49.9 Lower extremity artery disease

This section was reviewed and edited by The Task Force for the Management of Valvular Heart Disease of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS) Authors/Task Force Members: Helmut Baumgartner (ESC Chairperson) (Germany), Volkmar Falk (EACTS Chairperson) (Germany), Jeroen J. Bax (The Netherlands), Michele De Bonis (Italy), Christian Hamm (Germany), Per Johan Holm (Sweden), Bernard Iung (France), Patrizio Lancellotti (Belgium), Emmanuel Lansac (France), Daniel Rodriguez Muñoz (Spain), Raphael Rosenhek (Austria), Johan Sjögren (Sweden), Pilar Tornos Mas (Spain), Alec Vahanian (France), Thomas Walther (Germany), Olaf Wendler (UK), Stephan Windecker (Switzerland), Jose Luis Zamorano (Spain)

Most patients with LEAD are asymptomatic. Walking capacity must be assessed to detect clinically masked LEAD. The clinical signs vary broadly. Atypical symptoms are frequent. Even asymptomatic patients with LEAD are at high risk of CV events and must benefit from most CV preventive strategies, especially strict control of risk factors. Antithrombotic therapies are indicated in patients with symptomatic LEAD. There is no proven benefit for their use in asymptomatic patients. Ankle-brachial index is indicated as first-line test for screening and diagnosis of LEAD. DUS is the first imaging method. Data from anatomical imaging tests should always be analysed in conjunction with symptoms and haemodynamic tests prior to treatment decision. In patients with intermittent claudication, CV prevention and exercise training are the cornerstones of management. If daily life activity is severely compromised, first-line revascularization can be proposed, along with exercise therapy. Chronic limb-threatening ischaemia specifies clinical patterns with a vulnerable limb viability related to several factors. The risk is stratified according to the severity of ischaemia, wounds, and infection. Early recognition of tissue loss and/or infection and referral to the vascular specialist is mandatory for limb salvage by a multidisciplinary approach. Revascularization is indicated whenever feasible. Acute limb ischaemia with neurological deficit mandates urgent revascularization.

LEAD has several different presentations, categorized according to the Fontaine or Rutherford classifications (Table 49.9.1). Even with a similar extent and level of disease progression, symptoms and their intensity may vary from one patient to another.

Most patients are asymptomatic, detected either by a low ABI (<0.90) or pulse abolition. Among these, a subset may have severe disease without symptoms, which can be related to their incapacity to walk enough to reveal symptoms (e.g. heart failure) or reduced pain sensitivity (e.g. diabetic neuropathy), or both of these. This subgroup should be qualified as ‘masked LEAD’. In a study of 460 patients with LEAD, one-third of asymptomatic patients were unable to walk more than six blocks, corresponding to this concept.¹ These patients were older, more often women, with higher rates of neuropathy and multiple co-morbidities. While all asymptomatic patients are at increased risk of CV events, the subgroup with masked LEAD is also at high risk of limb events. This situation explains how a subset of patients presents a specific path with ‘asymptomatic’ disease shifting rapidly to severe LEAD. A typical presentation is an elderly patient with several co-morbidities who presents with toe necrosis after a trivial wound (e.g. after aggressive nail clipping). Identifying these patients is important to educate about foot protection. Hence, prior to the estimation of pain when walking, a clinical assessment of walking abilities is necessary, and clinical examination should also look for neuropathy. LEAD can also be clinically masked in one leg when the other one has more disabling disease.

In symptomatic patients, the most typical presentation is IC. The Edinburgh Claudication Questionnaire is a standardized method to screen and diagnose typical IC.²

CLTI is the recent denomination of the clinical state defined by the presence of ischaemic rest pain, with or without tissue loss (ulcers, gangrene) or infection. When present, arterial ulcers are usually painful, and often complicated by local infection and inflammation. When pain is absent, peripheral neuropathy should be considered. While CLTI is a clinical diagnosis, it is often associated with an ankle pressure less than 50 mmHg or toe pressure less than 30 mmHg.³ Investigation of the microcirculation (i.e. transcutaneous oxygen pressure or TcPO₂) is helpful in some cases of medial calcinosis.

Regular clinical examination is important in elderly patients, especially diabetic patients.⁴ Early recognition of tissue loss and referral to the vascular specialist is mandatory to improve limb salvage. Primary major amputation rates in patients unsuitable for revascularization are high (20–25%).⁵ CLTI is also a marker for generalized, severe atherosclerosis, with a threefold increased risk of myocardial infarction (MI), stroke, and vascular death as compared to patients with IC.^3,5

Clinical examination is fundamental but the diagnosis must be confirmed by objective tests. Pulse palpation should be systematic. Abdominal or groin auscultation (or both) is poorly sensitive. In severe cases, inspection may show foot pallor in a resting leg, with extended recoloration time (>2 s) after finger pressure.

