RevIewS. Interventions for lower extremity peripheral artery disease

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1 RevIewS Interventions for lower extremity peripheral artery disease Jade S. Hiramoto 1, Martin Teraa 2, Gert J. de Borst 2 and Michael S. Conte 1 * Abstract Peripheral artery disease (PAD) of the lower extremities is a common manifestation of atherosclerosis that is increasing in global prevalence and in the associated public health costs. Ageing of the general population, combined with the pandemics of diabetes mellitus, metabolic syndrome, and tobacco use, is a major underlying factor. A broad range of care providers are involved in the management of patients with PAD, and all health- care professionals require familiarity with the risk factors, diagnosis, and treatment options for this common disease. Although medical therapies are the cornerstone of secondary prevention in atherosclerotic disease, they have limited direct limb- related benefits in advanced PAD. Despite a major evolution in technologies for limb revascularization, the increasing array of treatment options has not been accompanied by adequate evidence of their comparative effectiveness, which is needed to guide treatment decisions. This Review provides a framework for examining the current status of interventions for PAD, including an overview of disease staging, treatment goals, and the key factors associated with outcomes in defined subgroups. The status of evolving approaches to PAD, such as cell- based and gene- based therapies, and persistent unmet therapeutic needs in this field are also discussed. 1 Division of Vascular and Endovascular Surgery, University of California, San Francisco, CA, USA. 2 Departments of Surgery and Vascular Surgery, University Medical Center Utrecht, Utrecht, Netherlands. *e- mail: michael.conte2@ ucsf.edu s Peripheral artery disease (PAD) is a common manifestation of atherosclerotic disease that leads to impaired circulation to the lower extremities. In epidemiological studies, the global population with PAD is estimated to exceed 200 million individuals, and this figure has risen by >20% over the past decade 1,2. The prevalence of PAD increases with age, from ~5% in individuals aged years to nearly 20% in octogenarians 3. Major risk factors for PAD include diabetes mellitus, cigarette smoking, dyslipidaemia, and hypertension. The current upward trends in these risk factors, combined with ageing of the general population, portend a growing public health burden of PAD across all nations and socioeconomic levels. Improved survival from coronary artery and cerebrovascular disease, which is attributable to improved medical and invasive therapies, is also likely to contribute to the accumulating burden of PAD in developed populations. The majority of individuals with PAD have no or minimal symptoms. PAD can be diagnosed in asymptomatic individuals by a combination of physical examination and simple, noninvasive Doppler ultrasonography to measure the ankle brachial index. Patients with symptomatic PAD experience walking impairment and declines in physical performance and quality of life. At the extreme end of the clinical spectrum, patients with severe PAD have ischaemic pain at rest and develop nonhealing or gangrenous wounds that might necessitate limb amputation. All individuals with PAD have an increased risk of cardiovascular events and should undergo a comprehensive risk factor evaluation and treatment to reduce morbidity and mortality. This Review focuses on the treatment of lower extremity PAD in symptomatic individuals. As medical therapies for PAD have been thoroughly reviewed elsewhere 4 6, we focus on interventions that aim to improve tissue perfusion. This rapidly evolving field is under going technological advances (including improved drugs, devices, and regenerative medicine approaches) at the bench and in the clinic. Clinical syndromes and treatment goals The prevalence of PAD based on ankle brachial index screening is 3 10% in epidemiological studies 7, but the majority of these individuals are asymptomatic. Patients with symptomatic PAD generally present with one of the two major clinical syndromes: either intermittent claudication or atypical ischaemic leg pain, and chronic limb- threatening ischaemia (CLTI). The presentation, prognosis, and treatment goals for these two subgroups are distinct and important to consider in advance of any discussion of interventions.

2 Key points Lower extremity peripheral artery disease (PAD) is associated with considerable morbidity, diminished quality of life, and mortality; reducing the risk of cardiovascular events is the primary goal of medical treatment. Intermittent claudication is the most common symptom of PAD; treatment aims to improve ambulatory function through smoking cessation, medical therapy, exercise, and (selective) revascularization. Chronic limb- threatening ischaemia is associated with increased amputation risk and mortality; treatment is based on effective revascularization, which aims to relieve pain, heal wounds, and preserve limb function. Advances in endovascular technologies and open surgical approaches have created a growing range of revascularization options for PAD, although their outcomes are highly dependent on the anatomical pattern of disease. Active areas of investigation in PAD include cell- based and gene- based therapies, tissue- engineered vascular conduits, and drug- eluting, biomimetic, and bioresorbable scaffolds. Intermittent claudication Intermittent claudication is the most common manifestation of symptomatic PAD and presents as muscle pain, typically in the calves, that begins with exercise and is relieved with rest. Patients with PAD might also have atypical leg pain, such as pain that occurs on walking but is also present when standing or sitting 2. In cross- sectional studies of patients with PAD, these so- called atypical leg pain symptoms are described more frequently than classic intermittent claudication. Intermittent claudication can substantially reduce patients quality of life as a result of bodily pain, walking impairment, loss of independence, decline in physical condition, and depression. Treatment of patients with intermittent claudication focuses on reducing cardiovascular risk and improving lower extremity function. With appropriate treatment, the annual rate of major amputation in patients with intermittent claudication is <1%, and <10% of patients progress to CLTI 8,9. However, a substantial subset (20 40%) of patients with intermittent claudication have severe disability despite optimal medical therapy and are candidates for revascularization 10. Given that PAD typically occurs in individuals aged >50 years, common comorbidities (such as arthritis, heart disease, and respiratory dysfunction) can contribute to loss of physical function and greatly influence decisions regarding invasive treatment. Noninvasive and objective assessments of haemodynamic compromise, such as resting and/or treadmill ankle brachial index, are important to document both the severity of disease and responses to treatment. However, haemodynamic measures and findings on anatomical imaging studies correlate poorly with functional impairment in patients with intermittent claudication. Thus, treatment of these patients generally involves a staged approach that initially emphasizes lifestyle changes (such as smoking cessation), medical therapy, and supervised exercise. An individualized risk benefit analysis is essential before considering invasive procedures. Chronic limb- threatening ischaemia CLTI is the end stage of PAD. Patients have ischaemic pain at rest and/or tissue loss in the foot, which are manifestations of severely impaired perfusion. Although CLTI occurs in a small proportion (2%) of the population with PAD, it confers a considerable public health burden with high costs related to invasive procedures and hospitalization. Risk factors for CLTI are broadly the same as for PAD, but diabetes, smoking, and renal disease are of particular importance. Patients with CLTI have severe haemo dynamic impairment (ankle pressures are typically <50 70 mmhg) associated with complex anatomical patterns of arterial disease. CLTI also shows a broad spectrum of disease severity, and clinical staging can provide important information for assessing prognosis and outcomes 11. The Society for Vascular Surgery Lower Extremity Threatened Limb Classification Scheme describes four clinical stages of CLTI based on three critical parameters that determine the level of limb threat: the presence and extent of wounds, the severity of ischaemia, and associated foot infection (WIfI staging). Early validation studies suggest that WIfI staging is useful to predict the risk of amputation and other hard end points 12. Goals of treatment in CLTI include pain relief, wound healing, and preservation of a functional limb. A multidisciplinary team, which is often led by vascular specialists and podiatrists, is essential to provide wound care, improve limb perfusion, treat underlying infections and comorbidities, and support rehabilitation 13. In the absence of effective revascularization, >20% of patients with CLTI require a major amputation within 12 months, and a similar proportion die from cardiovascular causes. This high- risk population of patients requires rapid assessment, comprehensive medical manage ment, effective limb revascularization, and coordinated wound and foot care to achieve positive outcomes for life and limb. Medical therapies for PAD The first international PAD treatment guideline was published in 2000 by the Transatlantic Societal Consensus (TASC) 14. Subsequent guidelines included secondary prevention measures, such as smoking cessation, management of hypertension and diabetes mellitus, and lipid- lowering and antiplatelet therapy 7, Statins, antiplatelet therapy, angiotensin- converting enzyme (ACE) inhibitors and angiotensin- receptor blockers (ARBs) are universally accepted to be effective for the secondary prevention of cardiovascular events in patients with PAD 7,14 17,19,20. By contrast, evidence that medical therapies reduce limb- related adverse events, improve quality of life, and enhance performance status is fairly scarce 4,5. Moreover, CLTI- specific data are lacking, and treatments for this group are often extrapolated from studies in heterogeneous populations with PAD 21. Antithrombotic therapy The role of antiplatelet therapies in patients with PAD is not yet fully defined; however, bleeding risk in patients with PAD taking antiplatelet agents can, for unknown reasons, be higher than in antiplatelet- treated patients with coronary artery disease 22. The rationale for antiplatelet therapy in patients with PAD is largely based on the Antithrombotic Trialists Collaboration meta- analysis, which showed that in 9,214 patients with PAD from 42 trials, antiplatelet therapy (primarily aspirin) reduced the risk of serious vascular events (a composite

