Expert Recommendations on Antithrombotic Management of Peripheral Artery Disease: Perspectives from Indian Interventional Radiologists

Abstract

Peripheral artery disease (PAD) imposes a heavy burden of major adverse cardiovascular events (MACE) that are associated with considerable mortality and morbidity and major adverse limb events (MALE) (e.g., thrombectomy, revascularization, amputation) that can substantially impact patients' daily functioning and quality of life. Epidemiological studies have indicated that PAD is an underdiagnosed disease in India, and its associated risk factors remain inadequately controlled. Antithrombotic therapy for PAD is underutilized in India. Revascularization procedures are done in acute or advanced stages. While such invasive strategies are effective in some patients with PAD, these strategies are costly and carry risks, and many patients are not amenable to invasive therapy, especially in low-resource settings like in India. In recent years, dual pathway inhibition (DPI) has emerged as a promising approach to improve the treatment of coronary artery diseases and represented a long-awaited major advancement for the medical treatment of PAD, as demonstrated by the Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) and Vascular Outcomes Study of ASA (acetylsalicylic acid) Along with Rivaroxaban in Endovascular or Surgical Limb Revascularization for PAD (VOYAGER-PAD) trials. DPI with rivaroxaban 2.5 mg twice daily + aspirin 100 mg once daily can be used to decrease the risk of MACE or cerebrovascular events and MALE, in PAD patients without high bleeding risk. Clinical evidence, clinical expertise, and real-world practice were integrated to form expert opinions and a clinical algorithm for using DPI as antithrombotic management in patients with PAD. The expert opinions and algorithms can be adopted not only by interventional radiologists in India involved in the clinical management of patients with PAD but also by vascular surgeons and general practitioners in rural areas, aiming to improve the totality of PAD patient care in India.

Keywords

dual pathway inhibition - revascularization - peripheral artery disease - rivaroxaban - antithrombotic therapy - major adverse limb events

Introduction

Peripheral arterial disease (PAD) is one of the most common clinical manifestations of systemic atherosclerosis. In India, the occurrence of PAD ranges between 7.6 and 26.7%.[1] [2] Reported PAD prevalence rates in the Asia-Pacific region have ranged between 5% in the Philippines, 5.2% in Thailand, 8.2% in Singapore, 10.1% in Australia, and 12.1% in Japan.[3] As per global data, 72.91% of patients with PAD reside in low- and middle-income countries.[4] Despite its prevalence, PAD remains underdiagnosed, undertreated, and understudied.[5] The clinical consequences of atherosclerosis leading to the development of PAD are linked to major risk factors, including smoking, a sedentary lifestyle, old age, diabetes, dyslipidemia, hypertension, hyperhomocysteinemia, and history of albuminuria or chronic kidney disease (CKD).[6]

The presentation symptoms of PAD vary from asymptomatic, atypical leg symptoms, intermittent claudication (IC), and ischemic rest pain to tissue loss.[6] Irrespective of presentation, PAD patients exhibit walking impairment and face a higher incidence of major cardiovascular (CV) events (myocardial infarction [MI], stroke, CV death) compared to age-matched controls. Despite standard care, they remain at high risk for disease progression, major adverse cardiovascular events (MACE), and major adverse limb events (MALE).

In the Reduction of Atherothrombosis for Continued Health (REACH) registry, it was reported that the incidence of CV death, MI, stroke, or hospitalization from atherothrombotic events was highest among PAD patients (21.14% PAD vs. 15.2% coronary artery diseases [CADs] vs. 14.35 CV diseases [CVDs]). Recent studies show medium-term major CV event rates of 10 to 20% in PAD and polyvascular disease populations. Despite available guideline-based preventive therapies, usage remains suboptimal, and PAD patients continue to experience high rates of vascular events and related hospitalizations.[3]

Given the significant prevalence of atherosclerotic CVD risk factors in India, diagnosing and treating PAD is essential to improve outcomes for both asymptomatic and symptomatic patients.[7] [8] The management of PAD is multifaceted, requiring both medical and interventional approaches. Recommendations for the management of PAD can be found in an expanding body of literature, including guidelines from the major European and American cardiology and vascular societies and associations and recently published treatment algorithms from the American College of Cardiology and American Heart Association (ACC/AHA).[6] Apart from lifestyle modifications and proactive management of comorbidities, medical therapy should be implemented across the different stages of the PAD disease spectrum—from IC or chronic limb threatening ischemia (CLTI), requiring lower extremity revascularization and postendovascular revascularization, to the long-term management of chronic PAD.

Managing PAD in India poses unique challenges that demand tailored approaches. High rates of comorbidities like diabetes and CKD complicate treatment, while limited health care access, especially in rural areas, often leads to late diagnosis and advanced disease at presentation. Low health literacy, socioeconomic barriers, and patient noncompliance further exacerbate these issues. Despite PAD's impact—affecting over 230 million globally—it remains underdiagnosed and undertreated in India due to limited provider awareness and inadequate access to diagnostic tools like ankle-brachial index (ABI). Competing priorities often shift focus away from PAD management, resulting in patients receiving care only when they present with severe complications such as CLTI or acute limb ischemia (ALI). Additionally, a lack of specific guidelines or consensus recommendations for PAD management in India leaves clinicians relying on Western data that may not accurately reflect local patient demographics and treatment responses.[9] [10]

Revascularization procedures used in the treatment of PAD include endovascular procedures like balloon angioplasty (plain balloon, specialized balloon, or drug-coated); bare-metal, drug-eluting, or covered stent placement; and plaque removal (atherectomy) and surgical procedures like endarterectomy and bypass grafting (autogenous or prosthetic).[11] These procedures increase the risk of CV death, MI, stroke, stent thrombosis, limb amputation, and ALI, with surgical revascularization further heightening the risk of thrombotic bypass occlusion. A robust antithrombotic strategy postrevascularization is essential for interventional radiologists.[11] [12] This article aims to provide clinical recommendations for antithrombotic management of PAD in Indian patients postrevascularization.

