Peripheral artery disease (PAD) is present in a substantial proportion of people with diabetic foot ulcers, and it is among the strongest predictors of poor healing and major amputation. Revascularisation restores blood flow, but the arteries and bypass grafts that are treated remain vulnerable to thrombosis, and the person’s wider vascular bed remains at risk of heart attack and stroke. Antithrombotic therapy is therefore a central, and often under-discussed, part of limb preservation. This article reviews what large randomised trials and recent guidelines say about antiplatelet and low-dose anticoagulant therapy in people with diabetes and PAD.
Why diabetes changes the antithrombotic question
People with diabetes and PAD carry a higher baseline risk of both cardiovascular events and adverse limb outcomes than people with PAD alone. Diabetes is associated with a pro-thrombotic state, more diffuse infrapopliteal disease, and a higher rate of amputation. Because the baseline risk is higher, a therapy that lowers relative risk by a given proportion tends to prevent more events in absolute terms in this population. This principle underlies much of the interest in intensified antithrombotic strategies for diabetic PAD.
Antiplatelet therapy: the long-standing foundation
Single antiplatelet therapy, usually aspirin or clopidogrel, has been the standard for symptomatic PAD. Attempts to improve on this with a more potent single agent have not succeeded. In the EUCLID trial (Hiatt et al., New England Journal of Medicine, 2017), ticagrelor was not superior to clopidogrel for cardiovascular events or limb outcomes in symptomatic PAD, and bleeding was similar. This result suggests that simply escalating the potency of one platelet inhibitor does not reliably protect the limb, which prompted interest in a different mechanism: reducing thrombin generation alongside platelet inhibition.
Dual-pathway inhibition: COMPASS and VOYAGER PAD
The COMPASS trial (Eikelboom et al., New England Journal of Medicine, 2017) randomised more than 27,000 people with stable coronary or peripheral artery disease to rivaroxaban 2.5 mg twice daily plus aspirin, rivaroxaban alone, or aspirin alone. The combination reduced major adverse cardiovascular events relative to aspirin alone (hazard ratio about 0.76) but increased major bleeding (about 3.1% versus 1.9%). In the PAD analysis (Anand et al., The Lancet, 2018), the combination reduced major adverse limb events, including major amputation, by roughly half compared with aspirin alone, with a particularly large relative reduction in major amputation.
A prespecified analysis of people with diabetes in COMPASS (Bhatt et al., Circulation, 2020) found that the relative benefit of dual-pathway inhibition was consistent regardless of diabetes status. Because people with diabetes had higher baseline event rates, their absolute risk reduction tended to be larger, which strengthens the net clinical benefit in this subgroup.
COMPASS enrolled people with stable disease. VOYAGER PAD (Bonaca et al., New England Journal of Medicine, 2020) addressed a higher-risk moment: 6,564 people with symptomatic PAD who had just undergone endovascular or surgical lower-extremity revascularisation. Rivaroxaban 2.5 mg twice daily plus aspirin reduced the primary composite of acute limb ischaemia, major amputation of vascular cause, myocardial infarction, ischaemic stroke, or cardiovascular death (17.3% versus 19.9% at three years; hazard ratio 0.85). Acute limb ischaemia, the largest driver of the benefit, was substantially reduced. Rates of TIMI major bleeding were not significantly different, although more major bleeding by other definitions occurred with the combination. Roughly 40% of participants had diabetes, and the benefit was directionally consistent in this group.
What guidelines recommend and where caution is needed
The intersocietal IWGDF, ESVS and SVS guidelines on peripheral artery disease in people with diabetes and a foot ulcer (Fitridge et al., 2023) emphasise that revascularisation decisions should be made by a multidisciplinary team and that cardiovascular risk reduction, including antithrombotic therapy, statins, and glycaemic and blood pressure management, should accompany any limb-directed intervention.
Bleeding remains the principal trade-off. Patients with prior gastrointestinal or intracranial haemorrhage, severe renal impairment, anaemia, or a need for concurrent anticoagulation require individual assessment. Impaired kidney function is common in diabetic foot disease and affects both bleeding risk and drug choice. The trials also enrolled selected populations, and the results may not apply equally to people with advanced chronic limb-threatening ischaemia, extensive tissue loss, or frailty.
Key takeaways
Antiplatelet monotherapy remains the baseline for diabetic PAD, and more potent single agents have not improved limb outcomes. Adding low-dose rivaroxaban to aspirin has reduced major adverse limb events and cardiovascular events in large trials, with the largest absolute gains in higher-risk groups such as people with diabetes, at the cost of more bleeding. Treatment choice should weigh ischaemic risk, bleeding risk, kidney function, and the timing of revascularisation, and should be coordinated within a multidisciplinary framework.
References
- Eikelboom JW, Connolly SJ, Bosch J, et al. Rivaroxaban with or without aspirin in stable cardiovascular disease (COMPASS). N Engl J Med. 2017.
- Anand SS, Bosch J, Eikelboom JW, et al. Rivaroxaban with or without aspirin in patients with stable peripheral or carotid artery disease. Lancet. 2018.
- Bhatt DL, Eikelboom JW, Connolly SJ, et al. Role of combination antiplatelet and anticoagulation therapy in diabetes mellitus and cardiovascular disease: insights from the COMPASS trial. Circulation. 2020.
- Bonaca MP, Bauersachs RM, Anand SS, et al. Rivaroxaban in peripheral artery disease after revascularization (VOYAGER PAD). N Engl J Med. 2020.
- Hiatt WR, Fowkes FGR, Heizer G, et al. Ticagrelor versus clopidogrel in symptomatic peripheral artery disease (EUCLID). N Engl J Med. 2017.
- Fitridge R, Chuter V, Mills J, et al. The intersocietal IWGDF, ESVS, SVS guidelines on peripheral artery disease in people with diabetes and a foot ulcer. Diabetes Metab Res Rev. 2023.
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