Table 3.

Antithrombotic therapy in peripheral vascular disease

Trial	Sample size	Population	Investigation	Control	% with diabetes	Follow-up	Outcomes	Absolute and relative benefits	Absolute and relative harms	Other comments
Asymptomatic
POPADAD (2008)44	1276	Type 1 or 2 diabetes mellitus and ABPI ≤0.99 with no PAD symptoms	Aspirin 100 mg ± antioxidant	Placebo ± antioxidant	100%	Median   6.7 years	MACCE or above ankle amputation for critical limb ischaemia	18.2% vs. 18.3%   HR 0.98 (0.76–1.26); P = 0.86	GI bleed   4.4% vs. 4.9%   HR 0.90 (0.53–1.52); P = 0.69
AAA (2010)121	3350	ABPI ≤0.95; free from clinical CV disease	Aspirin 100 mg	Placebo	3%	Mean   8.2 years	MACCE or revascularization	13.7 vs. 13.3 events/1000 person-years   HR 1.03 (0.84–1.27)	Major bleed   2.0% vs. 1.2%   HR 1.71 (0.99–2.97)
Symptomatic
ATT Collaboration (2009)42	17 000	Meta-analysis of secondary prevention trials (not PAD specific)	Aspirin 75–500 mg	No aspirin	Not stated	NA	MACCE	6.7% vs. 8.2% per year;   HR 0.81 (0.75–0.87); P < 0.0001	Major extracranial bleed (incompletely reported)   23 vs. 6 events   HR 2.69 (1.25–5.76)	Non-significant increase haemorrhagic stroke, significant decrease ischaemic stroke and coronary events
CAPRIE (1996)86	6452	Symptomatic PAD and ABPI ≤0.85; or symptomatic PAD with previous amputation or revascularization	Clopidogrel 75 mg	Aspirin 325 mg	21%	Mean   1.9 years	MACCE	3.71% vs. 4.86% per year;   RR 23.8% (8.9–36.2); P = 0.0028	GI bleed 1.99% vs. 2.66%; P < 0.002 (for the whole group)	No difference in amputation rate across CAPRIE cohorts; not reported specific to PAD subgroup
EUCLID (2017)122	13 885	PAD with ABPI ≤0.8 or previous lower limb revascularization >30 days before randomization	Ticagrelor 90 mg b.i.d.	Clopidogrel 75 mg	38%	Median   30 months	MACCE	10.8% vs. 10.6%   HR 1.02 (0.92–1.13); P = 0.65	TIMI major bleeding   1.6% vs. 1.6%   HR 1.10 (0.84–1.43); P = 0.49
							Lower limb revascularization	12.2% vs. 12.8%   HR 0.95 (0.87–1.05); P = 0.30
CHARISMA   subgroup PAD (2009)123	3096   (2838 symptomatic, 258 asymptomatic)	Symptomatic PAD and ABPI ≤0.85; or symptomatic PAD with previous amputation or revascularization; asymptomatic with APBI <0.9 identified within those with other eligibility for CHARISMA study	Aspirin   75–162 mg + clopidogrel 75 mg (DAPT)	Aspirin   75–162 mg + placebo	36%	Median   28 months	MACCE	7.6% vs. 8.9%   HR 0.85 (0.66–1.08); P = 0.183	Severe bleeding   1.7% vs. 1.7%   HR 0.97 (0.56–1.66); P = 0.90   Minor bleeding 34.4% vs. 20.8%   HR 1.99 (1.69–2.34); P < 0.001	Non-significant trend towards increase of fatal, intracranial, and moderate bleeding with DAPT
TRA2°P-TIMI 50 (2013)124	3787	Symptomatic PAD and ABPI <0.85 or previous lower limb revascularization	Vorapaxar 2.5 mg	Placebo	36%	Median   36 months	MACCE	11.3% vs. 11.9%   HR 0.94 (0.78–1.14); P = 0.53	GUSTO moderate/severe bleeding:   7.4% vs. 4.5%   HR 1.62 (1.21–2.18); P = 0.001
							Acute limb ischaemia	2.3% vs. 3.9%   HR 0.58 (0.39–0.86); P = 0.006
							Revascularization	18.4% vs. 22.2%   HR 0.84 (0.73–0.97); P = 0.017