Traditionally, treatment with antithrombotic agents has involved a single antiplatelet agent (SAPT) (e.g., aspirin or clopidogrel), evolving toward dual antiplatelet therapy (DAPT) of various combinations of antithrombotic agents. The Indian Consensus Statement for the Management of Lower Extremity Peripheral Artery Disease (2023) acknowledges the benefits of DAPT in select PAD patients, particularly those at high risk for thrombotic events.[10]

The pivotal results from the Cardiovascular Outcomes for People using Anticoagulation Strategies (COMPASS) and Vascular Outcomes study of ASA along with rivaroxaban in Endovascular or surgical limb Revascularization for PAD (VOYAGER-PAD) studies introduced dual pathway inhibition (DPI) by combining aspirin with rivaroxaban. This novel antithrombotic strategy reduces PAD and CV event risk by targeting platelet aggregation and fibrin formation.[13] Based on COMPASS results, DPI is recommended by the European Society for Vascular Medicine for PAD patients without high bleeding risk or contraindications.[13]

Need for Expert Opinion

Despite PAD's prevalence in India, there is a notable absence of tailored guidelines or recommendations. This underscores the need for comprehensive, India-specific strategies to address PAD's unique challenges and optimize patient care.

Repeat revascularization may be needed to restore blood flow and prevent amputation due to PAD progression. Restenosis was observed in 12.5% of patients in a retrospective study by Gheini et al.[14] Hence, the increased risk of adverse events postrevascularization highlights the importance of a robust antithrombotic strategy for interventional radiologists.[14] This expert opinion offers recommendations for antithrombotic management with DPI in PAD patients, combining evidence-based guidance and Indian expert insights into a clinical algorithm for managing postrevascularization (with/without stent), symptomatic PAD, and CLTI.

Methodology

A panel of 14 interventional radiologists convened for an expert group meeting to discuss the antithrombotic management of patients with PAD following revascularization, as well as those with chronic PAD and CLTI. The discussions covered the current challenges, practices, and clinical practice recommendations for managing various patient profiles mentioned above. The recommendations discussed in the meeting were documented and a clinical algorithm was proposed for the management of PAD.

Overarching Principles and Definitions

The overarching principles and definitions are detailed in [Table 1].

Table 1 Overarching principles and definitions for PAD management

Overarching principles and definitions	Description
Immediate initiation*	Once hemostasis is achieved or at time of discharge
High bleeding risk criteria[a]	Medical history or active clinically significant bleeding, lesions, or conditions within the last 6 months, significant risk for major bleeding (including but not limited to): i. Current medically confirmed gastrointestinal ulceration ii. Presence of malignant neoplasms at high risk of bleeding iii. Current or recent (within 30 days) brain or spinal injury iv. Known esophageal varices v. Vascular aneurysms of the large arteries or major intraspinal or intracerebral vascular abnormalities vi. Known hepatic disease associated with coagulopathy or bleeding risk vii. CKD with eGFR < 15 mL/min/1.73 m2
Claudication	A classical symptom of PAD that presents as exercise-induced lower extremity discomfort relieved by rest
Symptomatic PAD	Defined by symptoms including claudication
Asymptomatic PAD	Patients lack typical claudication symptoms but require risk reduction due to atherosclerosis
CLTI or CLI	CLI involves chronic rest pain or ischemic skin lesions lasting ≥ 2 weeks
Acute limb ischemia	Signifies a sudden decrease in limb perfusion, posing a threat to limb viability, with symptoms including the “6 Ps”: pain, paralysis, paresthesia, pulselessness, poikilothermia, and pallor, occurring within 2 weeks

Abbreviations: CKD, chronic kidney disease; CLI, chronic limb ischemia; CLTI, chronic limb threatening ischemia; eGFR, estimated glomerular filtration rate; PAD, peripheral artery disease.

^a High bleeding risk criteria: Medical history or active clinically significant bleeding, lesions, or conditions within the last 6 months, significant risk for major bleeding (this may include current medically confirmed gastrointestinal ulceration, presence of malignant neoplasms at high risk of bleeding, current or recent brain or spinal injury, known esophageal varices, vascular aneurysms of the large arteries or major intraspinal or intracerebral vascular abnormalities, known hepatic disease associated with coagulopathy or bleeding risk, CKD with eGFR < 15 mL/min/1.73 m²).

Current Evidence and Practice Recommendations in the Management of PAD

Postrevascularization

Interventional Therapy Landscape in India

Interventional therapies for PAD in India encompass various endovascular procedures, including balloon angioplasty (plain, specialized, or drug-coated), bare-metal and drug-eluting stent placement, and plaque removal (atherectomy). The 2016 ACC/AHA guidelines advocate for endovascular revascularization in patients with lifestyle-limiting claudication and hemodynamically significant femoropopliteal disease. In contrast, surgical options such as endarterectomy, bypass grafting (autogenous or prosthetic), and femorotibial artery bypass are recommended for patients with lifestyle-limiting claudication who do not respond adequately to guideline-directed medical therapy.[11] [15] These principles are particularly relevant to the Indian context, where PAD presents distinct challenges and risk factors. The Indian Consensus Statement on Lower Extremity PAD management emphasizes DPI with combined antiplatelet and anticoagulant therapy in select high-risk patients postrevascularization.[10]

The burden of PAD in India is substantial, with studies showing rising prevalence and a need for timely interventions. A 2024 systematic review and meta-analysis emphasized the rising incidence of PAD in India, particularly in individuals with diabetes and metabolic syndrome,[16] emphasizing the importance of effective revascularization strategies in the Indian population.

Endothelial damage following peripheral endovascular interventions can lead to acute thrombosis or long-term restenosis, reinforcing the importance of postprocedural antithrombotic therapy.[9] The clinical prognosis for Indian PAD patients remains a concern despite advancements in interventional techniques and devices.[10] A retrospective study at a tertiary care center in India revealed a high rate of MALE and reinterventions following lower extremity revascularization, highlighting the need for optimized secondary prevention strategies.[17]

The Indian Consensus Statement for the Management of Lower Extremity Peripheral Artery Disease recommends DPI of aspirin plus rivaroxaban in all PAD patients to reduce the risk of MALE and MACE.[10] This aligns with the recent 2024 ACC/AHA guidelines recommending low-dose rivaroxaban combined with low-dose aspirin after endovascular or surgical revascularization for PAD to reduce the risk of MACE and MALE.[18]

In conclusion, while global guidelines provide a foundation, optimizing PAD management in India requires tailored guidelines and further research to address local challenges, especially in the postrevascularization phase.

