American College of Cardiology

American College of Cardiology

Perspective from Carl J. Pepine, MD
March 28, 2020
4 min read

Low-dose rivaroxaban reduces risk in PAD post-revascularization

Perspective from Carl J. Pepine, MD
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Marc P. Bonaca

In the VOYAGER PAD trial, patients with symptomatic peripheral artery disease who underwent lower-extremity revascularization had a lower incidence of major adverse limb and CV events compared if treated with low-dose rivaroxaban twice daily plus aspirin, compared with aspirin only.

Among more than 6,500 patients with PAD who were followed for a median of 28 months, the cumulative incidence of acute limb ischemia, major amputation for vascular cause, MI, ischemic stroke or CV death was 17.3% in those who received rivaroxaban (Xarelto, Bayer/Janssen) 2.5 mg twice daily on top of aspirin 100 mg daily compared with 19.9% in those who received a matching placebo plus aspirin (HR = 0.85; 95% CI, 0.76-0.96; P = .0085).

The benefit of rivaroxaban was “apparent early and continued over time,” Marc P. Bonaca, MD, associate professor and director of vascular research at University of Colorado School of Medicine, said while presenting the results during the virtual American College of Cardiology Scientific Session.

In terms of bleeding, the incidence of TIMI major bleeding, the primary safety endpoint, did not significantly differ between the two treatment groups, occurring in 2.7% of patients assigned rivaroxaban plus aspirin compared with 1.9% assigned aspirin only (HR = 1.43; 95% CI, 0.97-2.1; P = .0694). However, ISTH major bleeding, a secondary endpoint, was higher with rivaroxaban (5.9% vs. 4.1%; HR = 1.42; 95% CI, 1.1-1.84; P = .0068).

“There was a numerical increase in TIMI major bleeding and significantly increased ISTH major bleeding, but no excess in intracranial or fatal bleeding,” Bonaca said.

Taken together, with the rivaroxaban-aspirin treatment strategy “there is about a sixfold increase in the number of ischemic events prevented relative to bleeds caused,” Bonaca said.

The VOYAGER PAD results were published simultaneously in The New England Journal of Medicine.

‘The STEMI equivalent of the limb’

More than 200 million people worldwide have lower-extremity PAD and are at heightened risk for major adverse cardiac events. Moreover, patients with PAD who require revascularization are at particularly high risk for limb events and CV outcomes following revascularization. Patients who undergo revascularization have a fourfold risk for acute limb ischemia compared with those who do not undergo revascularization, according to Bonaca.

“Acute limb ischemia is the STEMI equivalent of the limb,” he told the virtual attendees.

VOYAGER PAD “brings acute limb ischemia to the CV treating community. ... Acute limb ischemia is a severe event that comes with a significant amount of morbidity and mortality, and it’s something to be feared and avoided as much as possible,” Joshua Beckman, MD, director of vascular medicine and professor of medicine at Vanderbilt University Medical Center, said during a discussion of the trial.


In VOYAGER PAD, acute limb ischemia was the most frequent adverse outcome among patients assigned placebo, and the data demonstrated a robust reduction with rivaroxaban, Bonaca said.

There have been few studies in patients with PAD in this setting. Further, there are no class I recommendations for antithrombotic therapy beyond aspirin or clopidogrel, and no recommendations specific to the post-revascularization setting for those with PAD.

“This [trial] really expands our understanding of the value of rivaroxaban in patients with PAD. ... Moreover, I think this points quite clearly to the point in time of care when this medication can be applied, and to a specific population of treating clinicians the application of these therapies after either endovascular or surgical revascularization is a perfect point in time to begin,” Beckman said.

Broad PAD population studied

VOYAGER PAD was an international study that enrolled a broad population of 6,564 patients with lower-extremity PAD who underwent a recent successful revascularization procedure. Patients were assigned rivaroxaban or placebo on top of aspirin. A limited course of clopidogrel was allowed at the investigator’s discretion.

At baseline, the median age was 67 years, one-quarter were women and the majority were white. Bonaca noted that risk factors were common, including diabetes (40%), active smoking (35%) and renal dysfunction (20%). In spite of this risk profile, he said, less than one-third had known CAD and only 11% had a previous MI at baseline. Background therapy included statins in 80%, ACE inhibitors or angiotensin receptor blockers in 63% and clopidogrel in 50%.

All patients had symptomatic PAD at baseline and more than one-third had a history of revascularization. The median ankle-brachial index before intervention was 0.56. Claudication was the primary indication for revascularization in three-quarters of patients, and critical limb ischemia in one-quarter. Most patients underwent endovascular or hybrid revascularization and one-third underwent surgical revascularization.

The primary results of VOYAGER PAD showed a consistent benefit across major subgroups and broad benefits including reductions in unplanned index limb revascularization, according to Bonaca. There was no benefit of rivaroxaban on CV death in this study.

To put the findings in context, “in patients with PAD requiring revascularization, for 100,000 patients treated for 1 year with rivaroxaban 2.5 mg twice daily with aspirin vs. aspirin alone, there would be the prevention of 181 first ischemic events. ... The cost of this would be 29 TIMI major bleeds, without any excess in intracranial hemorrhage or fatal bleeding,” Bonaca said.


The VOYAGER PAD investigators noted in NEJM that these results “extend and complement the observations in the COMPASS trial,” which also evaluated low-dose rivaroxaban plus aspirin in patients with PAD and CAD.

“Together, these trials show the efficacy of rivaroxaban at a dose of 2.5 mg twice daily added to aspirin in peripheral artery disease from its initiation after the lower-extremity intervention and continuing through long-term prevention,” the investigators wrote in NEJM. by Katie Kalvaitis


Bonaca MP, et al. Joint American College of Cardiology and Journal of the American College of Cardiology Late-Breaking Clinical Trials. Presented at: American College of Cardiology Scientific Session; March 28-30, 2020 (virtual meeting).

Bonaca MP, et al. N Engl J Med. 2020;doi:10.1056/NEJMoa2000052.

Disclosures: The VOYAGER PAD trial was funded by Bayer and Janssen. Bonaca reports he receives grant support to Colorado Prevention Center Clinical Research from Amgen, Aralez, AstraZeneca, Bayer, Janssen, Merck, Novo Nordisk, Pfizer and Sanofi.