Management of chronic limb-threatening ischemia

INTRODUCTION — Management decisions in the patient with chronic limb-threatening ischemia (CLTI) are derived from the clinical presentation, physical examination, and review of noninvasive vascular studies, with consideration of risk factors that impact a decision for intervention or conservative care.

The approach is tailored to each patient based upon numerous factors, including presence and degree of tissue loss, patient-specific vascular anatomy, availability of vascular conduit for revascularization, and comorbidities such as cardiac risk (may impact the magnitude of intervention) and renal insufficiency (may impact options for contrast agents and likelihood of procedural success) [1]. If intervention is pursued, the interaction of the limb status, patient comorbidities, and the patient's vascular anatomy determine the best form of revascularization. As revascularization options have evolved and improved, more patients have become candidates. Unfortunately, for some patients, the most appropriate course of treatment may be primary amputation or palliation.

The overall management of CLTI ischemia is reviewed. The clinical manifestations and diagnosis of CLTI, the approach to revascularization, as well as techniques for surgical and endovascular revascularization are reviewed separately. (See "Clinical features and diagnosis of lower extremity peripheral artery disease" and "Clinical features and diagnosis of acute lower extremity ischemia".)

CLINICAL FEATURES AND DIAGNOSIS

Clinical presentations — Patients with CLTI may present with ischemic rest pain, which is pain across the base of the metatarsal heads at rest relieved by dependency, or with tissue loss, which can be ulceration, dry gangrene, or wet gangrene (infection) occurring in the lower extremities due to atherosclerotic occlusive disease of the iliac, femoral, popliteal, tibial, or pedal arteries [1]. The patient can present initially without an antecedent history of peripheral artery disease (PAD). Such a primary presentation may be more likely in patients with a history of diabetes, heart failure, stroke, or renal failure [2]. (See "Clinical features and diagnosis of lower extremity peripheral artery disease", section on 'Lower extremity pain' and "Clinical features and diagnosis of lower extremity peripheral artery disease", section on 'Nonhealing wound/ulcer' and "Clinical features and diagnosis of lower extremity peripheral artery disease", section on 'Skin discoloration/gangrene'.)

Ischemic pain and pain progression — Patients with PAD may provide a description of extremity pain that progresses over time when questioned. The classic presentation is a patient who initially experienced pain in the muscles of the lower extremity, most often the calf, with walking that is relieved by rest (ie, claudication), which, over months or years, progresses to ischemic rest pain (ie, CLTI). However, perhaps more often than not, patients do not describe such a progression. For a variety of reasons (obesity, shortness of breath, lumbar spine disease, diabetic sensory neuropathy, general frailty), many patients with PAD are sedentary and do not experience claudication. In such patients, it is only when PAD progresses to the point that perfusion at rest is insufficient to support tissue metabolism that ischemic rest pain or signs of tissue loss reveal themselves. Sometimes a relatively minor injury can uncover underlying PAD and initiate a cascade of deterioration.

A variety of conditions can mimic ischemic rest pain, including neuropathy, arthritis, and gout. Here, experience, a careful history and physical examination including palpation of peripheral pulses, and properly performed Doppler pressures and waveforms can help make the proper diagnosis. Examination of peripheral pulses may be challenging due to calcification, edema, or wounds, and there should be a very low threshold to obtaining noninvasive vascular studies in patients with lower leg and foot wounds. (See "Noninvasive diagnosis of upper and lower extremity arterial disease", section on 'Ankle-brachial index' and "Noninvasive diagnosis of upper and lower extremity arterial disease", section on 'Physiologic testing'.)

Foot or toe pain in a patient with absent pulses and a significantly abnormal ankle-brachial index (ABI) should be presumed to be ischemic pain. Further complicating the assessment, diabetes adds an additional level of complexity. Individuals with diabetes may be insensate due to neuropathy and may not be aware of developing wounds or ulcers. Associated tibial artery calcification, which is common with diabetes, may lead to falsely elevated or even noncompressible Doppler pressures. The complexities of the diabetic foot in association with PAD are reviewed separately. (See "Overview of peripheral artery disease in patients with diabetes mellitus".)

Wounds in a limb at risk — Marginal perfusion to the extremity may be adequate to sustain healthy tissue at rest but can be insufficient to provide the increased energy required for wound healing. Wounds may arise spontaneously or be the result of surgical procedures (picture 1) or minor trauma. A surgical wound may begin to appear to heal, but healing stalls or the wound separates and breaks down (picture 2).

Protection of the feet and toes in patients with known CLTI is paramount. Ill-fitting footwear can cause pressure wounds from straps or simply by being too tight. Patients need to be warned not to walk in bare feet or in the dark to avoid injury from objects or furniture. Shoes should be checked for small objects such as pebbles or dropped insulin needles before being worn. Patients also need to be warned about avoiding injury related to nail clipping and should be instructed to share their history of PAD with other providers, such as podiatrists. Patients with skin breakdown should be referred to a healthcare provider with expertise in wound care.