Clinical studies indicate an increased risk of adverse limb events and revascularization in PAD patients. In the 5-year (German Epidemiological Trial on Ankle Brachial Index [getABI]) study, Diehm et al reported revascularization rates rising from 1.5/1,000 PY (patient-years) in individuals without PAD to 20/1000 PY in those with PAD.[19] Approximately 20 to 25% of PAD patients require revascularization, with 5% progressing to chronic limb ischemia (CLI).[10]

Damage to the endothelium caused by peripheral endovascular interventions might result in either acute thrombosis or long-term restenosis. Postprocedural antithrombotic therapy aims to minimize bleeding risk, enhance revascularization, and reduce systemic effects, including MACE.[20] The clinical prognosis for patients with PAD in India is still inadequate, despite technological advancements in invasive interventional therapy devices and procedures.[6]

Currently, controlled studies lack sufficient data to justify long-term DAPT use postlower extremity revascularization. As an advancement in PAD care, DPI offers an antithrombotic approach beyond traditional antiplatelet therapy. Despite benefits of revascularization, a recent U.S. study showed PAD patients still face high risks, with a 9.8% risk of MI or stroke and 41.9% risk of major amputation or further revascularization over a 2.7-year median follow-up. This underscores the need for more intensive postprocedural prevention.[21] In PAD patients not previously on DPI, the regimen should be started as soon as hemostasis is established following the endovascular revascularization assuming no contraindications have surfaced.[6]

Postrevascularization without Stent

Current evidence: The VOYAGER-PAD trial evaluated the efficacy of DPI with rivaroxaban 2.5 mg twice a day + low-dose aspirin versus aspirin alone in PAD patients undergoing revascularization. The primary efficacy outcome was a composite of ALI, major amputation for vascular causes, MI, ischemic stroke, or death from CV causes. Around 65% of patients were treated with endovascular revascularization (without stent) and 35% with surgical procedures. The results suggest that DPI with rivaroxaban 2.5 mg twice a day + aspirin can be initiated as soon as the revascularization procedure is completed ([Table 2]).[22]

Table 2 Clinical trial summary for DPI in patients postrevascularization without stent

i. Summary of evidence
Trial	Study design	Duration	Inclusion criteria	Intervention	Results
Bonaca et al[22] and VOYAGER-PAD	International, multicenter, randomized, double-blind, placebo-controlled, event-driven phase 3 study	30 months	-Age ≥ 50 years -Documented moderate to severe symptomatic lower extremity PAD	Rivaroxaban 2.5 mg bid + low-dose aspirin (N = 3,286) Aspirin + placebo (N = 3,278)	Reduction in primary endpoint: Rivaroxaban 2.5 mg bid + aspirin: 15.4% Aspirin + placebo: 17.8% (p = 0.009) Reduction in risk of ALI or major amputation: Rivaroxaban 2.5 mg bid + aspirin: 30% Aspirin + placebo: 17.8% (p = 0.005) Reduction in ALI: Rivaroxaban 2.5 mg bid + aspirin: 4.7% Aspirin + placebo: 6.9% (HR 0.67) Reduction in major amputation for vascular causes: Rivaroxaban 2.5 mg bid + aspirin: 3.1% Aspirin + placebo: 3.5% (p = 0.009)
ii. Guideline recommendations
ACC/AHA 2024				“After endovascular or surgical revascularization for PAD, low-dose rivaroxaban (2.5 mg twice daily) combined with low-dose aspirin is recommended to reduce the risk of MACE and MALE (1A)”

Abbreviations: ACC/AHA, American College of Cardiology and American Heart Association; ALI, acute limb ischemia; bid, twice a day; CAD, coronary artery disease; DPI, dual pathway inhibition; HR, hazard ratio; MACE, major adverse cardiovascular events; MALE, major adverse limb events; PAD, peripheral artery disease.

The 2021 European Society of Cardiology (ESC) consensus proposes the use of low-dose aspirin and rivaroxaban 2.5 mg twice a day in patients undergoing revascularization (surgical or endovascular) for lower extremity PAD with no increased risk of bleeding.[23] This is in line with the recent 2024 ACC/AHA guidelines.[18]

The management of PAD, especially regarding antithrombotic therapy, has significantly evolved with DPI strategies. Recent trials, such as the VOYAGER-PAD trial, provide robust evidence supporting rivaroxaban combined with low-dose aspirin for patients postrevascularization, regardless of stent use. This combination reduced the risk of MALE, including ALI and major amputation, compared to aspirin alone (p < 0.05).[22] This underscores DPI's potential in enhancing clinical outcomes in PAD patients who are at high risk for CV events. Thus, incorporating these findings into clinical practice could enhance patient outcomes in India, where PAD is prevalent yet often underdiagnosed. However, careful assessment of bleeding risks is essential, as the absence of high bleeding risk criteria is crucial for recommending DPI.

Fig. 1 Antithrombotic management algorithm for patients with PAD postendovascular revascularization with or without stent. DPI, dual pathway inhibition; PAD, peripheral artery disease.

Postrevascularization with Stent

Current evidence: The VOYAGER-PAD trial showed that in patients with PAD undergoing endovascular revascularization (with stent), DPI with rivaroxaban 2.5 mg twice a day + low-dose aspirin significantly reduced the risk of major CV and limb events.[22] The 2021 ESC consensus proposes the use of low-dose aspirin and rivaroxaban 2.5 mg twice a day in patients undergoing revascularization (surgical or endovascular) for PAD with no increased risk of bleeding.[23]

Chronic PAD

Asymptomatic PAD

Current evidence: Asymptomatic PAD patients (including asymptomatic carotid stenosis patients) lack typical claudication symptoms but need risk reduction due to atherosclerosis. Patients with a history of PAD in lower extremities, carotid arteries, or CAD were included in the study. The patients were randomized into three arms: rivaroxaban 2.5 mg twice a day + low-dose aspirin, rivaroxaban 5 mg twice a day, and aspirin alone. The primary CV efficacy outcome was the composite of CV death, MI, or stroke. A significant reduction in the primary endpoint was observed in the rivaroxaban 2.5 mg twice a day + low-dose aspirin group compared to other groups (hazard ratio [HR] 0.72; p = 0.0047). In patients with carotid stenosis or a history of carotid revascularization, the efficacy of DPI with rivaroxaban 2.5 mg twice a day + low-dose aspirin has been demonstrated in the COMPASS trial ([Table 3]).[23] Rivaroxaban alone did not significantly reduce the primary endpoint (HR 0.86; p = 0.19) but reduced the incidence of MALE, including major amputation (HR 0.67; p = 0.05).

