Recommendations for Antiplatelet Agents
COR	LOE	Recommendations
I	A	Antiplatelet therapy with aspirin alone (range 75–325 mg per day) or clopidogrel alone (75 mg per day) is recommended to reduce MI, stroke, and vascular death in patients with symptomatic PAD. 139–142
See Online Data Supplement 13.		The effect of antiplatelet therapy on cardiovascular events has been systematically reviewed by the Antithrombotic Trialists' Collaboration.139 Of note, this meta-analysis included studies of antiplatelet agents other than aspirin or clopidogrel. Among patients with symptomatic PAD treated with antiplatelet therapy, there was a 22% odds reduction for cardiovascular events, including MI, stroke, or vascular death.139 Symptomatic patients with lower extremity PAD included both those with claudication and those with prior lower extremity revascularization. The Antithrombotic Trialists' Collaboration meta-analysis also compared the efficacy of different doses of aspirin.139 The proportional reduction in vascular events was 32% with 75 to 150 mg daily, 26% with 160 to 325 mg daily, and 19% with 500 to 1500 mg daily, whereas there was a significantly smaller (13%) reduction in cardiovascular events in patients being treated with <75 mg of aspirin per day.139 CLIPS (Critical Leg Ischaemia Prevention Study) demonstrated a benefit of aspirin (100 mg daily) compared with placebo in preventing vascular events, but the study was too small to derive meaningful conclusions.140 A meta-analysis of trials of aspirin (alone or in combination with dipyridamole) for prevention of cardiovascular events in patients with PAD found a non–statistically significant reduction in the primary endpoint of cardiovascular death, MI, and stroke and a statistically significant reduction in the secondary endpoint of nonfatal stroke with aspirin versus placebo.141 The CAPRIE (Clopidogrel Versus Aspirin in Patients at Risk of Ischemic Events) trial demonstrated a benefit of clopidogrel as compared with aspirin in cardiovascular risk reduction and bleeding events in a population of patients with symptomatic atherosclerotic vascular disease, including a subgroup of patients with symptomatic PAD.142
IIa	C-EO	In asymptomatic patients with PAD (ABI ≤0.90), antiplatelet therapy is reasonable to reduce the risk of MI, stroke, or vascular death.
See Online Data Supplement 13.		Patients with PAD (ie, ABI ≤0.90) who do not have claudication may have leg symptoms atypical for claudication or may be too functionally limited to allow for adequate leg symptom assessment. Patients with PAD without claudication are at increased cardiovascular risk.79 Subgroup analysis in a trial evaluating asymptomatic patients did not show an effect of aspirin in patients with an abnormally low ABI (<0.80 or ≤0.90).76 However, the trial was not powered to analyze subgroups, and the uncertainty of the result does not rule out the possibility that aspirin could provide benefit in such patients, especially in those at increased risk of cardiovascular events. Another trial that included asymptomatic patients was too small to derive meaningful conclusions.140
IIb	B-R	In asymptomatic patients with borderline ABI (0.91–0.99), the usefulness of antiplatelet therapy to reduce the risk of MI, stroke, or vascular death is uncertain.75,76
See Online Data Supplement 13.		In asymptomatic patients with an abnormal or borderline ABI, 2 RCTs found that aspirin had no effect in reducing cardiovascular events75,76 and might increase bleeding.76 However, the trials were not powered to examine patients with borderline ABI separately. Given that cardiovascular risk is lower in patients with borderline ABI than in those with abnormal ABI,80 it would be unlikely that aspirin would have a meaningful effect in this subgroup when there was no evidence of an effect in the total trial populations.
IIb	B-R	The effectiveness of dual antiplatelet therapy (DAPT) (aspirin and clopidogrel) to reduce the risk of cardiovascular ischemic events in patients with symptomatic PAD is not well established.143,144
See Online Data Supplement 13.		Based on findings from a subset of patients with PAD in the CHARISMA (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance) trial, DAPT with aspirin plus clopidogrel may be considered for patients with PAD at particularly high risk of cardiovascular ischemic events who are not at high risk of bleeding.143,144 Currently, there are sparse data on newer P2Y12 antagonists for PAD. There is uncertainty about the net benefit of long-term DAPT for patients with PAD—specifically the balance of risks of cardiovascular ischemic events versus major bleeding. Additional clinical trials are needed in the population with PAD. Refer to the DAPT guideline focused update for DAPT recommendations specifically for CAD.20
IIb	C-LD	DAPT (aspirin and clopidogrel) may be reasonable to reduce the risk of limb-related events in patients with symptomatic PAD after lower extremity revascularization.145–148
See Online Data Supplements 13 and 14.		There are sparse data on DAPT after lower extremity revascularization. Still, DAPT is prescribed in up to 55% of patients after endovascular revascularization for CLI.146 One small RCT of aspirin or aspirin plus clopidogrel in patients undergoing endovascular revascularization demonstrated that patients with DAPT had fewer repeat revascularization procedures for clinical symptoms.145 A subsequent small RCT of aspirin plus placebo or aspirin plus clopidogrel in patients after endovascular revascularization also showed a decrease in the need for repeat revascularization at 6 months in patients receiving clopidogrel.147 An RCT of aspirin plus placebo or aspirin plus clopidogrel in patients who underwent below-knee bypass graft showed a decrease in limb-related events only in the prespecified subgroup of patients with prosthetic bypass grafts.148 Refer to the DAPT guideline focused update for DAPT recommendations specifically for CAD.20
IIb	B-R	The overall clinical benefit of vorapaxar added to existing antiplatelet therapy in patients with symptomatic PAD is uncertain.149–152
See Online Data Supplement 13.		This novel antagonist of protease-activated receptor-1 added to existing antiplatelet therapy reduced the risk of cardiovascular ischemic events in patients with atherosclerosis who were receiving standard therapy in an RCT.150,151 However, it also increased the risk of moderate or severe bleeding. Although the cardiovascular benefit was not demonstrated in the subgroup with symptomatic PAD, there was a reduction in limb-related events with vorapaxar, specifically in acute limb ischemia (ALI) and peripheral revascularization.149,152 More than half of ALI events in the PAD subset were due to thrombosis of lower extremity bypass grafts.149 Unfortunately, the benefit in limb events in patients with PAD was accompanied by an increased risk of bleeding.149,152 Therefore, the overall clinical benefit of vorapaxar in patients with PAD is uncertain.