Marginally perfused feet are at high risk in the hospital or nursing facility settings. Potential sites of pressure (most often the heels) must be meticulously and continuously off-loaded to prevent pressure-induced injuries, which in the face of ischemia are unlikely to heal without revascularization. In addition, since CLTI is often relatively symmetric, patients who are hospitalized for limb revascularization are at risk for developing a pressure-induced injury on the "good" leg. The contralateral foot in a patient recovering from lower extremity revascularization must not be ignored; it should be examined regularly during the hospitalization and off-loaded.

Often patients in whom a diagnosis of PAD has not yet been made have wounds of the lower legs and feet that have been attributed to nonarterial causes (eg, surgery, infection, injury, pressure-induced injury, chronic venous disease). In this setting, undiagnosed PAD can lead to nonhealing and progression of the wounds to the point that the limb may become unsalvageable.

Vascular assessment — Signs of advanced CLTI on noninvasive testing may include an ABI less than 0.4, toe pressure less than 30 to 40 mmHg, a flat metatarsal waveform on pulse volume recording, and low or absent pedal flow on duplex ultrasonography [3]; however, ischemia and limb threat are part of a spectrum, and less severe levels of hemodynamic impairment may contribute to delayed wound healing and increased amputation risk [4]. (See 'Limb staging by severity of limb threat' below and "Clinical features and diagnosis of lower extremity peripheral artery disease", section on 'Diagnosis of lower extremity PAD'.)

INITIAL MANAGEMENT — Once admitted, the patient with CLTI benefits from inpatient pain services; anticoagulation, which may help relieve rest pain in the short term; off-loading of areas of tissue loss and the heels from surfaces; optimal wound care; antimicrobial therapy (as indicated); and importantly, expedited diagnostic imaging, cardiac risk assessment, perioperative optimization, and revascularization.

General care

●Pain control – Ischemic rest pain is often severe and may be unbearable. It is not unusual for the patient to require admission to the hospital, not because revascularization is immediately required, but because rest pain can be unmanageable in an outpatient setting. (See "Approach to the management of chronic non-cancer pain in adults".)

●Systemic anticoagulation – Systemic anticoagulation is initiated in some cases to limit propagation of any areas of acute thrombosis. Acute occlusion of chronic atherosclerotic lesions (or prior stented or bypassed region) is a common source and may contribute to worsening ischemia limb pain.

●Off-loading – Pressure is avoided at any area of tissue injury and areas at risk for injury (eg, heels). Unlike trauma and other etiologies of arterial occlusion, atherosclerotic PAD is a systemic disease, and therefore the contralateral limb is usually not spared and is at increased risk of ischemic complications. So continued protection and monitoring of the contralateral limb is indicated to mitigate against the development of contralateral limb ischemic complications of injury or tissue loss. (See "Prevention of pressure-induced skin and soft tissue injury".)

●Wound care – Areas of skin breakdown or gangrene should be inspected regularly for any signs of progression or infection. Management should focus on pressure off-loading and avoidance of further injury, and perhaps even more importantly, the non-affected limb should be carefully off-loaded as well. (See "Basic principles of wound management" and "Overview of treatment of chronic wounds" and "Prevention of pressure-induced skin and soft tissue injury".)

•Skin ulceration – Clean ulcers in patients with ischemia should generally not be debrided prior to revascularization and can be covered with a moist dressing and lightly wrapped. Wound sites with necrotic material may need chemical or mechanical debridement.

•Dry gangrene – For patients with dry gangrene (picture 3), the wound can be lightly wrapped with a bulky dry gauze. Avoid excessive pressure that could aggravate ischemia and lead to additional wounds (picture 4).

•Wet gangrene – For patients with wet gangrene or abscess, urgent or emergency surgery is necessary to debride the wound and drain any fluid collections.

●Antimicrobial therapy – Empiric antimicrobial therapy is initiated to treat soft tissue infection or osteomyelitis. Definitive therapy is directed toward organisms cultured from tissue and bone biopsy specimens obtained during surgical debridement procedures. (See 'Limb staging by severity of limb threat' below and "Acute cellulitis and erysipelas in adults: Treatment" and "Clinical manifestations, diagnosis, and management of diabetic infections of the lower extremities".)

Clinical scenarios

●Ischemia without tissue loss or infection – Patients with minimal ischemia (ie, mild rest pain) without tissue loss or infection can often be initially managed conservatively, controlling pain and providing treatments to reduce the risk of future cardiovascular events. (See 'Ongoing medical therapy and follow-up' below.)

Severe rest pain requires revascularization, provided it can be accomplished with acceptable risks. (See 'Approach to the patient' below and 'Revascularization' below.)

●Ischemia with ulceration or tissue loss – Appropriately selected patients with tissue loss will require revascularization to achieve wound healing, provided it can be accomplished with acceptable risks. (See 'Approach to the patient' below and 'Revascularization' below.)

With infection – Patients with ischemia and ulceration or tissue loss with infection require expeditious management. The patient will require aggressive antibiotic therapy, drainage, and/or debridement in addition to urgent vascular evaluation and revascularization. The necessary procedures are typically staged. Active infection must be controlled and necrotic infected tissue removed, but further tissue necrosis will usually occur if restoration of adequate blood flow is not achieved soon thereafter.

Without infection – Patients with ischemia or ulceration or tissue loss without infection can undergo less urgent evaluation, optimization, and revascularization. The wound is likely to be more stable compared with one that is actively infected.

