Referral, Diagnosis, and Pharmacological Management of Peripheral Artery Disease: Perspectives from Taiwan

Abstract

Peripheral artery disease (PAD) imposes a heavy burden of major adverse cardiovascular events that are associated with considerable mortality and morbidity, and major adverse limb events (e.g., thrombectomy, revascularization, amputation) that can substantially impact patients’ daily functioning and quality of life. Global registry data have indicated that PAD is an underdiagnosed disease in Taiwan, and its associated risk factors remain inadequately controlled. This review discusses the burden of PAD in Taiwan, major guidelines on PAD management, and the latest clinical trial outcomes. Practical experience, opinions, and the latest trial data were integrated to derive a series of clinical algorithms – patient referral, PAD diagnosis, and the antithrombotic management of PAD. These algorithms can be adapted not only by physicians in Taiwan involved in the clinical management of patients with PAD but also by general practitioners in local clinics and regional hospital settings, with the ultimate aim of improving the totality of PAD patient care in Taiwan.

Abbreviations

ABI, Ankle-brachial index

ACS, Acute coronary syndrome

AF, Atrial fibrillation

AHA/ACC, American Heart Association/American College of Cardiology

ALI, Acute limb ischemia

CAD, Coronary artery disease

CCDS, Color-coded duplex sonography

CI, Confidence interval

CKD, Chronic kidney disease

CLTI, Chronic limb-threatening ischemia

COMPASS, Cardiovascular OutcoMes for People using Anticoagulation StrategieS

CTA, Computed tomographic angiography

CV, Cardiovascular

DAPT, Dual antiplatelet therapy

DPI, Dual pathway inhibition

ESC, European Society of Cardiology

ESVM, European Society for Vascular Medicine

ESVS, European Society for Vascular Surgery

EUCLID, Examining Use of tiCagreLorIn paD

EVT, Endovascular therapy

GPs, General practitioners

HR, Hazard ratio

ISTH, International Society on Thrombosis and Hemostasis

MACE, Major adverse CV events

MALE, Major adverse limb events

MI, Myocardial infarction

MRA, Magnetic resonance angiography

NHIRD, National Health Insurance Research Database

PAD, Peripheral artery disease

REACH, REduction of Atherothrombosis for Continued Health

TBI, Toe-brachial index

TIMI, Thrombolysis In Myocardial Infarction

T-SPARCLE, Taiwanese Secondary Prevention for Patients with AtheRosCLErotic Disease

SAPT, Single antiplatelet agent

VOYAGER PAD, Vascular Outcomes studY of ASA alonG with rivaroxaban in Endovascular or surgical limb Revascularization for Peripheral Artery Disease

PERIPHERAL ARTERY DISEASE

Peripheral artery disease (PAD) is a major disease caused by atherosclerosis of the peripheral vasculature.¹ During the early stages of atherosclerosis, PAD may be asymptomatic, however, as atherosclerosis progresses, symptoms caused by the reduction of blood flow in the peripheral arteries begin to arise.² Intermittent claudication (mild to moderate pain in the lower legs upon walking) is a common symptom at presentation. As the disease progresses, symptoms of claudication may pro-gress to a more severe state, with the patients experiencing ischemic pain even when at rest. Ultimately, when left untreated, PAD may jeopardize the viability of patients’ limbs, with the development of ulceration, and potentially gangrene and eventually amputation.³

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).^4,5 Patients with PAD are also at high risk of amputation and major cardiovascular (CV) events such as ischemic stroke, myocardial infarction (MI), and CV death.^1,6 Despite a multi-faceted approach – lifestyle improvements, medical therapies for CV risk factor control, revascularization strategies, and antithrombotic therapies – PAD continues to impose a substantial burden on patients, impeding theirphysical activities and impacting their mental well-being.⁷ Despite the current standard of care, patients remain at high risk of disease progression, major adverse CV events (MACE), and major adverse limb events (MALE).^6,8-10 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 healthcare providers, and poor awareness among patients.^11,12 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.^12,13

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,¹⁶ and recently published treatment algorithms from the American College of Cardiology and American Heart Association.^13,17 This review provides a snapshot of the PAD disease burden, epidemiology, risk factor management, pharmacological management, and revascularization experience of PAD patients in Taiwan. The findings are integrated with practical opinions from Taiwanese experts to derive evidence-based algorithms on the clinical management of PAD – patient referral, diagnosis, and the pharmacological management of patients.

