Critical lower limb ischemia (CLI): clinical guidelines

List of Abbreviations

CLTI Critical limb ischemia

IC Intermittent claudication

DFs Diabetic foot syndrome

Level of confidence of evidence (LoCE)

Level of recommendation consensus (LoRC)

IDSA  Infectious Diseases Society of America

CFA  Common femoral artery

PopA  Popliteal artery

DPA  Dorsalis pedis artery

PTA Posterior tibial artery

DM  Diabetes mellitus

DUS  Duplex ultrasound

CTA  Computed tomography angiography (Computed tomography angiography of one anatomical region)

MRA  Magnetic resonance angiography (Contrast-enhanced magnetic resonance angiography (one region))

Angio Angiography (Direct lower extremity arterial angiography)

DAP Digital arterial pressure (Blood pressure measurement on peripheral arteries)

TcPO2 Transcutaneous oximetry (Determination of soft tissue oxygen partial pressure (oximetry))

TcPO2  Transcutaneous oxygen tension (Transcutaneous monitoring of oxygen partial pressure)

CKD  Chronic kidney disease

VQI  Vascular Quality Initiative

IHD  Ischemic heart disease

CTCA + FFR  Computed tomography coronary angiography + measurement of fractional flow reserve

EGD Esophagogastroduodenoscopy (EGD)

GIB Gastrointestinal bleeding

GI  Gastrointestinal

ICA Internal carotid artery

Stroke  Acute cerebrovascular accident

CA  Carotid arteries

ASA  American Society of Anesthesiologists

NSQIP  National Surgical Quality Improvement Program

ESC  European Society of Cardiology

ESA  European Society of Anaesthesiology

AFB  Aortofemoral bypass (Aorto-profundaplasty)

AFBB Aortofemoral bifurcation bypass (Aortofemoral bifurcation bypass grafting)

CIA Common iliac artery

TASC Transatlantic Inter-Society Consensus for the Management of Peripheral Arterial Disease

DCB Drug-coated balloon (drug-eluting balloon dilatation catheter)

SFA  Superficial femoral artery

PopA  Popliteal artery

Femoropopliteal segment

FPB  Femoropopliteal bypass (A16.12.038.006)

PTFE  Polytetrafluoroethylene (polytetrafluoroethylene blood vessel grafts, synthetic blood vessel graft***)

PTEA  Semi-closed endarterectomy (A16.12.008 endarterectomy)

GLASS Global Limb Anatomic Staging System

CLTI: Chronic limb-threatening ischemia

MA: Mechanical atherectomy (Endovascular aspiration thrombectomy)

LA: Laser atherectomy (Endovascular aspiration thrombectomy)

PFA: Peroneal artery

DES: Drug-eluting stent (drug-coated peripheral stents)

rt-PA: Recombinant tissue plasminogen activator (Enzyme preparations, ATC code B01AD)

SD: Surgical debridement (surgical debridement of a wound or infected tissue)

LPS: Lumbar sympathetic denervation

SCS: Spinal cord stimulation (implantation of temporary electrodes for spinal cord and peripheral nerve neurostimulation)

PGE1: Prostaglandin E1

PGI2: Prostaglandin I2

ASA: Acetylsalicylic acid**

DAPT: Dual antiplatelet therapy

VKA: Vitamin K antagonists

INR: International normalized ratio

ABI: Ankle-brachial index (Screening study for the risk of lower extremity arterial disease using a system with automatic measurement of systolic blood pressure and calculation of the ankle-brachial index)

Terms and Definitions

Critical limb-threatening ischemia is a long-standing clinical condition characterized by impaired patency of the major arteries of the lower extremity in the presence of lower extremity pain at rest and/or tissue trophic defects of the limb.

Evidence-based medicine is the conscientious, explicit, and judicious use of current best evidence (clinical research results) in making decisions about the care and treatment of individual patients.

