Evidence-Experience Gap and Future Perspective on the Treatment of Peripheral Artery Disease

Peripheral artery disease (PAD) is a systemic disease associated with impaired limb function, poor quality of life, and increased cardiovascular morbidity. Its incidence has been dramatically increasing over years because of the emergence of an aging society and the increase in the number of patients with atherosclerotic risk factors. The clustering of these risk factors promotes disease development, reportedly leading to the differential location of atherosclerotic lesions in lower extremity arteries. The clinical presentations of PAD include intermittent claudication and chronic limb-threatening ischemia (CLTI). PAD is associated with a high risk of mortality and morbidity from both cardiovascular and limb events. The therapeutic goals for patients with PAD include 1) relief from PAD-related limb symptoms, 2) the prevention of new-onset and the development and recurrence of PAD, and 3) the prevention of concomitant adverse events due to coronary artery disease (CAD) and cerebrovascular disease (CVD). There are several types of antithrombotic agents, and their main role in patients with PAD is to reduce systemic events mainly including cardiovascular and lower extremity-related events. Currently, the efficacy of direct oral anticoagulant (DOAC) is also suggested by recent clinical trials. Although endovascular therapy (EVT) has been a first-line revascularization strategy for symptomatic PAD, whether clinical outcomes after EVT are comparable to those after surgical bypass therapy remains inconclusive.     

Antithrombotic Therapy in Peripheral Artery Disease: Risk Stratification and Clinical Decision Making

Patients with peripheral artery disease (PAD) are an underrecognised group with significant thrombotic risk. This risk is modifiable with the use of aggressive secondary preventative efforts, including optimisation of antithrombotic therapy. Appropriate antithrombotic selection for patients with PAD requires appropriate assessment of thrombotic and bleeding risk. Recent Canadian guidelines have recommended dual pathway therapy initiation for stable PAD and post-revascularisation patients. However, there is ongoing discussion about how to identify PAD patients who stand to benefit most from these therapies while trying to minimise harm from bleeding. Clinical equipoise also persists around questions such as the utility of dual antiplatelet therapy in conjunction with rivaroxaban after high-risk endovascular interventions and the optimal therapy for patients experiencing acute limb ischemia. In patients with chronic PAD and high-risk comorbidities or limb features, or in patients after revascularisation, dual pathway therapy with low-dose rivaroxaban and aspirin has emerged as the only regimen to reduce major adverse cardiovascular and limb events while maintaining an acceptable bleeding profile. After endovascular revascularisation, limited-duration (< 30 days) clopidogrel may be added to rivaroxaban and aspirin in selected high-risk patients at the provider’s discretion. After acute limb ischemia, the risk of another vascular event is exceptionally high, but there is no high-quality evidence to guide decision making for intensified antithrombotic therapy. Randomised investigations addressing this question are urgently needed to better serve this high-risk and vulnerable population.     

Therapy insight: peripheral arterial disease and diabetes--from pathogenesis to treatment guidelines

The increased risk of atherothrombotic events present in all patients with peripheral arterial disease (PAD) is amplified with concomitant diabetes. Moreover, diabetes is associated with increased PAD severity. This Review summarizes atherothrombosis and PAD in patients with diabetes, and American College of Cardiology and American Heart Association guidelines for management of patients with PAD. Patients with PAD and diabetes require optimal limb care and aggressive cardiovascular risk reduction. An LDL cholesterol level of less than 1.8 mmol/l (<70 mg/dl) is the therapeutic goal in these patients, and this target should be pursued using an aggressive statin regimen. Fibrate therapy can also be indicated. beta-blockers and angiotensin-converting-enzyme inhibitors reduce cardiovascular events in high-risk patient populations, and these agents are recommended for use in patients with both diabetes and PAD. Blood pressure of less than 130/80 mmHg should be achieved, and glycated hemoglobin should be reduced to below 7%. Patients should also receive indefinite antiplatelet therapy with aspirin or clopidogrel. For patients with claudication, a supervised exercise program and cilostazol therapy to improve PAD symptoms and walking distance form the main noninvasive components of therapy. Revascularization can also be indicated in carefully selected patients with claudication. For patients with critical limb ischemia, diagnostic testing by a vascular specialist will determine whether revascularization or amputation is feasible.     

