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Background Peripheral artery disease (PAD) is associated with heightened risk for major adverse cardiovascular and limb events, but data on the burden of risk for total (first and potentially subsequent) events, and the association with polyvascular disease, are limited. This post hoc analysis of the EUCLID (Examining Use of Ticagrelor in Peripheral Artery Disease) trial evaluated total cardiovascular and limb events among patients with symptomatic PAD, overall and by number of symptomatic vascular territories. Methods and Results In the EUCLID trial, patients with symptomatic PAD (lower extremity revascularization >30 days before randomization or ankle-brachial index ≤0.80) were randomized to treatment with ticagrelor or clopidogrel. Relative effects on total events (cardiovascular death; nonfatal myocardial infarction and ischemic stroke; acute limb ischemia, unstable angina, and transient ischemic attack requiring hospitalization; coronary, carotid, and peripheral revascularization procedures; and amputation for symptomatic PAD) were summarized by hazard ratios (HRs), whereas absolute risks were estimated by incidence rates and mean cumulative functions. Among 13 885 randomized patients, 7600 total cardiovascular and limb events occurred during a median 2.7 years of follow-up, translating to 60.0 and 62.5 events per 100 patients through 3 years for the ticagrelor and clopidogrel groups, respectively (HR, 0.96; 95% CI, 0.89-1.03; P =0.27). Among 1393 patients with disease in 3 vascular territories, event accrual rates through 3 years for the ticagrelor and clopidogrel groups were 87.3 and 97.7 events per 100 patients, respectively. Absolute risk reductions for ticagrelor relative to clopidogrel at 3 years were -0.2, 6.7, and 10.3 events per 100 patients for 1, 2, and 3 affected vascular territories, respectively ( P interaction =0.09). Conclusions Patients with symptomatic PAD have nearly double the number of total events than first events, with rates reflecting the number of affected vascular territories. These findings highlight the clinical relevance of quantifying disease burden in terms of total events and the need for long-term preventive treatments in high-risk patient populations. Registration URL: https://clinicaltrials.gov/; Unique identifier: NCT01732822.

Background: Recent trials have identified anti-diabetes mellitus agents that lower major adverse cardiovascular event (MACE) rates, although some increase rates of lower-extremity amputation (LEA). Patients with peripheral artery disease (PAD) have greater incidence of diabetes mellitus and risk for LEA, prompting this investigation of clinical outcomes in patients with diabetes mellitus and PAD in the EXSCEL trial (Exenatide Study of Cardiovascular Event Lowering)., Methods: EXSCEL evaluated the effects of once-weekly exenatide (a GLP-1 [glucagon-like peptide-1] receptor agonist) versus placebo on the rates of the primary composite MACE end point (cardiovascular death, myocardial infarction, or stroke) among patients with type 2 diabetes mellitus. In this post hoc analysis, we assessed the association of baseline PAD with rates of MACE, LEA, and the effects of exenatide versus placebo in patients with and without PAD., Results: EXSCEL included 2800 patients with PAD (19% of the trial population). These individuals had higher unadjusted and adjusted rates of MACE compared with patients without PAD (13.6% versus 11.4%, respectively) as well as a higher adjusted hazard ratio (adjusted hazard ratio, 1.13 [95% CI, 1.00-1.27]; P =0.047). Patients with PAD had higher all-cause mortality (adjusted hazard ratio 1.38 [95% CI, 1.20-1.60]; P <0.001) and more frequent LEA (adjusted hazard ratio 5.48 [95% CI, 4.16-7.22]; P <0.001). Patients treated with exenatide or placebo had similar rates of MACE and LEA, regardless of PAD status., Conclusions: EXSCEL participants with PAD had higher rates of all-cause mortality and LEA compared with those without PAD. There were no differences in MACE or LEA rates with exenatide versus placebo. Clinical Trial Registration URL: https://www.clinicaltrials.gov. Unique identifier: NCT01144338.

Background: The relationship between invasive vascular procedures and bleeding in patients with peripheral artery disease has not been well described in the literature. This post hoc analysis from the EUCLID trial (Examining Use of Ticagrelor in Peripheral Artery Disease) aimed to describe the incidence of major and minor postprocedural bleeding and characterize the timing and severity of bleeding events relative to the procedure., Methods: EUCLID was a multicenter, randomized controlled trial of 13 885 patients with symptomatic peripheral artery disease that tested the efficacy and safety of ticagrelor compared with clopidogrel for the prevention of major adverse cardiovascular events. A total of 2661 patients underwent 3062 coronary revascularization, peripheral revascularization, and amputation during the study. The primary safety end point was Thrombolysis in Myocardial Infarction major or minor bleeding. All bleeding events were formally adjudicated by a clinical end point classification group., Results: Major bleeding events most often occurred ≤7 days following the procedure. The incidence of Thrombolysis in Myocardial Infarction major or minor bleeding ≤7 days following peripheral revascularization (3.3%; 95% CI, 2.5%-4.1%) was similar to rates after coronary revascularization (4.0%; 95% CI, 2.6%-5.4%) and lower extremity amputation (2.3%; 95% CI, 0.8%-3.8%). The severity of bleeding events (as graded by drop in hemoglobin, need for transfusion, bleeding in a critical location, and fatal bleeding) was also similar following peripheral, coronary revascularization, and lower extremity amputation., Conclusions: The incidence of Thrombolysis in Myocardial Infarction major/minor bleeding following peripheral revascularization is comparable to rates after coronary revascularization and lower extremity amputation, and the majority of bleeding events occur within 7 days following the procedure. The severity of periprocedural bleeding is also similar after procedures, with the most frequently adjudicated reason being a drop in hemoglobin ≥2 g/dL. Future studies should be performed to enhance our understanding of bleeding risk related to revascularization and amputation procedures in peripheral artery disease patients.

Background: Acute 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., Methods: EUCLID (Examining Use of Ticagrelor in Peripheral Artery Disease) randomized patients with peripheral artery disease to ticagrelor versus clopidogrel. Enrollment criteria included an ankle-brachial index ≤0.80 or previous lower extremity revascularization. Patients were grouped according to the primary outcome, postrandomization 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 (myocardial infarction, cardiovascular death, ischemic stroke), all-cause mortality, and major amputation., Results: Among 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 previous peripheral revascularization and lower baseline ankle-brachial index. 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 previous peripheral revascularization (Hazard Ratio [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 ankle-brachial index ≤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 previous 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)., Conclusions: Previous peripheral revascularization, baseline atrial fibrillation, and lower ankle-brachial index identify peripheral artery disease patients at heightened risk for ALI, an event associated with subsequent cardiovascular and limb-related morbidity and mortality., Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01732822.