Disease - a disorder of structure or function in a human, resulting from the impact of pathogenic factors, impairing working capacity and the ability to adapt to changing environmental conditions (external and internal) with simultaneous alterations in the body's protective-compensatory and protective-adaptive reactions and mechanisms.

Instrumental diagnostics refers to diagnostics utilizing various devices, apparatuses, and instruments.

Outcome - any possible result arising from the impact of a causal factor, preventive or therapeutic intervention, all established health status changes arising as a consequence of the intervention.

Clinical trial means any investigation in human subjects intended to discover or verify the clinical, pharmacological and/or other pharmacodynamic effects of an investigational product(s), and/or to identify any adverse reactions to an investigational product(s), and/or to study absorption, distribution, metabolism and excretion of an investigational product(s) with the object of ascertaining its safety and/or efficacy. The terms "clinical trial" and "clinical study" are synonymous.

Laboratory diagnostics - a set of methods aimed at analyzing test material using various specialized equipment.

Medicinal products are pharmacological agents in pharmaceutical formulations used for the prevention, diagnosis, treatment of disease, rehabilitation, and for the preservation, prevention, or termination of pregnancy.

Patient is an individual who receives medical care or has applied for medical care regardless of whether they have a disease and regardless of their condition.

Working group for the development/updating of clinical guidelines is a team of specialists working together and in a coordinated manner to develop/update clinical guidelines and bearing joint responsibility for the results of this work.

Condition - changes in the body arising from the influence of pathogenic and/or physiological factors and requiring medical care.

Symptom is a sign of a disease, a statistically significant deviation of an indicator from its normal limits, or the emergence of a qualitatively new phenomenon uncharacteristic of a healthy organism.

Syndrome is a stable set of multiple symptoms with a unified pathogenesis.

Drug-eluting stent (drug-coated peripheral stents, drug-eluting stent for the femoral artery***) - a peripheral arterial stent from whose structures an antiproliferative substance is released for a certain period after implantation, preventing neointimal hyperplasia and thereby preventing/slowing down restenosis.

Thesis-recommendation is a statement reflecting the procedure and correct execution of a medical intervention with proven efficacy and safety.

Level of evidence (LoE) - the degree of confidence that the found effect of a medical intervention is true.

Level of certainty of recommendations (LCR) is the degree of confidence in the certainty of the intervention's effect and that following the recommendations will bring more benefit than harm in a particular situation.

Surgical (open) revascularization (Creation of a vascular anastomosis of a major artery) is a method for correcting hemodynamically significant changes in the arterial segment of a limb, which necessarily involves the dissection and connection of tissues during a surgical procedure.

Endovascular revascularization (Endovascular vascular wall reconstruction) is the restoration of blood flow in a stenosed area of the limb arterial bed using percutaneous introduction of necessary devices. Includes transluminal balloon angioplasty, stenting, and modern innovative technologies.

Hybrid intervention (creation of a major artery vascular anastomosis + endovascular vascular wall reconstruction) is a combination of surgical and endovascular methods aimed at revascularizing various segments of the patient's limb arterial bed within a single clinical episode.

Conditionally radical surgical debridement (Surgical debridement of a wound or infected tissue) is a primary surgical intervention in the area of trophic and infectious-inflammatory changes, the purpose of which is to relieve acute infectious inflammation in the limb tissues and/or remove the bulk of necrotic tissues throughout the depth of the lesion (incision and drainage of a purulent-necrotic focus, necrectomy, minor amputation).

Debridement (Surgical debridement of a wound or infected tissue) is the removal of superficial dead tissues at the edges of an ulcer or amputation wound, cleaning it from dense exudate and hyperkeratosis to accelerate the epithelization of the trophic or amputation defect.

Primary antithrombotic prophylaxis is the prevention of atherothrombotic complications occurring as acute ischemia or chronic critical limb ischemia in patients with chronic obliterating lower extremity arterial diseases without clinical symptoms of arterial ischemia or in the intermittent claudication stage.

Secondary antithrombotic prophylaxis is the prevention of arterial thrombotic complications in the area of arterial reconstruction in the early and late postoperative period.