3 of nonfatal myocardial infarction (MI), cerebrovascular accident, or vascular death) by 23% versus control treatment (5.8% versus 7.1%; P = 0.004), and the risk reduction was similar in patients with claudication, those undergoing peripheral bypass surgery, and individuals undergoing endovascular interventions 23. A meta- analysis focusing specifically on aspirin treatment also showed a significant reduction in vascular death, nonfatal MI, and nonfatal stroke (6.7% versus 8.2% per year; P < ) 24, although specific results in patients with PAD were not reported. Another meta- analysis showed a decreased risk of cardiovascular events (nonfatal MI, nonfatal stroke, and cardiovascular death) in patients taking aspirin compared with a control group 25. The efficacy of aspirin for the secondary prevention of cardiovascular events in patients with symptomatic PAD is not in doubt. However, in patients with asymptomatic PAD, the benefit of aspirin is less clear. This agent was not effective in reducing nonfatal or fatal coronary events, stroke or transient ischaemic attack, incident claudication or the need for revascularization, and all- cause mortality in a placebo- controlled study in asymptomatic PAD 26. Low- dose aspirin seems to be as effective as high- dose aspirin in preventing re- occlusion or restenosis 12 months after vascular interventions 27. Another thoroughly studied group of antiplatelet agents is the thienopyridines (such as ticlopidine, clopidogrel, and prasugrel), of which clopidogrel is most widely used 20. The CAPRIE trial 28 established the role of clopidogrel monotherapy for the prevention of cardio vascular events in patients with PAD. In this trial, clopidogrel was at least equal to aspirin in reducing the risk of the primary outcome (a composite of vascular death, ischaemic stroke, or MI), an effect that was most pronounced in the subgroup of patients with PAD 28. Moreover, a beneficial risk:benefit ratio for clopidogrel was confirmed in a network meta- analysis 29. In a large contemporary trial, ticagrelor (a platelet P2Y 12 antagonist) was no more effective than clopidogrel monotherapy in reducing cardiovascular events or limb ischaemia in patients with symptomatic PAD 30,31. Current practice guidelines recommend monotherapy with either aspirin or clopidogrel for the secondary prevention of cardiovascular events in patients with PAD 18,20. By contrast, data on the effects of antiplatelet therapy on limb- specific outcomes are conflicting 4. The rationale for dual- agent antiplatelet therapy in patients with PAD (namely, improved patency after revascularization) is based on extrapolation from studies in patients with coronary artery disease 32,33. Dual- agent antiplatelet therapy is often used after endovascular revascularization in patients with PAD, although high- quality evidence of its efficacy from randomized trials is lacking A registry study that compared dual- agent antiplatelet therapy with aspirin monotherapy showed that dual- agent therapy reduced the risk of major cardiovascular events and reduced all- cause mortality, without a difference in amputation risk, in patients with symptomatic PAD following peripheral vascular intervention 39. Oral anticoagulation with warfarin did not demonstrate any benefit in the secondary prevention of cardiovascular or limb adverse events in patients with PAD and was associated with an increased risk of bleeding 40. However, a multicentre, randomized trial found that low- dose rivaroxaban in combination with aspirin reduced the rates of major cardiovascular adverse events (cardiovascular death, MI, or stroke) and major limb adverse events compared with aspirin alone 41. Ongoing and planned studies of antithrombotic therapy in patients with PAD are focusing on proteinase- activated receptor 1 (PAR1) antagonists 42,43. Statins The benefit of statins in preventing cardiovascular events probably results from pleiotropic effects beyond their lipid- lowering function 44. Statins reduce both cardiovascular events and all- cause mortality in patients with PAD and are considered a cornerstone of secondary prevention 7,14 16,20. Statins have also shown positive results on limb- related outcomes in patients with CLTI, including improved claudication, prolonged walking time 45,46, improved infrainguinal autogenous graft patency rates 47, reduced restenosis rates 48,49, and improved limb salvage after intervention 50. However, the strength of the evidence for these limb- specific benefits is modest. Current studies are investigating inhibitors of the enzyme PCSK9, a novel class of lipid- lowering drugs that have shown potential benefit in patients at high risk of cardiovascular events 51,52. In a subgroup analysis of patients with PAD from the FOURIER trial 53, lowering of LDL- cholesterol levels with evolocumab treatment significantly reduced the risk of death from cardiovascular causes, MI, stroke, unstable angina, or coronary revascularization as well as major adverse limb events. ACE inhibitors and ARBs All current guidelines advise antihypertensive therapy in patients with hypertension and PAD to achieve systolic and diastolic blood pressures of <140 mmhg and <90 mmhg, respectively 7,15,16,19,20, which are effective in preventing major adverse cardiovascular events 54. ACE inhibitors and ARBs both have secondary prevention benefits beyond their blood- pressure-lowering function in patients with PAD 55,56. However, whether these agents also reduce the risk of major amputation or the need for major vascular reintervention in patients with PAD has not yet been proved 56. Other agents Cilostazol is an oral phosphodiesterase 3 inhibitor that induces smooth muscle relaxation and reduces platelet aggregation. Cilostazol improved claudication and maximum walking distance by 35 67% in patients with intermittent claudication 57,58. Moreover, treatment with cilostazol is associated with reduced in- stent restenosis after drug- eluting stent placement in femoropopliteal lesions 59, reduced reintervention rates after endovascular intervention, and a decreased amputation risk 60. Guidelines recommend cilostazol as a first- line treatment in patients with PAD but without heart failure (cilostazol is contraindicated in heart failure) 15,18,20. Naftidrofuryl is a serotonin- receptor antagonist that is at least as effective as (and probably more cost- effective than 61 ) cilostazol treatment in patients with claudication 62. However, naftidrofuryl is not available in

4 the USA and is not included in international guidelines. Studies of pentoxifylline have yielded conflicting results. Pentoxifylline is less effective than either cilostazol or naftidrofuryl in reducing symptoms in patients with intermittent claudication 61,62. Consequently, pentoxifylline is not currently recommended for the treatment of PAD 20. The effect of prostanoids has been studied in several PAD trials, and their results have been aggregated in meta- analyses, which did not show convincing improvements in performance status in patients with intermittent claudication 63 or any reductions in mortality or amputation risk in patients with CLTI Therefore, no scientific foundation exists for prostanoid treatment in patients with intermittent claudication or CLTI 20. Supervised exercise therapy Patients with PAD have impaired exercise capacity and often reduce their gait speed or avoid walking altogether. This reduction in functional performance correlates with a profound reduction in quality of life. Consequently, exercise is a central component of the treatment of intermittent claudication (Box 1). Supervised exercise programmes improve quality of life and functional performance, as well as redu cing all- cause and cardiovascular mortality in patients with PAD Supervised training programmes are superior to community- based or unsupervised training programmes 70, although programmed home- based exercise is also effective 71. Some studies have compared supervised exercise with endovascular revasculariza tion, such as the CLEVER trial 72, which randomly allocated patients with aortoiliac disease to supervised exercise (n = 43), stenting (n = 46), or optimal medical therapy (n = 22). The supervised exercise and stenting groups both showed improvements compared with the optimal medical therapy group at 6 months of follow- up. However, peak walking time improved most in the supervised exercise group, whereas the stenting group showed the greatest improvements in patient- reported outcomes, such as quality of life 72. These improvements persisted at 18 months of follow- up but did not differ significantly between the supervised exercise and stenting groups 73. The randomized ERASE trial 74 showed that the combination of endovascular therapy plus supervised exercise (n = 106) was more effective than supervised exercise alone (n = 106), although both groups showed improvements in maximal walking distance, Box 1 Components of optimal medical therapy for Pad Smoking cessation Antiplatelet therapy Statin therapy Treatment of hypertension (with an angiotensin- converting enzyme inhibitor or angiotensin- receptor blocker as the first choice) to recommended goals Treatment of diabetes mellitus to recommended goals Trial of cilostazol (100 mg twice daily) for intermittent claudication, unless contraindicated owing to heart failure Supervised exercise therapy (goal: 30 min of walking 3 5 times each week) Monitoring for treatment effects and signs of progression to chronic limb- threatening ischaemia PAD, peripheral artery disease. pain- free walking distance, and quality of life at 1 year of follow- up. To summarize, supervised exercise therapy improves functional capacity and quality of life effectively in patients with intermittent claudication, but combinations of supervised exercise and revascularization therapy seem to be even more effective, regardless of whether they are given in a parallel 74 or sequential 75 manner. Revascularization strategies Risk factor modification, optimal medical therapy, and supervised exercise are the first- line therapies for patients with intermittent claudication. However, revascularization is a critical component of treatment for individuals with severe symptoms or CLTI. The different treatment goals of intermittent claudication and CLTI have direct implications for the timing and choice of vascular interventions (Box 2). Advances in imaging and endovascular technologies have greatly expanded the treatment options for patients with advanced PAD. Patterns of occlusive disease in these patients are typically categorized by anatomical location as aortoiliac, femoropopliteal, or infrapopliteal PAD. The technical challenges and expected outcomes of revascularization treatment are strongly influenced by both disease severity (intermittent claudication or CLTI) and anatomical location. In general, revascularization of short lesions in large vessels yields favourable outcomes; outcomes become increasingly unfavourable with increasing occlusion lengths, more- distal (infrapopliteal) disease, and smaller- calibre arteries. Multilevel disease is common, particularly in patients with CLTI. Correction of inflow impairment (namely, aortoiliac disease) always takes prece dence over correction of distal lesions. When intermittent claudication is the presenting symptom, treatment of a proximal obstruction might provide adequate improvement even when distal disease is also present. By contrast, in patients with CLTI and tissue loss due to ulceration or gangrene, providing direct in- line blood flow to the foot is a primary goal of revascularization. Bilateral disease is common in patients with PAD and of particular importance in those with intermittent claudication. Vascular specialists must carefully weigh the individual patient s symptoms and treatment goals, along with the anticipated risks and limitations of each procedure, before advising patients on an optimal revascularization strategy. Anatomical durability is an important consideration, particularly in patients with intermittent claudication 18. Unfortunately, evidence from high- quality randomized trials and comparative effectiveness studies is limited, despite the substantial prevalence of PAD and the high frequency of interventions. Below, we provide a brief description of current techniques and expected outcomes, organized by anatomical disease level. Endovascular revascularization Endovascular treatment has greatly broadened the revascularization options for PAD and is especially important in patients with severe comorbidities who are at increased surgical risk from open procedures. Successful endovascular intervention relies on a combination of

5 Box 2 revascularization in Pad intermittent claudication Goals Improve walking performance and reduce claudication- specific disability strategies Correct haemodynamically relevant obstructions related to major muscle groups Staged approach in multilevel disease (inflow correction alone is often adequate) Consider bilateral severity of disease at outset Anatomical durability is important for maximal clinical benefit Adjunctive optimal medical therapy and supervised exercise therapy Chronic limb- threatening ischaemia Goals Preserve a functional foot, relieve pain, heal wounds, and prevent major amputation strategies Intervention to achieve direct in- line flow to foot, especially when tissue loss is present Magnitude and durability of revascularization correlate with the severity of limb threat (disease stage) Foot and wound care is paramount to success Surveillance and reintervention as needed PAD, peripheral artery disease. Atherectomy The removal of obstructive atherosclerotic disease from the arterial lumen. careful patient selection, operator expertise, and the appropriate application of devices and technologies. These technologies include plain balloon angioplasty, drug- coated balloons, bare- metal or drug- eluting stents, covered stents, and plaque removal (atherectomy). In general, endovascular techniques are less successful for occlusions than for stenoses and for long than for short or focal lesions. Small vessel diameters and severe or bulky calcification are other important impediments (Box 3). Although the durability of endovascular therapy in aortoiliac disease is similar to that of open repair, long- term outcomes of interventions in femoropopliteal and infrapopliteal arterial segments are worse for endovascular therapy than for surgical bypass. Therefore, endovascular treatment of infrapopliteal arteries should be reserved for patients with CLTI. Open surgical revascularization Open surgical interventions for PAD (such as endarterectomy and bypass) have been employed for >50 years, and many advances date from the last decades of the 20th century. These advances include surgical autogenous vein bypass to distal targets, use of prosthetic and biological grafts as arterial substitutes, and improved antithrombotic pharmacotherapy. Patients who undergo open surgical limb revascularization should be routinely included in a post- procedure surveillance programme and should be informed that reintervention is often necessary; these initiatives extend conduit patency. Today, hybrid procedures combinations of open surgical and endovascular techniques done simultaneously are becoming increasingly common owing to the availability of advanced intraoperative imaging, improved technologies, and training. Hybrid strategies provide great flexibility and enable complex disease patterns to be treated during a single procedure (Fig. 1). Classification of disease severity Various anatomical classification schemes for PAD have been developed to assist in the assessment of treatment outcomes and obtain regulatory approval of new devices. Each has limitations, and efforts in this area are ongoing to bridge the gap between technology assessment and evidence- based medicine. The most- utilized system was developed by the TASC and is a segmental or lesion- based approach that has undergone several iterations The four TASC categories of increasing lesion complexity (A D) primarily reflect the likelihood of technical success and the durability of endovascular intervention. At each disease level, TASC type A lesions are focal and highly suitable for endovascular repair, whereas type D lesions are complex, diffuse, and more suitable for open surgical repair. Few studies have directly compared open surgery with endovascular approaches in patients with advanced PAD. The BASIL trial 79,80 remains the only multicentre, randomized, controlled trial to directly compare an endovascular- first versus surgery- first revascularization strategy for patients with CLTI. BASIL included 452 patients from 27 UK hospitals. An intention- to-treat analysis of the entire follow- up period ( ) showed no significant difference in amputation- free or overall survival between the two groups. However, in the ~70% of patients who survived for >2 years, assignment to open surgery resulted in improved overall survival (HR 0.65, P = 0.009) and a trend towards amputation- free survival (HR 0.85, P = 0.108). The per- protocol analysis showed that bypasses using prosthetic conduits performed very poorly (worse than angioplasty) and that patients who underwent bypass after a failed initial angioplasty had considerably worse outcomes than patients who received bypass as their initial treatment 81. Criticisms of BASIL include the singular endovascular technology employed (balloon angioplasty), a lack of generalizability of the study population, and low statistical power 82. Current efforts to improve evidence in the field include the BEST- CLI trial 83 in the USA and the follow- up BASIL-2 and BASIL-3 studies 84,85 in the UK, which all involve patients with CLTI. Remarkably, no large- scale, randomized, controlled trials have directly compared the efficacy of open versus endovascular interventions for intermittent claudication. Therefore, at present, low- quality evidence, physician experience, and the preferences of individual vascular specialists often guide treatment decisions in this setting. Treatment of aortoiliac disease The majority of patients with aortoiliac PAD have disease patterns that are amenable to endovascular interventions, such as balloon angioplasty and/or stenting (using bare- metal or covered stents), which result in high technical success rates and favourable durability (Fig. 2). For patients with severe occlusions (such as complete occlusion of the aorta and/or bilateral iliac arteries or diffuse disease in small and heavily calcified iliac arteries) or those with failure of prior endovascular interventions, open surgical treatment remains a highly effective option as long as the level of operative risk is acceptable.