Table 3 Clinical trial summary for DPI in patients with chronic PAD

Trial	Study design	Duration	Inclusion criteria	Intervention	Results
Eikelboom et al[26] COMPASS trial	Multicenter, double-blind, randomized, placebo-controlled trial	38 weeks	History of PAD of the lower “extremities,” carotid arteries, or CAD with an ankle-brachial index of less than 0.90	Rivaroxaban 2.5 mg bid + aspirin 100 mg once daily (N = 2,492) Rivaroxaban 5 mg bid (N = 2,474) Aspirin 100 mg once a day (N = 2,504)	Occurrence of primary outcome: Rivaroxaban 2.5 mg bid + aspirin: 4.1% Rivaroxaban 5 mg: 4.9% Aspirin 100 mg: 5.4% (HR 0.76; p < 0.001) Occurrence of secondary outcome: Rivaroxaban 2.5 mg bid + aspirin: 3.6% Rivaroxaban 5 mg: 4.4% Aspirin 100 mg: 4.9% (HR 0.72; p < 0.001) Occurrence of venous thromboembolism: Rivaroxaban 2.5 mg bid + aspirin: 0.3% Rivaroxaban 5 mg: 0.4% Aspirin 100 mg: 0.4% (HR 0.61, p < 0.05)
Anand et al[25] COMPASS trial (carotid subgroup analysis)	Multicenter, double-blind, randomized, placebo-controlled trial	38 weeks Treatment duration: 21 months	History of PAD of the lower “extremities,” carotid arteries, or CAD with an ankle-brachial index of less than 0.90	Rivaroxaban 2.5 mg bid + aspirin 100 mg once daily (N = 2,492) Rivaroxaban 5 mg bid (N = 2,474) Aspirin 100 mg once a day (N = 2,504)	Occurrence of primary cardiovascular efficacy outcome: Rivaroxaban 2.5 mg bid + aspirin: 5% Rivaroxaban 5 mg: 6% Aspirin 100 mg: 7% (HR 0.72; p = 0.0047) Occurrence of MALE events: Rivaroxaban 2.5 mg bid + aspirin: 1% Rivaroxaban 5 mg: 1% Aspirin 100 mg: 2% (HR 0.54, p = 0.0054)

Abbreviations: bid, twice a day; CAD, coronary artery disease; DPI, dual pathway inhibition; HR, hazard ratio; MALE, major adverse limb events; PAD, peripheral artery disease.

The COMPASS-PAD subgroup analysis revealed that DPI with rivaroxaban 2.5 mg twice daily and low-dose aspirin led to a 46% relative risk reduction in MALE (HR: 0.54, 95% confidence interval [CI]: 0.35–0.82) and a 28% reduction in MACE compared to aspirin alone. Although there was a 61% increase in major bleeding events (p = 0.0043), fatal and intracranial bleeding rates were unchanged. The DPI strategy also resulted in a 29% relative reduction in the composite net clinical benefit, encompassing CV death, MI, stroke, MALE, major amputation, fatal bleeding, and critical organ bleeding.[24]

The results of a meta-analysis by Anand et al showed that treatment with rivaroxaban plus low-dose aspirin reduced the composite outcome of CV death, MI, ischemic stroke, ALI, or major vascular amputation by 21% compared to aspirin alone, with moderate heterogeneity between trials. While there was a significant increase in International Society on Thrombosis and Haemostasis (ISTH) major bleeding, severe bleeding (fatal or symptomatic bleeding into critical organs) rates did not change.[25] Similarly, when analyzing only the subgroup of patients with lower extremity arterial disease (LEAD), MALE (including ALI or major vascular amputation) decreased by 27%, showing no heterogeneity. The authors estimated that treating 1,000 LEAD patients with rivaroxaban and aspirin would prevent 13 major CV or limb events but result in eight additional major bleeds, including one fatality.[25]

Fig. 2 Antithrombotic therapy algorithm for asymptomatic chronic PAD. ABI, ankle-brachial index; DPI, dual pathway inhibition; MI, myocardial infarction; PAD, peripheral vascular disease; SAPT, single antiplatelet therapy; T2DM, type 2 diabetes mellitus.

Symptomatic PAD

Current evidence: Regarding patients with symptomatic PAD, the 2024 ACC/AHA recommended “low-dose rivaroxaban (2.5 mg twice daily) combined with low-dose aspirin is effective to reduce the risk of MACE and MALE [1A].”[18] The COMPASS trial showed that in patients with atherosclerotic vascular disease DPI with rivaroxaban 2.5 mg twice a day + low-dose aspirin showed better CV outcomes ([Table 3]). The primary outcomes included CV death, stroke, or MI; secondary outcomes included ischemic stroke, MI, ALI, or death from coronary heart disease.[26]

Fig. 3 Antithrombotic management algorithm for patients with symptomatic chronic PAD with or without intermittent claudication. DPI, dual pathway inhibition; PAD, peripheral artery disease.

Chronic Limb Threatening Ischemia

Current evidence: In the VOYAGER-PAD trial, 1,533 patients with CLI who underwent revascularization benefited from DPI using rivaroxaban 2.5 mg twice daily plus low-dose aspirin, which significantly reduced the risk of ALI or major amputation (p < 0.005). The trial also showed a 15% relative risk reduction in the composite incidence of ALI, major amputation due to vascular causes, MI, ischemic stroke, or CV death (HR: 0.85, CI: 0.76–0.96), without significant major thrombolysis in MI (TIMI) bleeding (p = 0.07) ([Table 4]).[22] The Global Vascular Guidelines recommend considering DPI strategy to reduce adverse CV events and lower extremity ischemic events in patients with CLTI.[27]

Table 4 Clinical trial summary of VOYAGER-PAD in patients with CLTI

Trial	Study design	Duration	Inclusion criteria	Intervention	Results
Bonaca et al[22] VOYAGER-PAD	International, multicenter, randomized, double-blind, placebo-controlled, event-driven phase 3 study	30 months	-Age ≥ 50 years -Documented moderate to severe symptomatic lower extremity PAD	Rivaroxaban 2.5 mg bid + low-dose aspirin (N = 3,286) Placebo+ aspirin (N = 3,278)	Reduction in the risk of ALI or major amputation of a vascular pathogenesis Rivaroxaban 2.5 mg bid + aspirin: 30% (HR, 0.70; p = 0.005) Occurrence of secondary efficacy outcomes: Rivaroxaban 2.5 mg bid + aspirin: 13.2% Placebo + aspirin: 16.1% (p < 0.001) Hospitalization for coronary or peripheral event of a thrombotic nature: Rivaroxaban 2.5 mg bid + aspirin: 8.0% Placebo + aspirin: 10.9%

Abbreviations: ALI, acute limb ischemia; bid, twice a day; CLTI, chronic limb threatening ischemia; HR, hazard ratio; MI, myocardial infarction; PAD, peripheral artery disease.