Therapeutic angiogenesis for peripheral artery disease: stem cell therapy

Peripheral arterial disease (PAD) is a common manifestation of systemic atherosclerosis that is associated with a significant limitation in limb function due to ischaemia and high risk of cardiovascular mortality. The lower limb manifestations of PAD principally fall into the categories of chronic stable claudication, critical leg ischaemia, and, rarely, acute limb ischaemia. Lower limb ischaemia induced by PAD is a major health problem. In the absence of effective pharmacological, interventional or surgical treatment, amputation is undertaken at the end-stage as a solution to unbearable symptoms. The concept of "therapeutic angiogenesis" has become widely accepted during the past few years. Bone marrow consists of multiple cell populations, including endothelial progenitor cells, which have been shown to differentiate into endothelial cells and release several angiogenic factors and thereby enhance neovascularisation in animal models of hind limb ischaemia. The promising results from various preclinical studies provide the basis for clinical trials using bone marrow-derived cells or non-bone marrow cells, like cells from the peripheral blood or other tissues. However, the mechanisms by which these cells exert their positive effects are poorly understood until now. This review summarises the data from experimental and clinical studies related to peripheral arterial disease and cellular therapy.     

Use of statins in patients with peripheral artery disease

Atherosclerotic peripheral artery disease (PAD) is a growing health issue that affects more than 200 million individuals worldwide, conferring a high risk of cardiovascular events and death. In spite of its high prevalence, PAD has often been neglected in the past and the heightened cardiovascular risk of patients with PAD has been consistently under-recognized by practitioners. Considering that an integrated approach to reduce cardiovascular events and lower limb complications is necessary in this setting, statins represent the cornerstone of therapy as reported by current American and European guidelines. Literature has extensive data about the importance of lipid-lowering therapy in patients with PAD demonstrating that statins reduce symptoms, cardiovascular events and mortality. Despite data extrapolated from many studies on coronary artery diseases, moderate-dose statin therapy seems to be safe, and the minor risks posed in terms of myopathy-related symptoms are greatly outweighed by benefits. Other lipid-lowering drugs did not show the same results in terms of outcome and they should not be considered as first line therapy in these patients. The role of anti-PCSK9 inhibitors is emerging in the literature but further data are necessary to understand their superiority over statins.     

Metabolic,endocrine and haemodynamic risk factors in the patient with peripheral arterial disease

The morbidity and mortality associated with peripheral arterial disease (PAD) creates a huge burden in terms of costs both to the patient and to the health service. PAD is a deleterious and progressive condition that causes a marked increase in the risk of cardiovascular and cerebrovascular events. Further, PAD has a major negative impact on quality of life and mortality, and is associated with an increased risk of limb amputation. The clinical profile of patients at risk of PAD overlaps considerably with the known cardiovascular risk factors. These include, increasing age, smoking habit, diabetes, hypertension, dyslipidaemia, male sex and hyperhomocysteinaemia. For women, hormone replacement therapy appears to be associated with a reduced risk of PAD. Published PAD guidelines recommend aggressive management of risk factors, stressing the importance of lifestyle modification, antiplatelet agents, treating dyslipidaemia and diabetes. However, a large number of patients with PAD go undetected, either because they do not report their symptoms or because they are asymptomatic. It is therefore important to improve detection rates so that these patients can receive appropriate risk factor management.     

