Optimal Antithrombotic Regimens Across Atherosclerotic Vascular Beds: Toward Mechanism and Risk-Oriented Strategies

Arterial thrombosis emerges from the interplay between plaque disruption, platelet activation, and coagulation pathway amplification on a background of heterogeneous ischemic and bleeding risk. Optimal antithrombotic therapy therefore varies across clinical settings, from acute coronary syndromes (ACS) to chronic coronary syndromes (CCS), ischemic stroke, peripheral artery disease (PAD), and atrial fibrillation (AF) associated with atherosclerotic disease. Contemporary European and North American guidelines endorse an increasingly individualized approach, moving away from rigid “one-size-fits-all” dual antiplatelet therapy (DAPT) duration and intensity and incorporating dual pathway inhibition with low-dose rivaroxaban plus aspirin in selected high-risk CCS and PAD patients. In ischemic stroke, short-course DAPT is confined to minor events and transient ischemic attacks, whereas long-term monotherapy remains standard, and the coexistence of AF typically shifts the balance toward oral anticoagulation. Across all scenarios, antithrombotic benefit must be weighed against bleeding, especially in elderly, frail, or comorbid patients. Evidence gaps remain substantial, particularly in patients with overlapping vascular territories, AF plus atherosclerotic disease, and after ischemic stroke of complex or mixed mechanisms. This narrative review summarizes current evidence and guideline-based strategies in major atherosclerotic settings, proposes a unifying conceptual framework, and highlights key uncertainties and research directions for truly personalized antithrombotic care.