COMPASS (2018)126	7470   (4129 symptomatic lower limb; 1422 asymptomatic lower limb; 1919 carotid disease)	Previous lower limb revascularization or amputation; symptomatic PAD and ABPI <0.9 or stenosis ≥50% on arterial imaging; carotid revascularization or asymptomatic carotid artery stenosis ≥50%	Rivaroxaban 2.5 mg b.i.d + aspirin 100 mg	Aspirin 100 mg + placebo	44%	Median   21 months	MACCE	5% vs. 7%   HR 0.72 (0.57–0.90); P = 0.005	Major bleeding 3.1% vs. 1.9%   HR 1.61 (1.12–2.31); P = 0.009
							Major adverse limb event (acute/chronic ischaemia; amputation)	1.2% vs. 2.2%   HR 0.54 (0.35–0.84); P = 0.005
Post-revascularization
CASPAR (2010)127	851	Vascular bypass graft for treatment of PAD	Aspirin 75–100 mg + clopidogrel 75 mg (DAPT)	Aspirin 75–100 mg + placebo	38%	Median   12 months	Graft occlusion/revascularization/amputation/death	All grafts   35.4% vs. 35.0%   HR 0.98 (0.78–1.23)   Venous   23.8% vs. 20.0%   HR 1.25 (0.94–1.67)   Prosthetic   37.5% vs. 52.8%   HR 0.65 (0.45–0.95); P = 0.025	Total bleeding   16.7% vs. 7.1%; P < 0.001   Severe bleeding   2.1% vs. 1.2%; P = NS	Graft occlusion   HR 0.63 (0.42–0.93) and amputation   HR 0.48 (0.24–0.96) significantly reduced in prosthetic but not vein bypass
BOA (2000)128	2690	Infrainguinal bypass graft for obstructive arterial disease	Oral anticoagulants (target INR 3.0–4.5)	Pulverized carbasalate calcium 100 mg (equivalent to aspirin 80 mg)	26%	Mean   21 months	Occlusion	23.2% vs. 24.3%   HR 0.95 (0.82–1.11)	Total bleeding   119 vs. 59 events   Fatal bleeding   16 vs. 12 events   Gastrointestinal bleeding   51 vs. 29 events   Intracranial bleeding   18 vs. 4 events	Fatal intracranial bleeding events were higher (8 vs. 3 events) in oral anticoagulants, whereas bleeding events in other sites were similar between groups
							MACE plus amputation	18.7% vs. 20.8%   HR 0.89 (0.75–1.06)
							Vein graft occlusion	14.3% vs. 20.3%   HR 0.69 (0.54–0.88)
							Non-vein grafts occlusion	36% vs. 30%   HR 1.26 (1.03–1.55)
Sarac et al. (1998)129	56	Infrainguinal bypass with autogenous vein and deemed high risk for graft occlusion (suboptimal venous conduit, poor arterial runoff or redo bypass)	Warfarin (target INR 2–3) + aspirin 325 mg	Aspirin 325 mg	64%	Not stated   (outcomes derived from Kaplan–Meier survival curves)	30-day graft patency	97.3% vs. 85.2%; P = 0.07	Haematoma   32% vs. 4%; P = 0.004   GI bleeding   3% vs. 11%; P = NS   Intracranial bleeding   3% vs. 4%; P = NS
							30-day amputation rate	0% vs. 11.1%; P = 0.04
							3-year primary assisted patency:	77% vs. 56%; P = 0.05
							3-year secondary patency	81% vs. 56%; P = 0.02
VOYAGER-PAD (2020)130	6564	Post-lower limb revascularization	Rivaroxaban 2.5 mg b.i.d. + aspirin 100 mg	Aspirin 100 mg + placebo	40%	Median 28 months	MACE plus acute limb ischaemia or amputation	15.5% vs. 17.8%   HR 0.85 (0.76–0.96)	Major bleeding   1.9% vs. 1.35%   HR 1.43 (0.97–2.10); P = 0.07

Summary of antiplatelet and anticoagulant studies in individuals with peripheral vascular disease.

Significant differences are highlighted in bold.

ABPI, ankle brachial pressure index; b.i.d., twice daily; CV, cardiovascular; DAPT, dual antiplatelet therapy; GI, gastrointestinal; HR, hazard ratio; INR, international normalized ratio; MACE, major adverse cardiovascular or cerebrovascular events; NA, not available; PAD, peripheral artery disease.