Regarding the natural history, in a recent meta-analysis,⁶ most patients with IC present increased 5-year cumulative CV-related morbidity at 13% versus 5% in the reference population. Regarding the limb risk, at 5 years, 21% of patients progress to CLTI, of whom 4–27% have amputations.³

ABI is the first diagnostic step after clinical examination (see Chapter 49.3). An ABI of 0.90 or less has 75% sensitivity and 86% specificity to diagnose LEAD.⁷ Its sensitivity is poorer in patients with diabetes or end-stage chronic kidney disease because of medial calcification.⁸ Patients with borderline (0.90–1.00) ABI need further diagnostic tests (see Table 49.3.4 in Chapter 49.3). When clinically suspected, a normal ABI (>0.90) does not definitely rule out the diagnosis of LEAD; further post-exercise ABI and/or DUS are necessary. In case of high ABI (>1.40) related to medial calcification, alternative tests such as toe pressure, toe–brachial index (TBI), or Doppler waveform analysis of ankle arteries are useful. Along with DUS, ABI can be used during patient follow-up. It is also a good tool for stratifying the CV risk (see Chapter 49.3).⁹

See Table 49.9.2 for recommendations for ABI measurement.^8,10,11

The treadmill test (usually using the Strandness protocol, at 3 km/h speed and 10% slope) is an excellent tool for objective functional assessment, unmasking moderate stenosis, as well as for exercise rehabilitation follow-up. It is also helpful when the ischaemic origin of limb pain is uncertain. The test is stopped when the patient is unable to walk further because of pain, defining maximal walking distance (WD). A post-exercise ankle-systolic blood pressure drop greater than 30 mmHg or a post-exercise ABI drop greater than 20% is diagnostic for LEAD.⁸

DUS provides extensive information on arterial anatomy and haemodynamics. It must be combined with ABI measurement. DUS has a sensitivity of 85–90% and specificity of greater than 95% to detect a stenosis greater than 50%.¹² A normal DUS at rest should be completed by a post-exercise test when iliac stenosis is suspected, because of lower sensitivity. DUS is operator dependent and good training is mandatory. DUS does not present as a roadmap the entire vasculature. Another imaging technique is usually required when revascularization is considered. DUS is also important to address vein quality for bypass substitutes. It is the method of choice for routine follow-up after revascularization.

In a meta-analysis, the reported sensitivity and specificity of computed tomography angiography (CTA) to detect aorto-iliac stenoses greater than 50% were 96% and 98%, respectively, with similar sensitivity (97%) and specificity (94%) for the femoro-popliteal region.¹³ Main advantages are visualization of calcifications, clips, stents, bypasses, and concomitant aneurysms. Beyond general limitations (radiation, nephrotoxicity, and allergies), pitfalls are severe calcifications (impeding the appreciation of stenosis, mostly in distal arteries).

The sensitivity and specificity of magnetic resonance angiography (MRA) are approximately 95% for diagnosing segmental stenosis and occlusion. However, MRA tends to overestimate the degree of stenosis.¹⁴ It cannot visualize arterial calcifications, useful for the estimation of stenosis severity in highly calcified lesions, but is a limitation for the selection of the anastomotic site of surgical bypass. The visualization of steel stents is poor. In expert centres, MRA has a higher diagnostic accuracy for tibial arteries than DUS and CTA.

Digital subtraction angiography (DSA) is often required for guiding percutaneous peripheral interventional procedures or for the identification of patent arteries for distal bypass. It is also often needed for below-the-knee arteries, especially in patients with CLTI, because of the limitation of all other imaging tools to detect ankle/pedal segments suitable for distal bypass.

Patients with LEAD have often other concomitant arterial lesions, including other peripheral arterial diseases and abdominal aorta aneurysm (AAA).

LEAD is often associated with AAAs.¹⁵ In observational studies, the prevalence of AAAs (aortic diameter ≥3 cm) was higher in patients with symptomatic LEAD than in the general population and in a population of patients with atherosclerotic risk factors. The prevalence of AAA among patients with LEAD increased with age, beginning in patients 55 years of age and older, and was highest in patients 75 years of age or older. Often AAA is incidentally detected in patients with LEAD during imaging assessment.

The prevalence of atherosclerosis in the coronary, carotid, and renal arteries is higher in patients with LEAD than in those without. For details refer to Chapter 49.10.

