Voyaging to Safety: Anticoagulation in Peripheral Artery Disease and Limb Revascularisation

Abstract

This chapter provides a comprehensive evaluation of the impact of the Vascular Outcomes Study of Acetylsalicylic Acid (ASA) Along with Rivaroxaban in Endovascular or Surgical Limb Revascularization for Peripheral Artery Disease (VOYAGER PAD) trial for the use of the direct acting oral anticoagulant (DOAC) rivaroxaban after surgical revascularisation of lower limb peripheral arterial disease (PAD). The VOYAGER PAD trial, a multinational, double-blind, randomized control trial, evidenced the benefits of a combined low-dose rivaroxaban and aspirin therapy over aspirin alone in reducing major limb adverse events such as acute limb ischemia, major amputations, and cardiovascular-related mortality following surgical revascularisation for severe PAD. However, an increased bleeding risk was also associated with this regimen, particularly in females and patients with a history of bleeding, underscoring the need for careful patient selection, risk stratification, and vigilant monitoring. Special attention is therefore needed when considering this treatment for certain population groups at higher risk of bleeding. Despite these considerations, the results of the trial offer significant promise for improving PAD management and limb revascularization and present numerous opportunities for future research. Investigations into patient-specific factors, precise indications, and dosage optimization could further refine the therapeutic strategies involving rivaroxaban.

1. Introduction

1.1 Peripheral arterial disease and its management

Peripheral Artery Disease (PAD) is a common condition in lower limbs caused by partial or total blockage of arterial blood flow due to atherosclerosis [1]. This chronic condition is marked by inflammation, endothelial dysfunction, and lipid build-up in arterial walls, leading to narrowing of the artery and reduced blood flow to the lower limbs [2]. Over time, these atherosclerotic plaques can grow, leading to arterial stenosis or occlusion, further diminishing blood and oxygen supply to the tissues [2].

PAD affects more than 200 million people worldwide, with its prevalence increasing with age [3]. It is more common in smokers, individuals with diabetes, those with a history of heart disease, and those with chronic kidney disease. PAD is more prevalent in men compared to women and in non-Hispanic blacks compared to other racial or ethnic groups [4]. Despite its high prevalence, PAD is often underdiagnosed and undertreated [3].

PAD is a systemic disease that can manifest on a spectrum ranging from asymptomatic stenosis or occlusion to necrosis and loss of limb. It most commonly manifests with mild symptoms, including intermittent claudication, characterized by leg pain that occurs during exercise and is relieved by rest [5]. Although intermittent claudication results in lifestyle limiting symptoms, the disease can remain quite stable with only approximately 25% of patients experiencing significant deterioration in symptoms [5]. If untreated, PAD may progress to chronic limb threatening ischemia (CLTI), a severe condition characterized by chronic pain at rest, non-healing ulcers, and gangrene [5]. PAD can be estimated using non-invasive tests such as the ankle-brachial pressure index (ABI) [5]. A resting ABI of less than <0.9 indicates hemodynamically significant arterial disease or toe pressures [5]. Risk factors for progression to of asymptomatic disease or claudication to CLTI include age greater than 65, ABI <0.5, patients with diabetes and current smokers. Asymptomatic PAD and claudication can be treated with medical therapy, but once the disease has progressed to CLTI, it ultimately requires surgical revascularisation [5].

Surgical arterial revascularisation is a therapeutic intervention aimed at restoring blood flow to ischemic limbs in patients with PAD [6]. There are two primary options for limb revascularisation within current practice: open surgical revascularisation (e.g., bypass surgery, endarterectomy) or endovascular revascularisation (e.g., angioplasty, stenting) [6]. The choice of which option is best attempted is based on multiple factors, including the patient’s overall health, the location and extent of the arterial disease, and the expected outcomes [6].

1.2 Introduction to antiplatelets and anticoagulants

Antiplatelet medications belong to a class of drugs specifically formulated to prevent blood clotting by inhibiting platelet aggregation, and have been the mainstay for secondary prevention of cardiovascular conditions like strokes or heart attacks [7]. Aspirin is one of the most widely recognized and used antiplatelet medications, also appreciated for its analgesic, antipyretic, and anti-inflammatory effects [7]. Its mechanism of action involves the irreversible inhibition of the cyclooxygenase (COX) enzyme, subsequently suppressing the production of thromboxane A2, a powerful promoter of platelet aggregation [7]. Antiplatelet drugs play a vital role in managing numerous cardiovascular diseases, including PAD, and they are recognized as a crucial component of optimal medical therapy for such conditions.

