Prescription of aspirin plus low-dose rivaroxaban in patients with peripheral artery disease after lower-extremity revascularization

VOYAGER PAD demonstrated the efficacy and favorable benefit/risk of dual pathway inhibition (DPI), utilizing aspirin plus low-dose rivaroxaban (2.5 mg twice daily), after lower-extremity revascularization (LER) in patients affected by symptomatic peripheral artery disease (PAD). After a 3-year median follow up, DPI significantly reduced the major adverse cardiovascular events (MACE) and major adverse limb events (MALE) of 15% of patients with a not significant excess in thrombolysis in myocardial infarction (TIMI) major bleeding compared to aspirin plus placebo with an overall 6:1 benefit risk ratio in absolute terms. ¹ In 2021, the US Food and Drug Administration (FDA) expanded rivaroxaban’s indication to include reducing the risk of major thrombotic vascular events in patients with PAD. More recently, the American 2024 intersociety PAD guidelines endorsed DPI in patients with PAD who underwent LER. ² Multiple efforts are underway to improve the adoption of guideline-directed medical therapy (GDMT). Get With The Guidelines (GWTG) is a hospital-based quality improvement program by the American Heart Association (AHA) which encompasses different cardiovascular diseases (i.e., coronary artery disease, heart failure, stroke). The aim of GWTG is to promote the wide adoption of GDMT as well as to collect data and information to improve care. ³ Despite evidence-based benefits, FDA approval, and guideline recommendation, real-world prescription of DPI may be underutilized.

We assessed DPI prescription, including aspirin plus low-dose rivaroxaban, in patients with PAD who underwent LER from January 2022 to August 2024 in the University of Colorado health system (TriNetX). The encounters were identified according to the International Classification of Diseases, 10th Revision (ICD-10) codes, as previously described. ⁴ In particular, encounters with symptomatic PAD according to ICD-10 codes’ definition of series I.70 and I.73 were identified, selecting those who underwent LER according to current procedural terminology (CPT) and Healthcare Common Procedure Coding System (HCPCS) codes. Among the patients with PAD who underwent LER, we selected encounters which met the clinical eligibility criteria of VOYAGER PAD. Those selected were aged ≥ 50 years with symptomatic PAD who underwent LER; exclusion criteria included therapeutic anticoagulation (e.g., atrial fibrillation, venous thromboembolism), chronic kidney disease stage V or dialysis, recent acute coronary syndrome (i.e., in the previous 30 days), intracranial hemorrhage, transient ischemic attack, stroke, or history of malignancy. Prescription of medications within the same antithrombotic group was assessed over the study time using the p for trend test. The Ethics Committee of the Colorado Multiple Institutional Review Board approved the study and provided a waiver of consent for ethics approval and patient consent for the collection, analysis, and publication of the retrospectively obtained and anonymized data for this noninterventional study.

There were 1120 LERs for symptomatic PAD encounters between January 2022 and August 2024, of which 730 (65%) met the eligibility criteria for VOYAGER PAD. The mean age was 72 years with 62% of male sex. Hypertension, hyperlipidemia, and diabetes mellitus resulted in 88%, 77%, and 50% of patients, respectively; 23% had previous myocardial infarction (Supplemental Table 1). Overall, dual antiplatelet therapy (DAPT) with aspirin and clopidogrel was the most frequently prescribed regimen (Figure 1), followed by DPI, therapeutic anticoagulation, and aspirin monotherapy. Use of DPI increased from 14% in 2022 to 28% in 2024 (p for trend < 0.01); the majority of DPI in 2024 was prescribed without concomitant clopidogrel. Prescription of DAPT numerically decreased from 78% in 2022 to 72% in 2024 (p for trend 0.40) with no significant changes in prescription of aspirin or oral anticoagulants (11% and 17% in 2024, respectively).

Figure 1.

Antithrombotic therapies prescribed to patients with peripheral artery disease who underwent lower-extremity revascularization, 2022–2024. Dual antiplatelet therapy, predominantly aspirin + clopidogrel, was the most commonly prescribed regimen; dual pathway inhibition (rivaroxaban + aspirin with or without clopidogrel) was the second most common. Use of dual pathway inhibition increased from 2022 to 2024 (p for trend < 0.01). No significant trend was observed for any of the other regimens.

The analysis highlights the underutilization of DPI in patients undergoing LER in a large US health system. The limited use of GDMT according to American College of Cardiology (ACC) / AHA / Society for Vascular Medicine (SVM) clinical practice guidelines in patients with PAD has been previously demonstrated for lipid lowering and antihypertensive medications. ⁴ However, given the relatively recent completion of VOYAGER PAD, less data have been published on real-world prescription of DPI in PAD. A survey from the European Society of Cardiology (ESC) found a similar rate of DPI prescription in patients who underwent LER for chronic limb-threatening ischemia (CLTI) and detected variability in antithrombotic use by type of provider and location. ⁵ Reasons for the suboptimal prescription of DPI may vary, including differences in the adoption of ACC/AHA/SVM PAD guideline implementation strategies, clinical inertia, differences in PAD management by provider specialty, and patients’ insurance status.

The most recent PAD guidelines highlighted the key role of the Vascular Team in patient care.^2,6 The efficacy of a multidisciplinary management to improve GDMT adoption has been recently assessed in the OPTIMIZE PAD-1 randomized trial, which compared lipid-lowering management in patients with PAD by an algorithm-supported, multiprofessional vascular team versus standard of care. After the 12-month follow up, the low-density lipoprotein cholesterol (LDL-C) reduction was about 50% in the vascular care team group compared to 5% with standard of care. ⁷ The benefit was observed after 1 month and persisted through the 12-month follow up. A similar approach to implementing all GDMT, including DPI, should be considered to avoid the prescription of full oral anticoagulation following LER, given its association with worse outcomes.^8,9 Implementation science studies such as OPTIMIZE PAD are designed to evaluate interventions to reduce the gap between scientific evidence and real-world management, as well as to assess the sustainability and cost-effectiveness of the interventions in a real-world setting. ³

This study has limitations. The analysis was conducted on retrospective, pooled observational data from a single health system and did not include patient-level information on type of service, provider, or insurance. Moreover, the single-center study reflects local practice, where the prescription of DPI may be overestimated following participation in the VOYAGER PAD study. Additionally, given the relatively recent publication of the updated PAD guidelines in 2024, their full impact is likely not reflected in these data.

In conclusion, in one large, integrated US health system, DPI including aspirin plus low-dose rivaroxaban remains underutilized, and DAPT, including aspirin plus clopidogrel, represents the most frequent regimen in patients with PAD who underwent LER. However, the use of DPI increased over the course of the study. These data highlight opportunities for optimization of antithrombotic therapies to improve clinical outcomes in patients affected by PAD.

Supplemental Material

sj-docx-1-vmj-10.1177_1358863X251331561 – Supplemental material for Prescription of aspirin plus low-dose rivaroxaban in patients with peripheral artery disease after lower-extremity revascularization

Supplemental material, sj-docx-1-vmj-10.1177_1358863X251331561 for Prescription of aspirin plus low-dose rivaroxaban in patients with peripheral artery disease after lower-extremity revascularization by Mario Enrico Canonico, Connie N Hess, Sivan Naveh, R Kevin Rogers, Mark R Nehler, Shea E Hogan, Judith A Hsia, Scott D Berkowitz and Marc P Bonaca in Vascular Medicine