Toe systolic blood pressure, TBI, and TcPO₂ are useful in patients with medial calcinosis and incompressible arteries.

In healthy young adults, normal values of TBI for men and women are, respectively, at 0.98±0.12 and 0.95±0.12.¹⁵ There are discrepancies in the literature regarding the cut-off value,¹¹ ranging from 0.60 to 0.75, but TBI is mostly considered as abnormal when less than 0.70. The diagnostic accuracy varied in small studies, with sensitivity and specificity ranges of 45–100% and 16–100%, respectively. Overall, the TBI had good performance in patients with diabetes, claudicants, and those at risk of LEAD. Toe pressure and TcPO₂ are useful for CLTI assessment.

To define CLTI, pressure cut-offs of less than 50 mmHg, less than 30 mmHg, and less than 30 mmHg are proposed for ankle pressure, toe pressure, and TcPO₂, respectively. TcPO₂ is often used to determine the healing capacity after amputation. If TcPO₂ is 10 mmHg or less, wound healing is improbable. If TcPO₂ is greater than 40 mmHg, wound healing capacity is good after minor amputation. For values in between (10–40 mmHg), provocation tests allow better stratification. For a provocation test, TcPO₂ is measured in addition to supine position, when the patient breaths 60% O₂ or when the patient’s leg is elevated. The following results in provocation tests may predict sufficient wound healing capacity and minor amputation should be attempted if there is no revascularization possibilities: increase in TcPO₂ greater than 10 mmHg or 50% or higher from the baseline value when the patient is breathing oxygen, or decrease less than 10 mmHg when leg is elevated.

See Table 49.9.3 for recommendations on imaging in patients with LEAD.^12,13,14,15

The therapeutic options addressed here are those to improve limb symptoms/salvage. Treatments proposed to reduce other CV events and mortality are addressed in Chapter 49.3.

General prevention strategies can improve limb events. Smoking cessation provides the most noticeable improvement in WD when combined with regular exercise, especially when lesions are located below the femoral arteries. In patients with IC, the natural history is deteriorated by ongoing tobacco use, with increased risk of amputation.^17,18

Several studies have shown that statins improve significantly the CV prognosis of patients with IC or CLTI.^19,20 Additionally, several meta-analyses showed a relevant improvement in pain-free and maximal WD with use of statins.^19,21 It is suggested that statins could limit adverse limb events in patients with LEAD (see Chapter 5.9).²²

In subjects with hypertension, calcium antagonists or ACEIs/ARBs should be preferred because of their potential in peripheral arterial dilatation (see Chapter 5.1). A meta-analysis²³ showed improved maximal- and pain-free WD when using ACEI over placebo; however, two out of six randomized clinical trial (RCT) reports have been recently withdrawn because of unreliable data, and the meta-analysis of the remaining studies is inconclusive.²⁴ The benefit of verapamil in improving WD in LEAD has been shown in a randomized study.²⁵ Because of co-morbidities such as heart failure, beta blockers are indicated in some patients with LEAD. Studies showed that beta blockers, in particular nebivolol, are safe in patients with IC without negative effects on WD (see Chapter 5.3).²⁶ Metoprolol and nebivolol have been compared in a double-blind RCT including 128 beta blocker-naive patients with IC and hypertension.²⁷ After a 48-week treatment period, both drugs had been well tolerated and decreased blood pressure equally. In both groups maximal WD improved significantly. Nebivolol showed an advantage with significant improvement in pain-free WD (+34% (p <0.003) versus + 17% for metoprolol (p <0.12)). In a single-centre study of 1873 consecutive CLTI patients who received endovascular therapy, those treated with other beta blockers did not have a poorer clinical outcome.²⁸ In a multicentre registry of 1273 patients hospitalized for severe LEAD (of whom 65% had CLTI and 28% were under beta-blocker therapy), death and amputation rates did not differ among those with versus without beta blocker.²⁹

The rapid progress in the field of endovascular therapy has led to the extension of its use for complex lesions. The mainstay technique is balloon angioplasty; however, restenosis occurs very frequently in lower limb arteries, with lowest rates in the common iliac artery and increasing distally as well as with lesion lengthening, calcification, poor quality run-off, diabetes, and chronic kidney disease. Therefore, stenting is often performed to improve an insufficient primary result (residual stenosis, extensive recoil, flow-limiting dissection) and long-term patency. Several types of stents with different mechanical properties are available. In-stent restenosis is more frequent in lower limb arteries, and is generally more difficult to treat than restenosis after balloon angioplasty. Stents should generally be avoided in bending areas (hip and knee joints), as well as in arterial segments suited as a landing zone for a potential bypass. The recent innovations to improve the results of endovascular therapy are drug-eluting stents and balloons, which decrease the development of neointimal hyperplasia. The results have been better compared to conventional balloon dilatation or bare-metal stents up to 24-month follow-up, but results beyond 2 years are lacking. Additional endovascular tools with a niche role include atherectomy catheters and devices for crossing chronic total occlusions.

