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.