Anticoagulation medications are therapeutic agents designed to interrupt the coagulation cascade. Unlike antiplatelet drugs, which primarily inhibit platelet aggregation and primary hemostasis, anticoagulants work by directly or indirectly targeting clotting factors, inhibiting secondary hemostasis [8]. Rivaroxaban is a direct oral anticoagulant (DOAC) that functions by inhibiting factor Xa, a crucial enzyme in the coagulation cascade, thereby effectively disrupting the formation of blood clots [8]. The mechanism of action involves selective and direct inhibition of both free and prothrombinase-bound factor Xa [8]. Factor Xa plays a pivotal role in the generation of thrombin, which is involved in multiple stages of the clotting cascade, including the conversion of fibrinogen to fibrin, activation of platelets, and the further catalysation of additional thrombin [8]. This mechanism prevents the development of thrombus within the blood vessels. Therefore, rivaroxaban is indicated in the treatment of conditions associated with thrombosis, such as deep vein thrombosis (DVT), pulmonary embolism (PE), stroke in patients with atrial fibrillation, and systemic embolism [8].

2. Historical overview

2.1 Timeline of key studies and trials on anticoagulation in PAD and limb revascularization (2003–2023)

Over the past two decades, several key studies and trials have significantly contributed to the understanding and use of antiplatelets and anticoagulants in PAD:

• In 2003, the CAPRIE (Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events) trial established the slight superiority of clopidogrel over aspirin in reducing the risk of vascular events in patients with PAD [9].

• In 2007, the CHARISMA (Clopidogrel and Aspirin versus Aspirin Alone for the Prevention of Atherothrombotic Events) trial found no significant reduction in the primary efficacy endpoint with dual antiplatelet therapy versus single antiplatelet therapy, while demonstrating an increased risk of moderate bleeding. The trial focussed on major cardiovascular events, strokes and death from cardiovascular events, but included patients with symptomatic PAD [10].

• The 2013 EUCLID (Examining Use of Ticagrelor in PAD) trial evaluated the efficacy of ticagrelor compared to clopidogrel for the reduction of cardiovascular events in patients with symptomatic PAD. The trial found that ticagrelor was not superior to clopidogrel in reducing cardiovascular events [11].

• The COMPASS trial in 2017 demonstrated that low dose rivaroxaban (2.5 mg twice a day) plus aspirin resulted in better cardiovascular outcomes (reduction in stroke and cardiovascular death) compared to aspirin alone. It was associated with a higher risk of bleeding [12].

• The VOYAGER PAD trial in 2020 revealed the superiority of low dose rivaroxaban (2.5 mg twice a day) plus aspirin over aspirin alone in reducing acute limb ischemia, major amputation for vascular causes, myocardial infarction, ischemic stroke, or death from cardiovascular causes in patients with moderate-severe PAD and recent surgical revascularisation [13].

Each of these trials contributed unique and significant findings to the evolving understanding of anticoagulation in PAD. The strengths of these trials included their large sample sizes, rigorous study designs, and the inclusion of diverse patient populations. However, the trials also had limitations such as the lack of direct comparison between different antiplatelet and anticoagulant regimens, and in some trials, a high rate of patient dropout or medication nonadherence [14].

Despite the knowledge gained from previous trials, a significant gap remained in the understanding of the use of anticoagulation in patients undergoing limb revascularization for PAD. Most previous trials focused on medical management of PAD, and none specifically assessed the efficacy and safety of rivaroxaban in combination with aspirin in this patient population. Finally, the results from the COMPASS trial, demonstrating the efficacy of low dose rivaroxaban with aspirin in reducing ischaemic risks in a population with chronic stable arterial disease, aided in generating the hypothesis that this efficacy could be replicated in patients with CLTI post limb revascularisation [12]. This prompted the initiation of the VOYAGER PAD trial [15].