For patients who are not candidates for revascularization (inadequate anatomy or prohibitive medical risk), primary amputation may be a better option. Palliative measures can be considered for those who do not desire amputation. (See 'Counseling the high-risk patient' below.)

APPROACH TO THE PATIENT — Overall, most patients with CLTI had average perioperative risk and were predicted to survive beyond two years in one large database review, and thus, most can be considered candidates for limb salvage [5]. Although decisions regarding revascularization are often complex, a three-step approach that takes into account limb staging, the anatomic pattern of disease, and patient risk has been recommended [6].

Limb staging by severity of limb threat — Several clinical classifications can be used to stratify the clinical severity of disease. CLTI represents stages 4 to 6 in the Rutherford classification and stages 3 or 4 in the Fontaine classification. The Rutherford and Fontaine classifications, which are decades old, were designed to classify chronic limb-threatening ischemia (formerly termed critical limb ischemia) among patients with pure ischemia due to peripheral artery disease (PAD); however, due to marked demographic shifts, particularly a dramatic rise in diabetes prevalence, these classifications are less useful for appropriately classifying patients with diabetes, neuropathy, or patient with an index wound with or without infection, across a broader spectrum of PAD severity. In such patients, limb perfusion is only one determinant of outcome. Wound extent and infection also significantly impact the threat to a limb.

The Society for Vascular Surgery (SVS) Lower Extremity Threatened Limb Classification System to Stratify Amputation Risk, Wound, Ischemia, and foot Infection (WIfI) is an updated system for classifying the severity of limb threat that is intended to more accurately reflect important clinical considerations, such as the presence and extent of ischemia, wounds, and infection, which impacts management and amputation risk [7]. The classification can be visualized as three intersecting rings of risk (figure 1) [4,8]. WIfI also helps identify which of these risks is "dominant" during a given time period throughout the patient's life. The wound, ischemia, and infection grades are described in detail in the linked topic. (See "Classification of acute and chronic lower extremity ischemia".)

The Global Vascular Guidelines for the management of CLTI recommend staging the limb using WIfI [6]. WIfI grades three factors: the wound, the severity of ischemia, and the presence of foot infection. The combinations of grades correspond to one of four clinical limb stages (1 through 4) that correlate with the potential for wound healing and one-year risk of amputation (table 1). The staging system is not intended to dictate treatment but rather to more precisely stratify patients according to their initial disease burden in a manner that is analogous to Tumor-Nodes-Metastasis staging for cancer. Patients with clinical stage 1 limbs rarely require revascularization and can usually heal with simple wound care and offloading. By contrast, patients with clinical stage 4 limbs have a very high amputation risk. Clinical stages 2 and 3 are intermediate in threat to the limb. It is important to remember that the stage of limb threat, not the individual grades of wound, ischemia, or infection, drive urgency and potential need for admission and revascularization. WIfI also allows comparison of therapeutic alternatives among patients with threatened limbs who have a similar risk for amputation. The complete classification is available as an open access document from the SVS on the Journal of Vascular Surgery website [9], and as an Interactive Practice Guideline (iPG) app [10].

The WIfI threatened limb classification has been validated in multiple studies and provides a pragmatic means to assess the likelihood of wound healing and amputation risk in patients with a spectrum of CLTI ischemia [4,11-15]. WIfI stages at presentation have correlated strongly with wound healing time and wound healing rate at one year [16-20]. The use of WIfI to stratify amputation risk has been reported from multiple centers across the United States and from France, Italy, Germany, Spain, and Japan [16,21-23]. In a systematic review, the one-year major amputation rate (four studies, 569 patients) was 0 percent, 8 percent, 11 percent, and 38 percent, for WIfI stages I, II, III, and IV, respectively [24]. The likelihood of amputation after one year was also increased for patients with CLTI and higher WIfI stages, providing important prognostic information. Two publications suggest that WIfI clinical stage 4 patients have a very low wound healing rate (44 percent) and high reintervention rate (46 percent) after endovascular therapy [17].

Anatomic pattern of disease — Computed tomographic angiography aids the diagnosis and treatment planning for CLTI; however, most patients with CLTI will undergo conventional catheter-based digital subtraction arteriography to identify the anatomic pattern of disease and to identify target lesions for revascularization and possible inflow and outflow vessels for bypass surgery. (See "Advanced vascular imaging for lower extremity peripheral artery disease", section on 'Digital subtraction angiography'.)

The Global Limb Anatomic Staging System (GLASS) is an anatomic scheme proposed in the 2019 global vascular guidelines on the management of CLTI [6]. The GLASS classification stratifies anatomic severity of infrainguinal occlusive disease and provides a framework for evidence-based lower extremity revascularization for CLTI. GLASS involves grading the level of disease in the femoropopliteal and infrapopliteal segments of the preferred target arterial path for revascularization (table 2). These are combined to provide a grade of overall complexity that is intended to estimate limb-based patency of lower extremity interventions for CLTI.

GLASS is predictive of limb outcomes following revascularization, but its predictability differs for endovascular intervention compared with surgical bypass. A systematic review pooled outcomes for 2204 patients with CLTI (2483 limbs) stratified by GLASS from eight studies (seven retrospective cohort studies, one randomized trial) [25].

