VOYAGER PAD - the Vascular Outcomes Study of ASA (acetylsalicylic acid) Along with Rivaroxaban in Endovascular or Surgical Limb Revascularization for PAD

The Vascular Outcomes Study of ASA (acetylsalicylic acid) Along with Rivaroxaban in Endovascular or Surgical Limb Revascularization for PAD (peripheral artery disease) (VOYAGER PAD) was designed to test the hypothesis that rivaroxaban at 2.5 mg twice daily added to aspirin, as compared with aspirin alone, would reduce the risk of a composite of acute limb ischemia, major amputation for vascular causes, myocardial infarction, ischemic stroke, or death from cardiovascular causes in patients with symptomatic peripheral artery disease who had undergone lower-extremity revascularization

VOYAGER PAD study

• a double-blind trial, patients with peripheral artery disease who had undergone revascularization were randomly assigned to receive rivaroxaban (2.5 mg twice daily) plus aspirin or placebo plus aspirin
• primary efficacy outcome was a composite of acute limb ischemia, major amputation for vascular causes, myocardial infarction, ischemic stroke, or death from cardiovascular causes
• principal safety outcome was major bleeding, defined according to the Thrombolysis in Myocardial Infarction (TIMI) classification; major bleeding as defined by the International Society on Thrombosis and Haemostasis (ISTH) was a secondary safety outcome.

Study Results:

• a total of 6564 patients underwent randomization; 3286 were assigned to the rivaroxaban group, and 3278 were assigned to the placebo group
• primary efficacy outcome occurred in 508 patients in the rivaroxaban group and in 584 in the placebo group; the Kaplan-Meier estimates of the incidence at 3 years were 17.3% and 19.9%, respectively (hazard ratio, 0.85, 95% confidence interval [CI], 0.76 to 0.96; P=0.009)
• TIMI major bleeding occurred in 62 patients in the rivaroxaban group and in 44 patients in the placebo group (2.65% and 1.87%; hazard ratio, 1.43; 95% CI, 0.97 to 2.10; P=0.07)
• ISTH major bleeding occurred in 140 patients in the rivaroxaban group, as compared with 100 patients in the placebo group (5.94% and 4.06%; hazard ratio, 1.42; 95% CI, 1.10 to 1.84; P=0.007).

Study authors concluded

• in patients with peripheral artery disease who had undergone lower-extremity revascularization, rivaroxaban at a dose of 2.5 mg twice daily plus aspirin was associated with a significantly lower incidence of the composite outcome of acute limb ischemia, major amputation for vascular causes, myocardial infarction, ischemic stroke, or death from cardiovascular causes than aspirin alone

"In this trial, which involved a broad population of patients who had undergone lower-extremity revascularization, nearly 1 in 5 patients in the placebo group had the primary composite outcome of acute limb ischemia, major amputation for vascular causes, myocardial infarction, ischemic stroke, or death from cardiovascular causes at 3 years. The addition of rivaroxaban at a dose of 2.5 mg twice daily to aspirin reduced this risk by approximately 15%. The benefit was apparent early, with the Kaplan-Meier curves separating at 3 months, was consistent among subgroups, and continued to accrue over time.

In VOYAGER PAD, there was a numerical increase in TIMI major bleeding and significantly increased ISTH major bleeding but no excess in intracranial or fatal bleeding.

At a median follow-up of 28 months, the incidence of the composite primary endpoint (acute limb ischemia, major amputation for vascular cause, heart attack, ischemic stroke or cardiovascular death) was 17.3% in the rivaroxaban plus aspirin group and 19.9% in the aspirin and placebo group (HR 0.85; 95% CI 0.76-0.96). To put the relative risk reduction into context, at 6 months there was a 1.5% absolute risk reduction and a number-needed-to-treat (NNT) of 65. At 12 months, there was a 2% risk reduction and an NNT of 50, and at 3 years, there was a 2.6% risk reduction and an NNT of 39.

This study provides more evidence of benefit of dual therapy with aspirin plus low dose rivaroxaban in peripheral arterial disease - in this study following revascularization surgery. There was however an increase in bleeding associated with dual therapy, although no excess in intracranial or fatal bleeding" (2)

Reduction in thromboembolism risk (3)

• secondary analysis of the COMPASS trial (27,395) and data review from the VOYAGER PAD study found the vascular benefits of adding rivaroxaban 2.5mg twice daily to aspirin were consistent across age, cancer status number of vascular beds involved and renal function

Reference:

1. Bonaca MP et al. Rivaroxaban in Peripheral Artery Disease after Revascularization. N Engl J Med 2020; 382:1994-2004
2. Commentary - Dr Jim McMorran (Editor in Chief, GPnotebook) May 18th 2021
3. Pogosova N et al. Rivaroxaban 2.5 mg Twice Daily Plus Aspirin Reduces Venous Thromboembolism in Patients With Chronic Atherosclerosis. Circulation, June 2022