanisms underlying these potential synergistic/nonantithrombotic effects remain elusive. Extracellular vesicles (EVs) are crucial messengers regulating a myriad of biological/pathological processes and are highly implicated in CVD. OBJECTIVES: We hypothesized that circulating EV profiles reflect the cardioprotective properties of the COMPASS regime. METHODS: A cohort of stable CVD patients (N = 40) who participated in the COMPASS trial and were previously randomized 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-month follow-up. Plasma EV concentration, size, and origin were analyzed by nanoparticle tracking analysis and flow cytometry. EVs were enriched by ultracentrifugation for proteomic analysis. RESULTS: The COMPASS regime fundamentally altered small (<200 nm) and large (200-1000 nm) EV concentration and size compared with aspirin alone. Crucially, levels of platelet-derived and myeloperoxidase-positive EVs became significantly decreased at follow-up. Comparative proteomic characterization further revealed a significant decrease in highly proinflammatory protein expression at follow-up. CONCLUSION: The observed changes in EV subpopulations, together with the differential protein expression profiles, suggest amelioration of an underlying proinflammatory and prothrombotic state upon dual therapy, which may be of clinical relevance toward understanding the fundamental mechanism underlying the reported superior cardiovascular outcomes associated with this antithrombotic regimen.

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$a Weiss, Luisa $u UCD Conway SPHERE Research Group, Conway Institute, University College Dublin, Dublin, Ireland; School of Biomolecular and Biomedical Science, University College Dublin, Dublin, Ireland; AI for Healthcare Hub, Institute for Discovery, O'Brien Centre for Science, University College Dublin, Dublin, Ireland. Electronic address: https://twitter.com/lweiss1311
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$a BACKGROUND: Despite secondary prevention with aspirin, patients with stable cardiovascular disease (CVD) remain at elevated long-term risk of major adverse cardiovascular events. The Cardiovascular Outcomes in People Using Anticoagulant Strategies (COMPASS) double-blind, randomized clinical trial demonstrated that aspirin plus low-dose rivaroxaban (COMPASS regime) significantly decreased the incidence of major adverse cardiovascular events by 24% compared with aspirin alone. However, the mechanisms underlying these potential synergistic/nonantithrombotic effects remain elusive. Extracellular vesicles (EVs) are crucial messengers regulating a myriad of biological/pathological processes and are highly implicated in CVD. OBJECTIVES: We hypothesized that circulating EV profiles reflect the cardioprotective properties of the COMPASS regime. METHODS: A cohort of stable CVD patients (N = 40) who participated in the COMPASS trial and were previously randomized 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-month follow-up. Plasma EV concentration, size, and origin were analyzed by nanoparticle tracking analysis and flow cytometry. EVs were enriched by ultracentrifugation for proteomic analysis. RESULTS: The COMPASS regime fundamentally altered small (<200 nm) and large (200-1000 nm) EV concentration and size compared with aspirin alone. Crucially, levels of platelet-derived and myeloperoxidase-positive EVs became significantly decreased at follow-up. Comparative proteomic characterization further revealed a significant decrease in highly proinflammatory protein expression at follow-up. CONCLUSION: The observed changes in EV subpopulations, together with the differential protein expression profiles, suggest amelioration of an underlying proinflammatory and prothrombotic state upon dual therapy, which may be of clinical relevance toward understanding the fundamental mechanism underlying the reported superior cardiovascular outcomes associated with this antithrombotic regimen.
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$a O'Doherty, Aideen $u Health Research Board Clinical Research Facility Galway, School of Medicine, University of Galway, Galway, Ireland
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$a Uhrig, Wido $u UCD Conway SPHERE Research Group, Conway Institute, University College Dublin, Dublin, Ireland
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$a Szklanna, Paulina B $u UCD Conway SPHERE Research Group, Conway Institute, University College Dublin, Dublin, Ireland; School of Biomolecular and Biomedical Science, University College Dublin, Dublin, Ireland
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$a Hong-Minh, Molly $u UCD Conway SPHERE Research Group, Conway Institute, University College Dublin, Dublin, Ireland; School of Biomolecular and Biomedical Science, University College Dublin, Dublin, Ireland
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$a Wynne, Kieran $u Mass Spectrometry Core, Systems Biology Ireland, University College Dublin, Dublin, Ireland
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$a Blanco, Alfonso $u Flow Cytometry Core, Conway Institute, University College Dublin, Dublin, Ireland
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$a Zivny, Jan $u Institute of Pathological Physiology, First Faculty of Medicine, Charles University, Prague, Czech Republic
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$a Lima Passos, Valeria $u School of Pharmacy and Biomolecular Science, Royal College of Surgeons in Ireland, Dublin, Ireland
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$a Kevane, Barry $u UCD Conway SPHERE Research Group, Conway Institute, University College Dublin, Dublin, Ireland; Department of Haematology, Mater Misericordiae University Hospital, Dublin, Ireland; School of Medicine, University College Dublin, Dublin, Ireland
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$a Murphy, Seán $u School of Medicine, University College Dublin, Dublin, Ireland; Department for Stroke Medicine, Mater Misericordiae University Hospital, Dublin, Ireland; School of Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland
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$a Ní Áinle, Fionnuala $u UCD Conway SPHERE Research Group, Conway Institute, University College Dublin, Dublin, Ireland; Department of Haematology, Mater Misericordiae University Hospital, Dublin, Ireland; School of Medicine, University College Dublin, Dublin, Ireland; Department of Haematology, Rotunda Hospital, Dublin, Ireland. Electronic address: https://twitter.com/ConwaySPHERE
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$a O'Donnell, Martin $u Health Research Board Clinical Research Facility Galway, School of Medicine, University of Galway, Galway, Ireland. Electronic address: martin.odonnell@universityofgalway.ie
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$a Maguire, Patricia B $u UCD Conway SPHERE Research Group, Conway Institute, University College Dublin, Dublin, Ireland; School of Biomolecular and Biomedical Science, University College Dublin, Dublin, Ireland; AI for Healthcare Hub, Institute for Discovery, O'Brien Centre for Science, University College Dublin, Dublin, Ireland. Electronic address: patricia.maguire@ucd.ie
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