6 Box 3 revascularization of advanced Pad Endovascular revascularization Techniques Balloon angioplasty, drug- coated balloon, bare- metal stents, drug- eluting stents, covered stents, and atherectomy Advantages Minimally invasive Low morbidity Often repeatable Favourable outcomes in large arteries, short lesions, and stenosis (versus occlusion) Limitations Long lesion length, small vessel diameter, and severe calcification Common femoral artery and popliteal artery disease is unfavourable Reduced anatomic durability for femoropopliteal and infrapopliteal interventions In- stent restenosis is difficult to treat open surgical revascularization Techniques Endarterectomy and open bypass using prosthetic or autogenous vein conduits Advantages Flexibility to address diverse anatomic patterns and lesions Can be combined with endovascular revascularization in hybrid approaches Improved anatomical durability Limitations Invasive and increased risk for patient Wound morbidity and systemic complications Adequate- quality autogenous vein is absent in 20 40% of patients who require a distal bypass Poor outcomes for non- autogenous conduits in below- knee bypass PAD, peripheral artery disease. Endovascular intervention Endovascular therapy is generally recommended as the first- line treatment for TASC type A or B aortoiliac lesions and achieves 1-year primary patency rates of >95% 86. The endovascular options for TASC type A or B lesions include primary stenting (using balloon- expandable or self- expanding uncovered or covered stents) or balloon angioplasty with selective stenting. No consensus has been reached as to whether advanced aortoiliac lesions should also be treated using an endovascular- first strategy and whether covered stents offer a substantial benefit over uncovered stents in this setting. In the hands of skilled operators, even the most extensive aortoiliac lesions can be successfully treated by an endovascular approach (Table 1). Multiple single- centre studies report good patency rates for the treatment of extensive (TASC type C or D) aortoiliac disease. A systematic review of 19 nonrandomized, retrospective studies that included 1,711 patients (1,329 with extensive aortoiliac occlusive disease) demonstrated technical success rates of % and 30-day mortality of 6.7% 87. Primary patency rates were 70 97% at 1 year and 60 86% at 4 5 years. A subsequent meta- analysis that focused on the outcomes of 958 patients with TASC type C or D aortoiliac disease (from 16 studies, 8 of which were included in the previous systematic review) reported an estimated technical success rate of 93% and 1-year primary patency of 89% in the pooled analysis 88. Several reports have suggested that the outcomes of endovascular intervention for aortoiliac disease improve with the use of covered stents, with the primary benefit being a reduction in restenosis. Covered stents also offer protection against arterial rupture when used in the treatment of heavily calcified lesions. One retrospective study demonstrated superior patency rates at 2 years when covered, balloon- expandable kissing stents were used at the aortic bifurcation instead of bare- metal, balloon- expandable stents 89. Another study demonstrated similar 2-year primary patency rates for covered stents and bare- metal stents (93% and 80%, respectively; P = 0.14) in the treatment of TASC type C or D iliac artery lesions 90 ; however, 2-year primary patency rates were significantly higher for TASC type D lesions treated with covered rather than bare- metal stents (88% versus 57%; P = 0.03). The CERAB (covered endovascular reconstruction of the aortic bifurcation) technique, which utilizes covered stents, achieved high rates of technical success (95%) and 2-year primary patency (82%) in patients with mostly TASC type D disease 91. To date, the only randomized study that has directly compared the use of covered versus bare- metal stents in the treatment of iliac artery stenoses is COBEST 92, in which patients with TASC type B, C, or D lesions were randomly assigned to either a bare- metal stent or a specific covered stent. In this study, the covered- stent group had a substantially improved rate of freedom from restenosis at 1 year, which was largely attributable to favourable results in patients with TASC type C or D lesions. The randomized, controlled DISCOVER trial 93 comparing covered versus uncovered balloon- expandable stents in the treatment of common iliac artery lesions is underway. Open surgical repair Open surgical approaches for aortoiliac disease include direct and indirect (extra- anatomical) procedures. The most common approach is direct aortofemoral bypass grafting using a bifurcated prosthetic conduit. This is a major surgical procedure with an operative risk in the range of 1 4% and excellent long- term durability (typical 5-year patency rates of >85%) 94,95 (Table 1). Surgical endarterectomy (plaque removal) for aortoiliac disease is a direct approach whose indication is limited to focal plaques in the aorta or at its bifurcation and is now rarely performed as these lesions are also amenable to stenting, which is a less- invasive option. Extra- anatomical indirect procedures, such as femorofemoral or axillofemoral bypass grafting, are extremely useful in specific patterns of disease that are not amenable to endovascular treatment and are generally associated with lower surgical risk than direct aortic reconstruction. The long- term durability of these procedures is inferior to aortofemoral bypass grafting but remains quite acceptable 96,97 (Table 1), particularly in high- risk populations of patients. Common femoral artery disease is generally regarded as affecting the inflow system to the limb and deserves special mention. Patency of the common femoral and profunda femoris arteries is of central importance to long- term limb preservation and function. Common femoral artery disease is often localized, beginning at the inguinal ligament and extending to

7 Balloon-expandable covered stent Femoral endarterectomy with patch R Self-expanding stent Femoral-to-popliteal Fig. 1 Hybrid approaches for simultaneous, multilevel revascularization of advanced Pad. Hybrid (simultaneous open surgical and endovascular) procedures require an operating room equipped with advanced imaging capability, such as digital subtraction angiography. On the patient s right side (R), open femoral endarterectomy with patch angioplasty is combined with retrograde placement of a balloon- expandable covered stent in the common iliac artery to treat severe combined common femoral artery and common iliac artery disease. On the patient s left side (L), external iliac artery stenosis and long- segment occlusion of the superficial femoral artery are treated by placement of a self- expanding stent in the external iliac artery and a femoral- to-popliteal bypass graft. PAD, peripheral artery disease. L the bifurcation into the profunda femoris and superficial femoral arteries. Direct surgical endarterectomy of the common femoral artery is a low- risk, effective, and durable procedure that can be performed in isolation or combined with treatment of aortoiliac or femoropopliteal disease in a variety of hybrid procedures. The results of a trial published in 2017 suggest that stenting of the common femoral artery is associated with reduced perioperative morbidity compared with surgical revascularization 98, but long- term comparative effectiveness data are lacking. Endovascular interventions for common femoral artery disease might still have a role in highly selected patients (such as those with extensive scar tissue and a high risk of local wound complications or extremely high anaesthetic risk); however, surgical endarterectomy of the common femoral artery remains the gold- standard treatment 18,99. Complications Iliac artery rupture is a dangerous, potentially life- threatening complication that can occur during angioplasty and stenting, especially during the treatment of long- segment occlusions or heavily calcified arteries. In many cases, arterial rupture can be treated by immediate placement of a covered stent. Iliac artery dissection is another known complication that can be treated with sustained balloon inflation and/or additional stent placement. Stents placed in the common femoral artery, where they are subject to hip flexion stresses, have an increased risk of stent fracture. Moreover, stent placement across the orifice of the profunda femoris artery (termed jailing ) puts the long- term patency of this critical vessel at risk and, in the authors expert opinion, should be avoided. Other