Vascular (multidisciplinary) team is a group of multidisciplinary specialists involved in decision-making regarding the management tactics for a patient with critical limb-threatening ischemia within a single clinical episode.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Critical limb-threatening ischemia is a long-standing (more than 2 weeks) clinical condition characterized by impaired patency of major lower extremity arteries in the presence of lower extremity pain at rest and/or lower extremity tissue trophic defects.

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

The spectrum of potential causes of CLTI includes diseases and pathological conditions leading to impaired patency of the lower extremity arteries: atherosclerosis, thromboembolism, thrombosis, arteritis, aneurysmal dilatation of the artery, as well as restenosis and thrombotic complications of reconstructions performed on limb arteries for arterial insufficiency.

1.3 Epidemiology of the Disease or Condition

According to major national registries [1, 2], the incidence of CLTI reaches 150 new cases per 100,000 population per year. Altin S. et al. analyzed the results of 1,276,745 hospitalizations for CLTI in the USA between 2012 and 2015. The proportion of male patients was 61%. In 29% of observations, patients were under 66 years old, in 56% of cases they were 66–85 years old, and another 15% of patients were older than 85 years. Comorbidities in 79% of patients were represented by arterial hypertension (AH), in 69% by diabetes mellitus (DM), and in 46% by coronary artery disease (CAD). A history of smoking was identified in 36% [1]. Since lower extremity peripheral artery disease (LEPAD) dominates the structure of causes of CLTI, the main statistically significant risk factors for CLTI correspond to those for LEPAD and include smoking, DM, AH, and hypercholesterolemia [3].

Among the possible causes of CLTI, there are other, much rarer obliterating diseases of the lower extremity arteries, whose risk factors differ from those of atherosclerotic lesions. Thus, smoking is considered the primary risk factor for thromboangiitis obliterans (Buerger's disease) [4].

Takayasu arteritis is an autoimmune inflammatory disease of large and medium-sized arteries that predominantly affects women (82.9–87.5% of cases) aged 16–40 years (median age of onset 30.2–40.1) [5, 6]. According to Ortiz-Fernandez et al., certain human leukocyte antigen (HLA) alleles are statistically associated with an increased risk of developing this disease.

In addition to occlusive diseases, chronic limb-threatening ischemia (CLTI) can be caused by thrombotic arterial complications. Clinically, these most commonly manifest as acute limb ischemia, though in a number of patients they progress to chronic arterial insufficiency over time. These include arterial embolism due to atrial fibrillation, thrombosis of a previously performed arterial bypass, and paradoxical embolism via an atrial septal defect in the setting of phlebothrombosis [7]. Rare causes of thrombotic occlusion of lower extremity arteries also include popliteal artery aneurysm thrombosis, which is more frequently observed in smokers, patients with arterial hypertension, and those with aneurysmal dilation in other vascular beds [8].

Finally, certain types of coagulopathies, particularly coagulopathy associated with the novel coronavirus infection COVID-19, are also included in this group of pathogenetic mechanisms of CLTI [9].

1.4 Features of Coding the Disease or Condition

CLTI syndrome encompasses a wide spectrum of diseases and medical conditions. The ICD-10 codes for these nosological forms are listed below:

I70.0 – Atherosclerosis of aorta

I70.8 – Atherosclerosis of other arteries

I73.8 – Other specified peripheral vascular diseases

I79.2 – Peripheral angiopathy in diseases classified elsewhere

I79.8 – Other disorders of arteries, arterioles and capillaries in diseases classified elsewhere