Metabolic, endocrine and haemodynamic risk factors in the patient with peripheral arterial disease

The morbidity and mortality associated with peripheral arterial disease (PAD) creates a huge burden in terms of costs both to the patient and to the health service. PAD is a deleterious and progressive condition that causes a marked increase in the risk of cardiovascular and cerebrovascular events. Further, PAD has a major negative impact on quality of life and mortality, and is associated with an increased risk of limb amputation. The clinical profile of patients at risk of PAD overlaps considerably with the known cardiovascular risk factors. These include, increasing age, smoking habit, diabetes, hypertension, dyslipidaemia, male sex and hyperhomocysteinaemia. For women, hormone replacement therapy appears to be associated with a reduced risk of PAD. Published PAD guidelines recommend aggressive management of risk factors, stressing the importance of lifestyle modification, antiplatelet agents, treating dyslipidaemia and diabetes. However, a large number of patients with PAD go undetected, either because they do not report their symptoms or because they are asymptomatic. It is therefore important to improve detection rates so that these patients can receive appropriate risk factor management.     

Antithrombotic Therapy in Peripheral Artery Disease: Generating and Translating Evidence Into Practice

Atherosclerotic cardiovascular (CV) disease remains a major health concern affecting more than 200 million adults worldwide, and lower extremity peripheral artery disease (PAD) is associated with significant morbidity and mortality. Treatment strategies to reduce the burden of major adverse CV events and limb events have mainly involved the use of antiplatelet and statin medications. Unlike other types of atherosclerotic CV disease, the evidence base is not well developed for therapies in patients with PAD. Recently, studies from subgroups of patients with PAD and a large clinical trial of PAD patients have been published, signaling a burgeoning interest in studying this higher risk population. This review outlines the inherent CV risks of patients with PAD, risk reduction strategies, emerging clinical trial data, and opportunities for the CV community to generate evidence in real-world settings and translate evidence into practice as new therapies become available.     

Unusual causes of intermittent claudication: Popliteal artery entrapment syndrome, cystic adventitial disease, fibromuscular dysplasia, and endofibrosis

Opinion statement  In the general population, vascular causes of exercise-induced limb discomfort are most often the result of peripheral artery disease (PAD) due to atherosclerosis. However, several other clinical entities can often mimic the symptoms of atherosclerotic PAD of the lower extremities, particularly among younger patients with fewer risk factors for atherosclerosis, who often are more athletically fit than patients with PAD. Treatment for these entities often requires percutaneous or surgical intervention. This article reviews four uncommon vascular causes of exercise-induced limb discomfort: popliteal artery entrapment syndrome, cystic adventitial disease of the popliteal artery, fibromuscular dysplasia of the lower-extremity arteries, and endofibrosis of the iliac artery.     

Impact of diabetes and glycaemic control on peripheral artery disease in Japanese patients with end-stage renal disease: long-term follow-up study from the beginning of haemodialysis

Aims/hypothesis

End-stage renal disease (ESRD) patients with diabetes have been regarded as being at the highest risk of cardiovascular disease. We therefore investigated the relationship between diabetes and the incidence of peripheral artery disease (PAD) in new haemodialysis patients.

Methods

We enrolled 1,513 ESRD patients who had just begun haemodialysis therapy. They were divided into two groups: those with (n?=?739) and those without diabetes (n?=?774). The endpoint was the development of PAD, defined as ankle brachial pressure index ≤0.9 or toe brachial pressure index <0.7 in patients with an ankle brachial pressure index >0.9.

Results

According to the Kaplan–Meier method, the 10?year event-free rate for development of PAD and lower limb amputation was significantly lower in the diabetes group than in the non-diabetes group (60.3% vs 82.8%, HR 2.99, 95% CI 2.27, 3.92, p?p?=?0.0005 for PAD and lower limb amputation, respectively). In patients with diabetes, quartile analysis of HbA_1c levels showed that the highest quartile group (≥6.8% [51?mmol/mol]) had significant development of PAD and lower limb amputation compared with lower quartile groups (PAD HR 1.63, 95% CI 1.17, 2.28, p?=?0.0038; lower limb amputation HR 2.99, 95% CI 1.17, 7.70, p?=?0.023).

