Highlights of the VOYAGER-PAD Sub-analysis
Enhanced Risk Identification
Patients with peripheral artery disease (PAD) who have a history of prior lower extremity revascularization (LER) face a 58% higher risk of major adverse limb events (MALE) compared to those undergoing their first revascularization procedure.
Superior Efficacy in High-Risk Subgroups
The combination of low-dose rivaroxaban (2.5 mg twice daily) and aspirin significantly reduced the primary composite endpoint, with a more pronounced relative benefit in patients with a history of prior LER (HR 0.73) compared to those without (HR 0.94).
Consistent Safety Profile
While rivaroxaban increased the risk of Thrombolysis in Myocardial Infarction (TIMI) major bleeding, the relative safety profile remained consistent regardless of whether the patient had a history of prior limb revascularization.
The Burden of Recurrent Disease in Peripheral Artery Disease
Peripheral artery disease (PAD) represents a systemic manifestation of atherosclerosis that carries a high burden of morbidity and mortality. For patients with symptomatic PAD, lower extremity revascularization (LER)—whether via endovascular or surgical means—is a cornerstone of management intended to restore flow and prevent limb loss. However, LER is not a cure; rather, it is a point of transition in a chronic disease process. Following LER, patients remain at an exceptionally high risk for both Major Adverse Cardiovascular Events (MACE) and Major Adverse Limb Events (MALE), including acute limb ischemia and amputation.
Clinical experience has long suggested that a subset of PAD patients exists in a ‘revolving door’ of care, requiring multiple interventions over time. These patients often possess a more aggressive atherosclerotic phenotype, more complex anatomical lesions, or underlying biological factors that predispose them to thrombotic complications. Understanding how prior procedural history influences future risk and treatment response is critical for personalizing antithrombotic therapy in the post-revascularization setting.
Study Design: Probing the Impact of Prior Revascularization
The VOYAGER-PAD trial was a landmark phase 3, double-blind, randomized controlled trial that addressed the unmet need for effective antithrombotic strategies following LER. The trial randomized 6,564 patients with symptomatic PAD undergoing successful LER to receive either rivaroxaban 2.5 mg twice daily plus aspirin 100 mg daily or placebo plus aspirin.
This specific sub-analysis focused on the 2,336 patients (35.5% of the total cohort) who had a documented history of prior LER at baseline. The researchers sought to determine two primary factors: first, the baseline risk of the primary efficacy endpoint (a composite of acute limb ischemia, major amputation of a vascular cause, myocardial infarction, ischemic stroke, or cardiovascular death) based on prior LER status; and second, whether the therapeutic benefit of rivaroxaban was consistent across these subgroups. The principal safety outcome was defined as TIMI major bleeding.
Key Findings: Risk Stratification and Efficacy
The Prognostic Power of Prior LER
The data demonstrated a stark difference in baseline risk profiles. At the three-year mark, the Kaplan-Meier cumulative rate for the primary efficacy endpoint was 12.9% in patients with a history of prior LER, compared to only 8.0% in those without such a history. This represents a 58% increase in risk (Hazard Ratio [HR], 1.58; 95% CI, 1.25-1.99). This finding confirms that a history of prior revascularization is a potent clinical indicator of a high-risk patient who requires intensive secondary prevention.
Differential Treatment Benefit
Perhaps the most significant finding of this analysis was the interaction between prior LER status and the efficacy of rivaroxaban. In the group with a history of prior LER, rivaroxaban plus aspirin reduced the primary composite endpoint by 27% (HR, 0.73; 95% CI, 0.60-0.88). In contrast, in those without a prior history of LER, the reduction was numerically smaller and did not reach statistical significance (HR, 0.94; 95% CI, 0.81-1.10). The P-interaction was 0.036, suggesting that the relative benefit of the dual pathway inhibition (DPI) strategy is significantly greater in patients who have already failed at least one prior revascularization attempt.