The overall aim of this paper is to better understand how the various international guidelines and algorithms can be adapted to local practice in Taiwan, and to serve as a point of reference for regions with similar healthcare systems and medical resources availability.

PAD EPIDEMIOLOGY AND DISEASE BURDEN IN TAIWAN

A systematic review estimated that PAD affected 236.7 million patients worldwide in 2015, of whom 74.1 million were in the Western Pacific region.¹⁸ The international, prospective, observational REduction of Atherothrombosis for Continued Health (REACH) registry revealed a high disease burden in patients with PAD.¹⁹ Despite the availability of contemporary therapy, recurrent vascular events and rehospitalizations remain frequent, suggesting the need for improvement in the diagnosis and treatment of PAD.²⁰ The systematic underdiagnosis and undertreatment of PAD patients observed globally in the REACH registry was even more striking in the Taiwanese cohort, where an even lower percentage of Taiwanese patients were diagnosed with PAD alone or polyvascular diseases (2.7%) compared with the REACH registry’s global population (14.9%).²¹ From a risk factor perspective, a substantial portion of the Taiwanese cohort in the REACH registry were inadequately controlled, not achieving therapeutic target levels for hypertension, fasting hyperglycemia, hypercholesterolemia, and hypertriglyceridemia, confirming observations from the global REACH registry.²¹ A cross-sectional, epidemiology study of the Taiwanese population from 2003 to 2013 revealed an increase in the prevalence of critical atherosclerotic risk factors, including hypertension and diabetes, combined with an aging population. When examined across the atherosclerotic disease spectrum, obvious increases in the prevalence of coronary artery disease, cerebrovascular disease, and peripheral vascular disease were also observed. Strikingly, a universal increase in the prevalence of peripheral vascular disease was observed across all age groups (ranging from 20 years to more than 90 years of age). This further emphasizes the urgent need to improve the current diagnosis of PAD and its clinical management in Taiwan,²² where it remains a significant public health challenge, especially for the country’s aging population.

MANAGEMENT OF ATHEROSCLEROTIC RISK FACTORS IN TAIWAN

The most fundamental and critical aspect of the multi-layered management of PAD patients is to address and modify the underlying CV risk factors. Major guidelines have comprehensively discussed risk factor management, from smoking cessation and changes to lifestyle (diet and exercise) to promoting weight loss, and reducing hyperlipidemia and hypertension, which are important and components of the PAD treatment continuum.^5,23-25 However, achieving the guideline-recommended targets for hypertension, hyperglycemia, and hyperlipidemia through appropriate medical management among PAD patients remains inadequate. The Taiwanese Secondary Prevention for Patients with AtheRosCLErotic Disease (T-SPARCLE) registry study generated a longitudinal snapshot of the effectiveness of medical therapies in controlling risk factors associated with atherosclerotic diseases in Taiwan. Despite guideline-recommended targets for lipid and blood-pressure control in patients with CV diseases, such strategies remain suboptimal in Taiwan, further emphasizing the importance of increasing awareness and adherence to guideline-recommended management of atherosclerotic risk factors.²⁶ As part of a continuous effort to improve the clinical outcomes of atherosclerotic CV diseases in Taiwan, a practice guideline was implemented in 2019 by the Health Promotion Administration, incorporating recommendations from Taiwanese experts on risk factor control specifically for PAD patients.²⁷ Achieving risk factor modification targets for our PAD patients is of the utmost importance, and awareness of the significance and implementation at the national level will continue to play an essential role in improving clinical outcomes.