Surgical revascularization can be performed, either by open surgery techniques and/or by a hybrid procedure combining open and endovascular strategies.

Beyond clinical presentation and lesion distribution, one key element to discuss indications for open surgery is the availability of venous material for bypass grafting.

Surgical options range from a local procedure for limited femoral lesions to long full-leg bypasses. The optimal bypass material varies depending on the location of the lesion, outflow conditions, availability of material, and absence or presence of infection. For aortic or iliac bypass surgery, mostly prosthetic material (polyester or polytetrafluoroethylene) is used. In the infra-inguinal segment, autologous vein (e.g. great saphenous vein) is preferred. In selected patients arterial homografts or biological grafts from ovine or bovine pericardium are implanted. Few centres use human venous allografts under study conditions.

In patients with IC, ExT is effective and improves symptoms and quality of life and increases maximal WD. In 30 RCTs including 1816 patients with stable leg pain, compared with usual care, ExT improved maximal WD on treadmill by almost 5 min.³⁰ Pain-free and maximal WD were respectively increased on average by 82 and 109 m. Improvement was observed up to 2 years. Moreover, ExT improved quality of life. Exercise did not improve ABI. Whether ExT reduces CV events and improves life expectancy is still unclear. Supervised ExT is more effective than non-supervised ExT.^31,32 In 14 trials with participants assigned to either supervised ExT or non-supervised ExT (1002 participants), lasting from 6 weeks to 12 months, maximal and pain-free WD increased by almost 180 m in favour of supervised ExT. These benefits remained at 1 year. Most studies use programmes of at least 3 months, with a minimum of 3 h/week, with walking to the maximal or submaximal distance. Long-term benefits of ExT are less clear and largely depend on patient compliance. Supervised ExT is safe and routine cardiac screening beforehand is not required.³³ It is also more cost-effective than non-supervised ExT,³⁴ but is not reimbursed or available everywhere. Though home-based walking ExT is not as effective as supervised ExT, it is a useful alternative with positive effects on quality of life and functional walking capacity versus walking advice alone.^35,36 Alternative exercise modes (e.g. cycling, strength training, and upper-arm ergometry) may be useful when walking exercise is not an option for the patients as these have also been shown to be effective.³⁷ ExT is impossible in patients with CLTI but can be considered after successful revascularization.³⁸

Some antihypertensive drugs (e.g. verapamil),²⁵ statins,^39,40 antiplatelet agents, and prostanoids (prostaglandins I2 and E1)⁴¹ have some favourable effects on WD and leg functioning. Other pharmacological agents claim to increase more specifically WD in patients with IC without other effects on CV health. The drugs mostly studied are cilostazol, naftidrofuryl, pentoxifylline, buflomedil, carnitine, and propionyl-L-carnitine.^21,42 However, objective documentation of such an effect is limited. The beneficial effects on WD, if any, are generally mild to moderate, with large variability. Also, the incremental benefit of these treatments in addition to ExT and statins are unknown.

Cilostazol is an inhibitor of phosphodiesterase type III. Several clinical trials showed an improvement of maximal walking distance (MWD) by cilostazol compared with placebo as well as pentoxyfilline.^42,43,44 But there is a wide range of effects on MWD. In a current Cochrane analysis, 100 mg twice a day increased MWD to a mean of 76% compared to 20% in the placebo groups.⁴³ Another review described only an average improvement of 25% under cilostazol.⁴² Side effects like headache, flush symptoms, or diarrhoea are frequent. Cilostazol also has antiplatelet effects and should therefore be combined cautiously with other anticoagulant and antiplatelet substances.⁴⁴ Of interest, cilostazol reduced restenosis after endovascular therapy in randomized trials but also increased bleeding complications.⁴⁵

Naftidrofuryl oxalate has been tested in six older studies included in a Cochrane analysis.⁴⁶ Studies showed an increase in MWD of 74% on average and an improvement in quality of life.^46,47 In a systematic review the average improvement of absolute walking distance was 60% compared with placebo.⁴² Currently a dosage of 200 mg naftidrofuryl oxalate three times a day is recommended. Relevant side effects associated with naftidrofuryl are mainly gastrointestinal such as nausea, vomiting, or diarrhoea.