●Following endovascular intervention, the pooled estimates for amputation-free survival and limb salvage were worse for GLASS 3 compared with GLASS 1/2, and major adverse limb events were increased for higher GLASS stages. Immediate technical failure also increased with higher GLASS stage (GLASS 1: 3.9 percent; GLASS 2: 5.3 percent; GLASS 3: 27.9 percent).

●Following bypass surgery, observed differences in amputation-free survival, limb salvage rate, and major adverse limb events for GLASS 3 versus GLASS 1/2 were not significant.

●For GLASS 2 or GLASS 3, but not GLASS 1, the pooled rate of major adverse limb events was significantly better for bypass surgery compared with endovascular therapy.

Procedural risk assessment — Candidates for revascularization should undergo procedural risk assessment, which helps to determine candidacy for and approach to revascularization. (See 'Approach to revascularization' below.)

Risk assessment typically focuses on the risk of major adverse cardiac events for which risk assessment tools are available. (See "Evaluation of cardiac risk prior to noncardiac surgery".)

Although more difficult to assess, long-term survival should also be evaluated. In a review of the Vascular Quality Initiative (VQI) database, over 38,000 patients with CLTI who underwent revascularization were identified [5]. Subjects were stratified according to the following risk categories:

●High risk was defined as 30-day survival <95 percent and two-year survival <50 percent.

●Medium risk was defined as 30-day survival of 95 to 97 percent or two-year survival of 50 to 70 percent.

●Low risk was defined as 30-day survival >97 percent or two-year survival >70 percent.

The proportion of patients in the low-, medium-, and high-risk groups was 84, 10, and 6.5 percent, respectively. Patients in the high-risk group were significantly more likely to undergo endovascular intervention compared with those in the low-risk group (75 versus 59 percent). Independent predictors of death included age >80 years, oxygen-dependent chronic obstructive pulmonary disease, stage 5 chronic kidney disease, and bedbound status; these were similar for all three models.

It is important to remember that the risk assessment tools including VQI risk assessment tool have been developed using retrospectively collected data from patients who have undergone revascularization and have excluded conservatively managed patients or those who underwent primary amputation, and none have been prospectively tested and validated.

COUNSELING THE HIGH-RISK PATIENT

When to consider palliative care — A subset of patients with CLTI are poor candidates for revascularization because of comorbidities or unfavorable arterial anatomy. These patients can often be managed with conservative therapy consisting of medical optimization, pain control, aggressive wound care, and possibly pharmacologic therapies aimed at improving wound healing. The goal is to get the patient into a manageable, stable state. If pain is absent or not severe, a stable, chronic, nonhealing wound may be an acceptable situation (so-called "wound hospice"). This may also be incorporated into a revascularization plan. As an example, if the patient has multilevel lower extremity peripheral artery disease (PAD), a simpler intervention or procedure that improves flow proximally may improve perfusion sufficiently to stabilize the wound. However, if the patient has unremitting pain, primary amputation may be required as a component of a palliative care plan, since narcotics for ischemic limb pain is usually an untenable long-term option. (See 'Primary amputation versus revascularization' below.)

There are no data to support the routine use of primary pharmacologic therapy in patients with CLTI; the best therapeutic option is revascularization (endovascular, open); however, when revascularization is not possible, medical therapies may be considered. Therapies that have been investigated include prostaglandins, therapeutic angiogenesis, stem cell therapy, and spinal cord stimulation. These are reviewed separately. (See "Investigational therapies for treating symptoms of lower extremity peripheral artery disease".)

At Veterans Health Care Administration Hospitals involved in their mandatory Prevention of Amputation Care Team (PACT) programs, 49 patients were assigned to conservative management [26]. Inclusion criteria included the presence of a nonhealing wound (ulcer, gangrene, surgical wound) for at least six weeks, ankle-brachial index <0.9 but a TcPO₂ ≥30 mmHg. Patients were expected to be compliant with weekly or biweekly follow-up. Wounds healed with conservative management alone in 67 percent of the patients.

For patients with diabetes or chronic kidney disease, there does not appear to be any obvious subset of patients for whom revascularization strategies should differ from those without diabetes or chronic kidney disease, including in the management of CLTI. (See "Overview of peripheral artery disease in patients with diabetes mellitus", section on 'Revascularization'.)

Primary amputation versus revascularization — The majority of patients presenting with CLTI can be offered a reasonable attempt at limb salvage. Overall, only about 25 percent of patients with CLTI undergo amputation within one year [3,27].

The following have been identified as risk factors for amputation in patients with CLTI [3]:

●Significant necrosis of weight-bearing parts of the foot in ambulatory patients

●An uncorrectable flexion contracture

●Paresis of the extremity

●Sepsis

●Limited life expectancy due to comorbid disease

●Gangrene extending into the deep tissues of the foot

If the patient is reasonably healthy, a well-fitting prosthesis can provide excellent functionality. An above-knee primary amputation should be considered when the patient is unable to ambulate, communicate, or provide self-care. Relative disadvantages of below-knee amputations in this situation include a lower likelihood of healing compared with a more proximal amputation and the potential for development of severe contractures. (See "Techniques for lower extremity amputation" and "Lower extremity amputation", section on 'Amputation level'.)