Note: Secondary efficacy outcomes: ALI, major amputation for a vascular cause, MI, ischemic stroke, or death from coronary heart disease.

Fig. 4 Antithrombotic management in chronic limb threatening ischemia. DPI, dual pathway inhibition; PAD, peripheral artery disease.

Special Population

Current evidence: In the VOYAGER-PAD trial, approximately 1% of the patients had stage 4 CKD and 20% were elderly. Patients with more severe CKD exhibited higher rates of major limb and CV events. DPI with rivaroxaban 2.5 mg twice a day + low-dose aspirin reduced CV and limb events in patients with CKD and PAD following lower extremity revascularization. The primary endpoint of ALI, major amputation, MI, ischemic stroke, or CV death and safety outcome of TIMI major bleeding was assessed in those 75 or above (elderly) and < 75 years old. The results indicated greater benefits for elderly patients with DPI, with no increased bleeding risk observed ([Table 5]).[28] [29]

Table 5 Results of VOYAGER-PAD in elderly and CKD patients

Trial	Study design	Duration	Inclusion criteria	Intervention	Results
Hsia et al[28] and Krantz et al[29] VOYAGER-PAD	International, multicenter, randomized, double-blind, placebo-controlled, event-driven phase 3 study	30 months	-Age ≥ 50 years -Documented moderate to severe symptomatic lower extremity PAD	Rivaroxaban 2.5 mg bid + low-dose aspirin (N = 3,286) Placebo + aspirin (N = 3,278)	CKD patients Occurrence of major CV and limb events (p = 0.62): eGFR < 60: HR 0.55 eGFR ≥ 60: HR 0.77 Elderly patients -Major bleeding was infrequent with no heterogeneity by CKD category -Efficacy of rivaroxaban+ aspirin for the primary endpoint (p = 0.83) and safety for TMB (p = 0.38) were consistent by age -In the elderly, the primary endpoint benefits (ARR 3.8%, NNT 26) were not outweighed by TMB (ARI 0.81%, NNH 123).

Abbreviations: ARI, absolute risk increase; ARR, absolute risk reduction; CKD, chronic kidney disease; CV, cardiovascular; eGFR, estimated glomerular filtration rate; HR, hazard ratio; NNH, number needed to harm; NNT, number needed to treat; PAD, peripheral artery disease; TMB, thrombolysis in myocardial infarction major bleeding.

Type 2 Diabetes Mellitus

Lower extremity complications are very commonly observed in type 2 DM (T2DM) patients. According to a study by Bhandari et al, around 50% of patients undergoing revascularization for PAD have T2DM. It is an independent risk factor for major limb amputation and hospital readmissions.[30] The American Diabetes Association 2024 guidelines recommend the use of DPI with rivaroxaban 2.5 mg twice a day and low-dose aspirin in T2DM patients with PAD and low risk of bleeding.[31]

The VOYAGER-PAD had 40% T2DM patients at baseline. DPI with rivaroxaban 2.5 mg twice a day + low-dose aspirin resulted in a significant reduction in the primary composite outcomes. A subgroup analysis in the diabetes population concluded that the effects of DPI with rivaroxaban 2.5 mg twice a day and low-dose aspirin were similar to the main trial population.[32]

The COMPASS Diabetes study was a prespecified subgroup analysis of diabetic patients of the COMPASS trial. Around 38% of patients were diabetic. DPI with rivaroxaban 2.5 mg twice a day + low-dose aspirin resulted in significant reductions in the composite primary endpoint (HR 0.74, p = 0.002) ([Table 6]).[33]

Table 6 Results of COMPASS Diabetes subgroup analysis

Trial	Study design	Duration	Inclusion criteria	Intervention	Results
Bhatt et al[33] COMPASS Diabetes (subgroup analysis)	Multicenter, double-blind, randomized, placebo-controlled trial	38 weeks	Patients with or without T2DM	Rivaroxaban 2.5 mg bid + aspirin 100 mg once daily (N = 9,152) Placebo + aspirin 100 mg once a day (N = 9,126)	Occurrence of primary efficacy endpoint Rivaroxaban 2.5 mg bid + aspirin: 5.8% Placebo + aspirin: 7.8% (HR 0.73, p = 0.0007)

Abbreviations: bid, twice a day; HR, hazard ratio; T2DM, type 2 diabetes mellitus.

Fig. 5 Antithrombotic approach for special population. CKD, chronic kidney disease; DPI, dual pathway inhibition; eGFR, estimated glomerular filtration rate; PAD, peripheral artery disease; T2DM, type 2 diabetes mellitus.

Management of High Bleeding Risk in PAD Patients

Defining “High Bleeding Risk”

High bleeding risk in PAD patients can be assessed using validated scores like the Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile International Normalized Ratio (INR), Elderly, Drugs/Alcohol Concomitantly (HAS-BLED), with a score of ≥ 3 indicating significant risk. This score considers factors such as hypertension, abnormal renal/liver function, history of stroke or bleeding, labile INR (for warfarin users), age, and the use of drugs or alcohol that may heighten bleeding risk. Additionally, factors like prior bleeding, prosthetic limbs, below-knee bypass, suboptimal runoff, active cancer, and extensive lesions can further elevate the bleeding risk profile.

Therapy Choices Based on Bleeding Risk

The choice of antithrombotic therapy in PAD patients with high bleeding risk needs to balance the need for preventing ischemic events (like MI, stroke, or limb ischemia) with the risk of bleeding complications.

• High bleeding risk (HAS-BLED ≥3 or presence of additional risk factors from the algorithm)

  • ◦ SAPT: The preferred strategy for this group is to minimize bleeding risk using aspirin or clopidogrel. The algorithm specifically recommends SAPT, even with significant peripheral artery stenosis and diabetes, provided there is no concurrent ischemic heart or cerebrovascular disease.

  • ◦ DPI: Should generally be avoided in patients with high bleeding risk, even in those with recent revascularization or stent placement, due to the significantly increased bleeding risk.

  • ◦ DAPT: Generally contraindicated due to the high bleeding risk.

• Low to moderate bleeding risk (HAS-BLED < 3 and absence of additional risk factors from the algorithm)

  • ◦ SAPT: May be considered in patients with low ischemic risk.

  • ◦ DAPT: Can be considered for a short duration (1–3 months) after revascularization with stent placement, transitioning to SAPT. The algorithm suggests considering DAPT in patients with intermediate risk (peripheral artery stenosis > 50%, diabetes) or high risk (peripheral artery stenosis > 50%, diabetes, and ischemic heart disease/CVD) even without stent placement.

