Safety and efficacy of escalating antithrombotic therapy after lower extremity revascularization for chronic limb-threatening ischemia.

Abstract

The VOYAGER PAD trial demonstrated the benefit of low-dose dual pathway inhibition (LD-DPI) with aspirin and low-dose rivaroxaban in select populations, yet the balance between bleeding and limb-related outcomes in real-world practice remains unclear. We aimed to compare outcomes among patients on differing antithrombotic regimens after lower extremity revascularization for chronic limb-threatening ischemia (CLTI). All patients with available medication data undergoing first-time lower extremity revascularization for CLTI between 2005 and 2022 at a single institution were included. Patients were stratified by discharge medication regimen, including single antiplatelet therapy (SAPT; further stratified into aspirin monotherapy [SAPTasa] and P2y12 inhibitor monotherapy [SAPTp₂y]), prolonged (>90 days) dual antiplatelet therapy (DAPT), LD-DPI, standard DPI (SAPT + full-dose anticoagulation), and triple therapy (TT; DAPT + anticoagulation at any dose). Primary outcomes included gastrointestinal bleeding (GIB), any bleeding complication (bleeding necessitating transfusion of ≥2 units within 48 hours, bleeding leading to surgical intervention, or intracranial hemorrhage), stroke, myocardial infarction (MI), acute limb ischemia, primary patency, major adverse limb events (MALE), and mortality. Outcomes were analyzed with Kaplan-Meier and Cox regression analyses. Overall, 1286 patients were included: 402 SAPTasa, 85 SAPTp₂y, 359 DAPT, 35 LD-DPI, 257 DPI, and 148 TT. Baseline demographics varied, with SAPTasa and TT having the lowest and highest respective rates of coronary artery disease (49% vs 60%), hypertension (84% vs 95%), and atrial fibrillation (11% vs 60%) (all P < .05). Kaplan-Meier estimates showed significant differences between groups in 3-year rates of GIB (1.5% [SAPTasa] vs 2.6% [SAPTp2y] vs 8.8% [DAPT] vs 10% [LD-DPI] vs 10% [DPI] vs 15% [TT]), any bleeding complication (3.2% vs 2.6% vs 5.8% vs 7.8% vs 14% vs 21%), and death (37% vs 38% vs 38% vs 44% vs 43% vs 57%) (all P ≤ .001). No differences were noted in rates of MI, stroke, primary patency, or MALE. After adjustment, compared with SAPTasa, DAPT, DPI, and TT were associated with increasingly higher hazard of GIB (DAPT: hazard ratio [HR], 3.75; 95% confidence interval [CI], 1.60-8.76; DPI: HR, 5.48; 95% CI, 2.11-14.2; and TT: HR, 8.65; 95% CI, 3.07-24.3) and DPI and TT with higher hazard of any bleeding complication (HR, 5.07; 95% CI, 2.22-11.6; and HR, 9.65; 95% CI, 3.99-23.3). Compared with SAPTasa, TT had 40% higher hazard of mortality (HR, 1.40; 95% CI, 1.01-1.95). Escalation of antithrombotic therapy beyond SAPT after first-time lower extremity revascularization for CLTI is associated with higher bleeding risk, and TT with lower survival, possibly reflecting the vulnerability of frailer patients less able to tolerate bleeding complications. No differences were observed in MI, stroke, patency, or MALE, underscoring the challenge of balancing limb-related outcomes with bleeding risk. Careful monitoring, individualized risk stratification, and shared decision-making remain essential. Larger studies are needed to further define the relative efficacy and safety of intensified antithrombotic regimens.