Prevention of Arterial and Venous Vascular Events in Symptomatic Peripheral Arterial Disease Patients After Lower Extremity Revascularization in the VOYAGER PAD Trial: Dual Anticoagulant/Antiplatelet

Scott D. Berkowitz, M.D.
CPC Clinical Research/University of Colorado School of Medicine
Aurora, Colorado, U.S.

On Monday, July 19, 2021, Scott Darrell Berkowitz, M.D., Clinician/Scientist at CPC Clinical Research and Visiting Research Professor of Medicine at the University of Colorado School of Medicine in Aurora, Colorado, presented findings from late-breaking results of an analysis from the VOYAGER PAD trial, specifically around the prevention of arterial and venous thrombotic events in symptomatic peripheral arterial disease patients after lower extremity revascularization (LER). Accumulating evidence shows that atherosclerosis is associated with heightened risk of venous thromboembolism (VTE).  At the same time, patients with VTE are subject to an increased risk of atherothrombosis. Shared pathobiologies likely underlying these associations include endothelial dysfunction, inflammation, and thrombin and platelet activation. Strategies targeting more than one of these may have broad benefits for reducing thrombotic events across the spectrum of vascular territories in atherosclerosis.

The aim of the analysis was to describe the total burden of thrombotic events in patients with symptomatic peripheral artery disease (PAD) after LER and evaluate the efficacy of low-dose factor Xa inhibition added to low-dose antiplatelet therapy for the prevention of venous and arterial thrombotic events (first and total). A total of 6,564 patients were randomized to either rivaroxaban 2.5 mg twice a day or rivaroxaban placebo on a background of aspirin 100 mg daily, with clopidogrel permitted at the investigator’s discretion. Berkowitz explained that there were 1,372 total arterial and venous thrombotic events in the composite efficacy outcome of acute limb ischemia, major vascular amputation of a vascular etiology, myocardial infarction, ischemic stroke, and symptomatic VTE (DVT and PE). All events were adjudicated by a blinded Central Events Committee except for VTE, which was a prespecified, prospectively ascertained investigator-reported secondary endpoint.

The investigators discerned that approximately one in three who suffer a first thrombotic event will suffer another thrombotic event despite background therapy, with arterial the predominant type in both treatment arms. They found that the addition of rivaroxaban to aspirin reduced first thrombotic events by 24% and total arterial and venous thrombotic events by 23%, and that in absolute terms, for 100 patients initiated on treatment and followed for three years, rivaroxaban would prevent six thrombotic (arterial and venous) events.

In summary, the investigators observed that symptomatic PAD patients have a large thrombotic burden and are at high risk for both arterial (limb and cardiovascular) and venous thrombotic events after LER, despite standard available medical therapy. They concluded that VOYAGER PAD provides evidence for the benefit of combining low-dose anticoagulation with low-dose antiplatelet medication (dual pathway inhibition) over antiplatelet therapy alone in protecting against the adverse arterial and venous thrombotic risk profile of patients symptomatic for PAD who require surgical or endovascular revascularization. In addition, they advise that future clinical trials should continue this holistic focus, that is, comprehensive CV outcome assessment, including total and venous events, to capture the full picture and benefit.