Other pharmacological medications such as prostanoids, pentoxifylline, L-arginine, buflomedil, or Ginko biloba do not have enough consistent data from RCTs to be recommended in patients with IC.^41,48,49

The anatomical location and extension of arterial lesions has an impact on revascularization options.

Isolated aorto-iliac lesions are a common cause of claudication. In the case of short stenosis/occlusion (<5 cm) of iliac arteries, endovascular therapy gives good long-term patency (≥90% in 5 years) with low risk of complications.⁵⁰ In cases of iliofemoral lesions, a hybrid procedure is indicated, usually endarterectomy or bypass at the femoral level combined with the endovascular therapy of iliac arteries, even in most cases with long occlusions. If the occlusion extends to the infrarenal aorta, covered endovascular reconstruction of an aortic bifurcation can be considered. In a small series 1- and 2-year primary patency was at 87% and 82%, respectively.⁵¹ If the occlusion comprises the aorta up to the renal arteries and iliac arteries, aortobifemoral bypass surgery is indicated in fit patients with severe life-limiting claudication.⁵² In these extensive lesions, endovascular therapy may be an option but it is not free of perioperative risk and long-term occlusion. In the absence of any other alternative, extra-anatomic bypass (e.g. axillary to femoral bypass) may be considered.

Femoropopliteal lesions are common in claudicants. If the circulation to the profunda femoral artery is normal, there is a good possibility that the claudication will be relieved with ExT and intervention is mostly unnecessary. If revascularization is needed, endovascular therapy is the first choice in stenosis/occlusions smaller than 25 cm. If the occlusion/stenosis exceeds 25 cm, endovascular recanalization is still possible, but better long-term patency is achieved with surgical bypass, especially when using the great saphenous vein. No head-to-head trials comparing endovascular therapy and surgery are yet available. In the Zilver PTX trial, the 5-year primary patency with conventional and drug-eluting stents was 43% and 66%, respectively.⁵³ The 5-year patency after above-knee femoropopliteal bypass exceeds 80% with great saphenous vein and 67% with prosthetic conduits.⁵⁴ The challenge of endovascular therapy is the long-term patency and durability of stents in the femoropopliteal region, where the artery is very mobile. Several new endovascular solutions, such as atherectomy devices, drug-eluting balloons, and new stent designs, have been shown to improve long-term patency.

Several studies have demonstrated the efficacy of endovascular therapy and open surgery on symptom relief, WD, and quality of life in claudicants. However, these interventions have limited durability and may be associated with mortality and morbidity. Thus, they should be restricted to patients who do not respond favourably to ExT (e.g. after a 3-month period of ExT), or when disabling symptoms alter substantially daily life activities. A systematic review of 12 trials (1548 patients) comparing medical therapy, ExT, endovascular therapy, and open surgery in claudicants showed that, compared to the former, each of the three other alternatives were associated with improved WD, claudication symptoms, and quality of life.⁵⁵ Compared with endovascular therapy, open surgery may be associated with longer hospital stay and higher complication rate but results in more durable patency. The Claudication: Exercise Versus Endoluminal Revascularization (CLEVER) trial randomized 111 patients with IC and aorto-iliac lesions to BMT alone, or in combination with supervised-ExT or stenting.⁵⁶ At 6 months, changes in maximal WD were the greatest with supervised-ExT, while stenting provided greater improvement in peak walking time than BMT alone. At 18 months, the difference in terms of peak walking time was not statistically different between supervised-EXT and stenting.⁵⁶ The management of patients with IC is summarized in Figure 49.9.1.

See Table 49.9.4 for recommendations for the management of patients with IC.

See Table 49.9.5 for recommendations on revascularization of aorto-iliac occlusive lesions.

See Table 49.9.6 for recommendations on revascularization of femoropopliteal occlusive lesions.

This entity includes clinical patterns with a threatened limb viability related to several factors. In contrast to the formerly used term ‘critical limb ischaemia’, severe ischaemia is not the only underlying cause. Three issues must be considered with the former terminology of ‘critical limb ischaemia’. First, ‘critical’ implies that treatment is urgent to avoid limb loss, while some patients can keep their legs for long periods of time even in the absence of revascularization.⁷⁶ Second, the increasing predominance of diabetes in these situations, present in 50–70% of cases, presents mostly as neuro-ischaemic diabetic foot ulcers. Third, the risk of amputation does not only depend on the severity of ischaemia but also the presence of wound and infection. This explains why the ankle or toe pressures, measured to address LEAD severity, are not a definition component of CLTI.

