Peripheral artery disease (PAD) patients who have undergone lower-extremity revascularization and take rivaroxaban plus aspirin may have a lower incidence of major adverse limb and cardiovascular events than patients who take aspirin alone, according to results of the VOYAGER-PAD trial presented March 28 at ACC.20/WCC during a Late-Breaking Clinical Trial session and simultaneously published in the New England Journal of Medicine.

Marc P. Bonaca, MD, MPH, FACC, et al., randomly assigned 6,564 PAD patients who had undergone lower-extremity revascularization to take rivaroxaban 2.5 mg twice daily plus aspirin or a placebo and aspirin. The international trial involved 534 sites in 34 countries and ran from July 2015 to January 2018.

A total of 3,286 patients were assigned to the rivaroxaban group and 3,278 were assigned to the placebo group. The median age of patients was 67 years, and 26% were women. At baseline, 40% were diabetic, 60% had hyperlipidemia, and about 32% had coronary artery disease.

In terms of their PAD history, 95% had claudication, 35% prior revascularization and 6% amputation. The median ankle brachial index was 0.56. Critical limb ischemia was the indication for revascularization in 23% and claudication in 77%. Surgical revascularization was the approach in 35% and endovascular or a hybrid approach in 77%. 

The primary efficacy outcome – defined as a composite of acute limb ischemia, major amputation for vascular causes, myocardial infarction (MI), ischemic stroke or cardiovascular death – occurred in 508 patients in the rivaroxaban group, compared with 584 patients in the placebo group. The Kaplan-Meier estimates of incidence at three years were 17.3% for the rivaroxaban group vs. 19.9% for the placebo group (hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.76-0.96; p =0.009). The absolute risk reduction was 1.5% at six months, 2.0% at one year and 2.6% at three years.

The principal safety outcome – defined as major bleeding based on the Thrombolysis in Myocardial Infarction (TIMI) classification – occurred in 62 patients in the rivaroxaban group and 44 in the placebo group (HR, 1.43; 95% CI, 0.97-2.10, p=0.07). The secondary safety outcome – defined as International Society on Thrombosis and Haemostasis major bleeding – occurred in 5.9% and 4.1% of the rivaroxaban and placebo groups, respectively (HR, 1.42; 95% CI, 1.10-1.84; p=0.007).

According to the researchers, rivaroxaban significantly reduces the risk of acute limb ischemia, major amputation for vascular causes, MI, ischemic stroke or cardiovascular death, compared with aspirin alone in this population and setting. In addition, the researchers note the benefit of rivaroxaban was apparent early in treatment and was consistent over time across major subgroups, including patients with critical limb-threatening ischemia, and reduces the need for unplanned index limb revascularization. Although ISTH major bleeding was increased with rivaroxaban, there was no apparent excess in severe bleeding events.

"We found adding low-dose rivaroxaban after peripheral artery intervention significantly reduced the spectrum of complications that we fear most in PAD, which is acute limb ischemia, major vascular amputation, heart attack and stroke. This benefit was not only seen early on but was also maintained over time," says Bonaca, the study's lead author. "These data provide evidence of an antithrombotic regimen that effectively reduces risk, and although bleeding rates were higher, the overall risk-benefit remains quite favorable and could have a profound impact on patients' lives."

No Benefit in Adding Clopidogrel

Adding clopidogrel to the rivaroxaban and aspirin regime at the time of revascularization did not offer additional clinical benefit, according a VOYAGER-PAD subgroup analysis presented March 29 at ACC.20/WCC during a Late-Breaking Clinical Trial session.

For this prespecified subgroup analysis, William R. Hiatt, MD, et al., randomly assigned half of the patients to receive clopidogrel at the time of revascularization for up to six months. The patients receiving clopidogrel were more likely to undergo endovascular procedures (90.7%) vs. surgery (9.3%).

After a median follow up of 28 months, the addition of clopidogrel had no effect on the 15% reduction in the risk of major limb or cardiovascular complications among patients taking rivaroxaban. TIMI major bleeding was reported in 2.7% of patients who received clopidogrel vs. 2.6% of those who did not. Minor TIMI bleeding events occurred in 1.67% of patients in the clopidogrel group vs. 1.26% who did not take clopidogrel. In addition, ISTH major bleeding occurred in 6.5% of patients taking clopidogrel vs. 5.4% of those not taking the medication. Intracranial bleeds were infrequent and similar among those taking and not taking clopidogrel, respectively.

The benefits rivaroxaban and aspirin were consistent regardless of whether patients also took clopidogrel, but clopidogrel increased the risk of bleeding, the researchers conclude. "We found that in this [clinical] setting, where we are treating patients with symptomatic PAD with lower extremity revascularization procedures, the addition of clopidogrel [atop] rivaroxaban and aspirin does not provide any further benefit, but did increase bleeding risks, so there doesn't seem to be a compelling reason to use it," Hiatt says.

Clinical Topics: Heart Failure and Cardiomyopathies, Prevention, Vascular Medicine, Atherosclerotic Disease (CAD/PAD), Acute Heart Failure

Keywords: ACC Annual Scientific Session, acc20, Aspirin, Peripheral Arterial Disease, Heart Failure, Primary Prevention, Aneurysm

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