Data Show Rivaroxaban Lowers Severe Vascular Event Risk in Patients With PAD


Results of the phase 3 VOYAGER PAD clinical trial show rivaroxaban (Xarelto; Janssen Pharmaceutical Companies) plus aspirin lowers severe vascular events in patients with peripheral arterial disease after lower-extremity revascularization.

Data from the phase 3 VOYAGER PAD clinical trial found that rivaroxaban (Xarelto; Janssen Pharmaceutical Companies) at a vascular dose of 2.5 mg twice daily plus aspirin 100 mg once daily lowers severe vascular events in patients with peripheral arterial disease (PAD) following lower-extremity revascularization (LER).1

These findings, presented at the American College of Cardiology's (ACC) 71st Annual Scientific Session, highlight the impact of the rivaroxaban vascular dose in patients with PAD both with and without chronic kidney disease (CKD) and among those with and without a history of statin therapy, according to the study investigators.

"Patients with symptomatic PAD are already at a heightened risk of hospitalization following revascularization," said lead study author Mark Svet, MD, internal medicine resident, University of Colorado Anschutz School of Medicine, in a statement. "Previously reported primary data from the VOYAGER PAD clinical trial established the benefit of Xarelto plus aspirin in patients with PAD. Our research demonstrates the extension of this benefit to PAD patients with CKD in reducing rates of readmission following revascularization without increasing bleeding risk compared to those without CKD."

PAD affects an estimated 20 million adults in the United States and is the leading cause of amputations, with these rates continuing to rise. However, it frequently remains untreated, with only approximately 8.5 million individuals diagnosed with the condition. PAD causes blood vessels to narrow and decreases blood flow to the limbs, which most frequently affects the legs. These symptoms can become severe, requiring LER, which avoids amputation of the limb by restoring blood flow after the arteries have been clogged.2-5

The VOYAGER PAD trial randomized 6564 patients from 542 sites worldwide in a 1:1 ratio to receive either the rivaroxaban vascular dose at 2.5 mg twice daily plus aspirin 100 mg once daily (n=3286) or aspirin alone at 100 mg once daily (n=3278). The patients were followed for a median of 28 months.

Patients enrolled in the trial were stratified by either endovascular or surgical revascularization procedure type and by the use of clopidogrel administered at the treating physician's discretion.

The trial met the primary efficacy and principal safety endpoints, which illustrate the superiority of rivaroxaban compared with aspirin alone in lowering the risk of major adverse limb and cardiovascular events by 15% among individuals with symptomatic PAD after LER. The study investigators noted that the benefit of adding rivaroxaban to aspirin manifested early in the trial, was consistent across major subgroups, and continued to accrue over time. The researchers did not observe a significant increase in the TIMI risk score for major bleeding in patients administered the vascular dose of rivaroxaban versus aspirin alone (Kaplan-Meier estimate at 3 years 2.65% vs. 1.87%, respectively).

Further, the rivaroxaban vascular dose was found to significantly lower hospitalizations because of thrombotic events in patients who underwent LER versus those who took aspirin alone (Kaplan-Meier estimate at 3 years: 8.7% vs. 12.1%). In a subgroup analysis of patients with and without CKD, a consistent 4.7% absolute risk reduction was observed with rivaroxaban plus aspirin versus aspirin alone (Kaplan-Meier estimate at 3 years: 7.9% vs. 12.6%).

A moderated poster presentation at ACC.22 highlighted the role of rivaroxaban in patients with PAD both with and without a history of statin use. These findings were consistent with the overall VOYAGER PAD findings, showing that after LER, individuals administered the rivaroxaban vascular dose and statin therapy had a 19% drop in the primary endpoint composite of acute limb ischemia; major amputation for vascular cause; myocardial infarction; ischemic stroke or cardiovascular death; a 26% decrease in major adverse limb events (MALE); and a 32% decrease in acute limb injury compared with placebo and statin therapy.

Either with or without statin therapy, rivaroxaban was found to consistently lower the composite of major adverse cardiovascular events or MALE after LER for PAD.

In August 2021, the FDA approved an expanded indication for rivaroxaban plus aspirin for the treatment of patients following LER due to symptomatic PAD. The drug is the first and only therapy indicated for both coronary artery disease and PAD.

It is also the only anticoagulant in 20 years to show significant benefits in patients with PAD who are at high risk for major thrombotic events, including acute limb ischemia and amputation. Further, the vascular dose is the first and only approved treatment for PAD that uses dual pathway inhibition to target both clotting mechanisms, thrombin and platelet activation, according to Janssen.

"At Janssen, we are continuing to invest in clinical research to help evolve the standard of care for people living with serious cardiovascular diseases, like PAD, an area of critical unmet need," said James F. List, MD, PhD, Global Therapeutic Area Head, Cardiovascular, Metabolism, and Retina, Janssen Research & Development, LLC, in a statement. "Our research continues to support the use of the Xarelto vascular dose and is a treatment option physicians should consider for patients with PAD or coronary artery disease."


1. Data from New VOYAGER PAD Analyses at ACC.22 Reinforce Benefit of XARELTO® (rivaroxaban) Plus Aspirin in Patients with Peripheral Artery Disease (PAD) and Various Co-Morbid Conditions. Johnson & Johnson. [news release]. April 2, 2022.

2. Afzal N, Sohn S, Scott CG, Liu H, Kullo IJ, Arruda-Olson AM. Surveillance of peripheral arterial disease cases using natural language processing of clinical notes. AMIA Jt Summits Transl Sci Proc. 2017;2017:28-36. Retrieved June 2, 2021 from Accessed April 2, 2022.
3. Racial Disparities in Vascular Care. (n.d.). Accessed April 2, 2022
4. American Heart Association. PAD Toolkit for Health Care Professionals. Accessed April 2, 2022.
5. Creager MA, Matsushita K, Arya S, et al. Reducing nontraumatic lower-extremity amputations by 20% by 2030: time to get to our feet: a policy statement from the American Heart Association. Circulation. 2021;143(17):e875-e891. doi:10.1161/CIR.000000000000096. Accessed April 2, 2022.

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