A new classification system (WIfI) has been proposed as the initial assessment of all patients with ischaemic rest pain or wounds.⁷⁷ The target population for this system includes any patient with:

The three primary factors that constitute and contribute to the risk of limb threat are: Wound (W), Ischaemia (I), and foot Infection (fI).

Each factor is graded into four categories (0 = none; 1 = mild; 2 = moderate; 3 = severe). Table 49.9.7 displays the coding and clinical staging according to the WIfI classification. Table 49.9.8 provides an estimation of the amputation risk at 1 year according to the WIfI classification. The management of patients with CLTI should consider the three components of this classification system. Revascularization should always be discussed as its suitability is increased with more severe stages (except stage 5).

The management of patients with CLTI is summarized in Figure 49.9.2. All patients with CLTI must have the BMT with correction of risk factors (see ‘Medical treatment’). In those with diabetes, glycaemic control is particularly important, with improved limb-related outcomes, including lower rates of major amputation and increased patency after infra-popliteal revascularization.^78,79 Proper wound care must be started immediately, as well as adapted shoe wear, treatment of concomitant infection, and pain control.

Revascularization should be attempted as much as possible.^3,80,81,82 So far, only one randomized trial, the Bypass versus Angioplasty in Severe Ischaemia of the Leg (BASIL) trial, has directly compared endovascular therapy to open surgery in CLTI patients.⁷⁴ At 2 years, there was no significant difference between endovascular therapy and surgery regarding amputation-free survival. In survivors after 2 years, bypass surgery was associated with improved survival (on average 7 months, p = 0.02) and amputation-free survival (6 months, p = 0.06).⁸³ These data are challenged by more recent endovascular therapy techniques. So far, drug-eluding balloons in below-the-knee disease have shown no superiority over plain balloon angioplasty.⁸⁴ The results of two ongoing RCTs, BASIL-2 and Best Endovascular vs. Best Surgical Therapy in Patients with Critical Limb Ischaemia (BEST-CLI), are awaited.^85,86 Meanwhile, in each anatomical region, both revascularization options should be individually discussed.

CLTI is almost never related to isolated aorto-iliac disease, and downstream lesions are often concomitant. In addition to CTA and/or MRA, complete DSA down to the plantar arches is required for proper arterial network assessment and procedure planning.⁸⁷ Hybrid procedures (e.g. aorto-iliac stenting and distal bypass) should be encouraged in a one-step modality when necessary.

CLTI is unlikely to be related to isolated superficial femoral artery lesions; usually femoropopliteal involvement combined with aorto-iliac or below-the-knee disease are found. In up to 40% of cases, inflow treatment is needed.⁸⁴ The revascularization strategy should be judged upon lesion complexity. If endovascular therapy is chosen first, landing zones for potential bypass grafts should be preserved. When bypass surgery is decided, the bypass should be as short as possible, using the saphenous vein.

Extended infrapopliteal artery disease is mainly seen in diabetic patients, often associated with superficial femoral artery lesions (inflow disease). Full-leg DSA down to the plantar arches is mandatory to explore all revascularization options.⁸⁷ In stenotic lesions and short occlusions, endovascular therapy can be the first choice. In long occlusions of crural arteries, bypass with an autologous vein gives superior long-term patency and leg survival. If the patient has increased risk for surgery or does not have an autologous vein, endovascular therapy can be attempted. The decision of revascularization should also consider the angiosome concept, to target at best the ischaemic tissues.

Despite an aggressive approach for revascularization, amputation rates of up to 20% can occur despite a patent bypass in patients with CLTI and tissue loss.⁸⁸ This has led to the proposal of an angiosome-based revascularization strategy (where the specific artery perfusing the corresponding diseased territory is revascularized).⁸⁹

There is no question that clinicians would opt to revascularize the blood vessel which directly feeds an involved angiosome if the vessel is accessible and open to the foot. Several meta-analyses compare outcomes after direct and indirect revascularization strategies and suggest that there may be a benefit for patients undergoing direct versus indirect revascularization for wound healing.^90,91 However, the quality of evidence on which these conclusions are based is low. Most of the studies have used historical data and retrospectively applied criteria. Furthermore, details on the status and quality of the pedal arch were not consistently evaluated. Some authors reported that time to healing for foot tissue loss was significantly influenced by the patency of the pedal arch rather than the revascularized angiosome.⁹²

In summary, the angiosome model should not be used as an absolute strategy for interventions on patients with CLTI. Further well-structured prospective studies are needed to assess the value of the angiosome concept.