Older adult patients with PAD have a higher mortality than age-matched controls. On the other hand, older adult patients are also less able to function with a prosthesis, and limb salvage in a previously ambulatory individual may mean the difference between self-care, with a good quality of life and independence, and nursing home dependence with markedly increased costs. Data suggest that older patients have satisfactory results that do not justify withholding revascularization based on age alone [28-30].

●A retrospective study evaluated 88 patients over 80 years of age who underwent revascularization primarily for limb salvage and were then followed for a 10-year period [28]. An infrainguinal bypass was performed in 85 percent, while 15 percent had an extra-anatomic bypass (eg, axillobifemoral or femoral-femoral grafting). Perioperative mortality rate was 6 percent with a mean hospital stay of 18 days. The following results were noted:

•Primary graft patency was 88 and 66 percent at one and three years, respectively

•Limb salvage was 94 and 91 percent at one and three years, respectively

•Patient survival was 73 and 51 percent at one and three years, respectively

•The percent of survivors living at home and ambulatory at one and three years was 100 and 84 percent, respectively

●A later study that used United States Medicare data from 10,784 long-term nursing patients who underwent lower extremity revascularization (open or endovascular) sought to determine functional status trajectories, changes in ambulatory status, and survival after lower extremity revascularization in nursing home residents [31]. Approximately one-third had emergency procedures. Among the 1672 who were ambulatory before surgery, 63 percent were nonambulatory or had died in the first year. Among the 7188 who were nonambulatory, 89 percent were nonambulatory or had died. There were no significant differences in the combined outcome of nonambulatory status or death when comparing open versus endovascular revascularization. After multivariate analysis, factors independently associated with nonambulatory status or death were cognitive impairment (adjusted hazard ratio [aHR] 1.23, 95% CI 1.18-1.29), heart failure (aHR 1.16, 95% CI 1.11-1.22), renal failure (aHR 1.09, 95% CI 1.04-1.14), emergency surgery (aHR 1.29, 95% CI 1.23-1.35), nonambulatory status before surgery (aHR 1.88, 95% CI 1.78-1.99), age older than 80 years (aHR 1.28, 95% CI 1.16-1.40), and decline in activities of daily living before surgery (aHR 1.23, 95% CI 1.18-1.28).

Some may conclude from the latter study that in a nursing home population, revascularization should be viewed as palliative, rather than to extend life or ambulatory function. Although a patient may technically not be ambulatory, the ability to pivot to transfer out of bed can significantly impact a patient's quality of life. In addition, even older adult patients have strong biases with respect to efforts to attempt limb salvage versus primary amputation. The majority treated in the study suffered from CLTI and likely faced amputation (not without its own risks) if revascularization was withheld. Thus, as in most cases in medicine and surgery, the treatment plan needs to be individualized according to each patient's vascular condition, comorbidities, and wishes.

REVASCULARIZATION — Optimal treatment of patients with CLTI requires expertise in both endovascular and open revascularization techniques to manage this heterogeneous population. Details of these techniques are reviewed separately.

●Endovascular – Percutaneous intervention (angioplasty, stent) is a less invasive alternative to surgery in patients with CLTI that is associated with improved periprocedural outcomes but is less durable. However, given the often limited life-expectancy of patients with CLTI, durability may not be the most important factor to consider. (See "Endovascular techniques for lower extremity revascularization".)

●Surgery – For patients expected to live longer than two years and who are good surgical candidates with adequate autogenous vein, the reduced intervention rate and durability of bypass surgery probably outweighs the short-term increase in morbidity. (See "Lower extremity surgical bypass techniques".)

Indications for and goals of revascularization — Most patients with CLTI can be offered a reasonable attempt at limb salvage; however, primary amputation may be more appropriate for some patients. (See 'Primary amputation versus revascularization' above.)

The goals of revascularization are to:

●Alleviate rest pain

●Heal wounds

●Improve physical functioning

Approach to revascularization — Patients with CLTI often have multilevel disease and the extent of revascularization depends on the goals of revascularization. The Global Vascular guidelines emphasize the importance of an approach that is tailored to the individual patient based upon numerous factors including the presence and degree of tissue loss; patient-specific vascular anatomy; availability of vascular conduit; comorbidities such as cardiac risk, which impacts the magnitude of intervention; and presence of diabetes or chronic kidney disease, which impacts options with respect to use of contrast agents and likelihood of procedural success [6]. To alleviate ischemic rest pain, restoration of flow into the lower extremity (ie, inflow) by treating aortoiliac and/or common femoral artery disease may be adequate. For patients with tissue loss, in-line flow to the region of ulceration or gangrene on the distal extremity is generally necessary to permit wound healing. Achieving in-line flow can be accomplished using endovascular or open surgical revascularization.

●For aortoiliac disease, an endovascular-first approach is recommended. Surgical revascularization (eg, aortoiliac, aortofemoral, or extra-anatomic bypass) may be warranted following failed endovascular intervention. For common femoral artery disease, common femoral endarterectomy with patch angioplasty ensuring adequate flow into the deep femoral artery can be performed concomitantly with an inflow procedure (eg, iliac stenting), lower extremity bypass procedure (eg, femoropopliteal bypass, femoral-tibial bypass), or lower extremity stenting (eg, superficial femoral artery).