INTERVENTIONAL THERAPY LANDSCAPE IN TAIWAN

The feasibility of reconstructing arteries in the lower extremities via open surgical procedures or endovascular therapy (EVT) should be assessed during the various symptomatic stages of PAD – from intermittent claudication,⁵ to chronic limb-threatening ischemia (CLTI),^5,23 and acute limb ischemia.^5,24 A balanced evaluation of the benefits and risks associated with invasive interventional treatment options must be discussed with patients. The incidence of invasively treated PAD increased from 3.73 to 7.48 per 10,000 from 2000 to 2011, and the average annual treatment cost per patient with PAD was USD 4,600-5,100.²⁸ Several studies have provided data on EVT outcomes in Taiwanese patients with more severe forms of PAD. A study of 936 patients with lower extremity PAD treated with EVT in Taiwan reported 5-year rates of all-cause mortality, MACE, and non-fatal CV events of 45.1%, 32.9%, and 43.4%, respectively.²⁹ Local studies have evaluated EVT in older patients (≥ 80 years) with lower extremity PAD and found EVT to be feasible in such patients,³⁰ although those with malnutrition, inflammation, and stroke risk factors had worse 2-year survival than those without.³¹ An observational study of EVT from 2005 to 2011 in 333 consecutive Taiwanese patients with critical limb ischemia revealed a high procedural success rate of 89%, with 3-year overall survival and limb salvage rates of 70% and 90%, respectively.²⁹ The PAD treatment landscape in Taiwan has evolved in line with international studies suggesting that EVT produces better outcomes in PAD than surgical bypass.^32,33 An analysis of data from the National Health Insurance Research Database (NHIRD) of Taiwan from 2000 to 2011 reported a drastic increase in the treatment of lower extremity PAD with EVT (from fewer than 1,000 to over 9,000 procedures annually), with the utility of bypass surgery remaining relatively consistent throughout the study period (approximately 1,000 procedures performed annually).²⁸

PAD DIAGNOSIS RECOMMENDATIONS FROM AMERICAN AND EUROPEAN GUIDELINES

Initially, patients often present with pain upon exertion in the legs and hips that resolves with rest.^4,34 Major American and European cardiology and vascular societies – including the American Heart Association/American College of Cardiology (AHA/ACC), European Society of Cardiology (ESC), European Society for Vascular Surgery (ESVS), and European Society for Vascular Medicine (EVSM) – have highlighted the need for a complete PAD diagnostic approach, beginning with an assessment of the patient’s family history of CV diseases and risk factors, personal medical history, and physical examination including palpation by bilateral comparison, and auscultation over extremity arteries. Additionally, the skin should be examined for atrophy and lesions,^14-16 and the ankle-brachial index (ABI) measured by duplex ultrasonography, with resting ABI values ≤ 0.9 considered abnormal and indicative of PAD diagnosis.^15,16 It should be noted, however, that an ABI of > 0.9 does not definitively rule out the diagnosis of PAD. For patients at an increased risk of PAD, with a history of PAD-associated symptoms, and/or abnormal findings upon physical examination suggestive of PAD, exercise ABI should be determined.^14-16 An ABI > 1.4 may be indicative of non-compressible ankle arteries, and toe-brachial index (TBI) should be determined as part of the PAD diagnostic algorithm.

A comprehensive and personalized clinical management plan for PAD patients must include a feasibility assessment for arterial reconstruction. Color-coded duplex sonography (CCDS) is the imaging modality of choice to evaluate the arterial architecture, anatomic assessment of lesion location, and visualization of vascular stenoses and occlusions.¹⁵ Magnetic resonance angiography (MRA), computed tomographic angiography (CTA), or digital subtraction angiography is recommended only if CCDS fails to sufficiently reveal the underlying pathology if proceeding to elective surgical revascularization.¹⁵ AHA/ACC guidelines limit CCDS, MRA, and invasive angiography to patients with ABI ≤ 0.9 and lifestyle-limiting claudication.¹⁶ In summary, before deciding on any treatment approach, a complete diagnostic workup, including family and personal medical history, physical examination, physiology testing, and anatomic imaging, should be completed.

EXPERT OPINION ON THE REFERRAL FROM GENERAL PRACTITIONERS OF PATIENTS WHO ARE AT RISK OF DEVELOPING PAD IN TAIWAN

Patients at high risk of developing PAD and subsequent complications include those aged ≥ 65 years, those with diabetes, CKD [defined as stage IV and higher, including end-stage renal disease, and a requirement for dialysis], imaging evidence of atherosclerosis, risk and/or a history of coronary artery disease, and those who smoke. These high-risk patients should be screened annually using the ABI, and if a patient presents with clinical symptoms of PAD (i.e., claudication, limb ischemia, vascular-related wounds in the lower limbs) and needs revascularization, anatomical imaging using CCDS and MRA/CTA should be performed to identify the lesion site. Implementation of ABI screening as the standard of care for diabetic and dialysis patients should be promoted in collaboration with the Health Promotion Administration and the Association of Diabetes Educators. Institutional referral algorithms and multidisciplinary teams consisting of orthopedic physicians, vascular/plastic surgeons, metabolic and endocrinology specialists, and cardiologists, should be established to manage patients with vascular wounds and to prevent amputation of salvageable limbs.