See Table 49.9.9 for recommendations on revascularization of infrapopliteal occlusive lesions.

Spinal cord stimulation can improve limb salvage and pain relief in selected patients with CLTI who are unfit for revascularization or experience persistent ischaemic-related pain following revascularization. Due to the costs of the device and the risk of relatively mild complications, candidates must be selected using a microcirculatory evaluation (baseline and changes in TcPO₂ measurements) and after a trial period with an external device.⁹³

Angiogenic gene and stem cell therapy are still being investigated with insufficient evidence in favour of these treatments.^94,95

The development of therapeutic angiogenesis is based on the use of angiogenic factors or stem cells to promote revascularization and remodelling of collaterals, with the aim of reducing ischaemia, ameliorating symptoms, and preventing amputation. Several trials reported relief of ischaemic symptoms, functional improvement, and prevention of amputation, but others failed to confirm this early promise of efficacy.^96,97,98

In a meta-analysis of 12 RCTs, autologous cell therapy was effective in improving surrogate indexes of ischaemia, subjective symptoms, and hard endpoints (ulcer healing and amputation). Patients with thromboangiitis obliterans showed greater benefits than patients with atherosclerotic LEAD.⁹⁹ The largest randomized placebo-controlled trial of gene therapy is the Efficacy and Safety of XRP0038/NV1FGF in Critical Limb Ischemia Patients With Skin Lesions (TAMARIS) study, including 520 patients from 30 countries with CLTI and skin lesions, unsuitable for standard revascularization. This study found no statistical difference between the two groups regarding the primary efficacy endpoint of death or first major amputation on the treated leg, whichever came first (37.0% vs 33.2%; p = 0.48).⁹⁴

In case of CLTI, minor amputation (up to the forefoot level) is often necessary to remove necrotic tissues with minor consequences on a patient’s mobility. Revascularization is needed before amputation to improve wound healing. Foot TcPO₂ and toe pressure can be useful to delineate the amputation zone (see ‘Other tests’).

Patients with extensive necrosis or infectious gangrene and those who are non-ambulatory with severe co-morbidities may be best served with primary major amputation. This remains the last option to avoid or halt general complications of irreversible limb ischaemia, allowing in some cases patient recovery with rehabilitation and prosthesis. For a moribund patient, adequate analgesia and other supportive measures may also be the best option.

Secondary amputation should be performed when revascularization has failed and reintervention is no longer possible, or when the limb continues to deteriorate because of infection or necrosis despite patent graft and optimal management. In any case infragenicular amputation should be preferred because the knee joint allows better mobility with a prosthesis. For bedridden patients, femoral amputation may be the best option.

See Table 49.9.10 for recommendations on the management of CLTI.

Acute limb ischaemia is caused by an abrupt decrease in arterial perfusion of the limb. Potential causes are artery disease progression, cardiac embolization, aortic dissection or embolization, graft thrombosis, thrombosis of a popliteal aneurysm or cyst, popliteal artery entrapment syndrome, trauma, phlegmasia cerulea dolens, ergotism, hypercoagulable states, and iatrogenic complications related to vascular procedures. Limb viability is threatened and prompt management is needed for limb salvage.

Once the clinical diagnosis is established, treatment with unfractionated heparin should be given, along with appropriate analgesia.^3,100 The emergency level and the choice of therapeutic strategy depend on the clinical presentation, mainly the presence of neurological deficits. The clinical categories are presented in Table 49.9.11.¹⁰¹

In the case of neurological deficit, urgent revascularization is mandatory; imaging should not delay intervention. The imaging method depends on its immediate availability. DUS and DSA are mostly used in these situations.

Different revascularization modalities can be applied including percutaneous catheter directed thrombolytic therapy, percutaneous mechanical thrombus extraction or thrombo-aspiration (with or without thrombolytic therapy), and surgical thrombectomy, bypass, and/or arterial repair. The strategy will depend on the presence of a neurological deficit, ischaemia duration, its localization, co-morbidities, type of conduit (artery or graft), and therapy-related risks and outcomes. Owing to reduced morbidity and mortality, endovascular therapy is often preferred, especially in patients with severe co-morbidities. Thrombus extraction, thrombo-aspiration, and surgical thrombectomy are indicated in the case of neurological deficit, while catheter-directed thrombolytic therapy is more appropriate in less severe cases without neurological deficit. The modern concept of the combination of intra-arterial thrombolysis and catheter-based clot removal is associated with 6-month amputation rates less than 10%.³ Systemic thrombolysis has no role in the treatment of patients with acute limb ischaemia.