  • ◦ DPI: May be considered in select patients with high ischemic risk and low bleeding risk, with careful monitoring. The algorithm recommends DPI for intermediate and high-risk patients.[9] [34]

Comparison of Antithrombotic Strategies in Reducing MALE and Other Outcomes

PAD represents a considerable health concern, impacting an estimated 240 million people worldwide and significantly increases the risk of both MALE and MACE. These risks are exacerbated in individuals undergoing revascularization procedures, as they may experience CLI, ALI, or even amputation due to thrombus formation or plaque rupture, making effective antithrombotic strategies essential for management.[35]

Efficacy of Antithrombotic Strategies

Recent studies, including the COMPASS and VOYAGER trials, have demonstrated that DPI significantly reduces the risk of MALE and MACE in patients with PAD compared to traditional therapies. In these studies, the outcomes were assessed using HRs for ISTH major bleeding and fatal bleeding alongside MALE events ([Table 7]).[35]

Table 7 Summary of endpoints of COMPASS and VOYAGER-PAD studies

Aspect	DPI (rivaroxaban + aspirin)	SAPT (aspirin alone)
Study	COMPASS and VOYAGER trials	COMPASS and VOYAGER trials
Primary outcome	Cardiovascular death, stroke, MI	Cardiovascular death, stroke, MI
MALE outcome	17.3% in the DPI group	19.9% in the placebo/aspirin group
HR for MACE[22] [35]	COMPASS trial: 0.76 (95% CI: 0.66–0.86; p < 0.001) VOYAGER-PAD trial: 0.85 (95% CI: 0.76–0.96, p = 0.009)
Major bleeding risk[35]	1.7-fold increased risk compared to aspirin alone
ISTH major bleeding	Significant increase in gastrointestinal bleeding	Lower incidence of gastrointestinal bleeding
Notable findings	313 deaths (3.4%) in DPI vs. 378 deaths (4.1%) in aspirin (HR: 0.82; p = 0.01)	Higher rates of MACE, necessitating effective management
Overall clinical benefit	Maintained net clinical benefit despite bleeding risks	Limited protective effects against MALE
Patient profile	Patients with PAD, especially those undergoing revascularization	Patients with PAD

Abbreviations: CI, confidence interval; DPI, dual pathway inhibition; HR, hazard ratio; ISTH, International Society on Thrombosis and Haemostasis; MACE, major adverse cardiovascular events; MALE, major adverse limb events; MI, myocardial infarction; PAD, peripheral artery disease; SAPT, single antiplatelet agent.

Implications of the Results

The findings from these trials emphasize the need for a tailored antithrombotic approach in PAD patients, particularly those undergoing revascularization. While DPI effectively reduces MALE and MACE, it significantly increases bleeding risks, especially gastrointestinal bleeding, requiring careful monitoring in vulnerable populations like the elderly. The ongoing risk of MALE postrevascularization highlights the importance of vigilant antithrombotic management, as revascularization does not eliminate the risk of further vascular complications.

Discussion

The clinical decision-making algorithm is a suitable approach that can be referred to and adapted for the management of patients with PAD in India. A balanced and careful assessment of the combined risk of CV and bleeding events should be performed for all patients with PAD.

DPI with rivaroxaban 2.5 mg twice a day + aspirin should be considered as antithrombotic therapy (to be initiated immediately*) for postendovascular revascularization (without/with stent) in PAD to reduce major limb and CV events in the absence of high bleeding risk^# ([Fig. 6]).

Fig. 6 Algorithm for antithrombotic management of PAD. CKD, chronic kidney disease; T2DM, type 2 diabetes mellitus; MI, myocardial infarction; SAPT, single antiplatelet therapy.

When Should DPI be Stopped Before the Revascularization Procedure?

Physicians should stop rivaroxaban 2.5 mg twice daily for 12 to 24 hours before the revascularization procedure for patients with PAD who are already on the DPI regimen, and presenting with claudication or CLTI requiring lower extremity revascularization[6] ([Fig. 6]).

In asymptomatic PAD patients, defined as those having an abnormal ABI < 0.9 or peripheral stenosis of at least 50%, SAPT should be considered; however, DPI with rivaroxaban 2.5 mg twice a day + aspirin may be considered in patients with very high risk because of associated comorbidities (DM, MI, polyvascular patients) to reduce major limb and CV events in the absence of high bleeding risk^# ([Fig. 6]).

In patients with CLTI or PAD and IC, DPI with rivaroxaban 2.5 mg twice a day + aspirin should be considered as antithrombotic therapy to reduce major limb and CV events in the absence of high bleeding risk^# ([Fig. 6]).

In summary, the experts recommend that patients with PAD who are at high risk of CV events should be prioritized for treatment with DPI. This includes patients with polyvascular disease, comorbidities such as diabetes and CKD (stage III or worse, but with an estimated glomerular filtration rate of ≥ 15 mL/min/1.73 m²), acute or CLTI, and history of amputation.

Disentangling the interplay between thrombosis, inflammation, and antithrombotics is crucial to refine our treatment strategies and represents the keystone of CVD prevention. Finally, the role of thromboinflammation on the progression of atherosclerotic diseases, the anti-inflammatory properties of antithrombotics and their influence on the natural history of CVD, is now an area of research.[36] The prospective observational real-world study by Russo et al confirmed that DPI with low-dose rivaroxaban and aspirin lead to the reduction of inflammation biomarkers (interleukin-6, fibrinogen, growth differentiation factor 15) in patients with CAD and/or PAD ([Table 8]).[37]

Table 8 Effect of DPI on plasma markers in patients with CAD and/or PAD

Trial	Study design	Duration	Inclusion criteria	Intervention	Results
Russo et al[37]	Explorative prospective observational real-world study	Follow-up: 6 months	- Patients with an established diagnosis of CAD and/or PAD	Rivaroxaban 2.5 mg bid + aspirin 100 mg once daily (N = 54)	Change in IL-6 serum levels: Baseline: 4.6 (3.5–6.5) pg/mL Week 24: 3.4 (2.4–4.3) pg/mL (p = 0.0001) Changes in fibrinogen levels: Baseline: 336 (290–390) mg/dL Week 24: 310 (275–364) mg/dL (p = 0.04) Changes in GDF-15 serum levels: Baseline: 1309 (974–1961) pg/mL Week 24: 1538 (1286–2913) pg/mL (p = 0.002) Anti-Xa activity: Baseline: 0.005 (0–0.02) Week 24: 0.2 (0.1–0.34) (p < 0.0001)

Abbreviations: bid, twice a day; CAD, coronary artery disease; DPI, dual pathway inhibition; GDF-15, growth differentiation factor 15; IL-6, interlukin-6; PAD, peripheral artery disease.

