Individualized antithrombotic therapy in acute coronary syndrome: The role of thrombin pathway inhibition and aspirin

Platelet-fibrin clot generation at the site of vascular injury in coronary arteries is a primary pathophysiologic event that leads to vascular occlusion and the subsequent clinical manifestations of acute coronary syndrome (ACS). Therefore, a strategy to optimally inhibit both platelet and coagulation pathways simultaneously - known as dual pathway inhibition (DPI) - has been proposed. In this strategy, when bleeding risk is acceptable, patients suffering from ACS are often treated with potent parenteral antiplatelet and anticoagulant therapies to facilitate efficient reperfusion and prevent reocclusion of coronary arteries. With the development of safer direct oral anticoagulants in recent years, a DPI strategy has been explored for the long-term management of patients with a history of ACS. It has been hypothesized that FXIa and FXIIa are essential for the amplification of thrombin generation beyond the initial burst of thrombin generated by tissue factor, and for the growth and stabilization of pathological clot, but not for normal hemostasis. In this scenario, potential oral agents include FXa (rivaroxaban, apixaban, edoxaban), FXIa (asundexian and milvexian), and FXIIa inhibitors. However, trials of full-dose FXa inhibitors added to an antiplatelet agent were associated with an unacceptable risk of bleeding. In patients with recent ACS, very low dose (2.5 mg bid) was associated with a significant reduction in efficacy endpoints compared to dual antiplatelet therapy and lower bleeding compared to 5 mg bid rivaroxaban dose. In patients with chronic atherosclerotic vascular disease, very low dose rivaroxaban plus aspirin compared to aspirin alone was associated with favorable net clinical benefits. Understanding the relative contributions of platelet and coagulation pathways to clot formation in an individual patient is likely critical to achieve a balance between anti-ischemic effects and bleeding risk. In this line, we discuss the importance of objectively measuring thrombogenicity and its potential role in personalizing DPI strategies in patients with ACS.