Analgorithm for the referral from general practitioners (GPs) in Taiwan of at-risk patients has been drawn up (Figure 1). This algorithm revolves around awareness of indicators, which are known high-risk factors for atherosclerosis, that GPs should proactively look for, focusing on the routine evaluation of the extremities in at-risk populations. For those who do not present with symptoms in the extremities, an annual re-evaluation by GPs is recommended. GPs should refer the patients to specialists for further evaluation and a more complete anatomic assessment if symptoms in the extremities present upon re-evaluation or at initial screening.

Figure 1.

PAD referral algorithm for general practitioners. * Indicates population at very high risk. ABI, ankle-brachial index; GP, general practitioner; PAD, peripheral artery disease.

The current educational campaign must be expanded to raise public awareness of PAD and allow for the early identification of individuals at risk. The referral algorithm (Figure 1) should be implemented in neighborhood clinics and regional hospitals that do not have a dedicated CV outpatient clinic. In Taiwan, some hospitals do perform annual ABI screening of diabetic patients, but unless presenting with severe symptoms in the extremities, no further clinical action is taken for patients with abnormal ABI measurements. Primary care providers should be instructed to refer all patients with ABI < 0.9 and Fontaine class IIB claudication (claudication at a distance < 200 m)³⁵ for further assessment by a CV specialist. Upon referral to specialist care, patients should be managed by a multidisciplinary team including cardiology, endocrinology/metabolism, and vascular/plastic, or orthopedic surgery, if necessary.

EXPERT OPINION ON THE DIAGNOSIS OF PATIENTS WITH PAD IN TAIWAN

A modified diagnostic algorithm for individuals with suspected PAD or CLTI (Figure 2, left and central panel) must start with a resting ABI measurement (or exercise ABI, if available at the institute), followed by duplex ultrasonography. When revascularization is considered, patients will undergo anatomic assessment imaging with CTA/MRA. If a patient has suspected PAD but cannot be assessed with ABI or ultrasonography (i.e., non-compressible arteries or gangrene/wound), they should be assessed with CTA/MRA, although with caution in patients with renal insufficiency due to the need to administer contrast agents. Some institutes have the equipment to measure ABI, but the availability of exercise ABI and TBI is very limited. Patients with a normal ABI should be encouraged to increase their daily walking distance, as some may not have noticed the presence of claudication because extended walking time is not part of their daily routine. Patients with abnormal resting ABI (< 0.9) with or without symptoms (claudication, abnormal pallor, reduced temperature in the extremities) should receive exercise ABI (if available) or echo/ultrasonography to evaluate the presence of stenosis.

Figure 2.

Diagnostic algorithm for suspected PAD, CLTI or ALI in Taiwan. Based on Gerhard-Herman et al.¹⁶ with modification according to Taiwan’s clinical landscape. Dashed items indicate diagnostic steps in the algorithm that, while not mandatory, should be performed if the diagnostic modality is available. * Unless contraindication. ABI, ankle-brachial index; ALI, acute limb ischemia; CLTI, chronic limb-threatening ischemia; CTA, computed tomography angiography; GDMT, guideline-directed management, and therapy; MRA, magnetic resonance angiography; TBI, toe-brachial index.

A modified general diagnostic algorithm for individuals with suspected acute limb ischemia (ALI) (Figure 2, right panel) should immediately assess their clinical symptoms (i.e., duration and intensity), evaluate the motor and sensory deficit severity (i.e., limb viability), and arterial and venous audibility. Implementing emergency and appropriate interventional therapy with concomitant anticoagulation with heparin and/or pain management is essential for limb salvage. ALI is a medical emergency and must be recognized rapidly. The longer ALI is present, the less likely the possibility of limb salvage.⁴