potential complications include distal embolization and access- site injuries. Open surgical procedures are sometimes complicated by postoperative cardiovascular events, wound complications, and late occurrences such as anastomotic aneurysms, graft infections, and abdominal adhesions 94,95. Treatment of femoropopliteal disease The superficial femoral artery is commonly involved in patients with peripheral atherosclerosis. Patients with femoropopliteal disease might have only intermittent claudication or extensive patterns of occlusion and CLTI. Endovascular treatment of femoropopliteal disease is very widely performed, primarily because of its high technical success rates and low procedural morbidity (Fig. 3). However, technical success and anatomical durability vary with the extent of disease. Factors such as long- segment ( 20 cm) disease, chronic total occlusions, popliteal artery involvement, extensive calcification, and small- calibre ( 5 mm) arterial disease are linked to poor outcomes of endovascular therapy. In these circumstances, and particularly when symptoms are advanced or prior endovascular treatments have failed, open surgical bypass grafting provides an effective and more durable alternative to endovascular treatment. Endovascular approaches The mainstays of endovascular treatment of femoropopliteal disease include balloon angioplasty, stenting, and atherectomy. Although a number of comparative studies have been published, the majority of trials have been conducted for regulatory purposes and have focused on patients with intermittent claudication and moderate disease (lesion lengths <15 cm) 100. Therefore, considerable debate persists around optimal approaches for real- world patients with femoropopliteal disease. Bare nitinol self- expandable stents versus balloon angioplasty. Because the superficial femoral artery is subjected to compression, torsion, and flexion forces, flexible nitinol stents are a better option than stainless steel stents for the treatment of this arterial segment. Over the past decade, several randomized trials have compared the placement of self- expanding bare- metal nitinol stents with balloon angioplasty in the treatment of femoropopliteal disease Most of these trials demonstrated the superiority of bare- metal stents, with two notable exceptions 101,102 at opposing ends of the disease severity spectrum. In FAST 101, conducted in 244 patients with short (mean lesion length 45 mm) lesions of the superficial femoral artery who were randomly assigned to either bare- metal stent placement or balloon angioplasty, the two groups showed no significant difference in restenosis rates at 1 year. A randomized trial of balloon

8 a b c Infrarenal abdominal aorta Large lumbar collaterals Guidewires in abdominal aorta Kissing balloons loaded with stents Aortic stenosis Aortic stenosis Common iliac arteries d e f Occluded Kissing stents in common iliac artery iliac arteries Patent distal Right common iliac artery iliac artery Common iliac artery External iliac artery Internal iliac artery Fig. 2 aortoiliac intervention for Pad. a Angiogram showing high- grade stenosis of the distal abdominal aorta just above the bifurcation (red arrow); large lumbar collateral arteries (white arrows) are visible above the stenosis. b Fluoroscopy image showing placement of balloon- expandable kissing stents into the aorta and bilateral iliac arteries in the same patient (white arrows). A prominent waist is visible at the area of aortic stenosis (red arrows). c Completion angiography in this individual shows widely patent aortoiliac artery stents with resolution of the stenosis. d Angiogram of a different patient showing complete occlusion of the left common iliac artery to the level of the aortic bifurcation (red arrow). e Reconstitution of flow in the distal left common iliac artery reveals the end of the occluded segment (red arrow). f Successful recanalization of the occluded left common iliac artery with placement of kissing stents (red arrows) into the bilateral iliac arteries. Black arrows, patent vessels; PAD, peripheral artery disease. angioplasty versus bare- metal stent placement in patients with ~120 mm, highly occluded (>90%) superficial femoral artery lesions also reported no significant difference between groups in the restenosis rate at 12 months 102. By contrast, several randomized trials have demonstrated important benefits of bare- metal stents over balloon angioplasty in the treatment of femoropopliteal lesions of various lengths. In the ASTRON trial 103, even though the average length of the treated segments was significantly longer in the bare- metal stent group, restenosis rates were lower than in the balloon angioplasty and/or optional stenting group at 3, 6, and 12 months. This benefit of stenting was associated with improved walking capacity at 6 months and 12 months 103. In the RESILIENT trial 104, primary bare- metal stent implantation was associated with significantly improved 1-year primary patency rate (81% versus 37%; P < 0.001) and freedom from target- lesion revascularization rate (87% versus 45%; P < 0.001) compared with balloon angioplasty and/or bailout stenting. In another randomized trial of 104 patients with superficial femoral artery lesions or occlusions (~130 mm), patients treated with bare- metal stents had much lower restenosis rates on angiography at 6 months and duplex ultrasono graphy at 12 months and were able to walk further on a treadmill at 6 months and 12 months than those who underwent balloon angioplasty 105. The aforementioned trials primarily included patients with superficial femoral artery lesions; in some individuals, disease extended into the popliteal artery. Many clinicians would argue that the outcomes of endovascular treatment are worse in isolated popliteal artery disease than in femoropopliteal disease and that treatment of lesions in the knee area deserves caution. As for stent placement in the common femoral artery, complex motion at the knee joint places metal stents placed in the popliteal artery at high risk of fracture and stenosis. Moreover, the popliteal artery is a common surgical bypass target, and permanent stent implantation in this location might jeopardize future surgical

9 Table 1 Treatment outcomes in extensive aortoiliac occlusive Pad outcomes of treatment aortofemoral bypass (%) Endovascular repair (%) 30-Day mortality 2 3 <1 Perioperative cardiac complications 2 7 <2 Perioperative renal complications Perioperative pneumonia 1 11 <2 1-Year primary patency rate Year patency rate PAD, peripheral artery disease. options. Investigators in the ETAP study 106 randomly assigned 246 patients with single popliteal artery stenosis or occlusion to either bare- metal stent placement or balloon angioplasty. At 2 years of follow- up, the primary patency rate was significantly higher in the stent group than the angioplasty group (64% versus 31%; P = 0.001) 106. Flexible (biomimetic) stents are designed to accommodate high biomechanical stresses such as those occurring in the femoropopliteal segment. In the SUPERB trial 107, a biomimetic self- expanding nitinol stent showed excellent results in superficial femoral artery and proximal popliteal artery lesions, with 86% patency and no fractures reported at 1 year. Larger comparative studies are needed in this area. Bare nitinol stents versus covered stents. The predominant mode of failure of a bare- metal stent is diffuse in- stent restenosis. Given the preponderance of trial results favouring bare- metal stent placement over balloon angioplasty in femoropopliteal lesions, many clinicians believed that a covered stent would yield even better results in this setting. The VIABAHN endoprosthesis is a polytetrafluoroethylene- lined nitinol stent- graft that has been used to treat femoropopliteal disease. However, two randomized trials failed to demonstrate superiority of the VIABAHN device over a bare- metal stent. In the randomized VIBRANT trial 108 involving 148 patients with superficial femoral artery disease and symptoms of claudication or pain at rest, no significant difference in primary patency rates was observed at 3 years between patients treated with the VIABAHN stent- graft and those who received bare- metal stents. The randomized VIASTAR trial 109 in 141 patients with symptomatic femoropopliteal disease compared heparin- bonded VIABAHN stent- grafts (PROPATEN) with bare- metal stents and found no significant difference in 12-month primary patency rates between the two treatment groups. However, in the subgroup of patients with long lesions ( 20 cm), 12-month patency rates were