Clopidogrel exposure along with aspirin and rivaroxaban should be ‘minimized or avoided’ in PAD revascularization

William R. Hiatt

“More bleeding with background clopidogrel, even if not severe by adjudication, may be associated with broad consequences, including discontinuation of therapies. In the absence of clear benefit, clopidogrel exposure along with aspirin and rivaroxaban should be minimized or avoided to reduce this risk,” concluded William R. Hiatt, MD, the Novartis Foundation endowed professor for cardiovascular research in the University of Colorado Anschutz School of Medicine, Aurora, Colorado.

Hiatt was presenting a subgroup analysis of the VOYAGER PAD trial during the American College of Cardiology/World Congress of Cardiology’s virtual scientific sessions (ACC.20/WCC Virtual)—originally scheduled to take place March 28–30 in Chicago.

He detailed that VOYAGER PAD aimed to assess the benefit and risk of rivaroxaban plus aspirin in patients with peripheral arterial disease (PAD) after lower extremity revascularization with and without concomitant clopidogrel.

This subgroup analysis evaluated further the efficacy and safety of concomitant clopidogrel use at baseline. More specifically, the investigators aimed to determine if, in symptomatic PAD patients undergoing lower-extremity revascularization randomized to rivaroxaban 2.5mg twice daily with aspirin versus aspirin alone, the efficacy and safety of rivaroxaban were consistent regardless of background clopidogrel use, and to explore temporal patterns of bleeding in relation to exposure and duration of clopidogrel.

“In patients with symptomatic PAD undergoing revascularization, the benefit of dual antiplatelet therapy (DAPT) is uncertain, with the only randomized controlled trial in surgical bypass showing no benefit and significantly increasing bleeding,” Hiatt said.

“Rivaroxaban added to aspirin significantly reduces limb and cardiovascular risk with consistent benefits regardless of clopidogrel; the safety and risk/benefit of rivaroxaban plus aspirin are consistent regardless of background clopidogrel; and, in patients receiving rivaroxaban, the addition of clopidogrel as a third agent, is associated with higher rates of bleeding during exposure.”


The VOYAGER PAD trial found that treatment with aspirin plus rivaroxaban following lower-extremity revascularization 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. This conclusion was presented yesterday at ACC.20/WCC Virtual by Marc Bonaca, a cardiologist at the University of Colorado Anschutz School of Medicine) and simultaneously published in the New England Journal of Medicine (NEJM).

The trial 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 ischemia, major vascular amputation, myocardial infarction, ischemic 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.

A total of 6,564 patients were randomized into VOYAGER PAD and followed for a median of approximately three years with complete accrual of primary events through September 2019.


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