Barriers that may be particularly prominent in lower-income settings include limited resources for interventional cardiology and radiology procedures and reduced access to vascular surgeons.[6]

As per the experts, the barriers for prescribing DPI with rivaroxaban 2.5 mg twice a day + aspirin in all stages of chronic PAD and endovascular revascularization are bleeding risk concerns, adoption of DAPT, and cost of therapy. Reported barriers to improving care for PAD patients include late presentation of patients, lack of training, poor availability of diagnostic equipment, time constraints for diagnostic procedures, lack of education among health care providers, and poor awareness among patients.

Expert Recommendations

The expert recommendations have been summarized in [Table 9].

Table 9 Expert recommendations on antithrombotic management of PAD

Expert opinion	Recommendation
Postsurgical or endovascular revascularization without stent	DPI with rivaroxaban 2.5 mg bid + aspirin should be considered as antithrombotic therapy (to be initiated immediately*) to reduce major limb and CV events in the absence of high bleeding risk
Postsurgical or endovascular revascularization with stent	DPI with rivaroxaban 2.5 mg bid + aspirin should be considered as antithrombotic therapy (to be initiated immediately*) to reduce major limb and CV events in the absence of high bleeding risk
Asymptomatic PAD patients	Although antithrombotic therapy with SAPT is recommended, DPI with rivaroxaban 2.5 mg bid + aspirin may be considered for very high-risk patients (e.g., DM, MI, polyvascular) to reduce major limb and CV events in the absence of high bleeding risk
IC patients	DPI with rivaroxaban 2.5 mg bid + aspirin should be considered as antithrombotic therapy to reduce major limb and CV events in the absence of high bleeding risk
CLTI patients	DPI with rivaroxaban 2.5 mg bid + aspirin should be considered as antithrombotic therapy to reduce major limb and CV events in the absence of high bleeding risk
Patients with T2DM, stage 4 CKD, or elderly patients	DPI with rivaroxaban 2.5 mg bid + aspirin should be considered as antithrombotic therapy for postrevascularization (with/without stent) to reduce major limb and CV events in the absence of high bleeding risk

Abbreviations: bid, twice a day; CKD, chronic kidney disease; CLTI, chronic limb-threatening ischemia; CV, cardiovascular; DM, diabetes mellitus; DPI, dual pathway inhibition; IC, intermittent claudication; MI, myocardial infarction; PAD, peripheral artery disease; SAPT, single antiplatelet therapy; T2DM, type 2 diabetes mellitus.

Conclusion

With an aging population and increasing prevalence of PAD and its associated CV risk factors, implementing a risk-based pharmacological management approach in India is crucial to alleviate the burden on the health care system. Utilizing DPI with low-dose rivaroxaban and aspirin among interventional radiologists and vascular surgeons, along with raising awareness of PAD among general practitioners in rural areas, can help reduce delays in diagnosis and the impact of uncontrolled disease. Clinical benefits of low-dose rivaroxaban and aspirin are evident in postrevascularization, as well as in patients with IC and CLTI. Patients with high-risk features (polyvascular disease, diabetes, or renal dysfunction) are likely to benefit particularly from DPI therapy. Adapting treatment algorithms to the Indian clinical landscape will enhance PAD management and improve patient outcomes.

Conflict of Interest

None declared.

Acknowledgment

We acknowledge IntelliMed Healthcare Solutions Pvt. Ltd., Mumbai, India, for medical writing support.