The VOYAGER PAD trial made a unique contribution to the field by focusing on patients undergoing limb revascularization for severe PAD and examining a combined regimen of low-dose rivaroxaban and aspirin [13]. The trial’s key finding was that the combination of low dose rivaroxaban and aspirin reduced the incidence of acute limb ischemia, major amputation for vascular causes, myocardial infarction, ischemic stroke, or death from cardiovascular causes [13]. This led to a change in practice and updated guidelines recommending this regimen in suitable patients [13].

2.2 Previous evidence for aspirin alone in PAD

Aspirin has long been a mainstay in the management of PAD and limb revascularization due to its antiplatelet properties. The Antiplatelet Trialists’ Collaboration (APTC) conducted a meta-analysis, highlighting the benefits of aspirin in reducing systemic vascular events by approximately 23% in patients with vascular disease [16]. These vascular events included non-fatal myocardial infarction, non-fatal stroke, or vascular death.

A significant study, the Prevention Of Progression of Arterial Disease and Diabetes (POPADAD) trial, did not find aspirin alone to significantly reduce the risk of cardiovascular events or death in patients with diabetes and asymptomatic PAD [17]. However, aspirin has consistently demonstrated modest benefits in symptomatic PAD and following limb revascularization procedures [17].

While aspirin has proven benefits and is generally well-tolerated, its benefits are limited particularly in PAD and limb revascularization patients. Aspirin alone provides a modest reduction in vascular events; however, aspirin does not significantly reduce limb-specific events such as acute limb ischemia and major amputation [17].

On the other hand, the addition of low dose rivaroxaban to aspirin in the management of PAD post-revascularisation appears to provide improved outcomes, as aforementioned. However, it seems that the benefit does not come without a modest increase in bleeding risk. Analysis of the safety profile in VOYAGER PAD shows an increase in TIMI major bleeding (not including intracranial or fatal bleeding), seen in 2.65% in the rivaroxaban group versus 1.87% in the placebo group (P = 0.012) [13]. Nevertheless, there was no significant increase in intracranial or fatal bleeding, suggesting the bleeding risks may be manageable [13].

3. VOYAGER PAD trial methodology

3.1 Study design and patient population

The VOYAGER PAD trial was an international, multicentre, double-blind, randomized controlled trial [13]. The study involved 6564 patients from 34 countries, who had undergone recent revascularization for peripheral arterial disease. These included both open surgical and endovascular procedures [13]. The patients were evenly randomized into two groups: one group receiving rivaroxaban (2.5 mg twice daily) plus aspirin (100 mg once daily), and the other group receiving placebo plus aspirin (100 mg once daily) [13].

3.2 Primary endpoints and rationale

The primary efficacy endpoint of the trial was a composite of acute limb ischemia, major amputation for vascular causes, myocardial infarction, ischemic stroke, or death from cardiovascular causes [13]. This composite endpoint was chosen because these events are clinically meaningful outcomes that could be directly affected by antithrombotic therapy. The primary safety endpoint was major bleeding as defined by the Thrombolysis in Myocardial Infarction (TIMI) classification [13].

3.3 Statistical analysis: techniques used and their importance

The trial used time-to-event analysis methods to analyze the primary efficacy and safety endpoints, which provided clinically relevant information [13]. A Cox proportional-hazards model was used to compare the treatment groups with respect to the primary efficacy endpoint and the primary safety endpoint, with stratification according to the use or non-use of clopidogrel at randomization [13]. The results were reported as hazard ratios with 95% confidence intervals, providing a reliable estimate of the relative risk associated with the use of rivaroxaban [13]. These techniques allowed for a comprehensive analysis of the time-dependent nature of the trial’s primary and secondary endpoints [18].

3.4 Methodological strengths and weaknesses

The key strength of the VOYAGER PAD trial was its randomized double-blind design, which minimized bias. The large, diverse, and international patient population increased the generalizability of the findings. The focus on a targeted population of patients with symptomatic PAD (who had undergone recent revascularization) added to the clinical applicability of the trial’s findings.