RECENT ADVANCES IN THE ANTITHROMBOTIC MANAGEMENT OF PAD AND RECOMMENDATIONS FROM AMERICAN AND EUROPEAN GUIDELINES

Despite the technological progress in devices and techniques associated with invasive interventional treatment, the clinical outcome for PAD patients in Taiwan remains unsatisfactory. A longitudinal analysis of patients with lower extremity PAD in Taiwan revealed a lower-end amputation incidence ranging from 4,100 to 5,100 per year, with no obvious reduction in the incidence over 12 years (from 2000 to 2011).²⁸ More recently, a survey of a database registry of patients who had undergone EVT for lower extremity PAD between 2005 and 2017 reported 5-year freedom rates from all-cause mortality, MACE, and non-fatal CV events of 54.9%, 67.%, and 56.6%, respectively, indicating that there is room for even greater improvement in the clinical management of PAD patients in Taiwan.³⁶ The integration of antithrombotic agents as part of the multi-pronged clinical management of PAD patients represents an important strategy to improve the clinical outcomes of PAD patients. In a sub-analysis of the Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events trial, clopidogrel was more effective than aspirin in reducing MACE [hazard ratio (HR): 0.76, 95% confidence interval (CI): 0.64-0.91] in patients with symptomatic PAD.³⁷ In the randomized Examining Use of tiCagreLor In paD (EUCLID) trial, ticagrelor was compared to clopidogrel but failed to show any difference regarding MACE (HR: 1.02, 95% CI: 0.92-1.13) or major Thrombolysis In Myocardial Infarction (TIMI) bleeding (HR: 1.10, 95% CI: 0.84-1.43) in patients with symptomatic lower extremity artery disease.³⁸ Of note, studies on ticagrelor have been prematurely discontinued more often than those on clopidogrel due to the side effects of dyspnea and minor bleeding. Traditionally, treatment with antithrombotic agents has involved a single antiplatelet agent (SAPT; e.g., aspirin or clopidogrel), evolving towards dual antiplatelet therapy (DAPT) of various combinations of antithrombotic agents. The pivotal results from the Cardiovascular OutcoMes for People using Anticoagulation StrategieS (COMPASS) study and the Vascular Outcomes studY of ASA alonG with rivaroxaban in Endovascular or surgical limb Revascularization for Peripheral Artery Disease (VOYAGER PAD) study, which combined antiplatelet aspirin with the novel oral anticoagulant rivaroxaban, present a new antithrombotic strategy – dual pathway inhibition (DPI).^39,40,43 Comprehensive reviews of key antithrombotic-agent studies in patients with chronic PAD who also underwent lower extremity revascularization have been reported in several recent guidelines and review articles.^{17,23,25,27,44-47}

The COMPASS PAD subgroup analysis showed that DPI resulted in a significant 46% relative risk reduction in MALE, including major amputation (HR: 0.54, 95% CI: 0.35-0.82), combined with a 28% relative risk reduction in MACE (stroke, myocardial infarction, CV death), in the rivaroxaban 2.5 mg twice daily + aspirin 100 mg daily arm over the aspirin 100 mg only daily arm. Despite a significant (p = 0.0043) 61% increase in modified International Society on Thrombosis and Hemostasis (ISTH) major bleeding events, no differences were observed in fatal and intracranial bleeding, with the DPI strategy associated with a 29% relative reduction in the risk of the prespecified composite net clinical benefit outcome (a composite of CV death, myocardial infarction, stroke, MALE, major amputation, fatal bleeding, and critical organ bleeding).⁴³ In light of the COMPASS results, DPI has been recommended by the European Society for Vascular Medicine (ESVM) in PAD patients without a high risk of bleeding or other contraindications.¹⁵ The Global Vascular Guidelines on the management of chronic limb-threatening ischemia recommended considering the DPI strategy to reduce adverse CV events and lower extremity ischemic events in patients with CLTI.²³ More recently, the findings from the VOYAGER PAD trial further cemented the clinical benefit of the DPI strategy in PAD patients after lower extremity revascularization, demonstrating a significant 15% relative risk reduction in the composite incidence of acute limb ischemia (ALI), major amputation of a vascular etiology, myocardial infarction, ischemic stroke or CV death (HR: 0.85, CI: 0.76-0.96), in the absence of significant (p = 0.07) major TIMI bleeding.⁴⁰

Patients who require oral anticoagulants, for example, those with atrial fibrillation (AF), share many common risk factors to those with PAD. Therefore, the frequent coexistence of these two conditions is expected, and a worse outcome has been reported in PAD patients with AF compared to those without.^43,44 Generally, patients with AF who meet the guideline recommendations should receive oral anticoagulants alone regardless of the presence of PAD, as concomitant antiplatelet therapy has not been shown to improve CV events, but may increase bleeding events.⁴⁴ Combined therapy should be considered as brief as possible only if the bleeding risk is low compared with the ischemic risk after endovascular revascularization.¹⁴