Conclusions/interpretation

Diabetes was a strong predictor of PAD after initiation of haemodialysis therapy in patients with ESRD. In addition, higher HbA_1c levels were associated with increased risk of developing PAD and requiring limb amputation in such diabetic populations.     

Meta-analysis of randomized, controlled clinical trials in angiogenesis: gene and cell therapy in peripheral arterial disease

We aim to determine the efficacy and safety of gene and cell angiogenic therapies in the treatment of peripheral arterial disease (PAD) and evaluate them for the first time by a meta-analysis. We include in the formal meta-analysis only the randomized placebo-controlled phase 2 studies with any angiogenic gene or cell therapy modality to treat patients with PAD (intermittent claudication, ulcer or critical ischemia) identified by electronic search in MEDLINE and EMBASE databases (1980 to date). Altogether, 543 patients are analyzed from six randomized, controlled trials that are comparable with regard to patient selection, study design, and endpoints. We perform the meta-analysis regarding clinical improvement (improvement of peak walk time, relief in rest pain, ulcer healing or limb salvage) and rate of adverse events. At the end of treatment, therapeutic angiogenesis shows a significantly clinical improvement as compared to placebo in patients with PAD (odds ratio [OR] = 1.437; 95% confidence interval [CI] = 1.03?2.00; P = 0.033). The response rate (improvement of peak walk time) of the pooled groups according to clinical severity does not significantly differ for gene therapy as compared with placebo in the treatment of claudicating patients (OR = 1.304; 95% CI = 0.90?1.89; P = 0.16). Otherwise, we find significant efficacy of the treatment in critical ischemia (OR = 2.20; 95% CI = 1.01?4.79; P = 0.046). The adverse events rates show a slightly significantly higher risk of potential nonserious adverse events (edema, hypotension, proteinuria) in the treated group (OR = 1.81; 95% CI = 1.01?3.38; P = 0.045). We find no differences in mortality from any cause, malignancy, or retinopathy. The patients with PAD, and particularly those with critical ischemia, improve their symptoms when treated with angiogenic gene and cell therapy with acceptable tolerability.     

Peripheral arterial disease in the elderly

Smoking should be stopped and hypertension, diabetes mellitus, dyslipidemia, and hypothyroidism treated in elderly patients with peripheral arterial disease (PAD) of the lower extremities. Statins reduce the incidence of intermittent claudication and improve exercise duration until the onset of intermittent claudication in patients with PAD and hypercholesterolemia. Antiplatelet drugs such as aspirin or clopidogrel, especially clopidogrel, angiotensin-converting enzyme inhibitors, and statins should be given to all elderly patients with PAD without contraindications to these drugs. Beta blockers should be given if coronary artery disease is present. Exercise rehabilitation programs and cilostazol increase exercise time until intermittent claudication develops. Chelation therapy should be avoided. Indications for lower extremity percutaneous transluminal angioplasty or bypass surgery are (1) incapacitating claudication in patients interfering with work or lifestyle; (2) limb salvage in patients with limb-threatening ischemia as manifested by rest pain, nonhealing ulcers, and/or infection or gangrene; and (3) vasculogenic impotence.     

Antithrombotic Therapy for Peripheral Artery Disease: Recent Advances

Peripheral artery disease (PAD) affects over 200 million people globally and is a cause of significant morbidity, mortality, and disability due to limb loss. Although secondary prevention with antithrombotic therapy is a mainstay of treatment to prevent adverse cardiovascular events, PAD patients are often undertreated with antithrombotic agents. Furthermore, there is a paucity of high-quality data from randomized controlled trials of PAD patients, leading to wide variations in clinical practice and guideline recommendations. Recently, there have been important advances that have further increased the number of antiplatelet and anticoagulant choices potentially available for patients with PAD. In this context, this paper aims to summarize the current available evidence for the safety and efficacy of various antithrombotic agents in PAD, and discuss how to integrate this emerging evidence into actual clinical practice. An evidenced-based approach to PAD patients is essential to achieve optimal outcomes, weighing cardiovascular and limb benefits against bleeding risks.     