However, the trial also had limitations. Firstly, the study excluded a number of high-risk patients such as those with acute limb ischemia, severe tissue loss, and chronic kidney disease [13]. This exclusion of such significant groups may affect the generalizability of the study’s results to the broader population of patients with PAD. Secondly, the definition of major bleeding in the VOYAGER trial was not specified beyond stating that it met the TIMI Major Bleeding criteria [19]. The lack of clear details about bleeding could lead to ambiguity in interpreting and applying the study’s findings. Additionally, while the study population included patients who underwent both open bypass and endovascular revascularization, the specifics of these revascularization procedures were not reviewed in the trial’s discussion [19]. Moreover, it was not explicitly stated whether patients without successful revascularization were excluded, further adding to potential ambiguity. The study also excluded patients requiring dialysis and those with poorly controlled diabetes and hypertension—key risk factors for PAD progression [13]. It also did not assess quality of life or functional status as a primary outcome. These are crucial elements when considering the management of patients with PAD. Lastly, the follow-up period was relatively short, and longer-term effects of the combination therapy remain to be seen [13].

4. Interpretation of the results

4.1 Primary outcomes and secondary outcomes

The VOYAGER PAD trial reported a 15% relative risk reduction in the primary endpoint for patients treated with rivaroxaban plus aspirin compared to those treated with aspirin alone (17.3% vs. 19.9%; hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.76 to 0.96; P = 0.009) [13]. This difference was primarily driven by the reduction in acute limb ischemia and major amputation. This highlights rivaroxaban’s potential in reducing serious limb events in PAD patients following revascularization.

Regarding secondary outcomes, there was a significant reduction in the composite of myocardial infarction, stroke, or cardiovascular death with rivaroxaban plus aspirin (7.3% vs. 8.8%; HR, 0.82; 95% CI, 0.71 to 0.94; P = 0.005) [13]. This substantiates the potential systemic benefits of rivaroxaban in patients with PAD who undergo surgical limb revascularization.

4.2 Subgroup analyses: highlighting important variations

Subgroup analyses in the VOYAGER PAD trial revealed consistent benefits across various subgroups, including patients with varying degrees of renal function and different revascularization techniques [13]. The consistency of these findings across subgroups reinforces the study’s primary conclusions and broadens the generalizability of the results.

Significantly, the trial reported consistent benefits of rivaroxaban plus aspirin across several key subgroups:

1. Type of Revascularization: The study incorporated patients who had undergone either open surgical or endovascular revascularization. In both subgroups, rivaroxaban plus aspirin demonstrated superiority over aspirin alone in reducing the primary composite outcome, with Hazard Ratios (HR) of 0.79 (95% CI, 0.66–0.95) for open surgical and 0.90 (95% CI, 0.77–1.05) for endovascular revascularization [13].

2. Renal Function: Patients were categorized based on their kidney function at baseline, as measured by estimated glomerular filtration rate (eGFR). The protective effect of rivaroxaban remained consistent across varying levels of renal function, including those with mild to moderate renal impairment, with a HR of 0.90 (95% CI, 0.71–1.15) for patients with normal renal function and 0.85 (95% CI, 0.73–0.97) for those with renal impairment [13]. This is especially noteworthy given the high prevalence of chronic kidney disease among patients with PAD.

3. Sex: The benefits of rivaroxaban therapy were examined across both male and female patients. Despite known differences in the natural history and management of PAD between sexes, the addition of rivaroxaban to aspirin demonstrated a clinical benefit in both sexes. In male patients, the HR was 0.82 (95% CI, 0.71–0.94), while in female patients, the HR was 0.97 (95% CI, 0.76–1.23) [13].

The consistency of the benefits of rivaroxaban plus aspirin across these subgroups reinforces the applicability of the results and confirms its role in a wide spectrum of PAD patients undergoing limb revascularization. The trial notably established the efficacy of a lower dose of rivaroxaban (2.5 mg twice daily) in combination with aspirin, demonstrating statistically significant improvements in primary and secondary endpoints compared to aspirin alone [13].

5. Adverse effects and safety considerations

Rivaroxaban has been associated with a number of adverse effects, including moderate and severe bleeding complications, which cause the higher morbidity and mortality for patients [20]. Furthermore, some patients may experience minor adverse effects such as nausea, lower abdominal pain, or minor bleeding, such as epistaxis or gingival bleeding [20, 23].