EXPERT OPINION ON THE ANTITHROMBOTIC MANAGEMENT OF PATIENTS WITH PAD IN TAIWAN

The pharmacological decision-making algorithm from Hussain and colleagues is a suitable approach that should be referred to and adapted for the management of patients with PAD in Taiwan (Figure 3).¹⁷ A balanced and careful assessment of the combined risk of CV and bleeding events should be performed for all patients with PAD. SAPT should be considered for all patients, with aspirin being the most commonly used agent in Taiwan, followed by clopidogrel for patients who are intolerant to aspirin. Cilostazol is prescribed for symptom control and to increase walking distance in patients with intermittent claudication. Although cilostazol has been recommended in American and European guidelines,^16,23 based on evidence indicating that cilostazol is effective for improving walking distance in patients with intermittent claudication and reducing limb-related and arterial patency-related outcomes in patients with advanced PAD, there is insufficient data to consistently support a mortality benefit in PAD patients.^48,49

Figure 3.

Algorithm for the antithrombotic management of patients with PAD. Based on Hussain et al.¹⁷ with modification according to Taiwan’s clinical landscape. * Rivaroxaban 2.5 mg twice daily + aspirin 100 mg once daily, showed a decreased risk of MACE or cerebrovascular events and MALE, but an increased bleeding risk. ABI, ankle-brachial index; ACS, acute coronary syndrome; CKD, chronic kidney disease; DAPT, dual antiplatelet therapy; DPI, dual pathway inhibition; HF, heart failure; MI, myocardial infarction; OAC, oral anticoagulant; PAD, peripheral artery disease; SAPT, single antiplatelet therapy.

In asymptomatic PAD patients, defined as those having an abnormal ABI (< 0.9) or peripheral stenosis of at least 50%, SAPT should be considered. In symptomatic PAD patients, defined as those having an abnormal ABI (< 0.9) or peripheral stenosis of at least 50% (claudication or peripheral revascularization or lower limb amputation), but no revascularization undertaken, SAPT may be considered for those with a lower risk of CV events and higher risk of bleeding (Figure 3, inset table). DPI should be considered for symptomatic PAD patients who are at high risk of CV events but relatively lower risk of bleeding. For PAD patients with a recent coronary stent or acute coronary syndrome (ACS) event, DAPT should be considered for 3 to 12 months, after which, a complete CV event and bleeding risk assessment should be completed before making a clinical decision between SAPT or DPI. For symptomatic PAD patients who have undergone endovascular revascularization (with or without a stent), the duration of DAPT should be limited to 6 months. Such patients may be subsequently treated with SAPT or DPI, depending on their CV and bleeding risk profile. For symptomatic patients who have undergone surgical revascularization, the same CV event and bleeding risk profiling should be performed to determine between a SAPT or DPI strategy. Concomitant clopidogrel use was allowed at the discretion of the VOYAGER PAD investigators for up to 6 months after revascularization; several international guidelines recommend either aspirin or clopidogrel, or a combination of the two, for background therapy for PAD patients following peripheral revascularization.²⁵ Of the 6,564 subjects randomized in the VOYAGER PAD study, approximately half (50.6%) received concomitant clopidogrel. A sub-analysis of these patients revealed that the efficacy of DPI with rivaroxaban and aspirin versus aspirin alone was consistent regardless of background clopidogrel use, demonstrating a similar relative risk reduction in the primary endpoint [HR: 0.85, 95% CI: 0.71-1.01 (with clopidogrel) and HR: 0.86, 95% CI: 0.73-1.01 (without clopidogrel)].³⁰ However, the concomitant use of clopidogrel in addition to DPI for > 30 days was associated with an increased, but not statistically significant, risk of major bleeding. This VOYAGER PAD sub-analysis suggests that if clopidogrel is to be prescribed with DPI to reduce procedural complications associated with lower extremity revascularization, a reduced course of no more than 30 days should be considered.⁵⁰

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), and acute or chronic limb-threatening ischemia, and history of amputation.

