Peripheral interventions and antiplatelet therapy: Role in current practice

Table 1 Results of clinical trials initially designed for patients with coronary artery disease, with subgroup analysis in peripheral arterial disease

Clinical trial	No. of patients	Patient population	Drugs studied	Primary end point	Outcomes
PEGASUS TIMI-54 subgroup analysis[40] (2016)	1143	CAD and concomitant PAD	Ticagrelor 90 mg BID + aspirin vs Ticagrelor 60 mg BID + aspirin vs Placebo + aspirin	Cardiovascular death, MI and stroke Acute limb ischemia and peripheral revascularization for ischemia	15.2% in ticagrelor (pooled group) and 19.3% in placebo. ARR 4.1% in ticagrelor (pooled group) 60 mg dose more beneficial (ARR of 5.2%) 0.46% in ticagrelor (pooled group) and 0.71% in placebo (HR 0.65; 95%CI: 0.44-0.95; P = 0.026)
PLATO-subgroup analysis[32] (2015)	1144	CAD and concomitant PAD	Ticagrelor vs clopidogrel	Cardiovascular death, MI and stroke	18% in ticagrelor group and 20.6% in clopidogrel group (HR: 0.85; 95%CI: 0.64–1.11; P =0.99)
TRA 2P-TIMI 50[35] (2012)	26449	Previous history of MI or ischemic stroke within the previous 2 wk-12 mo or PAD	Vorapaxar vs placebo	Cardiovascular death, MI, and stroke	9.3% in vorapaxar group and 10.5% in placebo (P < 0.001) Subgroup analysis in PAD patients showed no difference between groups for the primary endpoint Rate of intracranial hemorrhage (1% vorapaxar vs 0.5% placebo; P < 0.001)
CHARISMA[38] (2006)	15603	Patients with either clinically documented vascular disease or risk factors for atherothrombotic disease	Aspirin plus clopidogrel vs aspirin monotherapy	MI, stroke or cardiovascular death	6.8% in clopidogrel plus aspirin group and 7.3% in aspirin group (P = 0.22) Subgroup analysis in PAD patients: no benefit was derived from dual antiplatelet therapy
CAPRIE[15] (1996)	19185	Recent MI, recent ischemic stroke or symptomatic PAD	Aspirin vs clopidogrel	MI, stroke and vascular death	RRR of 8.7% clopidogrel group (P = 0.043; 95%CI: 0.3-16.5) Subgroup analysis in PAD patients: 23.8% RRR in clopidogrel over aspirin (P = 0.0028; 95%CI: 8.9-36.2)

MI: Myocardial infarction; PAD: Peripheral arterial disease; ARR: Absolute risk reduction; RRR: Relative risk reduction.

Table 2 Results of clinical trials designed for patients with peripheral arterial disease

Clinical trial	No. of patients	Patient population	Drugs studied	Primary end point	Outcomes
COMPASS[44,45] (2017)	27402	Peripheral arterial disease or coronary artery disease	Rivaroxaban plus aspirin or rivaroxaban alone vs aspirin alone	Myocardial infarction, stroke, CV death and the time from randomization to the first occurrence of major bleeding	Preliminary results: Trial stopped prematurely. One of rivaroxaban arms proved to be superior to aspirin alone No disclosed information on the primary bleeding endpoint or the regimen that showed superiority to aspirin alone
EUCLID[41] (2016)	13885	PAD (ABI ≤ 0.80 or prior (> 30 d) revascularization of the lower extremities)	Ticagrelor vs clopidogrel	CV death, MI, or ischemic stroke	10.8% in ticagrelor group vs 10.6% in clopidogrel group (P = 0.65)
MIRROR[39] (2012)	80	PAD treated with endovascular therapy	Dual antiplatelet therapy (aspirin plus clopidogrel) vs aspirin monotherapy	Local concentrations of platelet activation markers β-thromboglobulin and CD40L	Reduced peri-interventional platelet activation and improved functional outcome in the dual antiplatelet therapy group
Berger et al[13] (Meta-analysis-2009)	5269	PAD (patients with claudication, those undergoing percutaneous intervention or bypass surgery, and asymptomatic patients with an ABI of 0.99 or less)	Aspirin or combination of aspirin plus dipyridamole vs placebo	Composite end point of non-fatal MI, nonfatal stroke, and CV death	8.9% in aspirin or combination of aspirin and dipyridamole, 11% in placebo (95%CI: 0.76-1.04)
WAVE[43] (2007)	2161	PAD (atherosclerosis of the arteries of lower extremities, carotid arteries or subclavian arteries)	Antiplatelet agent plus oral anticoagulant vs antiplatelet therapy in patients with PAD	CV death, MI and stroke	12.2% in combination therapy group and 13.3% in antiplatelet therapy alone (95%CI: 0.73 to 1.16; P = 0.48)
Thompson et al[29] (Meta-analysis-2002)	2702	PAD (stable, moderate to severe claudication)	Cilostazol vs placebo	MWD, pain free walking distance	MWD: 44% and 50% (cilostazol 50 mg and 100 mg respectively) and 21.4% in placebo (P < 0.05) Pain-free walking distance: 60% and 67% (cilostazol 50 and 100 mg respectively) and 40% in placebo group (P < 0.05)
BOA[42] (2000)	2690	Patients undergone infra-inguinal bypass surgery	Warfarin vs aspirin	Graft occlusion	No observed difference in warfarin compared to aspirin (HR = 0.95; 95%CI: 0.82-1.11)

ABI: Ankle brachial index; CV: Cardiovascular; HR: Hazard ratio; MI: Myocardial infarction; MWD: Mean walking distance.

Table 3 Current available guidelines addressing antiplatelet therapy for peripheral arterial disease

Class of recommendation	Guidelines
Class Ia	Aspirin in daily doses of 75 to 325 mg or clopidogrel 75 mg/d is recommended to reduce the risk of MI, stroke, or vascular death in individuals with symptomatic atherosclerotic lower extremity PAD
Class IIa	Antiplatelet therapy is reasonable to manage asymptomatic individuals with an ABI less than or equal to 0.90 to reduce the risk of MI, stroke, or vascular death
Class IIb	Dual-antiplatelet therapy (aspirin and clopidogrel) may be reasonable to reduce the risk of limb-related events in patients with symptomatic PAD after lower extremity revascularization

PAD: Peripheral arterial disease; MI: Myocardial infarction.