5.1 Analysis of gastrointestinal bleeding risks

Gastrointestinal (GI) bleeding remains a significant safety consideration with anticoagulant therapies, including rivaroxaban. The risk of GI bleeding with rivaroxaban appears to be dose dependent [20]. A meta-analysis by Abraham et al., which included eight randomized controlled trials with over 25,000 patients, found that rivaroxaban was associated with a 1.48-fold higher risk of GI bleeding compared to warfarin [20]. This increased risk was predominantly seen in patients receiving higher doses of rivaroxaban (20 mg daily) [20].

In the context of the VOYAGER PAD trial, patients received a lower dose of rivaroxaban (2.5 mg twice daily) in combination with aspirin. The trial found that the rate of TIMI major bleeding (which includes GI bleeding) was slightly increased in the rivaroxaban-aspirin group compared to the aspirin-alone group (2.65% vs. 1.87%, HR 1.43; 95% CI, 1.10–1.88; P = 0.007) [13]. However, the study did not report the specific incidence of GI bleeding separately. It is important to note that there was no significant increase in fatal or intracranial bleeding in the rivaroxaban-aspirin group [13].

Although these statistics might raise concerns, the absolute increase in TIMI major bleeding was relatively low at 0.78% [13]. Furthermore, the higher bleeding risk must be interpreted in the context of the significant reduction in the primary composite outcome. Overall, the results showed a net benefit for the use of rivaroxaban-aspirin [13].

In managing potential adverse effects, clinicians should consider individual patient factors such as overall bleeding risk, kidney function, potential drug-drug interactions, and patient preferences. Patients at higher risk of bleeding may require more careful monitoring. Patient education about the signs and symptoms of bleeding and when to seek medical help is vital. The appropriate use of proton pump inhibitors can be considered in patients at a high risk of GI bleeding [21]. In the event of major bleeding, it is comforting to note that specific reversal agents, such as andexanet alfa, are available for rivaroxaban, although not yet widely accessed in Australia [22].

6. Practical aspects of using rivaroxaban in clinical practice

6.1 Patient selection: indications and contraindications

Patient selection in VOYAGER PAD trial has clearly defined a population group that benefits from the addition of low dose rivaroxaban to aspirin. The defined population consists of patients with CLTI who have undergone recent surgical revascularisation, either via open surgery or endovascular [13]. Generalizing the results to patients with a different level of disease, such as those who have not undergone revascularisation, or those with less severe disease, may not be appropriate.

In terms of contraindications, rivaroxaban should not be used in patients with active pathological bleeding, as the drug contributes to a pro-haemorrhagic state [13, 23]. Patients with a history of severe hypersensitivity reaction to rivaroxaban should also avoid the drug. Rivaroxaban is also contraindicated in patients receiving concurrent anticoagulant treatment unless there is a clinical need to switch therapies, given the additive risk of bleeding [23].

Patients with significant hepatic disease, which is associated with coagulopathy and a clinically relevant bleeding risk, should not be prescribed rivaroxaban due to the potential for exacerbated bleeding [23]. Rivaroxaban should be used with caution in patients with renal impairment, particularly in those with a creatinine clearance <15 ml/min. Rivaroxaban in renally cleared and impaired renal function may lead to excessive drug accumulation and an increased risk of bleeding [23].

In the context of PAD and post-revascularization care, the VOYAGER PAD trial used a low-dose regimen of rivaroxaban (2.5 mg twice daily) in combination with aspirin (100 mg daily). This regimen aims to balance the benefits of anticoagulation in reducing vascular events against the risk of bleeding. Patient education regarding adherence to this twice-daily regimen is important to ensure therapeutic efficacy [13].

6.2 Monitoring: key parameters and frequency

Rivaroxaban, like other DOACs, does not require routine monitoring of coagulation parameters under normal circumstances, representing a significant advantage over older anticoagulants such as warfarin [24]. This is primarily due to the predictable pharmacokinetics and pharmacodynamics of the drug [23].

Certain clinical situations may necessitate assessment of the anticoagulant effect of rivaroxaban. These include suspected overdose, acute bleeding, before surgical procedures, or in patients with hepatic or renal impairment [24].