EXPERT OPINION ON DPI MANAGEMENT IN PAD PATIENTS NEEDING REVASCULARIZATION IN TAIWAN

Apart from lifestyle modifications and proactive management of comorbidities, medical therapy should be implemented across the different stages of the PAD disease spectrum – from intermittent claudication or CLTI, requiring lower extremity revascularization and post-endovascular revascularization, to the long-term management of chronic PAD. Traditionally, DAPT is recommended for at least 1 month and up to 6 months after endovascular revascularization followed by lifelong SAPT, irrespective of angioplasty with or without a stent (bare metal or drug-eluted).^51,52 Nevertheless, there is currently insufficient evidence from controlled studies to support the use of DAPT post-endovascular lower extremity revascularization and the long-term use. Likewise, guideline recommendations vary on the use of antithrombotic therapy following surgical revascularization.^14,15,23 As a result, apart from the pure antiplatelet therapy approach, DPI represents an important advance in the antithrombotic management of PAD patients as previously discussed. An additional algorithm was drawn up to guide the clinical management of these patients focusing on those for whom the DPI strategy may be considered before endovascular or surgical lower extremity revascularization (Figure 4). 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. After the endovascular revascularization procedure, provided that no contraindications have emerged, the DPI regimen should be restarted as soon as hemostasis is achieved or initiated in PAD patients not previously on the DPI regimen. A recent observational study of PAD patients undergoing revascularization in the United States indicated that despite the significant benefits from lower extremity revascularization procedures, these patients still face a long-term elevated risk of subsequent myocardial infarction, stroke, major amputation, or peripheral revascularization. Over a median follow-up period of 2.7 years, these patients were associated with a 9.8% risk of MI or stroke, and a 41.9% risk of major amputation or peripheral revascularization, suggesting the need for improved and more aggressive secondary prevention post-procedure.⁵³

Figure 4.

Algorithm for DPI management in PAD patients needing revascularization. * According to the VOYAGER PAD protocol, patients are required to temporarily interrupt study medication for 12 to 24 hours before any invasive procedure associated with a standard or high risk of bleeding. Regardless of whether procedures are elective or urgent, VOYAGER PAD investigators were encouraged to restart DPI as soon as possible provided the clinical situation allows and adequate hemostasis has been established.^25,38 CLTI, chronic limb-threatening ischemia; DAPT, dual antiplatelet therapy; DPI, dual pathway inhibition; LE, lower extremity; PAD, peripheral artery disease; SAPT, single antiplatelet therapy.

A prespecified analysis from the VOYAGER PAD study addressed the long-term benefits of DPI in PAD patients. DPI not only significantly reduced the risk of the primary endpoint events by 14% (HR: 0.86, 95% CI: 0.75-0.98), but also led to a significant 14% relative risk reduction in total vascular events, including all primary endpoint events, peripheral revascularization, and venous thromboembolism (HR: 0.86, 95% CI: 0.79-0.95), over 3 years.⁵⁴ The continued benefits observed in the VOYAGER PAD study sub-analysis highlight the importance of long-term antithrombotic strategies for preventing subsequent vascular events in PAD patients. Combining these findings with those from the COMPASS PAD population⁴³ suggest that use of the DPI strategy could be extended to cover the PAD disease continuum from acute PAD patients undergoing revascularization to those with chronic PAD. The algorithm incorporates the initiation or continuation of the DPI strategy for the long-term management of PAD patients who had previously undergone lower extremity revascularization, regardless of prior experience with this regimen.

CONCLUSIONS

With an aging population and increasing prevalence of PAD and its associated CV risk factors, the implementation of timely referral, diagnosis, and a risk-based approach to the pharmacological management of patients with PAD in Taiwan will be essential to our ongoing efforts to minimize the burden of this disease on our healthcare system. Improving awareness of PAD among GPs and physicians in regional hospitals, combined with a simple referral algorithm, can reduce a delayed diagnosis and the consequences of uncontrolled disease. A variety of effective pharmacological approaches to PAD management, including various antithrombotic strategies, have been clinically validated. Recently, the clinical benefits of DPI have been proven in both chronic PAD patients and PAD patients undergoing lower extremity revascularization, further expanding the therapeutic armamentarium against PAD. Execution of the treatment algorithms that have been adapted to fit the clinical landscape in Taiwan will allow for better clinical management of PAD patients, and ultimately improve their clinical outcomes.

DECLARATION

We confirm that this work is original and has not been published elsewhere, nor is it for consideration for publication elsewhere.

We confirm that the authors declare there is no conflict of interest.

We confirm that all those designated as authors meet all criteria for authorship.

We confirm that the authors have no funding information to declare.