Combination of NOAC plus aspirin in older PAD patients after limb revascularization
Low-dose rivaroxaban plus aspirin in older patients with peripheral artery disease undergoing acute limb revascularization: insights from the VOYAGER PAD trial
Introduction and methods
Age is an important risk factor for peripheral artery disease (PAD). Because of concern of higher bleeding risk with advanced age, patients with PAD are often undertreated compared with coronary artery disease (CAD) counterparts . Bleedings scores as ACUITY, CRUSADE, DAPT and PRECISE-DAPT reinforce the clinical uncertainty with regard to benefit-risk ratio for initiation of antithrombotic therapy in older patients with atherosclerosis [2,3].
This study examined the benefit-risk balance of use of combination antithrombotic therapy in PAD patients ≥75 years, acutely after percutaneous or surgical lower extremity revascularization (LER) using data of the VOYAGER PAD trial .
VOYAGER PAD was a randomized, double-blind, placebo-controlled trial. Results showed that in PAD patients who had undergone LER, treatment with rivaroxaban (2.5 mg twice daily) with aspirin as compared to aspirin alone significantly reduced risk of ischemic limb and CV events. Older age in the study was pre-specified as ≥75 years. Primary efficacy outcome was composite of ALI, major amputation of a vascular etiology, MI, ischemic stroke or CV death. The principal safety outcome was TIMI major bleeding.
- 1330 Patients (20%) of the 6564 patients were ≥75 years.
- In placebo patients, risk of primary efficacy outcome and bleeding rates were higher in patients ≥75 years compared to those <75 years.
- Primary efficacy outcome was reduced by rivaroxaban in patients ≥75 years (HR 0.86, 95%CI: 0.64-1.05, P=0.058) and in those <75 years (HR 0.86, 95%CI: 0.75-0.98) (Pinteraction=0.83).
- Benefit of rivaroxaban in patients ≥75 years was mainly driven by reductions in limb vascular events including ALI and occurrence of major amputation of vascular etiology.
- Benefit of ALI appeared to be greater in those ≥75 years compared to those <75 years (HR 0.74, 95%CI: 0.60-0.93, Pinteraction=0.0193).
- Rivaroxaban reduced the first 5 secondary outcomes, without heterogeneity in treatment effect for those ≥75 years vs. <75 years.
- Rivaroxaban increased TIMI major bleeding overall with consistent results, regardless of age (≥75 years: HR 1.11, 95%CI: 0.55-2.26; <75 years: HR 1.60, 95%CI:1.01-2.55, Pinteraction=0.38). There was no heterogeneity for rates of ICH or fatal bleeding.
- Similar pattern for bleeding was observed for secondary bleeding outcomes including ISTH major and BARC 3b or greater events.
- Benefit-risk profile showed that when 1000 PAD patients ≥75 years after LER were followed for 3 years with rivaroxaban, 38 events would be prevented at the cost of 8 TIMI major bleeds, but no intracranial or fatal bleeding events.
This analysis of VOYAGER PAD showed that low-dose rivaroxaban in addition to aspirin reduced risk of ischemic events (including severe limb complications) with consistent benefit across the spectrum of age (comparing patients ≥75 years vs. < 75 years). TIMI major bleeding was increased by rivaroxaban, but not ICH or fatal bleeding. Overall, benefit-risk profile appears favorable in PAD patients, also in those ≥75 years.