Treatment of peripheral arterial disease in diabetes: A consensus of the Italian Societies of Diabetes (SID,AMD), Radiology (SIRM) and Vascular Endovascular Surgery (SICVE)

Diabetic foot (DF) is a chronic and highly disabling complication of diabetes. The prevalence of peripheral arterial disease (PAD) is high in diabetic patients and, associated or not with peripheral neuropathy (PN), can be found in 50% of cases of DF. It is worth pointing out that the number of major amputations in diabetic patients is still very high. Many PAD diabetic patients are not revascularised due to lack of technical expertise or, even worse, negative beliefs because of poor experience. This despite the progress obtained in the techniques of distal revascularisation that nowadays allow to reopen distal arteries of the leg and foot. Italy has one of the lowest prevalence rates of major amputations in Europe, and has a long tradition in the field of limb salvage by means of an aggressive approach in debridement, antibiotic therapy and distal revascularisation. Therefore, we believe it is appropriate to produce a consensus document concerning the treatment of PAD and limb salvage in diabetic patients, based on the Italian experience in this field, to share with the scientific community.     

Management of Infrapopliteal Peripheral Arterial Occlusive Disease

The management of infrapopliteal peripheral arterial occlusive disease (PAD) is challenging. For patients with asymptomatic disease or claudication, exercise and optimal medical management, including antiplatelet agents, blood pressure control, statin therapy and tight glucose control for patients with diabetes mellitus, are the mainstays of therapy. However, patients with isolated tibial artery occlusive disease often have diabetes mellitus or renal insufficiency and present with critical limb ischemia (CLI). CLI is advanced occlusive disease marked by the development of rest pain, ischemic ulceration, or gangrene and is associated with a high mortality rate. Limb salvage requires an intervention in cases of CLI, but careful operative planning is required as patients often have multilevel disease and limited options for revascularization. A surgical bypass with a vein graft remains the best treatment for infrapopliteal PAD, especially in patients with a life expectancy of over 2 years. Balloon angioplasty can play an important role in limb salvage, especially for patients lacking adequate vein for bypass, at high operative risk, or with a life expectancy of less than 2 years. However, a lack of rigorous trials has left unanswered questions as to the efficacy of infrapopliteal angioplasty with or without stents compared to bypass surgery. As such, endovascular therapy is currently not a proven treatment for intermittent claudication. Patients who are unable to undergo a revascularization procedure for infrapopliteal CLI have few options besides amputation or palliation. New therapies, such as drug-eluting stents, drug-coated balloons, and stem cell therapy are under development, but their efficacy and effectiveness remain unproven.     

Peripheral interventions and antiplatelet therapy: Role in current practice

Peripheral arterial disease(PAD) is a common disorder associated with a high risk of cardiovascular mortality and continues to be under-recognized. The major risk factors for PAD are similar to those for coronary and cerebrovascular disease. Management includes exercise program, pharmacologic therapy and revascularization including endovascular and surgical approach. The optimal revascularization strategy, endovascular or surgical intervention, is often debated due to the paucity of head to head randomized controlled studies. Despite significant advances in endovascular interventions resulting in increased utilization over surgical bypass, significant challenges still remain. Platelet activation and aggregation after percutaneous transluminal angioplasty of atherosclerotic arteries are important risk factors for re-occlusion/restenosis and life-threatening thrombosis following endovascular procedures. Antiplatelet agents are commonly prescribed to reduce the risk of myocardial infarction, stroke and death from cardiovascular causes in patients with PAD. Despite an abundance of data demonstrating efficacy of antiplatelet therapy in coronary artery disease and cerebrovascular disease, there is a paucity of clinical information, clinical guidelines and randomized controlled studies in the PAD population. Hence, data on antiplatelet therapy in coronary interventions is frequently extrapolated to peripheral interventions. The aim of this review article is to elucidate the current data on revascularization and the role and duration of antiplatelet and anticoagulant therapy in re-vascularized lower limb PAD patients.     

