SLR - June 2021 - Kaitlin T. Flavin

Rivaroxaban in Peripheral Artery Disease after Revascularization 

Reference: Bonaca M., Bauersachs R., Anand S., Debus S., Nehler M., & Patel M., et al. (2021). Rivaroxaban in Peripheral Artery Disease after Revascularization. The New England Journal of Medicine, 382:1994-2004. https://doi.org/10.1056/NEJMoa2000052

Level of Evidence: Level 2

Scientific Literature Review 

Reviewed By: Kaitlin T. Flavin, DPM
Residency Program: MetroWest Medical Center, Framingham, MA

Podiatric Relevance: Many podiatric patients suffer from peripheral arterial disease. Patients with symptomatic peripheral artery disease who have undergone lower-extremity revascularization remain at high risk for major adverse limb and cardiovascular events. The authors’ aim was to compare the efficacy and safety of rivaroxaban plus aspirin after lower extremity peripheral revascularization to aspirin alone. 

Methods: Participants were randomized to rivaroxaban or control groups, consisting of adults >50y, with peripheral arterial disease and recent revascularization (<10 d). Exclusion criteria included bleeding risk, clinically unstable, or taking prohibited concomitant medications. The rivaroxaban group took 2.5mg po BID plus 100mg aspirin po daily. The control group took aspirin and a placebo. Primary outcome measure included a composite of acute limb ischemia, major amputation for vascular causes, myocardial infarction, ischemic stroke, or death from cardiovascular causes. Primary and secondary safety measures evaluated bleeding.

Results:
• N=6564, randomized from 542 sites in 34 countries from 2015-2018; 3286 in the rivaroxaban group and 3278 for control. Results were event driven. Median follow up was 28 months. 
• The groups were well balanced for age, sex, BMI, race, medications, risk factors, and geographic region. Thirty-five percent were active smokers.
• The rivaroxaban group had significantly lower occurrence of the primary efficacy outcome; 508 patients in the rivaroxaban group and 584 in the placebo group. Kaplan–Meier estimates of the incidence of an event at three years were 17.3 percent and 19.9 percent, respectively (p=0.009). 
• Principal safety outcome: No significant difference was found between groups as major bleeding occurred in 62 patients from the rivaroxaban group and 44 in the control group (p=0.07). Of note, fatal bleeding occurred in six patients from each group. 
• Secondary safety outcomes of bleeding occurred in 140 of the rivaroxaban group and 100 of the control group, which was significant (p=0.007)

Conclusions: 
• Compared to aspirin alone, rivaroxaban plus aspirin was associated with significantly less occurrence of the primary efficacy outcome in patients after peripheral revascularization. Of note, one in five patients in the aspirin + placebo group had occurrence of the composite primary outcome above. 
• Rivaroxaban plus aspirin decreased the risk of the primary composite outcome by approximately 15 percent, and the benefit was observed early, around the three-month mark. 
• Secondary safety outcomes associated with bleeding were significantly higher in the treatment group. These included fatal bleeding, bleeding into a critical site, a decrease in hemoglobin level of =2 g per deciliter, or transfusion of at least two units of packed red cells or whole blood. 
• Limitations include that a large number of patients who received at least one dose of medication discontinued the trial prematurely. Additionally, though the authors claim no financial conflicts, it is of note that the study was sponsored by Bayer, the manufacturer of rivaroxaban.

More research is warranted on the usage of rivaroxaban, an orally active direct inhibitor of factor Xa, to adjunct aspirin therapy after revascularization, and balancing the risks of major and minor bleeding. As podiatrists, we should educate patients on their peripheral vascular health and ways to optimize it.

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