●For femoropopliteal artery disease, the selection of open surgical or endovascular revascularization depends on the length of the lesion. Surgical bypass is overall more durable for longer lesions compared with stenting [32]. For tibial vessel disease, the selection of open surgical or endovascular revascularization is complex and based on the combination of severity of limb threat, vascular anatomy, availability of suitable saphenous vein, the life expectancy of the patient, and shared surgeon-patient decision making. For patients who are judged to be suitable candidates for either open surgical bypass or endovascular revascularization and who have a suitable single segment of great saphenous vein, a bypass-first strategy is associated with less major adverse limb events or deaths, although some patients may still prefer an endovascular-first approach. For patients requiring infrapopliteal level bypass with or without additional infrainguinal intervention, endovascular-first strategy may be associated with better amputation-free survival. For those without an adequate single segment great saphenous vein, either surgical bypass or endovascular revascularization may be selected after fully informed, shared decision making.

Assessment of available saphenous vein by duplex imaging is an important early step in treating patients with infrainguinal disease, particularly those with CLTI, as saphenous vein availability and suitability has a major impact on selection of an open versus endovascular treatment approach. The Best Endovascular versus Best Surgical Therapy for Patients with Critical Limb Ischemia trial was a two parallel-trial cohort design that included over 1800 patients with CLTI and infrainguinal peripheral artery disease, with the goal of determining whether a surgery-first or endovascular-first approach is preferred for patients with CLTI judged to be suitable candidates for either approach [33,34]. In the first cohort, all patients had an available single segment of suitable great saphenous vein on preoperative ultrasound, whereas in the second cohort, none of the patients had an identifiable single segment of great saphenous vein. Initial procedural success was 98 and 100 percent in the first and second surgical cohorts, respectively, and 85 and 80.6 percent in the first and second endovascular cohorts, respectively. Following randomization to surgical bypass or endovascular revascularization, the technique used was at the discretion of the operator. The rates of adverse cardiovascular events and death were similar between the cohorts and were also similar between the groups within each cohort.

●In the first cohort, all patients had a suitable single segment of great saphenous vein and were randomly assigned to either surgical bypass (n = 718) or endovascular revascularization (n = 716). After a mean 2.7 years, the composite outcome of a major adverse limb event or death from any cause was significantly lower in the surgical bypass group (42.6 versus 57.4 percent; hazard ratio [HR] 0.68, 95% CI 0.59-0.79). Among the early failures in the endovascular group, 66 of 108 (61 percent) subsequently underwent surgical bypass. The rate of major reintervention was also lower in the surgical group (9.2 versus 23.5 percent; HR 0.35, 95% CI 0.27-0.47). The incidence of above-ankle amputation of the index limb was also lower in the surgical group (10.4 versus 14.9 percent; HR 0.73, 95% CI 0.54-0.98).

●In the second cohort, patients did not have a single segment of great saphenous vein and were randomly assigned to surgical bypass (48 alternative autogenous vein, 119 prosthetic grafts, 30 great saphenous vein identified on exploration) or endovascular revascularization (n = 199). After a mean 1.6 years follow-up, the composite primary outcome was also lower in the bypass cohort but was not statistically significant (42.8 versus 47.7 percent; 95% CI 0.58-1.06). Among the early failures in the endovascular group, 26 of 37 subsequently underwent surgical bypass. The rates of re-intervention and time to re-intervention were similar. The rate of above-ankle amputation was also similar between the groups.

The BASIL-2 trial randomized 345 patients with CLTI requiring infrapopliteal revascularization to a vein bypass first (VB; 172 participants) or best endovascular treatment first strategy (BET; 173 participants) with or without proximal infrainguinal revascularization [35]. Most vein bypasses used the great saphenous vein and originated from the common or superficial femoral arteries. Most endovascular interventions were plain balloon angioplasty; plain or drug eluting stents were used selectively. The rate of major amputation or death was lower in the BET group compared with the vein bypass group (53 versus 63 percent; adjusted hazard ratio [aHR] 1.35, 95% CI 1.02-1.80). This outcome was driven primarily by lower mortality in the BET group (45 versus 53 percent; aHR 1.37, 95% CI 1.00-1.87). Overall, median amputation-free survival was 3.8 years, 3.3 years in the VB group and 4.4 years in the BET group; these results are similar to those reported in the BASIL-1 trial [36].

The BASIL-2 trial differed from BASIL-1 trial, which showed better amputation-free survival with a surgery-first approach. However, in the BASIL-1 trial, approximately 25 percent of patients had infrapopliteal interventions, with a significant number of patients with bypass procedures that used nonautologous grafts, which could explain the different outcomes. The BASIL-2 trial also seemed to conflict with the results of the BEST-CLI trial. Over half of those in the BEST-CLI had infrapopliteal level revascularizations; however, the primary endpoints of the two studies differed. Although BASIL II and the BEST-CLI trial were developed, run, and analyzed entirely independently, the two groups of investigators have collaborated closely and entered into a data-sharing agreement before either trial was analyzed. Until an in-depth comparison of the two trials is made using individual, patient-level data meta-analysis, it will not be possible to make strong recommendations for patients with CLTI who need infrapopliteal revascularization.

