Peripheral Artery Disease and Antithrombotic Management: A Global Perspective on Efficacy, Safety, and Access

Peripheral artery disease (PAD) is a severe manifestation of systemic atherosclerosis, affecting over 230 million individuals worldwide and leading to both limb-threatening ischemia and catastrophic cardiovascular events. This progression is driven in part by thrombosis, which arises from complex interactions of endothelial dysfunction, platelet activation, and thrombin generation. These processes culminate in acute limb ischemia, major amputations, and myocardial infarction. Antithrombotic therapy is fundamental to PAD management, with antiplatelet monotherapy (aspirin or clopidogrel) remaining first-line for symptomatic patients. However, the paradigm has shifted with dual-pathway inhibition (DPI), combining low-dose rivaroxaban (2.5 mg twice daily) with aspirin, which reduces major adverse cardiovascular events by 24% and limb events by 46%, particularly in high-risk subgroups including postrevascularization or chronic limb-threatening ischemia patients. Despite these advances, bleeding risks (eg, gastrointestinal hemorrhage with DPI) and global disparities in access to therapies pose significant challenges. Current guidelines now stratify recommendations by risk: the American Heart Association/American College of Cardiology endorses DPI for postrevascularization (class IIa), while the European Society of Cardiology reserves it for recurrent ischemia (class IIb). Emerging strategies target residual inflammatory risk (eg, colchicine) and vascular regeneration (stem cell therapy), yet cost and scalability limit widespread adoption, especially in developing nations bearing 70% of the PAD burden. The future of PAD care demands personalized approaches that integrate antithrombotic efficacy, bleeding mitigation, and socioeconomic realities. Further research is needed to refine risk stratification, expand access to DPI, and develop adjunctive therapies for this growing global health crisis.