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The impact of low-dose anticoagulation therapy on peripheral artery disease: insights from the VOYAGER trial.

Even with modern medical therapy, patients with peripheral artery disease (PAD) remain at very high risk for major adverse cardiovascular events (MACE) and major adverse limb events (MALE). Several previous studies aimed at improving PAD-related outcomes have evaluated more intensive single antiplatelet therapies, dual antiplatelet regimens, and/or the addition of anticoagulation therapy. As elegantly reviewed by Kaplovitch and Anand, these attempts were largely underwhelming, and most trials failed to achieve the fine balance of reducing MACE/MALE without increasing bleeding risk. Recently, the COMPASS trial showed that in chronic stable PAD patients, low-dose rivaroxaban (2.5 mg twice daily) added to aspirin potently reduced both MACE [5% vs. 7%, hazard ratio (HR) 0.72] and MALE (1% vs. 2%, HR 0.54) compare to aspirin alone. This was accompanied by an increase in major bleeding, but not fatal bleeding or intracranial haemorrhage. Despite the fact that this trial was stopped early for its favourable net clinical benefit, the uptake of low-dose rivaroxaban amongst chronic PAD patients has remained low, presumably due to cost concerns and/or the perception that stable outpatients may not ‘need’ additional risk reduction, especially if it comes at the price of increased bleeding. The VOYAGER trial set out to determine if low-dose rivaroxaban would demonstrate an acceptable risk–benefit profile in PAD patients with more advanced disease who require revascularization (a group that might also be at higher bleeding risk). This international, multicentre, double-blinded trial examined low-dose rivaroxaban (2.5 mg twice daily) plus aspirin vs. placebo plus aspirin in symptomatic PAD patients following either endovascular or surgical revascularization. The primary efficacy endpoint was a composite of clinically relevant MACE and MALE components, and the principal safety outcome was major bleeding. Patients were enrolled within 10 days of a successful intervention and a second antiplatelet agent (clopidogrel) was allowed to be administered for up to 6 months at the discretion of the investigator. The trial included 6564 subjects from 34 countries who were followed for a median of 28 months with only 1% of patients lost to follow-up. Results showed significantly lower events in the rivaroxaban group for the primary outcome (17.3% vs. 19.9%, HR 0.85), with a particularly notable improvement in acute limb ischaemia compared to the placebo group (5.2% vs. 7.8%, HR 0.67). The Kaplan–Meier curves separated within the first 3 months and continued to improve over time with a number needed to treat of 39 at the terminal endpoint. Secondary outcomes including the need for recurrent revascularization (‘take backs’) and re-hospitalization (‘bounce backs’) were also significantly lower, though there was no improvement in all-cause mortality (HR 1.08, P = 0.34). Thrombolysis in myocardial infarction (TIMI) major bleeding (2.65% vs. 1.87%, P = 0.07) and fatal bleeding (six in each group) did not differ significantly, although the secondary safety outcome of International Society on Thrombosis and Haemostasis (ISTH) major bleeding was clearly higher in the rivaroxaban group at 3 years (5.94% vs. 4.06%, HR 1.42, P = 0.007). Importantly, there was no interaction by type of intervention performed (open vs. endovascular), nor by clopidogrel usage. The authors estimated that for every 10 000 patients treated for a year with low-dose rivaroxaban plus aspirin, 181 MACE/MALE events would be prevented at the cost of 29 bleeding events. There is both clinical and genetic evidence to support the rationale for the use of low-dose anticoagulation in this population. Narula et al. described the histopathological characteristics of lower extremity arterial occlusive disease and cited differences between the femoral and popliteal (FEM-POP) and infrapopliteal (INFRA-POP) vessels in PAD. There were significantly more atherosclerotic lesions noted in the FEM-POP arteries, while the INFRA-POP arteries were frequently occluded with acute or chronic thrombi. Interestingly, thrombotic occlusion was more likely to occur in the absence of significant atherosclerosis in the INFRAPOP arteries, where layered thrombi suggested repeated thromboembolic events. This is unlike the coronary arteries where atherosclerotic plaque rupture (and associated exposure of tissue factor) may play a greater role in promoting clinical events. It is also known that PAD shares some, but not all, pathophysiological determinants with other vascular disorders, such as coronary artery disease (CAD) and cerebrovascular disease (CVD). For example, Klarin et al. recently performed an elegant genomics study using data from the Million Veteran Program (MVP) and UK Biobank, which highlighted the similarities and differences among CAD, CVD, and PAD patients. Using genome-wide and phenome-wide association studies, the authors identified four loci which were uniquely associated with PAD, including a novel