Peripheral artery disease (PAD) is a chronic atherosclerotic condition predominantly affecting the arteries in the lower extremities, leading to compromised blood flow and subsequent ischemic symptoms (Bierowski et al., 2023). PAD poses a significant public health challenge, particularly among elderly populations with combined conditions such as diabetes, hypertension and hyperlipidemia. This disease not only significantly impairs health-related quality of life but also heightens the risk of major adverse cardiovascular events (MACE) and major adverse limb events (MALE), such as amputation (Shishehbor and Castro-Dominguez, 2022). Effective management of PAD is essential to prevent these severe complications and improve patient outcomes.

Recent randomized controlled trials (RCTs) have demonstrated that the combination therapy with aspirin and rivaroxaban significantly reduced the incidence of MACE and MALE in patients with PAD (Eikelboom et al., 2017; Bonaca et al., 2020). This dual antithrombotic strategy offered enhanced vascular protection compared to monotherapy and has become a new therapeutic option for PAD management. However, despite the proven benefits of aspirin combined with rivaroxaban, some patients were unable to tolerate aspirin due to contraindications or adverse effects. Aspirin intolerance could arise from various conditions, including a history of gastrointestinal bleeding, peptic ulcer disease, aspirin-exacerbated respiratory disease or hypersensitivity reactions (Galli et al., 2024). In such cases, alternative antiplatelet agents such as clopidogrel were critical options. Clopidogrel, a P2Y12 inhibitor, is widely utilized in patients who cannot tolerate aspirin, providing a comparable antiplatelet effect. Current guidelines recommend low-dose aspirin or clopidogrel in patients with symptomatic PAD for improving cardiovascular prognosis (Twine et al., 2023; Aboyans et al., 2021).

Despite the established use of clopidogrel as alternatives to aspirin, the efficacy and safety in combination with rivaroxaban have not been extensively studied. Understanding the outcomes associated with different combinations of antiplatelet agents and rivaroxaban is crucial for optimizing treatment strategies. This retrospective cohort study aimed to evaluate the safety and efficacy of clopidogrel combined with rivaroxaban, offering evidence-based recommendations for antithrombotic therapy in PAD patients who cannot tolerate aspirin.

Antithrombotic therapy played a crucial role in the secondary prevention of patients with peripheral artery disease. However, the optimal antithrombotic strategy in terms of duration and intensity remained a topic of debate, particularly in the long term (Golledge, 2022). Even with standard antiplatelet and lipid-lowering therapies, patients with symptomatic PAD still experienced a high incidence of adverse cardiovascular events, indicating the need for more intensive antithrombotic therapy (Polonsky and McDermott, 2021).

In this study, compared with the aspirin-rivaroxaban combination, rivaroxaban combined with clopidogrel significantly reduced the risk of MACE and MALE composite outcome. Major bleeding was a critical concern with dual antithrombotic therapy. The VOYAGER PAD trial reported an increased risk of major bleeding with aspirin and rivaroxaban compared to aspirin alone (Bonaca et al., 2020). Our study found similar major bleeding rates between the clopidogrel-rivaroxaban combination and aspirin-rivaroxaban combination. However, the incidence of the composite outcome among patients in our study who received rivaroxaban combined with aspirin was significantly higher than the incidence of that observed in VOYAGER PAD trial. This may be attributed to the higher proportion of patients with severe symptoms in our study, such as rest pain or tissue damage. These patients typically presented with more advanced vascular wall lesions and an elevated risk of vessel occlusion. In this context, clopidogrel-rivaroxaban combination remained effective in reducing the risk of composite outcome in high-risk PAD patients, providing more effective protection against cardiovascular adverse events.