ONGOING MEDICAL THERAPY AND FOLLOW-UP — Following revascularization for CLTI, regular follow-up is important [3]. Regardless of revascularization type, follow-up consists of periodic clinical evaluations that should note any return or progression of symptoms, the presence of pulses, and measurement of the ankle-brachial pressure index and toe systolic pressure. Duplex imaging of the revascularized limb (with bypass or endovascular means) with measurement of peak systolic velocity and calculation of velocity ratio across all lesions also plays an important role. (See "Noninvasive diagnosis of upper and lower extremity arterial disease", section on 'Ankle-brachial index'.)

●Surveillance ultrasound – Surveillance ultrasound is typically obtained following revascularization. Patients with autologous bypass are likely to benefit from routine surveillance. (See "Lower extremity surgical bypass techniques", section on 'Graft surveillance'.)

However, there is no consensus whether or when to obtain surveillance ultrasound following endovascular intervention or how best to manage asymptomatic restenosis when identified. The Global Vascular Guidelines note that data demonstrating a clinical benefit for surveillance after endovascular intervention are inadequate [6]. (See "Endovascular techniques for lower extremity revascularization", section on 'Surveillance after endovascular interventions'.)

Subgroups who may benefit more than others from close surveillance and early reintervention following endovascular intervention may include those with:

•Multiple failed angioplasties

•Previously failed bypasses or for whom conduits are unavailable

•Severe ischemia (eg, WIfI ischemia grade 3), unresolved tissue loss, or appearance of new inflow lesions

•Known poor runoff or long target vessel occlusion

●Wound evaluation and surveillance – Patients who have been successfully treated for CLTI are at relatively high risk for recurrence. Immediately following revascularization, wounds are followed to complete healing. Thereafter, the patient should be evaluated at least twice yearly by a vascular specialist and should be provided with verbal and written instructions for self-surveillance. Breakdown of the wound or appearance of new wounds may be indicative of a failing revascularization, and repeat intervention may be needed.

●Cardiovascular risk reduction – Antiplatelet therapy (aspirin 75 to 325 mg) is recommended to reduce the risk of myocardial infarction, stroke, and vascular death in individuals with symptomatic peripheral artery disease, including those with CLTI [27]. Clopidogrel is an effective alternative to aspirin in those who cannot take aspirin. Risk factor reduction strategies, including control of hypertension, hyperlipidemia, and blood sugar, as well as smoking cessation, are essential. Intensive-dose statin therapy (eg, rosuvastatin 20 to 40 mg daily, atorvastatin 40 to 80 mg daily) reduces cardiovascular events, mortality, and amputation rates in patients with PAD [37-39]. (See "Epidemiology, risk factors, and natural history of lower extremity peripheral artery disease".)

●Antithrombotic therapy — Following lower extremity revascularization, the benefits of the long-term antithrombotic therapy remain unclear. Antiplatelet agents or anticoagulants are often used to prevent graft occlusion, although data about their efficacy are limited [40]. There may be a benefit of direct oral anticoagulants for long-term use in patients with peripheral artery disease (PAD). (See "Overview of lower extremity peripheral artery disease", section on 'Adjuncts to improve patency of revascularization' and "Endovascular techniques for lower extremity revascularization", section on 'Antiplatelet therapy' and "Lower extremity surgical bypass techniques", section on 'Antithrombotic therapy'.)

•The Cardiovascular Outcomes for People Using Anticoagulation Strategies trial, a multicenter randomized trial of 7470 individuals with stable, mild to moderate PAD reported reduced major adverse cardiovascular events (death, myocardial infarction, or stroke) and major adverse limb events in patients who received low-dose rivaroxaban (an oral factor Xa inhibitor) in combination with aspirin compared with aspirin alone. However, in this study, only 8.5 percent of patients had an ankle-brachial index of <0.7 [41].

•In the Vascular Outcomes Study of Acetylsalicylic acid Along with Rivaroxaban in Endovascular or Surgical Limb Revascularization for PAD trial, 6564 patients who had undergone prior revascularization (30 percent CLTI, 65 percent endovascular) were randomly assigned to rivaroxaban (2.5 mg twice a day) plus aspirin, or placebo plus aspirin [42]. Low-dose rivaroxaban plus aspirin reduced the composite endpoint of acute limb ischemia, major amputation for vascular causes, myocardial infarction, ischemic stroke, or death from cardiovascular causes (17.3 versus 19.9 percent), with significant reduction in the incidence of acute limb ischemia (5.2 versus 7.8 percent) and the need for index-limb revascularization for recurrent limb ischemia (20.0 versus 22.5 percent). Major bleeding, defined according to the Thrombolysis in Myocardial Infarction classification, was 2.7 percent in the rivaroxaban group and 1.9 percent in the placebo group (HR 1.43, 95% CI 0.97-2.10). The incidence of International Society on Thrombosis and Haemostasis major bleeding was significantly increased for the rivaroxaban group compared with the placebo group (5.94 versus 4.06 percent; HR 1.42, 95% CI 1.10-1.84). Clopidogrel treatment, which was permitted for up to six months after the intervention, did not affect the primary efficacy or safety outcomes.

