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CLINICAL STATEMENTS AND GUIDELINES Circulation. 2024;149:e1313–e1410. DOI: 10.1161/CIR.0000000000001251 June 11, 2024 e1339 MACE is reasonable based on the increased cardiovascular risk in this population, the finding that a significant proportion of patients with asymptomatic PAD will have leg symptoms if administered an objective walking test, and studies that have demonstrated a high prevalence of CAD among patients with low ABI.27–30 Further, single antiplatelet therapy is recommended in patients with asymptomatic PAD and other clinical indications for this therapy (eg, known CAD, cerebrovascular disease, previous coronary or other arterial revascularization).31,32 10. Outside of the setting of recent revascularization, dual antiplatelet therapy has only been assessed in subgroups of patients with PAD enrolled in larger trials, usually in patients with previous MI, other atherosclerotic disease, or both. The value of dual antiplatelet therapy is uncertain, partly because these subgroups were underpowered to fully examine efficacy and safety (ie, risk of bleeding) in patients with PAD, such as in the PEGASUS-TIMI 54 (Prevention of Cardiovascular Events in Patients with Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin–Thrombolysis In Myocardial Infarction 54) trial and the CHARISMA (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance) trial.14,15 11 In the TRA 2P–TIMI 50 (Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events–Thrombolysis In Myocardial Infarction 50) trial, the antiplatelet agent vorapaxar, an antagonist of the protease activated receptor-1, in addition to antiplatelet therapy, generally with aspirin or clopidogrel, decreased the risk of MALE, including hospitalization for ALI and lower extremity revascularization in the cohort of 3787 patients with symptomatic PAD.16 In the PAD cohort, no significant difference in MACE was observed; however, a significantly higher risk of moderate to severe bleeding was observed among those randomized to vorapaxar compared with the placebo group, thus resulting in an uncertain net clinical benefit.16 Vorapaxar is contraindicated in patients with previous stroke due to an increased risk of intracranial hemorrhage.33 12 Data supporting dual antiplatelet therapy after lower extremity bypass grafting are limited and uncertain, but a subgroup analysis of the CASPAR (Clopidogrel and Acetylsalicylic Acid in Bypass Surgery for Peripheral Arterial Disease) trial found that the combination of low-dose aspirin plus clopidogrel 75 mg daily reduced a composite endpoint of MALE or death in patients who underwent prosthetic rather than autogenous vein grafts compared with low-dose aspirin alone.17 13 RCTs and observational studies have uniformly demonstrated that full-intensity oral anticoagulation therapy aimed at decreasing MACE among patients with PAD provided no benefit and resulted in increased morbidity rates.18–20,34 In the WAVE (Warfarin Antiplatelet Vascular Evaluation) trial of patients with atherosclerotic vascular disease, including PAD, no difference was observed in cardiovascular ischemic events among patients randomized to full-intensity oral anticoagulation and antiplatelet therapy versus antiplatelet therapy alone.18 In addition, an increase was seen in bleeding endpoints, including life-threatening and intracranial bleeding.18 One RCT demonstrated an increased death rate among patients randomized to warfarin plus aspirin versus aspirin alone after lower extremity bypass grafting.19 This recommendation regarding use of full-intensity oral anticoagulation in patients with PAD is distinct from recommendations regarding low-dose oral anticoagulation using rivaroxaban in combination with low-dose aspirin. Furthermore, this recommendation does not apply to patients for whom full-intensity oral anticoagulation is required for another clinical indication, such as atrial fibrillation or venous thromboembolism. Recent clinical practice guidelines for management of atrial fibrillation include recommendations for anticoagulation in the setting of other comorbidities, including PAD.26 5.2 Lipid-Lowering Therapy for PAD Recommendations for Lipid-Lowering Therapy for PAD Referenced studies that support the recommendations are summarized in the Online Data Supplement. COR LOE Recommendations 1 A 1 In patients with PAD, treatment with high-intensity statin therapy is indicated, with an aim of achieving a ≥50% reduction in low-density lipoprotein cholesterol (LDL-C) level.1–3 2a B-R 2 In patients with PAD who are on maximally tolerated statin therapy and have an LDL-C level of ≥70 mg/dL, it is reasonable to add PCSK9 inhibitor therapy.1,4–6 2a B-R 3 In patients with PAD who are on maximally tolerated statin therapy and have an LDL-C level of ≥70 mg/dL, it is reasonable to add ezetimibe therapy.1,7 Synopsis Dyslipidemia is a common atherosclerotic risk factor in patients with PAD. Lipid-lowering therapy with statin medications has been shown to improve outcomes (MACE and MALE) and should be prescribed for all patients with PAD.1–3 Despite significant evidence supporting its benefit, statin therapy is underprescribed among patients with PAD compared with patients with other atherosclerotic cardiovascular disorders, especially CAD.8,9 Evidence supports the use of high-intensity statins and Downloaded from http://ahajournals.org by on October 7, 2026