significantly better in the VIABAHN group than the bare- metal stent group (71% versus 37%; P = 0.01) 109. Drug- eluting stents versus balloon angioplasty. Drug- eluting stents are the primary endovascular treatment for coronary artery lesions, and their success led to the development of drug- eluting stents as a treatment for PAD. Paclitaxel is lipophilic, exhibits prolonged retention in arterial tissue, and is thought to inhibit neointimal hyperplasia owing to its antiproliferative effect. The results of a randomized trial of 474 patients assigned to either a polymer- free, paclitaxel- eluting nitinol stent placement or balloon angioplasty for symptomatic femoropopliteal lesions (average length 6.5 cm) showed that the drug- eluting stent group had substantial improvements in 12-month event- free survival and primary patency rate compared with the balloon angioplasty group, and these benefits were sustained for 5 years 110,111. Drug- coated balloons versus balloon angioplasty. Although drug- eluting stents have successfully been used in the treatment of femoropopliteal disease, the metal scaffold remains in the artery after the paclitaxel coating has been eluted and can initiate intimal hyperplasia and restenosis. Moreover, the treatment of in- stent restenosis remains a challenge and might alter subsequent surgical repair options. The main advantage of drug- coated balloons over drug- eluting stents is that the balloon is withdrawn, leaving nothing behind, after the paclitaxel has been applied to the arterial wall. Two randomized trials that compared a paclitaxel- coated balloon with standard balloon angioplasty in patients with femoropopliteal disease both demonstrated favourable results for the group treated with drug-coated balloons; both trials reported similar safety profiles 112,113. In the largest (n = 476) and most recent study 113, the 1-year primary patency rate was higher in the group treated with drug- coated balloons than in the conventional balloon angioplasty group (65% versus 53%; P = 0.02) 113. In the IN.PACT SFA trial 114, which included 331 patients with symptomatic femoropopliteal lesions of 180 mm in length (mean length 89 mm), the 2-year primary patency rate was higher in the group treated with a paclitaxel- coated balloon than in the conventional balloon angioplasty group (79% versus 50%; P < 0.001). Safety profiles and functional status improvements were similar in both groups, but 58% fewer repeat interventions were required in the group treated with paclitaxel- coated balloons 114. Atherectomy. In the DEFINITIVE LE prospective registry study 115, a total of 1,022 infrainguinal lesions in 800 patients were treated with a directional atherectomy device. The 12-month primary patency rates were 78% in patients with intermittent claudication and 71% in patients with CLTI. In total, 35.3% of patients required adjunctive therapy after atherectomy 115. A meta- analysis of six randomized, controlled trials that included 287 patients with femoropopliteal disease who underwent either atherectomy or balloon angioplasty showed that the rates of technical success, need for bailout stenting, and distal arterial embolization were similar in the two groups. Primary patency rates at follow- up (median 9 months) were also similar in the two groups 116. However, no large- scale comparative studies have demonstrated benefits for atherectomy over other endovascular approaches in any specific subsets of patients. Therefore, the role of atherectomy remains unclear, and prospective trials are needed.

10 a b c Common femoral artery Occluded superficial femoral artery Profunda femoris artery and branches Profunda femoris artery and branches Area of occluded superficial femoral artery Collateral vessels Reconstitution of flow in superficial femoral artery Popliteal artery Severe stenosis and occlusion of popliteal artery Reconstitution of flow in peroneal artery by collateral vessels Reconstitution of flow in anterior tibial artery by collateral vessels d e f Common femoral artery Stents in distal superficial femoral artery Stents in distal popliteal artery Profunda femoris artery and branches Stents throughout superficial femoral artery Stents in popliteal artery Anterior tibial artery Tibioperoneal trunk Peroneal artery Fig. 3 Femoropopliteal intervention for Pad. a Angiogram showing a patent common femoral artery and profunda femoris artery. The superficial femoral artery is completely occluded at its origin (red arrow). b Reconstitution of flow can be seen in the diseased distal superficial femoral artery (white arrows). c The popliteal artery is also severely diseased and occluded below the knee (red arrows), albeit with reconstitution of flow via collateral arteries (white arrows). d Completion angiography in this patient demonstrates successful placement of several stents (red arrows) into the proximal and mid superficial femoral artery, up to the origin of the profunda femoris artery. e Successful placement of stents into the distal superficial femoral artery (red arrows). f Successful placement of stents into the popliteal artery (red arrows). Black arrows, patent vessels; PAD, peripheral artery disease. Summary. Despite multiple studies comparing different endovascular treatment options for femoropopliteal disease, the optimal strategy is not yet clear. Many published trials were conducted for regulatory purposes and included mixed populations: patients with both intermittent claudication and CLTI who had superficial femoral artery lesions of varying types and lengths. These trials used different clinical end points, and the modalities used to assess primary patency also varied. Therefore, at this time, balloon angioplasty, bare- metal, covered, and drug- eluting stents, drug- coated balloons, and atherectomy all have a role in the treatment of femoropopliteal disease, depending on lesion characteristics, provider experience, and the patient s clinical status (Table 2). Further well- designed direct comparative studies are needed. Long- term durability remains a major limitation and a focus of new technology. Open surgical approaches Bypass grafting. Bypass grafting requires inflow and outflow vessels to be joined using a suitable conduit. In patients with femoropopliteal disease, the common femoral artery often serves as the inflow vessel and is connected to the popliteal artery (either above or below the knee) or a proximal tibial vessel (Fig. 4). The selected outflow vessel should have minimal PAD and provide continuous flow to the lower leg, ankle, and foot. Conduit quality has a dominant influence on the technical success and long- term patency of bypass grafts. The optimal conduit for infrainguinal bypass grafts is the great saphenous vein, preferably from the

11 Table 2 outcomes of infrainguinal revascularization Femoropopliteal revascularization infrapopliteal revascularization approach Patency rates approach Patency rates Open surgery Femoropopliteal bypass with vein 65 75% at 5 years Femorotibial bypass with vein 60 70% at 5 years Femoropopliteal bypass with prosthetic 30 60% at 5 years Femorotibial bypass with prosthetic 10% at 5 years NA NA Pedal bypass with vein 60 70% at 5 years Endovascular intervention Balloon angioplasty 30 60% at 1 year Balloon angioplasty 25 65% at 1 year Bare- metal stents 50 80% at 1 year Bare- metal stents 35 75% at 1 year Covered stents 45 70% at 1 year NA NA Drug- eluting stents 70 80% at 1 year Drug- eluting stents 50 85% at 1 year Drug- coated balloons 65 80% at 1 year Drug- coated balloons 60 70% at 1 year Atherectomy 70 80% a at 1 year Atherectomy 70 80% a at 1 year NA, not available. a Data obtained from a single registry study. All other data were compiled from multiple studies. Angiosome A concept based on anatomical studies that links major terminating branches of the tibial arteries to specific regions of perfusion in the foot. ipsilateral limb. Great saphenous vein conduits can be employed in either a reversed or nonreversed configuration; the nonreversed configuration requires valve disruption. Configuration choice is based on target- vessel size and surgical preference. Duplex ultrasonography is frequently employed as a preoperative examination to map the presence and assess the quality of superficial veins for use in bypass surgery. An adequate great saphenous vein segment is 3.5 mm in diameter, easily compressible, and free of wall thickening, calcifications, and varicosities. Between 20% and 40% of surgical candidates lack an adequate great saphenous vein conduit. Alternative conduits include other autogenous veins (lesser saphenous, cephalic, or