●Smoking cessation – The importance of smoking cessation cannot be overemphasized. Continued smoking significantly reduces the patency of revascularization, increasing the risk for subsequent amputation. (See "Overview of smoking cessation management in adults".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Occlusive carotid, aortic, renal, mesenteric, and peripheral atherosclerotic disease".)

PATIENT PERSPECTIVE TOPIC — Patient perspectives are provided for selected disorders to help clinicians better understand the patient experience and patient concerns. These narratives may offer insights into patient values and preferences not included in other UpToDate topics. (See "Patient perspective: Peripheral artery disease".)

SUMMARY AND RECOMMENDATIONS

●Chronic limb-threatening ischemia – Patients with chronic limb-threatening ischemia (CLTI) present with ischemic rest pain (pain across the base of the metatarsal heads at rest relieved by dependency) and/or tissue loss (ulceration, gangrene). The patient may or may not have a history of progressive peripheral artery disease (PAD) symptoms (eg, worsening claudication). Foot or toe pain in a patient with weak or absent pulses and abnormal ankle-brachial index (ABI) should be presumed to be due to ischemia. Nonhealing wounds in patients with undiagnosed PAD are often attributed to other causes, which can progress rapidly to a point that the limb may become unsalvageable. (See 'Clinical presentations' above.)

●Vascular assessment – An ABI <0.4, toe pressure <30 to 40 mmHg, flat metatarsal waveforms on pulse volume recording, and low or absent pedal flow on duplex ultrasonography are consistent with severe CLTI, but lesser degrees of ischemia may contribute to non-healing wounds and increased amputation risk. Marginal perfusion to the extremity may be adequate to sustain healthy tissue at rest but can be insufficient to provide the increased energy required for wound healing. (See 'Vascular assessment' above.)

●Initial management – The initial care of the patient with CLTI includes control of pain, which can be severe, anticoagulation to limit thrombus propagation in some cases, appropriate wound care, pressure off-loading, and treatment of infection, if present. (See 'Initial management' above.)

●Approach to the patient – The approach is tailored to the individual and involves a three-step approach that takes into account limb staging using the Society for Vascular Surgery Lower Extremity Threatened Limb Classification System, the anatomic pattern of disease, and assessment of the patient's procedural risk. (See 'Approach to the patient' above and 'Revascularization' above.)

•The Wound, Ischemia, and foot Infection classification grades the wound, the severity of ischemia, and the presence of foot infection (figure 1). The combinations of these grades correspond to one of four clinical stages (1 through 4) that correlate with the potential for wound healing and risk of amputation (table 1). The stage of limb threat drives the urgency and potential need for hospital admission and revascularization. (See 'Limb staging by severity of limb threat' above.)

•Angiography identifies the anatomic pattern of disease, possible target lesions for revascularization, and possible inflow and outflow vessels for bypass surgery. The Global Limb Anatomic Staging System (GLASS) (table 2) is a classification that stratifies anatomic severity by grading the level of disease along the potential target arterial path for revascularization. (See 'Anatomic pattern of disease' above.)

•Assessment of procedural risk helps determine candidacy for, approach to (endovascular, open surgical), and extent of revascularization. For a patient with high procedural risk, a limited revascularization may accomplish the intended goal. (See 'Procedural risk assessment' above.)

●Revascularization – Most patients with CLTI can be offered a reasonable attempt at limb salvage to alleviate rest pain, heal wounds, and improve physical functioning. Informed, shared decision making is important in making decisions regarding choice of revascularization. (See 'Revascularization' above.)

•To alleviate ischemic rest pain, restoration of flow into the lower extremity (ie, inflow) by treating aortoiliac and/or common femoral artery disease may be adequate. For patients with tissue loss, in-line flow to the region of ulceration or gangrene is generally necessary to permit wound healing.

•For infrainguinal disease in patients who are judged to be suitable candidates for either open surgical or endovascular revascularization and with a suitable single segment of great saphenous vein, surgical bypass offers a significantly lower risk of major adverse limb events and requirement for reintervention compared with endovascular therapy. For patients with CLTI and without a suitable single segment of great saphenous vein, either surgical bypass or an endovascular approach offers similar outcomes over time.

•A subset of patients has comorbidities or unfavorable arterial anatomy that preclude revascularization. For these patients, a more appropriate course of treatment may be primary amputation or palliation. (See 'Counseling the high-risk patient' above.)

●Follow-up and surveillance – Following revascularization, periodic clinical evaluations should note regression of pain, progression of wound healing, maintenance of pulses, and stability of the ABI/toe pressure. Duplex imaging of the revascularized region or bypass graft is performed periodically to evaluate for stenosis. (See 'Ongoing medical therapy and follow-up' above.)

●Cardiovascular risk management – Patients with PAD, including those with CLTI, should also be treated to reduce their risk for future cardiovascular events. Antiplatelet therapy and statin therapy should be initiated in all patients with PAD unless contraindicated. (See 'Ongoing medical therapy and follow-up' above.)