By Professor G.A. Dan , MD, PhD, FESC, FAHA, FACC, FEHRA* and Caterina Delcea, MD, PhD
The classical theory stated that pathophysiology of thrombosis was fundamentally different in venous and arterial sites: venous or red clots were considered to be mainly formed of red blood cells and fibrin, while arterial or white clots, usually associated with atherosclerosis and plaque rupture, were described to consist mostly of activated platelets1. Epidemiological studies, however, challenged this hypothesis, showing an association between atherothrombosis and venous thrombosis 2–4. This refers not only to common risk factors such as age, inflammation, metabolic syndrome, smoking, or thrombophilia abnormalities5,6, but also to the common mechanisms of thrombus formation7.
Recent data supports the interrelationship between the two main pathways for thrombus formation: one triggered by the exposure of subendothelial collagen that initiates platelet activation and aggregation and the other centered on the role of tissue factor to generate thrombin and initiate platelet activation7. Moreover, there is evidence to suggest that depending on the clinical setting and the underlying disease, both mechanisms can be involved in thrombus formation, with different predominance of all the similar components7. Moreover, all coagulation components (platelets, fibrin and tissue factor) are present in both forms of coagulation.
Current standard of care in atherotrombotic disease includes dual oral antiplatelet therapy, targeting thromboxane A2 and the P2Y12 ADP receptor. However, the thrombin and factor Xa pathways involving PARs to activate platelets and develop atherosclerosis are still active, representing a viable target to optimize thromboprophylaxis in this setting also 12,13, not only in atrial fibrillation or venous thrombosis.
The utility of adding vitamin K antagonist therapy to antiplatelet therapy in preventing major cardiovascular adverse events at price of increased risk of major bleeding14 paved the way to investigating the synergistic effect of direct anticoagulation associated to standard of care antiplatelet therapy. One of the first randomized controlled studies to support this hypothesis was the ESTEEM15 trial, proving that the lowest tested dose of ximelagatran in combination with aspirin was superior to aspirin alone in reducing the risk of major cardiovascular events with an acceptable safety profile.
A challenge in designing a proper study resides from the fact that the thrombosis mechanism is different in low-flow, low-pressure chambers (atria), low-pressure conduits with localized stasis (veins) and in systemic high-pressure and atherosclerotic conduits. Depending on the mechanism different dosages of the same drug may address the particular thrombotic potential.
Large clinical trials assessed efficacy and safety of adding direct anticoagulants to antiplatelet therapy in patients with atherosclerotic disease, with mixed results. In patients with acute coronary syndromes, the addition of apixaban16–18 or dabigatran19 to double antiplatelet therapy increased the risk of bleeding without significantly reducing the ischemic events, as shown in the APPRAISE16, APPRAISE-217, APPRAISE-J18, and the RE-DEEM19 studies, respectively. Regarding rivaroxaban, in the ATLAS ACS 2– TIMI 5121 study , a low rivaroxaban dose (2.5mg) on top of antiplatelet therapy in patients with high risk acute coronary syndromes, associated a lower all-cause mortality, lower cardiovascular mortality and lower incidence of myocardial infarction . This benefit on all-cause mortality was not observed in antiplatelet trials CAPRIE, CHARISMA, PEGASSUS or TRA2P-TIMI 50.
It was presumed that the success of adding rivaroxaban to antiplatelet therapy in achieving a significant reduction in major cardiovascular events with an acceptable risk of bleeding in patients with prior acute coronary syndromes relies on the dosing strategies used. While the studies with apixaban and dabigatran used similar dosing as in thromboprophylaxis in atrial fibrillation, after the results of ATLAS ACS–TIMI 4620 the dosage of rivaroxaban was decreased in ATLAS ACS 2– TIMI 5121 and this approach finally proved the utility of added anticoagulation with lower dosing. More so, the benefit of adding low-dose rivaroxaban to aspirin therapy was also demonstrated in patients with stable atherosclerotic vascular disease in the COMPASS trial22.
In conclusion, due to overlapping pathways in arterial and venous thrombosis, direct anticoagulant agents could be associated to antiplatelet therapy for further atherotrombotic risk reduction, with increasing evidence to support the efficient use of low-dose rivaroxaban in this setting23,24. Optimal risk-benefit ratio was achieved with adapted dosing strategies that enabled the possibility to reach maximum benefit in prevention of major cardiovascular events with the minimum risk of major bleeding.
Professor G.A. Dan, MD, PhD, FESC, FAHA, FACC, FEHRA
Head, Internal Medicine Clinic & Cardiology Department
Senior Consultant – Cardiology & Internal Medicine
Colentina University Hospital. “Carol Davila” University of Medicine, Bucharest, ROMANIA
Past President, ISCP
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