Although clotting studies cannot be used to monitor rivaroxaban, the drug can significantly prolong the prothrombin time (PT) and, to a lesser extent, the activated partial thromboplastin time (aPTT) [23]. Unfortunately, DOACs affect PT and aPTT unreliably, and these parameters cannot be used to estimate the degree of anticoagulation achieved with these medications [23]. If a measurement of the anticoagulant effect of rivaroxaban is required, a calibrated quantitative anti-Factor Xa is recommended [23].

Importantly, patients receiving rivaroxaban should be regularly assessed for signs and symptoms of bleeding, and the hemoglobin and hematocrit should be checked periodically. Any significant change in the patient’s status that suggests bleeding (e.g., a drop in hemoglobin) should trigger immediate evaluation [23].

Patients with renal impairment need particular monitoring as rivaroxaban is partially excreted by the kidneys [23, 25]. It is recommended to assess renal function, via measurement of creatinine clearance, at the initiation of therapy, regularly during treatment (at least annually), and when a change in renal function is suspected [25].

Patient adherence to medication should be regularly monitored due to the need for continuous anticoagulation in the setting of PAD and following revascularization.

6.3 Potential drug interactions

The metabolism of rivaroxaban primarily occurs through cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp) [23, 26]. Therefore, any drug that interferes with these systems has the potential to interact with rivaroxaban and modify its anticoagulant effect. Concomitant use of these drugs can result in an increased risk of bleeding or a decreased anticoagulant effect [23, 26].

Some important examples are:

1. Potent inhibitors of both CYP3A4 and P-gp: These drugs can significantly increase plasma concentrations of rivaroxaban, hence increasing the bleeding risk [23]. Examples include systemic azole antifungals (such as ketoconazole, itraconazole), HIV protease inhibitors (ritonavir), and the antibiotic clarithromycin. In these situations, rivaroxaban use should be carefully considered, and the patient should be closely monitored for signs of bleeding [23].

2. Potent inducers of both CYP3A4 and P-gp: These drugs can significantly reduce plasma concentrations of rivaroxaban, therefore potentially reducing its efficacy [23]. Examples include rifampicin, phenytoin, carbamazepine, phenobarbital, and St. John’s Wort. Co-administration with these drugs could lead to decreased efficacy of rivaroxaban and should be avoided or alternatives used when able [23].

3. Anticoagulants, antiplatelet agents, and NSAIDs: These drugs can add to the bleeding risk associated with rivaroxaban [23, 24]. Examples include warfarin, heparin, clopidogrel, and ibuprofen. If the combined use of these drugs is necessary, patients should be closely monitored for signs of bleeding [24].

4. Drugs affecting gastric pH: Antacids, H2 antagonists, and proton pump inhibitors (PPIs) can alter the absorption of rivaroxaban which is pH dependent [27]. However, studies suggest that the clinical relevance of this interaction is limited [27].

7. Special considerations

7.1 The elderly: age-related risks and benefits

Elderly patients are at an increased risk of both thrombotic and bleeding events. Age-associated physiological changes such as reduced renal function, reduced metabolism, and the presence of multiple comorbidities necessitate vigilant consideration [28].

One notable concern is the heightened risk of falls, which can lead to serious bleedings events, especially intracranial hemorrhage, when the patient is on anticoagulants [29]. As per the American Geriatrics Society’s updated Beers Criteria, the risk-benefit balance should be carefully assessed when prescribing anticoagulants to elderly patients at significant risk of falls [30]. Nevertheless, the fear of fall-related bleeding should not be a contraindication for anticoagulation in older adults, particularly those at high risk for thromboembolic events. The VOYAGER PAD trial showed benefits of rivaroxaban-aspirin in the elderly patient subset for the primary endpoints, however an increased bleeding risk was also reported [13]. Therefore, each patient needs to be individually assessed and closely monitored [13].

Another consideration for elderly patients is pill burden and polypharmacy. The term refers to the complexity of a drug regimen and can be amplified by the number of pills, frequency of dosing, and the necessity of specific administration instructions [31]. Increased pill burden has been linked to decreased medication adherence, a crucial aspect of anticoagulant therapy effectiveness [31].