A systematic review and meta-analysis evaluated the effectiveness and safety of low-dose-rivaroxaban in patients with coronary artery disease and/or peripheral artery disease taking antiplatelets (Bucci et al., 2024). The results showed that low-dose rivaroxaban combined with any antiplatelet agent reduced the risk of cardiovascular events. When anticoagulation and antiplatelet therapies were used in combination, they may significantly reduce thrombosis formation through a synergistic effect, as demonstrated in current studies. In addition to platelets activation and aggregation, coagulation was another crucial factor in thrombosis formation (Kim et al., 2020; Meah et al., 2020). Both thrombin and factor Xa, through the protease-activated receptors (PARs), enhanced platelet activation with a continuous cross-talk between the coagulation and platelet pathway (Petzold et al., 2020). Previous studies have indicated an increased platelet activation during the acute phase of myocardial infarction, whereas thrombin generation appeared to persist for an extended duration in the post-acute coronary syndrome phase (Ohman et al., 2017). Based on this evidence, several studies have explored the impact of combination therapies involving the addition of anticoagulants to antiplatelet drugs on residual cardiovascular risk (Bonaca et al., 2020; Zannad et al., 2018). The COMPASS trial demonstrated the benefits of combining aspirin with rivaroxaban, showing a significant reduction in major adverse cardiovascular events and major adverse limb events compared to aspirin alone (Eikelboom et al., 2017).

Compared to aspirin, which primarily inhibited cyclooxygenase and platelet aggregation, clopidogrel operated via a different mechanism, potentially providing more robust antithrombotic protection. Clopidogrel monotherapy has been evaluated in patients at risk of ischemic events (CAPRIE) enrolling a broad population with stable atherosclerotic cardiovascular disease (CAPRIE Steering Committee, 1996). In a subgroup analysis of this study, clopidogrel demonstrated a MACE reduction in patients with symptomatic PAD when compared to aspirin (HR: 0.78, 95%CI: 0.65–0.93) and showed no significant difference in intracranial hemorrhage risk. Apart from patients with PAD, clopidogrel has also shown superiority over aspirin monotherapy for secondary prevention following percutaneous coronary intervention (PCI). The HOST-EXAM trial showed that clopidogrel monotherapy, compared to aspirin monotherapy during the chronic maintenance period after PCI significantly reduced the risk of future adverse clinical events (Koo et al., 2021). This observation may be explained by the prior studies that P2Y12 receptor inhibition was associated with a greater reduction of platelet function and thrombin formation than cyclooxygenase inhibition in moderate-to high-risk patients with coronary artery disease (Park et al., 2021).

Furthermore, subgroup analysis was performed based on the age, diabetes, renal function, Rutherford classifications and lesion sites. There was no statistical difference between the treatment groups in different subgroups for composite outcome. Clopidogrel combined with rivaroxaban could significantly reduce the risk of MALE in the patients aged ≥75 years old, Rutherford classification grade Ⅲ and long-segment lesion compared to the corresponding subgroups, however, there was no significant interaction. In the post hoc analysis of HOST-EXAM trial (Rhee et al., 2023; Lee et al., 2024), clopidogrel monotherapy demonstrated a lower rate of major adverse cardiac events compared to aspirin monotherapy in patients requiring antiplatelet monotherapy after PCI, regardless of the presence of diabetes or age. In our study, the results of the subgroup analysis were consistent with those of the overall population, indicating that the efficacy was uniform across different subgroups. This suggested that the clopidogrel-rivaroxaban combination was equally effective in diverse patient groups, thus enhancing the reliability and generalizability of the findings.

This study has certain limitations that should be addressed in future research. Firstly, this was a retrospective cohort study which may not account for all potential confounding variables that could influence the observed outcomes, even though the IPTW method was used to balance the covariate differences between the groups. Secondly, the sample size in the study was insufficient that may not adequately represent the population, affecting the credibility and validity of the study. However, the high incidence rate of clinical outcomes meant that significant associations or effects can be more readily observed, potentially making study conclusions more apparent.

This study indicated that clopidogrel-rivaroxaban combination significantly reduced the composite outcome of adverse cardiovascular and limb events in patients with PAD, compared to aspirin-rivaroxaban combination, without increasing the incidence of major bleeding. Therefore, clopidogrel-rivaroxaban combination was a superior alternative to aspirin in dual antithrombotic therapy, highlighting its potential therapeutic benefit in this patient population.