basilic veins, which frequently require splicing to achieve an adequate length) or prosthetic grafts. Polyethylene terephthalate (Dacron) and expanded polytetrafluoroethylene are the most common materials used to make prosthetic grafts for use in femoropopliteal bypass. Surface coatings such as heparin have been employed to reduce the thrombogenicity of these conduits. Typical 5-year primary patency rates after femoropopliteal bypass are 65 75% for great saphenous vein conduits and 30 60% for prosthetic conduits (Table 2). Advances in tissue engineering have led to the development of biological conduits derived from human vascular cells and matrix, which offer the potential for improved patency rates and resistance to infection compared with prosthetics 122. Clinical trials of these tissue- engineered vascular grafts in patients with PAD are in the early stages. Complications. As in other anatomical locations, endovascular interventions for femoropopliteal disease can be complicated by access- site injuries and distal embolization. Restenosis rates within 2 years are considerable, and, in particular, in- stent restenosis is difficult to treat successfully with a percutaneous approach 123. An important but controversial question relates to the potential adverse effect of previous endovascular treatment failure on the outcomes of secondary bypass surgery 124. With careful patient selection and good perioperative care, infrainguinal bypass surgery can be accomplished with low mortality ( 2%). Local complications of femoropopliteal bypass include wound infections, haematomas or seromas, and graft thrombosis. Systemic complications, such as major cardiac events, venous thromboembolism, and sepsis, occur in 5 10% of patients. Treatment of infrapopliteal disease PAD involving the tibial and/or pedal vessels is frequently encountered in patients with CLTI. Diabetes and renal disease are common comorbidities in these patients. Infrapopliteal disease can be challenging to treat, because the arteries below the knee are small in calibre and tend to be calcified. Often, diffuse disease is present in multiple vessels. Because of the complexity of these lesions, long- term patency rates are low, and endovascular intervention should be limited to patients with CLTI. Although endovascular intervention has a high technical success rate and confers minimal morbidity, the restenosis and clinical failure rates are substantial (Table 2). A 2016 meta- analysis of infrapopliteal balloon angioplasty reported a 1-year primary patency rate of 63%, a major amputation rate of 15%, and mortality of 15% 125. Notably, only two studies included in that analysis involved tibial lesion lengths of >88 mm, highlighting the current limitations of endovascular treatment of infrapopliteal disease. These limitations are heightened in patients with advanced tissue loss and/or profound ischaemia, in whom the need for sustained improvements in perfusion is paramount. In the selection of a primary target artery for intervention, the concept of the angiosome has gained some acceptance when the indication for infrapopliteal revascularization is tissue loss in the foot 126,127. Frequently, however, the choice of target artery is based on practical considerations and technical feasibility. Data on the importance of angiosome- based target artery selection are conflicting and suggest that this technique is more important for endovascular intervention than for open surgery As yet, no data exist to support the efficacy of multivessel revascularization for infrapopliteal disease.

12 a b c Vein bypass Distal anastomosis of bypass popliteal artery Tibioperoneal trunk Occluded stents in distal superficial femoral artery Vein Popliteal artery Distal anastomosis posterior tibial Anterior artery tibial artery Anterior tibial artery Posterior tibial artery Vein bypass Distal vein anastomosis Common plantar artery Fig. 4 Bypass grafting to infrainguinal targets in Pad. Completion angiograms showing the distal anastomosis region in the following scenarios: after femoral- to-popliteal artery bypass graft (red arrows) to treat occlusion of a previously placed stent (white arrows; part a); after femoral- to-posterior tibial artery bypass graft (red arrows; part b); and after femoral- to-common plantar artery bypass graft (red arrows) in a patient with chronic limb- threatening ischaemia (part c). All grafts were performed using autogenous vein. Black arrows, patent vessels; PAD, peripheral artery disease. Severe distal disease at the ankle and involving the pedal arch creates a major challenge for effective revascularization in patients with CLTI 131. Technically successful endovascular treatment of PAD in the pedal arch has been described 132 ; however, the indications for and clinical effectiveness of this approach are unclear. Open surgical bypass can also be employed to treat PAD in the tarsal and plantar arteries, but the outcomes of this intervention are not well defined. Endovascular treatment Balloon angioplasty versus primary stenting. Although primary stenting has been successfully used to treat focal infrapopliteal disease, balloon angioplasty remains the mainstay of infrapopliteal endovascular intervention (Fig. 5). A meta- analysis of six prospective, randomized trials that compared percutaneous transluminal angioplasty with primary stenting demonstrated no significant differences between the two treatment groups with regard to rates of technical success, primary patency, secondary patency, limb salvage, or patient survival 133. However, methods of outcome assessment varied across the studies, and six different types of stents were used in the included trials. Drug- coated versus standard balloon angioplasty. The successful use of drug- coated balloon angioplasty to treat femoropopliteal disease has led to its use in infrapopliteal arteries. However, randomized trials of this approach in infrapopliteal PAD have reported disappointing results, and no FDA- approved drug- coated balloon is available for this indication 134. A meta- analysis of four randomized trials that compared paclitaxel- coated balloon angioplasty with standard balloon angioplasty in 612 patients with infrapopliteal disease demonstrated that the group treated with paclitaxel- coated balloon angioplasty tended to do better than the standard treatment group with regard to restenosis (as a binary phenomenon), late lumen loss, target- lesion revascularization, and major adverse events at 1 year. However, these differences were not significant 135. The use of drug- coated balloon angioplasty in infrapopliteal arteries is an important area of ongoing active investigation in patients with CLTI 136. Drug- eluting versus bare- metal stents. Six randomized trials have compared bare- metal stent placement or balloon angioplasty with drug- eluting stent placement in the treatment of short (<3 cm) infrapopliteal lesions. In all these studies, the drug- eluting stent groups had lower rates of restenosis and/or target- lesion revascularization than the comparator groups. Amputation rates in the groups of patients who received drug- eluting stents were either similar to or better than those in the comparator groups However, three of these studies included mixed cohorts of patients (with either claudication or CLTI). Two multicentre, randomized trials have examined the use of drug- eluting stents specifically in patients with CLTI who had infrapopliteal arterial lesions. In the first trial, 140 patients received either an everolimus- eluting stent or a bare- metal stent; the everolimus- eluting stent group demonstrated superior 1-year primary patency (85% versus 54%; P = ) and freedom from target- lesion revascularization (91% versus 66%; P = 0.001) rates 141. The second trial compared a paclitaxel- eluting stent with percutaneous transluminal angioplasty (the angioplasty group could also receive bailout bare- metal stent placement) 142. In the per- protocol analysis, 6-month patency rates were significantly better in the drug- eluting stent group than in the comparator group (52% versus 35%; P = 0.04). The drug- eluting stent group also had lowe)r amputation rates at 6 and 12 months than the percutaneous transluminal angioplasty group 142. Lesion lengths in all these drug- eluting stent trials have been short because the stents used are sized for coronary arteries. These drug- eluting coronary artery stents are not currently approved for use in tibial arteries in the USA and, therefore, they are largely limited to bailout use in patients with complications, such as focal dissections after balloon angioplasty.