Safety Analysis: Balancing Ischemic Protection and Bleeding Risk
As with any intensified antithrombotic regimen, the risk of bleeding is a primary concern for clinicians. In the VOYAGER-PAD trial, rivaroxaban was associated with an increase in TIMI major bleeding. This sub-analysis investigated whether this risk was exacerbated in the prior LER group.
The results showed that the relative increase in bleeding with rivaroxaban was consistent across both groups. For patients with prior LER, the HR for TIMI major bleeding was 1.08 (95% CI, 0.62-1.89). For those without prior LER, the HR was 1.88 (95% CI, 1.09-3.25). Although the numerical HR was higher in the no-prior LER group, the P-interaction of 0.16 indicates that there was no statistically significant difference in the safety profile between the two subgroups. This suggests that while bleeding risk is present, it does not specifically cluster or worsen in the highest-risk limb patients who stand to benefit the most from the therapy.
Clinical Perspective and Expert Commentary
The results of this VOYAGER-PAD insight provide a clear roadmap for clinicians managing PAD. The “Dual Pathway Inhibition” strategy—combining Factor Xa inhibition with antiplatelet therapy—addresses the dual role of thrombin and platelets in arterial thrombosis. This is particularly relevant in PAD, where the thrombotic milieu is often more complex than in coronary artery disease.
Mechanistic Insights
Why do patients with prior LER benefit more? It is likely that these patients have a more advanced systemic pro-thrombotic state or more significant endothelial dysfunction. Each subsequent revascularization procedure may also introduce more complex local hemodynamics, such as those seen in recurrent stenosis or graft failure, which are highly sensitive to thrombin-mediated thrombosis. By utilizing low-dose rivaroxaban, clinicians can more effectively suppress the coagulation cascade at a point of high vulnerability.
Guideline Alignment
These findings reinforce current trends in cardiovascular guidelines, which increasingly advocate for risk-stratified antithrombotic therapy. For a patient presenting for their second or third revascularization, the evidence for initiating rivaroxaban 2.5 mg twice daily alongside aspirin is now stronger than ever. The high absolute risk in this population means that the ‘Number Needed to Treat’ (NNT) to prevent a major limb or cardiovascular event is likely much lower than in the general PAD population.
Conclusion: Tailoring Antithrombotic Therapy
Patients with PAD and a history of prior LER represent a distinct, high-risk phenotype. The VOYAGER-PAD trial sub-analysis proves that these patients are not only at a higher risk of failing subsequent procedures but also derive the most significant benefit from intensified antithrombotic therapy with low-dose rivaroxaban and aspirin.
For the practicing clinician, the message is clear: a patient’s procedural history is a vital component of their risk profile. While all patients undergoing LER should be considered for DPI, those with a history of prior limb revascularization should be prioritized for this evidence-based strategy to mitigate the devastating risks of acute limb ischemia and major amputation.
Funding and ClinicalTrials.gov
The VOYAGER-PAD trial was funded by Bayer and Janssen Pharmaceuticals.
ClinicalTrials.gov Identifier: NCT02504216.
References
1. Canonico ME, Parr J, Debus ES, et al. Low-Dose Rivaroxaban Plus Aspirin in Patients With PAD Undergoing Lower Extremity Revascularization With and Without History of Prior Limb Revascularization: Insight From the VOYAGER-PAD Trial. Circ Cardiovasc Interv. 2026 Feb 27:e015229. doi: 10.1161/CIRCINTERVENTIONS.125.015229.
2. Bonaca MP, Bauersachs R, Anand SS, et al. Rivaroxaban in Peripheral Artery Disease after Revascularization. N Engl J Med. 2020;382(21):1994-2004.
3. Eikelboom JW, Connolly SJ, Bosch J, et al. Rivaroxaban with or without Aspirin in Stable Cardiovascular Disease. N Engl J Med. 2017;377(14):1319-1330.