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People who took rivaroxaban (Xarelto) after lower-extremity revascularization for peripheral artery disease (PAD) enjoyed fewer subsequent major adverse limb and cardiovascular events, according to the VOYAGER PAD trial.

The primary efficacy outcome -- a composite of acute limb ischemia, major amputation for vascular causes, MI, ischemic stroke, or death from cardiovascular causes at 3 years -- was observed in 17.3% of people on rivaroxaban and aspirin versus 19.93% of peers randomized to placebo and aspirin (hazard ratio 0.85, 95% CI 0.76-0.96).

Driving the difference between groups was a reduction in acute limb ischemia with rivaroxaban (5.24% vs 7.74%, HR 0.67, 95% CI 0.55-0.82), according to Marc Bonaca, MD, MPH, of the University of Colorado Anschutz School of Medicine in Aurora.

Bonaca revealed the VOYAGER PAD results during a of the virtual American College of Cardiology annual meeting. The trial results were simultaneously published online in the .

Depending on how major bleeding was counted in the study, patients on the direct oral anticoagulant either fared similarly to the placebo arm (TIMI major bleeding 2.65% vs 1.87%, HR 1.43, 95% CI 0.97-2.10) or were worse off (ISTH major bleeding 5.94% vs 4.06%, HR 1.42, 95% CI 1.10-1.84).

"Like all studies of antithrombotic therapy, VOYAGER demonstrates that 'there's no free lunch' and the bleeding hazard is prominent in the rivaroxaban group, despite having an overall low incidence overall," commented W. Schuyler Jones, MD, of Duke University School of Medicine in Durham, North Carolina.

TIMI major bleeding included fatal bleeds, intracranial hemorrhaging, decreases in hemoglobin of 5 g/dL or more, and hematocrit at least 15%. ISTH major bleeding counted fatal bleeding, bleeds into a critical site, hemoglobin reaching 2 g/dL, and transfusion of at least two units of packed red cells or whole blood.

"We estimate that for every 10,000 patients who were treated for 1 year, rivaroxaban at a dose of 2.5 mg twice daily added to aspirin would prevent 181 primary efficacy outcome events at the cost of 29 principal safety outcome events," Bonaca's group said.

The 2.5-mg dose of rivaroxaban was approved by the FDA in 2018 for long-term prevention for people with coronary artery disease and PAD, based on results from the COMPASS trial.

"In COMPASS, patients with PAD had a significantly lower rate of major adverse events when taking rivaroxaban when compared with placebo, so VOYAGER confirms this finding and extends it to the group of patients who are undergoing peripheral revascularization," according to Jones.

"The authors should be congratulated on the study results, as they measured things that patients with the disease truly care about," Jones told MedPage Today. However, the devil is in the details of this study, he suggested, as not all outcomes were consistently improved with rivaroxaban.

VOYAGER PAD was conducted at 534 sites in 34 countries. The double-blind trial included 6,564 PAD patients undergoing surgical or endovascular revascularization for ischemic symptoms.

All participants were randomized to either rivaroxaban 2.5 mg twice daily or placebo on top of aspirin therapy.

The two groups were well matched at baseline. Median age was 67, and 26% were women. The cohort had a median ankle brachial index of 0.56. Investigators noted that 81% were Caucasian, 40% had diabetes, and 35% were current smokers.

Most patients were on clopidogrel (Plavix), statins, or angiotensin converting enzyme inhibitors/angiotensin II receptor blockers at baseline.

More than three-quarters of study participants received revascularization for claudication; the remainder for critical limb ischemia. Endovascular or hybrid procedures accounted for two-thirds of the revascularizations in the trial.

Efficacy and safety results were consistent across prespecified subgroups, Bonaca reported.

One major limitation of VOYAGER PAD was the 14% annual rate of premature treatment discontinuation in the rivaroxaban group.

The investigators acknowledged that "the high percentage of patients with premature treatment cessation may have attenuated the benefits observed in the intention-to-treat analysis, as suggested by the on-treatment analysis."

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