• References

• 1 Krishnan MN, Geevar Z, Mohanan PP, Venugopal K, Devika S. Prevalence of peripheral artery disease and risk factors in the elderly: a community based cross-sectional study from northern Kerala, India. Indian Heart J 2018; 70 (06) 808-815
• 2 Eshcol J, Jebarani S, Anjana RM, Mohan V, Pradeepa R. Prevalence, incidence and progression of peripheral arterial disease in Asian Indian type 2 diabetic patients. J Diabetes Complications 2014; 28 (05) 627-631
• 3 Abola MTB, Golledge J, Miyata T. et al. Asia-Pacific consensus statement on the management of peripheral artery disease: a report from the Asian Pacific Society of Atherosclerosis and Vascular Disease Asia-Pacific Peripheral Artery Disease Consensus Statement Project Committee. J Atheroscler Thromb 2020; 27 (08) 809-907
• 4 Song P, Rudan D, Zhu Y. et al. Global, regional, and national prevalence and risk factors for peripheral artery disease in 2015: an updated systematic review and analysis. Lancet Glob Health 2019; 7 (08) e1020-e1030
• 5 Bethel M, Annex BH. Peripheral arterial disease: a small and large vessel problem. Am Heart J Plus 2023; 28: 100291
• 6 Lee J-K, Hsieh I-C, Su C-H. et al. Referral, diagnosis, and pharmacological management of peripheral artery disease: perspectives from Taiwan. Zhonghua Minguo Xinzangxue Hui Zazhi 2023; 39 (01) 97-108
• 7 Bevan GH, White Solaru KT. Evidence-based medical management of peripheral artery disease. Arterioscler Thromb Vasc Biol 2020; 40 (03) 541-553
• 8 Vartanian SM, Conte MS. Surgical intervention for peripheral arterial disease. Circ Res 2015; 116 (09) 1614-1628
• 9 Pai P, Bedi VS, Kamerkar DR. et al. Clinical practice recommendations for antithrombotic management of peripheral artery disease: an Indian perspective. Indian J Vasc Endovasc Surg. 2024; 11: 4
• 10 Khanna NN, Krishna V, Manjunath CN. et al. The Indian consensus statement for the management of lower extremity peripheral artery disease. J Indian Coll Cardiol 2023; 13: S1
• 11 Beckman JA, Schneider PA, Conte MS. Advances in revascularization for peripheral artery disease: revascularization in PAD. Circ Res 2021; 128 (12) 1885-1912
• 12 Espinola-Klein C, Weißer G, Schmitt V, Schwaderlapp M, Munzel T. Antithrombotic therapy in peripheral arterial disease. Front Cardiovasc Med 2022; 9: 927645
• 13 Frank U, Nikol S, Belch J. et al. ESVM Guideline on peripheral arterial disease. Vasa 2019; 48 (Suppl. 102) 1-79
• 14 Gheini A, Shakarami A, Namdari P, Namdari M, Pooria A. Frequency of recurrence of peripheral artery disease among angioplasty and stenting patients. Ann Med Surg (Lond) 2021; 72: 103146
• 15 Gerhard-Herman MD, Gornik HL, Barrett C. et al. 2016 AHA/ACC guideline on the management of patients with lower extremity peripheral artery disease: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation 2017; 135 (12) e686-e725
• 16 Arora E, Regan R, Surendra VU, Arumugam A. Prevalence of peripheral arterial disease among individuals with type 2 diabetes mellitus in India - a systematic review and meta-analysis. Diabetes Metab Syndr 2024; 18 (09) 103124
• 17 Khanna AK, Khanna D, Verma H, Singh T, Tiwary S, Gupta P. A hospital-based population screening for peripheral arterial diseases in a north-east university hospital of India. Indian J Surg 2021; •••: 85
• 18 Gornik HL, Aronow HD, Goodney PP. et al; Writing Committee Members. 2024 ACC/AHA/AACVPR/APMA/ABC/SCAI/SVM/SVN/SVS/SIR/VESS guideline for the management of lower extremity peripheral artery disease: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. J Am Coll Cardiol 2024; 83 (24) 2497-2604
• 19 Diehm C, Allenberg JR, Pittrow D. et al; German Epidemiological Trial on Ankle Brachial Index Study Group. Mortality and vascular morbidity in older adults with asymptomatic versus symptomatic peripheral artery disease. Circulation 2009; 120 (21) 2053-2061
• 20 Hess CN, Norgren L, Ansel GM. et al. A structured review of antithrombotic therapy in peripheral artery disease with a focus on revascularization: a TASC (InterSociety Consensus for the Management of Peripheral Artery Disease) initiative. Circulation 2017; 135 (25) 2534-2555
• 21 Hess CN, Wang TY, Weleski Fu J. et al. Long-term outcomes and associations with major adverse limb events after peripheral artery revascularization. J Am Coll Cardiol 2020; 75 (05) 498-508
• 22 Bonaca MP, Bauersachs RM, Anand SS. et al. Rivaroxaban in peripheral artery disease after revascularization. N Engl J Med 2020; 382 (21) 1994-2004
• 23 Aboyans V, Bauersachs R, Mazzolai L. et al. Antithrombotic therapies in aortic and peripheral arterial diseases in 2021: a consensus document from the ESC working group on aorta and peripheral vascular diseases, the ESC working group on thrombosis, and the ESC working group on cardiovascular pharmacotherapy. Eur Heart J 2021; 42 (39) 4013-4024
• 24 Anand SS, Bosch J, Eikelboom JW. et al; COMPASS Investigators. Rivaroxaban with or without aspirin in patients with stable peripheral or carotid artery disease: an international, randomised, double-blind, placebo-controlled trial. Lancet 2018; 391 (10117): 219-229
• 25 Anand SS, Hiatt W, Dyal L. et al. Low-dose rivaroxaban and aspirin among patients with peripheral artery disease: a meta-analysis of the COMPASS and VOYAGER trials. Eur J Prev Cardiol 2022; 29 (05) e181-e189
• 26 Eikelboom JW, Connolly SJ, Bosch J. et al; COMPASS Investigators. Rivaroxaban with or without aspirin in stable cardiovascular disease. N Engl J Med 2017; 377 (14) 1319-1330
• 27 Conte MS, Bradbury AW, Kolh P. et al; GVG Writing Group for the Joint Guidelines of the Society for Vascular Surgery (SVS), European Society for Vascular Surgery (ESVS), and World Federation of Vascular Societies (WFVS). Global vascular guidelines on the management of chronic limb-threatening ischemia. Eur J Vasc Endovasc Surg 2019; 58 (1S): S1-S109 , 109.e33
• 28 Hsia JA, Anand S, Nehler MR. et al. Abstract 13474: rivaroxaban reduces major cardiovascular and limb events in patients with the high-risk triad of chronic kidney disease, peripheral artery disease and recent lower extremity revascularization: insights from VOYAGER PAD. Circulation 2020; 142: A13474-A13474
• 29 Krantz M, Hiatt W, Anand S. et al. Efficacy and safety of rivaroxaban in elderly patients with symptomatic pad undergoing revascularization: insights from voyager pad. J Am Coll Cardiol 2021; 77: 1783-1783
• 30 Bhandari N, Newman JD, Berger JS, Smilowitz NR. Diabetes mellitus and outcomes of lower extremity revascularization for peripheral artery disease. Eur Heart J Qual Care Clin Outcomes 2022; 8 (03) 298-306
• 31 American Diabetes Association Professional Practice Committee. 10. Cardiovascular Disease and Risk Management: Standards of Care in Diabetes-2024. Diabetes Care 2024; 47 (Suppl. 01) S179-S218
• 32 VOYAGER PAD. Rivaroxaban in PAD with & without Comorbid Diabetes [Internet]. Accessed March 29, 2024 at: https://www.radcliffecardiology.com/video-index/voyager-pad-rivaroxaban-symptomatic-pad-without-comorbid-diabetes
• 33 Bhatt DL, Eikelboom JW, Connolly SJ. et al; COMPASS Steering Committee and Investigators. Role of combination antiplatelet and anticoagulation therapy in diabetes mellitus and cardiovascular disease: insights from the COMPASS trial. Circulation 2020; 141 (23) 1841-1854
• 34 Zhu W, He W, Guo L, Wang X, Hong K. The HAS-BLED score for predicting major bleeding risk in anticoagulated patients with atrial fibrillation: a systematic review and meta-analysis. Clin Cardiol 2015; 38 (09) 555-561
• 35 Visonà A, Zurlo C, Panzavolta C, Gobbo A, Zalunardo B. Bleeding risk in patients with peripheral arterial disease. Life (Basel) 2022; 13 (01) 47
• 36 Basili S, Romiti GF, Cangemi R, Corica B. Lesson learned from the COMPASS and VOYAGER PAD trials: dual pathway inhibition as a new antithrombotic paradigm?. Eur J Prev Cardiol 2022; 29 (05) e178-e180
• 37 Russo V, Fabiani D, Leonardi S. et al. Dual pathway inhibition with rivaroxaban and aspirin reduces inflammatory biomarkers in atherosclerosis. J Cardiovasc Pharmacol 2023; 81 (02) 129-133

Publikationsverlauf

Artikel online veröffentlicht:
22. Mai 2025