Increased Risk of Major Limb Events in Poor Clopidogrel Responders: Platelet Activity in Vascular Surgery and Cardiovascular Events (PACE) Study Subgroup Analysis

Whereas clopidogrel is effective at decreasing cardiovascular events in patients with peripheral artery disease, a substantial number of events continue to occur. This study investigated the variability in response to clopidogrel and its relationship with clinical outcomes. There were 300 patients enrolled in the Platelet Activity in Vascular Surgery and Cardiovascular Events (PACE) study before lower extremity revascularization, of whom 119 were receiving clopidogrel. Platelet aggregation was measured in response to adenosine diphosphate (ADP) 2M immediately before revascularization. Patients were observed longitudinally for a median follow-up of 18 months. The primary end point was major adverse limb events (MALEs), defined by major amputation or reoperation of the affected limb. Patients were stratified into groups according to the percentage ADP-induced aggregation at 300 seconds (<50% aggregation, normal responder; ≥50% aggregation, poor responder). Overall, the median age was 70 years (62-76 years), and 39.5% were female. Thirty-six (30.3%) patients had a MALE event (15 major amputation and 25 major reoperation); 60 patients underwent open or hybrid operations, and 50 patients underwent endovascular procedures. The remaining nine patients had no interventions. Of the group of 119 patients, 97 patients were taking aspirin. Overall, median aggregation to ADP 2M was 22.5% (Q1-Q3, 10%-50%), and 27 patients (26%) were clopidogrel nonresponders. Baseline aggregation was higher in patients who went on to develop a MALE than in those without a MALE (43% vs 20%; P = .018). Patients with aggregation > median (22.5%) were more likely to experience a MALE than were patients with aggregation < median (69% vs 31%; hazard ratio [HR], 2.71; 95% confidence interval [CI], 1.23-5.98; P = .013). After multivariable adjustment for age, sex, race/ethnicity, body mass index, diabetes, coronary artery disease, and aspirin, aggregation > median was associated with MALEs (adjusted HR, 2.67; 95% CI, 1.18-6.01; P = .018). When stratified by established cutoffs for responsiveness to clopidogrel (50% aggregation), 27 (26%) patients were poor responders. Poor responders were more likely to experience MALEs than normal responders (59% vs 41%; HR, 2.33; 95% CI, 1.11-4.89; P = .026). After multivariable adjustment, poor responder status trended toward an increased risk of MALE compared with a normal responder (adjusted HR, 2.18; 95% CI, 1.00-4.78; P = .051). Among patients undergoing lower extremity revascularization, poor response to clopidogrel is associated with increased risk for major adverse limb events. Preoperative screening to ensure therapeutic clopidogrel response should be considered in these patients.