Acute Limb Ischemia in Peripheral Artery Disease: Insights from EUCLID.

Abstract

BACKGROUND\nAcute limb ischemia (ALI) is an important clinical event and an emerging cardiovascular clinical trial outcome. Risk factors for and outcomes after ALI have not been fully evaluated.\n\n\nMETHODS\nEUCLID randomized patients with peripheral artery disease (PAD) to ticagrelor versus clopidogrel. Enrollment criteria included an ankle-brachial index (ABI) ≤0.80 or prior lower extremity revascularization. Patients were grouped according to the primary outcome, post-randomization ALI hospitalization. Baseline factors associated with ALI were identified using Cox proportional hazards modeling. Models with ALI hospitalization as a time-dependent covariate were developed for secondary outcomes of major adverse cardiovascular events (MACE: myocardial infarction, cardiovascular death, ischemic stroke), all-cause mortality, and major amputation.\n\n\nRESULTS\nAmong 13,885 patients, 1.7% (n=232) had 293 ALI hospitalizations (0.8 per 100 patient-years). Patients with versus without ALI were younger and more often had prior peripheral revascularization and lower baseline ABI. Treatment during ALI hospitalization included endovascular revascularization (39.2%, n=115), surgical bypass (24.6%, n=72), and major amputation (13.0%, n=38). After multivariable adjustment, any prior peripheral revascularization (HR 4.7, 95% CI 3.3-6.8, p<0.01), baseline atrial fibrillation (HR 1.8, 95% CI 1.1-3.2, p=0.03), and baseline ABI ≤0.60 (HR 1.3 per 0.10 decrease, 95% CI 1.1-1.5, p<0.01) were associated with higher ALI risk. Older age (HR 0.8 per 10-year increase, 95% CI 0.7-1.0, p=0.02) and baseline statin use (HR 0.7, 95% CI 0.5-0.9, p<0.01) were associated with lower risk for ALI. There was no relationship between randomized treatment to ticagrelor or clopidogrel and ALI. Among patients with prior revascularization, surgical versus endovascular procedures performed more than 6 months prior were associated with ALI (adjusted HR 2.63, 95% CI 1.75-3.96). In the overall population, ALI hospitalization was associated with subsequent MACE (adjusted HR 1.4, 95% CI 1.0-2.1, p=0.04), all-cause mortality (adjusted HR 3.3, 95% CI 2.4-4.6, p<0.01), and major amputation (adjusted HR 34.2, 95% CI 9.7-20.8, p<0.01).\n\n\nCONCLUSIONS\nPrior peripheral revascularization, baseline atrial fibrillation, and lower ABI identify PAD patients at heightened risk for ALI, an event associated with subsequent cardiovascular and limb-related morbidity and mortality.\n\n\nCLINICAL TRIAL REGISTRATION\nURL: https://clinicaltrials.gov Unique Identifier: NCT01732822.