Treatment with aspirin plus rivaroxaban following lower extremity revascularisation in patients with peripheral arterial disease (PAD) leads to a 15% reduction in the risk of major adverse limb and cardiovascular events when compared with aspirin alone.
The VOYAGER PAD study was presented at the American College of Cardiology/World Congress of Cardiology’s virtual scientific sessions (ACC.20/WCC Virtual)—originally scheduled to take place 28–30 March in Chicago, USA—and simultaneously published in the New England Journal of Medicine (NEJM). It found that a twice daily dose of 2.5mg rivaroxaban plus low dose aspirin is associated with significantly lower incidence of the composite primary efficacy outcome of acute limb ischaemia, major vascular amputation, myocardial infarction, ischaemic stroke, or death from cardiovascular causes than aspirin alone. On the principal safety outcome of Thrombolysis in Myocardial Infarction (TIMI) major bleeding there was no significant difference between the therapies. However, rivaroxaban plus aspirin was associated with a significantly higher incidence for the secondary safety outcome of International Society on Thrombosis and Haemostasis (ISTH) major bleeding.
Marc P Bonaca (University of Colorado Anschutz School of Medicine, Aurora, USA) outlined the findings for the virtual conference as part of a late-breaking session. He explained that the risks of major adverse limb and cardiovascular events are high in patients with PAD who have lower extremity revascularisation, but there is uncertainty about how effective and safe rivaroxaban is in this context. “In spite of this risk,” he said, “there are no proven antithrombotic strategies to reduce the risk of limb and cardiovascular outcomes after revascularisation. VOYAGER PAD was designed to address this gap.”
The double blind trial randomised 6,564 patients with PAD who had undergone revascularisation to receive either rivaroxaban 2.5mg twice daily plus aspirin (n=3,286) or placebo plus aspirin (n=3,278).
Baseline characteristics were well balanced across the two groups, with median age 67 years, and 26% of patients were female. Risk factors were common: 40% of patients had diabetes mellitus, 20% had an estimated glomerular filtration rate less than 60ml per minute per 1.73 m2 of body-surface area, and 35% were active smokers at randomisation. Less than one third of patients (31%) had known coronary artery disease, and 11% had previous myocardial infarction. The majority of patients (96%) had a history of claudication, and the median ankle–brachial index was 0.56. Bonaca described participants as “a sick population”.
The primary efficacy outcome occurred in 508 patients in the rivaroxaban group and 584 patients in the placebo group. Three-year Kaplan-Meier estimates of the incidence were 17.3% in the rivaroxaban arm and 19.9% in the placebo arm (hazard ratio [HR] 0.85, 95% confidence interval [CI] 0.76–0.96, p=0.009).
The incidences of the first five secondary outcomes in the testing hierarchy were all significantly lower in the rivaroxaban group than in the placebo group, including the incidence of unplanned index limb revascularisation for recurrent ischaemia (HR 0.88, 95% CI 0.79–0.99, p=0.03). All-cause mortality was not lower in the rivaroxaban group than in the placebo group (HR 1.08, 95% CI 0.92–1.27, p=0.34). Therefore, the researchers write in the NEJM: “In accordance with the prespecified hierarchical testing procedure, the assessment of the last secondary outcome (venous thromboembolism) was considered exploratory.”
There was no heterogeneity in the efficacy of rivaroxaban plus aspirin as compared with aspirin alone for the primary outcome across major subgroups, including those based on age, sex, and cardiovascular risk factors. Similarly, there was no heterogeneity on the basis of qualifying symptoms, type of intervention, ankle–brachial index at screening, or the presence of critical limb ischaemia at index revascularisation.
TIMI major bleeding occurred in 62 (2.65%) patients in the rivaroxaban group and 44 (1.87%) patients in the placebo group (HR 1.43, 95% CI 0.97-2.1, p=0.07.). Intracranial haemorrhage occurred in 13 patients in the rivaroxaban group and in 17 patients in the placebo group (hazard ratio, 0.78; 95% CI, 0.38 to 1.61). Fatal bleeding occurred in 6 patients in each group.
The second safety outcome of ISTH major bleeding occurred in 140 patients on rivaroxaban versus 100 patients in the placebo group (5.94% and 4.06%, respectively, HR 1.42, 95% CI 1.1–1.84, p=0.007).
Bonaca told the online audience: “To put these results into context, in patients with PAD requiring revascularisation, for 10,000 patients treated for one year with rivaroxaban 2.5mg twice daily with aspirin versus aspirin alone there would be the prevention of 181 first ischaemic events with the components of [the primary efficacy outcome events]. The cost of this would be 29 TIMI major bleeds without any excess in intracranial haemorrhage or fatal bleeding.”
Summing up he said: “In symptomatic peripheral arterial disease after revascularisation … in this population and in this setting, rivaroxaban 2.5mg twice daily with aspirin compared to aspirin alone significantly reduces this risk. The benefits appear early and continued over time, with consistent benefit across subgroups including those with critical limb ischaemia and broad benefits included reductions in the need for unplanned index limb revascularisation. It does increase bleeding and with VOYAGER PAD there was a numerical increase in TIMI major bleeding and statistically significant increase in ISTH major bleeding with no excess in intracranial or fatal bleeding, and putting them together there is about a six-fold increase in the number of ischaemic events prevented relative to bleeds caused.”