7.2 Patients with renal impairment: dosage adjustments and monitoring

Rivaroxaban is partially excreted by the kidneys, and renal impairment can lead to increased systemic exposure and risk of bleeding [32]. According to the manufacturer’s recommendations, no dose adjustment is needed for patients with mild to moderate renal impairment [23, 32]. However, in those with severe renal impairment (creatinine clearance 15–29 ml/min), the dose should be reduced to 2.5 mg twice daily, i.e. the VOYAGER PAD dose is safe in those with severe renal impairment [13, 23]. For patients with end-stage renal disease or on dialysis, rivaroxaban should be used with caution due to the lack of data in this population [23].

7.3 History of gastrointestinal bleeds: precautions and alternative approaches

Patients with a history of gastrointestinal bleeds represent a significant challenge in the management of PAD, as rivaroxaban is associated with an increased risk of such bleeds [33]. In these cases, the use of proton pump inhibitors or histamine H2-receptor antagonists may be beneficial for gastric protection [33]. Additionally, the choice of an alternative antithrombotic agent with a lower gastrointestinal bleeding risk may be considered [34].

7.4 Perioperative considerations for patients on rivaroxaban

The perioperative management of patients on rivaroxaban requires balancing the risks of thrombosis and bleeding. It is recommended to discontinue rivaroxaban at least 24 hours before elective surgery, or longer for surgeries with a high risk of bleeding or in patients with renal impairment [35]. Bridging anticoagulation is generally not needed. After surgery, rivaroxaban should be resumed as soon as hemostasis is established, generally within 24 hours [35]. Patients on low dose rivaroxaban do not need to be commenced on an additional agent for the prevention of venous thromboembolism (VTE) while hospitalized, low dose rivaroxaban acts as a VTE prophylactic agent [35].

8. Future directions

8.1 Potential areas for further research in anticoagulation for PAD and limb revascularization

There are numerous avenues for potential research in the realm of anticoagulation for PAD and limb revascularization. More specific analyses focusing on particular subsets of the PAD population, such as those with concurrent conditions like diabetes, may elucidate variations in treatment responses [1].

Studies aiming to identify predictive markers of response to rivaroxaban, or anticoagulation treatment generally, would greatly enhance patient stratification and personalized treatment approaches [36]. This could involve genomics, proteomics, or the study of specific biomarkers [37].

Further research is also warranted to understand the long-term safety and effectiveness of rivaroxaban in patients undergoing limb revascularization, especially in the elderly population, where anticoagulant-related risks may be magnified [36]. Additional investigation into strategies to manage and prevent bleeding risks in patients receiving anticoagulation therapy will be valuable as more patients are prescribed these medications [38].

8.2 Next steps in investigating the role of rivaroxaban

The VOYAGER PAD trial has set a precedent for future investigations of rivaroxaban in PAD and limb revascularization. Future trials could further evaluate the optimal timing and duration of rivaroxaban therapy following revascularization procedures [13].

Rivaroxaban’s role in combination with other antiplatelet or anticoagulant agents beyond aspirin has not been explored yet [39]. This may pave the way for new combination regimens that could maximize therapeutic benefits while minimizing adverse events [39].

A comparison of rivaroxaban with other DOACs could inform on whether the benefits observed are unique to rivaroxaban or a class effect.

9. Conclusion

The VOYAGER PAD trial is the first randomized control trial demonstrating the superiority of combined low-dose rivaroxaban and aspirin therapy over aspirin alone in the management of severe PAD [13]. This regimen reduces acute limb ischemia, major amputation, myocardial infarction, ischemic stroke, or cardiovascular-related death in patients with severe PAD who have undergone surgical limb revascularisation [13]. However, the trial also identified an increased bleeding risk, especially in females and patients with a history of bleeding [13].

Despite its advantages, this combination therapy is not a universal solution. Optimal application requires careful patient selection, risk stratification, and continuous monitoring due to rivaroxaban’s potential drug interactions. Special caution is needed for populations like the elderly and those with renal impairment or a history of gastrointestinal bleeds.

The role of rivaroxaban in PAD and limb revascularization still offers vast research opportunities. Future studies on precise indications, dosage, and patient-specific factors could enhance treatment strategies. As we strive for improved anticoagulation management in PAD and limb revascularization, it’s crucial for clinicians to stay abreast of evolving evidence to provide optimal patient care, guided by findings from studies like the VOYAGER PAD trial.

Conflict of interest

The authors declare no conflict of interest.