Reduction in Acute Limb Ischemia With Rivaroxaban Versus Placebo in Peripheral Artery Disease After Lower Extremity Revascularization: Insights From VOYAGER PAD

Abstract

Background: Patients with peripheral artery disease (PAD) are at heightened risk of acute limb ischemia (ALI), a thrombotic event associated with amputation, disability, and mortality. Prior lower extremity revascularization (LER) is associated with increased ALI risk in chronic PAD. However, the pattern of risk, clinical correlates, and outcomes after ALI early after LER are not well-studied, and effective therapies to reduce ALI post-LER are lacking. Methods: VOYAGER PAD (NCT02504216) randomized patients with PAD undergoing LER to rivaroxaban 2.5 mg twice daily or placebo on a background of low-dose aspirin. The primary outcome was a composite of ALI, major amputation of vascular cause, myocardial infarction, ischemic stroke, or cardiovascular death. ALI was prospectively ascertained and adjudicated by a blinded committee. The cumulative incidence of ALI was calculated using Kaplan Meier estimates, and Cox proportional-hazards models were used to generate hazard ratios and associated confidence intervals. Analyses were performed as intention-to-treat. Results: Among 6,564 patients followed for a median of 2.3 years, 382 (5.8%) had a total of 508 ALI events. In placebo patients, the 3-year cumulative incidence of ALI was 7.8%. After multivariable modeling, prior LER, baseline ABI <0.50, surgical LER, and longer target lesion length were associated with increased risk of ALI. Incident ALI was associated with subsequent all-cause mortality (HR 2.59, 95% CI 1.98-3.39) and major amputation (HR 24.87, 95% CI 18.68-33.12). Rivaroxaban reduced ALI relative to placebo by 33% (absolute risk reduction 2.6% at 3 years, HR 0.67, 95% CI 0.55-0.82, P=0.0001), with benefit starting early (HR 0.45, 95% CI 0.24-0.85, P=0.0068 at 30 days). Benefit was present for severe ALI (associated with death, amputation, or prolonged hospitalization and ICU stay, HR 0.58, 95% CI 0.40-0.83, P=0.003) and regardless of LER type (surgical vs endovascular revascularization, p-interaction=0.42) or clopidogrel use (p-interaction=0.59). Conclusions: After LER for symptomatic PAD, ALI is frequent, particularly early after LER, and is associated with poor prognosis. Low-dose rivaroxaban plus aspirin reduces ALI after LER, including ALI events associated with the most severe outcomes. The benefit of rivaroxaban for ALI appears early, continues over time, and is consistent regardless of revascularization approach or clopidogrel use.

A multicenter, randomized, open-labelled, non-inferiority trial of sustained-release sarpogrelate versus clopidogrel after femoropopliteal artery intervention

“…Three RCTs of small sample size have shown that cilostazol reduced angiographic restenosis after FP EVT [22][23][24] , and cilostazol was added as a possible alternative to clopidogrel in combination with aspirin in a recent guideline from the European Society of Vascular Medicine 25 . Recently, the VOYAGER PAD trial showed that low-dose rivaroxaban and aspirin reduced the risk of composite outcomes, including cardiovascular and limb events, in patients with lower extremity EVT compared to aspirin alone 26,27 . However, a direct comparison between the VOYAGER regimen and DAPT of aspirin plus clopidogrel is needed to prove its superiority or non-inferiority over the most commonly used regimen for post-EVT.…”

Prevention of arterial and venous thrombotic events in symptomatic peripheral arterial disease patients after lower extremity revascularization in the VOYAGER PAD trial: Dual anticoagulant/antiplatelet regimen vs antiplatelet therapy alone

“…Clopidogrel is regularly used as a short‐term adjunct to aspirin after endovascular revascularization, but in this clinical situation there is minimal primary evidence to underpin administering DAPT (dual antiplatelet therapy) 29 . In the VOYAGER PAD trial, rivaroxaban combined with aspirin diminished the risk of MACE and MALE with prompt benefit for reducing ALI regardless of clopidogrel use 28,30,31 . Potentiation of effect by combined antithrombotic action from inhibition of platelet function and coagulation is hypothesized but other possible effects of factor Xa inhibition and COX‐1 blockade facilitated through less well understood pathways must also be considered 32 …”

“…29 In the VOYAGER PAD trial, rivaroxaban combined with aspirin diminished the risk of MACE and MALE with prompt benefit for reducing ALI regardless of clopidogrel use. 28,30,31 Potentiation of effect by combined antithrombotic action from inhibition of platelet function and coagulation is hypothesized but other possible effects of factor Xa inhibition and COX-1 blockade facilitated through less well understood pathways must also be considered. 32 During the course of their disease, patients with symptomatic PAD after LER can have more than one thrombotic complication over time, more than one type of thrombosis (arterial or venous), and thrombosis at different sites (e.g., stroke, MI, PE, DVT).…”

“…As anticipated, adding rivaroxaban to aspirin did lead to more bleeding, with a number needed to harm of 125, but no excess in the irreversible harm events of intracranial hemorrhage or fatal bleeding. If 10 000 patients were treated for 1 year with rivaroxaban, 181 first severe cardiovascular and limb events would be prevented at a cost of 29 TIMI (Thrombolysis In Myocardial Infarction) major bleeding events, translating to an approximately 6:1 benefit risk ratio 16,28 . Clopidogrel is regularly used as a short‐term adjunct to aspirin after endovascular revascularization, but in this clinical situation there is minimal primary evidence to underpin administering DAPT (dual antiplatelet therapy) 29 .…”

“…If 10 000 patients were treated for 1 year with rivaroxaban, 181 first severe cardiovascular and limb events would be prevented at a cost of 29 TIMI (Thrombolysis In Myocardial Infarction) major bleeding events, translating to an approximately 6:1 benefit risk ratio. 16,28 Clopidogrel is regularly used as a short-term adjunct to aspirin after endovascular revascularization, but in this clinical situation there is minimal primary evidence to underpin administering DAPT (dual antiplatelet therapy). 29 In the VOYAGER PAD trial, rivaroxaban combined with aspirin diminished the risk of MACE and MALE with prompt benefit for reducing ALI regardless of clopidogrel use.…”