Antithrombotic Therapy After Peripheral Vascular Intervention

Cardioprotective medications and risk-factor modification are the hallmarks of treatment for all patients with peripheral artery disease (PAD). If symptoms are life-limiting and/or do not respond to conservative treatment, endovascular or surgical revascularization can be considered especially for patients with critical limb ischemia or acute limb ischemia. The rates of peripheral vascular intervention (PVI) have risen dramatically over the past few decades and much of this care have shifted from inpatient hospital settings to outpatient settings and office-based clinics. While PVI rates have surged and technology advancements have dramatically changed the face of PVI, the data behind optimal antithrombotic therapy following PVI is scant. Currently in the USA, most patients are treated with indefinite aspirin therapy and a variable duration of clopidogrel (or other P2Y12 inhibitor)—typically 1 month, 3 months, or indefinite therapy. More observational analyses and randomized clinical trials evaluating clinically relevant outcomes such as cardiovascular morbidity/mortality and the risk of bleeding are needed to guide the optimal role and duration of antithrombotic therapy post-PVI.     

Building Your Peripheral Artery Disease Toolkit: Medical Management of Peripheral Artery Disease in 2022

Peripheral artery disease (PAD) is associated with substantial morbidity, including a high risk of cardiovascular and limb events and death. A growing body of evidence has demonstrated the benefits of antithrombotic therapy, lipid lowering, blood pressure control, diabetes management, smoking cessation, and exercise programs on improving symptoms and reducing these complications. Guidelines make specific recommendations on how to use these strategies to prevent adverse cardiovascular and limb outcomes in patients with PAD. Unfortunately, antithrombotic therapies, statins, optimal antihypertensives, smoking cessation counselling and therapies, and exercise programs have all been consistently shown to be underutilised in PAD patients both in Canada and globally. A variety of barriers to optimal utilisation of evidence-based medical therapies have been described at the patient, health care provider, and system levels. These include lack of knowledge among patients and health care providers, and lack of access to secondary prevention programs. We review the evidence for preventive therapies in PAD, evidence for underutilisation of these therapies, and barriers to their use. Core elements of PAD secondary prevention clinics are proposed, and a summary of optimal medical therapies and relevant tools is provided. This review may help clinicians who treat patients with PAD to develop a toolkit to overcome these barriers in order to improve utilisation of medical therapies, with the ultimate goal of improving outcomes for PAD patients.     

The Medical and Endovascular Treatment of PAD: A Review of the Guidelines and Pivotal Clinical Trials

Peripheral arterial disease (PAD) is a global health problem. The risk factors for developing PAD have been clearly described in the literature, as have the medical therapies and preventative strategies for the prevention and treatment of PAD. Unfortunately, PAD patients remain undertreated with regard to guideline-directed medical therapy. During the last 2 decades, endovascular therapies for PAD have evolved such that randomized controlled trial level data are available for the treatment of lower extremity PAD at every major anatomic segment. Furthermore, endovascular therapy has evolved to the point that among experienced operators, an endovascular first strategy is reasonable for the treatment of most patients with intermittent claudication or critical limb ischemia.     

冠心病和外周血管疾病患者的抗凝和抗血小板治疗

近年来，冠心病（CHD）和外周血管疾病（PAD）成为威胁人类健康的主要疾病。对CHD和PAD的药物治疗主要在于预防新的动脉粥样硬化的形成及稳定已存在的病变，最常用的药物治疗方法是抗血小板和抗凝治疗。本文通过对比大量临床试验来比较抗血小板和抗凝药物治疗CHD和PAD患者的效果以及安全性，总结了更有效和更安全的方案来预防动脉粥样硬化事件的发生。