13 Tibioperoneal trunk Peroneal artery a b c Tibioperoneal trunk Anterior tibial artery Peroneal artery Diffusely diseased anterior tibial artery Resoration of flow in anterior tibial artery Dorsalis pedis artery Fig. 5 infrapopliteal intervention for Pad. Angiogram showing a severely diseased and occluded anterior tibial artery along its entire length (white arrows; part a). In this patient, balloon angioplasty resulted in restoration of brisk flow in the anterior tibial artery (red arrows; part b) and the dorsalis pedis artery into the foot; part c). Black arrows, patent vessels; PAD, peripheral artery disease. Drug- eluting stents versus drug- coated balloon angioplasty. A single randomized trial has compared paclitaxel- coated balloon angioplasty to drug- eluting (zotarolimus- eluting, sirolimus- eluting, and everolimus- eluting) stent placement in patients with long- segment infrapopliteal disease (lesion length 70 mm). The drug- eluting stent group had a significantly lower binary restenosis rate than the balloon angioplasty group at 6 months (28% versus 58%; P = 0.05) 143. However, the target- lesion revascularization rate was similar in both groups. This study included patients with intermittent claudication and patients with CLTI. Atherectomy. Given the low primary patency rates for balloon angioplasty and stenting in infrapopliteal disease, percutaneous atherectomy might have potential benefits, including avoidance of a permanent implant. However, atherectomy carries a higher risk of distal embolization than other endovascular therapies do, and the consequences of distal embolization are likely to be of increased concern when treating infrapopliteal disease in patients with CLTI who have limited distal runoff 144,145. In a subgroup analysis of patients with infrapopliteal lesions treated in the DEFINITIVE LE registry, the procedural success rate for atherectomy was 84% 146. Currently, no data exist from randomized trials supporting a benefit of atherectomy over conventional balloon angioplasty for infrapopliteal disease. Summary. Drug- eluting devices and atherectomy seem to hold the most promise for long- term patency in the treatment of infrapopliteal disease, but at present, these interventions are costly, and their availability remains limited. Balloon angioplasty is the current standard endovascular approach in infrapopliteal disease, with stenting often reserved for bailout treatment of short (<3 cm) lesions. In patients with CLTI and severe comorbidities or lacking a suitable autogenous conduit, endovascular treatment of infrapopliteal disease should be strongly considered. These procedures are less physiologically taxing and are associated with fewer wound complications than open surgical revascularization. However, owing to the nature of this population of patients, overall periprocedural mortality is similar for endovascular and open revascularization (1 7%). Open surgical treatment Surgical bypass grafts to tibial or pedal arteries is a well- established modality to restore limb perfusion, heal wounds, and prevent major amputation in patients with CLTI (Fig. 3). The common femoral artery, superficial femoral artery, or popliteal artery provides inflow for the distal graft, and short graft lengths are preferred as long as the inflow vessel is not haemodynamically compromised. Bypass to small- calibre ( 3 mm) target arteries is technically challenging and is highly dependent on the availability of a high- quality venous conduit, preferably the great saphenous vein. In several series of patients undergoing surgical bypass, tibial or pedal bypass graft patency rates are >60% at 3 5 years 120, (Table 2). Vein graft patency is strongly influenced by conduit diameter and, to a lesser degree, by graft length and outflow site 150. If the great saphenous vein conduit is not available, alternative veins (arm or lesser saphenous vein grafts) are preferred 151,152 ; the use of a prosthetic conduit for bypass to distal arteries is associated with dramatically reduced patency rates and increased amputation rates Complications of tibial or pedal bypass grafting are similar to those for femoropopliteal bypass, except that graft failure in patients with CLTI is more likely to

14 Transcutaneous oxygen The measurement of local oxygen released from the skin through the capillaries, which reflects the metabolic state of the lower limb. Biomimetic stents Stimulation of neovascularization lead to major limb amputation. In a large multicentre trial of infrainguinal vein bypass in patients with CLTI, 66% of grafts were performed to tibial or pedal targets. Mortality at 30 days was 2.7%, and 30-day graft failure and major amputation rates were 5.2% and 1.8%, respectively. One- quarter of the grafts involved either spliced veins or a small- calibre (<3 mm) conduit, which are considered to have a high risk of failure. At 1 year, the primary patency, primary- assisted patency, and secondary patency rates were 61%, 77%, and 80%, respectively 156. All patients who undergo lower extremity arterial interventions, whether endovascular or open surgery, require long- term follow- up, including clinical evaluation and noninvasive imaging studies when available. Routine ultrasonographic surveillance is associated with improved (primary and assisted) patency rates for vein grafts and probably also arterial stents. The threshold for reintervention should be based on the clinical status of the patient, level of disease, and type of procedure performed. Bioresorbable stents Tissue-engineered Regenerative treatments Diffuse arterial pathology (particularly at the infrapopliteal level) is invariably present in patients with CLTI and is often (in 20 40% of individuals) not amenable to conventional revascularization strategies 17,157. Novel treatment strategies are urgently needed for these patients. Although medical therapies reduce the risk of major cardiovascular events, they have not led to improvements in tissue perfusion, wound healing, and amputation rates. Regenerative approaches (growth factors and cell- based therapies) are a potential treatment option to improve tissue perfusion and limb- related outcomes in PAD (Fig. 6). Growth factor therapy Several growth factors are involved in angiogenesis and neovascularization. The most extensively studied are fibroblast growth factor, vascular endothelial growth factor, and hepatocyte growth factor, of which hepatocyte growth factor seems to be the most promising. The therapeutic application of these growth factors has been studied mainly in patients with nonrevascularizable CLTI. Initial pilot studies showed improvements in surrogate outcomes, such as ankle brachial index, transcutaneous oxygen levels, walking distance, and pain scores; hard clinical outcomes, such as amputation rates, also improved 158. However, randomized, placebo- controlled trials did not corroborate these initial promising results , in part because systemic administration of recombinant growth factors leads to ineffective, inconsistent, and uncontrolled tissue distribution and delivery. Accordingly, growth factor therapy now uses genetic vectors 161. Unfortunately, the large, phase III, randomized, placebo- controlled AnGes trial 162, which aimed to study the efficacy of an intramuscular injection of a DNA plasmid containing the HGF gene in patients with critical limb ischaemia (Rutherford grade 4 and 5), was terminated owing to poor enrolment (only 46 of the planned 500 patients were recruited). Future studies are needed to confirm a potential benefit of such approaches in large double- blind, placebo- controlled trials focusing on hard clinical outcomes. Fig. 6 Potential future therapeutic options for Pad. Biomimetic stents are designed to mimic the flow dynamics naturally present in the artery, which should protect against intimal hyperplasia and improve long- term patency. These stents are laser cut from a nitinol tube and have a special design that maintains their helical geometry and enables the stent to follow the shape of the original artery. Bioresorbable stents temporarily keep a stenosis open, which enables remodelling of the arterial wall, but they will eventually be completely broken down by the body. Although these stents gradually lose structural integrity over time, they are not subject to the potential drawbacks of a permanent arterial stent. In patients with peripheral artery disease or chronic limb- threatening ischaemia, neovascularization is dysfunctional and fails to repair the effects of ischaemic tissue damage. Administration of growth factors or cell- based therapies (such as mesenchymal stromal cells) stimulates neovascularization, improving blood flow and hence tissue perfusion. Bioresorbable arterial grafts can be used as a bypass conduit. After implantation, these grafts are slowly broken down and replaced by native tissue, forming a new native vessel. Such grafts are expected to have better patency than non- venous bypass grafts and might even outperform venous conduits. PAD, peripheral artery disease. Cell- based therapy The rationale for cell- based treatment of PAD was that the bone marrow functions as a reservoir of haematopoietic stem cells, including endothelial progenitor cells, which can induce angiogenesis. Endothelial progenitor cells are included in the mixture of progenitor cells contained in isolates of peripheral blood mononuclear cells (PBMCs) or bone- marrow mononuclear cells (BMMCs); thus, direct application of PBMCs or BMMCs might induce angiogenesis 163,164. Early non- controlled studies of PBMCs and BMMCs showed promising results, which unfortunately were not corroborated in subsequent well- designed, placebo- controlled trials. The largest such trial to date (the JUVENTAS trial 165 ) showed substantially improved outcomes (quality of life, ankle brachial index, pain scores, walking distance, and ulcer healing) in 160 BMMC- treated patients with CLTI, albeit without any difference between the BMMC and placebo groups. Moreover, the major amputation rate (the primary