Too much,too little,or just right: Tailoring postrevascularization antithrombotic therapy in PAD versus CAD when one size does not fit all

This is an invited commentary on Horie K et al. ⁵ Comparison of bleeding complications between patients with peripheral and coronary artery disease after revascularization: insights from ASPARAGUS, a prospective observational study. Vasc Med 2026; 31. DOI: 10.1177/1358863X251415140.

Patients with atherosclerotic cardiovascular disease (CVD) represent a wide spectrum and heterogenous population, yet clinical data have focused, historically, solely on individuals with coronary artery disease (CAD). Peripheral artery disease (PAD), despite its prevalence and prognostic burden, has long been overshadowed within the cardiovascular literature, with recommendations extrapolated from subgroups analysis of CAD trials.^{1 –3} Both randomized trials of antithrombotic agents and bleeding risk scores focusing on individualized therapy for patients with CVD highlight a central reality: patients with PAD differ from those with CAD in ischemic risk, bleeding vulnerability, and as a result, therapeutic management. ⁴ In this issue of Vascular Medicine, this phenomenon is perfectly demonstrated by findings of the ASPARAGUS (‘ASsessment of Prognosis in pAtients with coRonary or peripheral Artery disease underGoing percUtaneous or Surgical intervention’) study by Horie and colleagues, which compares bleeding risk between patients with PAD with CAD after revascularization. ⁵ As a transition is underway in redefining postrevascularization antithrombotic regimens—in particular, the recent Class I recommendation for dual pathway inhibition (DPI) involving rivaroxaban 2.5 mg twice daily in addition to low-dose aspirin ⁶ —it becomes essential to refine our understanding of how to prioritize safety with these agents among those with PAD yet conferring the necessary efficacy.

Although CAD and PAD share similar atherosclerotic mechanisms, their clinical trajectories differ. Patients with PAD experience a diffuse, systemic phenotype of atherosclerosis characterized by higher rates of major adverse limb events (MALE), polyvascular disease, and microvascular dysfunction, which translates to greater residual ischemic risk that remains even after revascularization or with guideline-directed medical therapy. Traditionally, single antiplatelet therapy (SAPT) has reduced cardiovascular events; however, in patients with PAD, persistent vulnerability to limb-related and systemic ischemic events has been demonstrated repeatedly in various trials.^7,8

In contrast to patients with PAD, those with CAD exhibit more predictable event rates and a more reliable response to SAPT. The heterogeneity of ischemic pathways in PAD, including thrombosis by endothelial dysfunction, advanced intimal calcification, and chronic inflammation, highlight why sole extrapolation of CAD therapy to PAD risk reduction does not fully translate. Thus, the risk of thrombosis has spurred the development of DPI that combines low-dose anticoagulation with antiplatelet therapy to suppress both thrombin-mediated clot propagation and platelet activation. ⁹

In the novel analysis of the ASPARAGUS study, Horie and colleagues ⁵ demonstrated that patients with PAD had higher Academic Research Consortium for High Bleeding Risk (ARC-HBR) ¹⁰ scores at baseline and a greater incidence of postrevascularization bleeding compared to patients with CAD. Although the phenotype of patients with PAD in this registry correlates with known risk factors for bleeding, such as older age, greater burden of frailty, diabetes, renal dysfunction, and polyvascular disease, additional procedural risk factors were identified that were related to residual increased risk. ⁴ Procedural risk factors such as emergent revascularization, multiple access sites, bilateral arterial calcification of the lower extremities, chronic arterial occlusion, and DPI use postprocedure all demonstrated significant associations with in-hospital bleeding in patients with PAD after revascularization. ⁴

The recognition that PAD is not fully protected by SAPT alone has paved the way for DPI. This was supported by the landmark COMPASS trial, ³ a study of participants with stable atherosclerotic vascular disease, followed by the VOYAGER trial, ⁹ a study of patients with PAD who had undergone revascularization—both demonstrating significant reduction in cardiovascular and limb-related events with DPI. However, the benefit of DPI must be balanced with an increased incidence of major bleeding. For instance, in the VOYAGER trial, ⁹ there was a 42% greater risk of bleeding in the low-dose rivaroxaban/aspirin group compared to aspirin alone. Thus, the question is not whether DPI works, but which patients with PAD derive the greatest benefit relative to their bleeding risk. This also differs to patients with CAD, where DPI has not reliably demonstrated a favorable risk-benefit profile to support its routine use. ¹¹

Bleeding risk scores used in modern clinical practice were developed mainly for individuals with CAD, often failing to capture PAD-specific risk factors such as frailty, prior lower-extremity revascularization, polyvascular disease, chronic limb-threatening ischemia, or previous lower-extremity amputations.^10,12 In addition, patients with symptomatic PAD often require endovascular and/or surgical revascularization, which increases short-term periprocedural bleeding risks and requires longer-term antithrombotic therapy. The ASPARAGUS study further demonstrates that patients with CAD and PAD cannot be treated the same. Thus, tailored patient-centered antithrombotic strategy should be individualized depending on the ischemic and bleeding risk profile, the primary atherosclerotic condition being treated, and the interventional strategy.

Data from the ASPARAGUS study further demonstrates the higher incidence of major bleeding and elevated ARC-HBR risk scores in patients with PAD compared to those with CAD after revascularization. ⁵ As therapeutic strategies continue to evolve, patients with PAD continue to stand alone in their need for individualization; with new guidelines recommending routine use of DPI, ⁶ additional efforts are needed to optimize and personalize these regimens.