Based on RCTs, there is no clear superiority of local thrombolysis versus open surgery on 30-day mortality or limb salvage.¹⁰² After thrombus removal, the pre-existing arterial lesion should be treated by endovascular therapy or open surgery. Lower extremity four-compartment fasciotomies should be performed in patients with long-lasting ischaemia to prevent a post-reperfusion compartment syndrome. The management of acute limb ischaemia is summarized in Figure 49.9.3.

See Table 49.9.12 for recommendations for the management of patients presenting with acute limb ischaemia.

Another clinical presentation is the blue toe syndrome characterized by a sudden cyanotic discoloration of one or more toes; it is usually due to embolic atherosclerotic debris from the proximal arteries.

Blue toe syndrome is the result of atheroembolism, a process in which emboli from proximal arterial lesions produce ischaemia in distal arterial beds. These emboli are due to atherosclerotic plaque fragmentation, with resulting showers of cholesterol debris and platelet aggregates. When it occurs in the lower extremities, arterioles are occluded and blue toe syndrome is demonstrated. The microembolic process can occur anywhere in the body; it was first reported by Flory¹⁰³ in 1945, and Hoye and colleagues¹⁰⁴ first described the clinical presentation in the lower extremities. The term ‘blue toe syndrome’ was first used by Karmody and colleagues¹⁰⁵ in 1975 in a series of 31 patients.

Controversy exists over the most appropriate treatment for these patients.^{106,107,108,109,110,111,112,113,114,115} Surgical treatment of these lesions has been aimed at removing the source lesion by means of endarterectomy or bypass. There are a few reports of intra-arterial treatment of these lesions, including thrombolytic administration,¹¹⁶ percutaneous atherectomy,^117,118 and balloon and stent angioplasty.^119,120 Often, antiplatelet therapy alone or in combination with surgical or endovascular treatment has been advocated. More controversial is the use of anticoagulation because there have been reports that indicate anticoagulation may promote atheroembolism.^{121,122,123,124,125,126,127}

Many of the lesions that are the source of blue toe syndrome also produce significant obstruction that could be appropriately treated.^128,129,130 Stents, although currently non-covered, could treat the obstruction and also stabilize these lesions from producing emboli.¹³¹

Atherosclerotic lesions that produce blue toe syndrome appear to be equally distributed from the aorta, and iliac and femoropopliteal regions.¹¹⁰ Classically, this entity presents as painful, blue or purple toes in patients without proximal obstruction but with multiple levels of disease, including ulcerated plaques, making determination of the source difficult.

The natural history of patients with blue toe syndrome is repeated microemboli, with a reported rate of tissue loss/amputation up to 45%.^112,115 Most reports advocate the isolation or removal of the embolic source.^111,115 Stents theoretically provide a scaffold that would prevent plaque embolization and promote remodelling of the lesion, but there is concern about producing additional emboli during stent placement.

Brewer and colleagues¹¹⁶ hypothesized the lesion producing blue toe syndrome could be adequately treated first by stabilizing the plaque with antiplatelet therapy, and then by percutaneous transluminal angioplasty 6 weeks later, if no new symptoms occurred. In another study, Kumpe and colleagues¹²⁰ reported successful results in treating ten patients with percutaneous transluminal angioplasty and antiplatelet therapy; only one patient experienced recurrent emboli, but the mortality rate in this group was high (60%). Karmody and colleagues¹⁰⁵ describe at least three recurrent embolic events in his group of 31 surgically treated patients (10%), with a 0% mortality rate and a 32% amputation rate. Wingo and colleagues¹¹⁵ reported the largest series of 48 patients (31 treated surgically, 11 treated medically, and 22 receiving no treatment) with no differences in outcomes between the groups with an overall rate of tissue loss of 38% in addition to the 22% amputation rate.

To compare reports of endovascular, surgical, and combinations of treatment for blue toe syndrome is difficult since most studies are retrospective, limited by small numbers of patients, with variations in treatments, undefined and short follow-up times, and variable endpoints.

Nevertheless, when applicable, stent placement appears to be as effective as surgical, medical, or other endovascular therapies. Considering the possible deleterious effects of vitamin K antagonists in patients with blue toe syndrome, the use of antiplatelet therapy has become standard.

In conclusion, whether treated surgically or by endovascular techniques with the association of antiplatelet therapy, there is a high risk of limb loss and a high mortality rate in patients with blue toe syndrome. Physicians should be aggressive in the diagnosis. Covered-stent placement is an alternative to bypass but further studies are needed to ensure efficacy and safety.