E13.5 – Other specified diabetes mellitus with peripheral circulatory disorders

E14.5 – Unspecified diabetes mellitus with peripheral circulatory disorders

1.5 Classification of the disease or condition

The concept of CLTI corresponds to stages 3 and 4 of chronic lower extremity arterial insufficiency according to the Pokrovsky-Fontaine classification and includes patients with rest pain, as well as those with trophic or infectious-inflammatory changes in limb tissues. Furthermore, these trophic and infectious-inflammatory changes may be provoked in nature, i.e., resulting from microtrauma with progressive foot infection [3, 10, 11]. It is important to note that clinically, CLTI is rarely the final stage of a continuous spectrum of arterial circulatory disorders in the limb and typically presents initially as a distinct nosological entity. Thus, the development of CLTI is rarely preceded by a prolonged history of intermittent claudication (IC) [12]. Unlike patients with IC, patients with CLTI—even in the event of successful limb revascularization (arterial bypass)—carry a significantly worse prognosis regarding perioperavite complications and long-term survival [12, 13]. Conversely, in IC, symptoms generally remain stable for many years, and only in isolated cases does the disease progress to CLTI [14]. Patients with IC have a significantly more favorable profile regarding perioperative complications and long-term outcomes compared to those with CLTI [12–14].

Unlike IC, the management of CLTI involves a vast array of challenges related to infectious and necrotic changes in the limb, the necessity of performing minor and major amputations (lower extremity amputation), and the use of reconstructive plastic surgeries (arterial bypass) to close tissue trophic defects. Therefore, for practical purposes, it is advisable to separate the classification of CLTI from intermittent claudication.

A simple binary clinical classification based on the Fontaine-Pokrovsky classification (see Appendix G1) appears practically convenient and includes two stages of CLTI:

1. Chronic arterial insufficiency (CAI) stage 3: persistent limb pain without trophic disorders (tissue defects);

2. Chronic arterial insufficiency stage 4: CLTI with trophic tissue disorders of the affected limb.

The Rutherford classification may also be used, wherein CAI stage 3 corresponds to grade II or category 4 ischemia, and CAI stage 3 [sic] to grades III–IV and categories 5–6 of ischemia (see Appendix G1).

To quantify the risk of major amputation (lower extremity amputation) and the urgency of limb revascularization (arterial bypass), the WIfI classification can be used (see Appendix G4). Practically, its use allows for a diversified approach to the routing of CLTI patients in settings where such an approach is feasible.

Undoubtedly, each of these clinical categories encompasses a wide variety of arterial lesion patterns, limb trophic defects, levels of perioperative risk, and consequently, vascular team action algorithms. However, from the perspective of healthcare regulation and resource allocation, these groups of patients represent two distinct populations. Indeed, the onset of trophic disorders is statistically associated with an increase in comorbidity, complication risks, and treatment costs, triggering a comprehensive shift in medical tactics and serving as the most critical factor influencing the entire scope of therapeutic interventions in CLTI [15–17].

1.6 Clinical presentation of the disease or condition

In accordance with the definition, etiopathogenesis, and proposed classification of CLTI, its key clinical manifestations are rest pain and/or the presence of a tissue trophic defect distal to the level of main limb artery obstruction.

The classic characteristics of pain in CLTI: pain occurs at rest, is typically constant, usually localized in the toes or metacarpal/metatarsal region (or at the site of a trophic defect if present), worsens when the limb is placed in a horizontal or elevated position as well as at night, and significantly diminishes (though does not disappear) when the foot is lowered [12, 18, 19]. In CLTI without trophic changes, ischemic rest pain is the primary symptom and is present in 100% of cases. Other characteristic symptoms of CLTI may also occur at this stage: coldness and numbness of the foot, as well as foot hyperemia, which may have a cyanotic tint and decreases or disappears when the limb is elevated (so-called positional hyperemia) [19].

Trophic changes in CLTI are located distal to the ankle joint in the vast majority of cases [19, 20], can be multiple, most frequently occur in the toes and forefoot [17, 21], are superficial (ulcer) or deep (necrosis, gangrene, abscess, phlegmon, osteomyelitis) in nature, are accompanied by more or less pronounced perifocal infectious inflammation, and in severe cases are complicated by signs of a systemic inflammatory response.

It is important to note that the presence of CLTI with trophic changes is not always accompanied by notable rest pain, particularly in diabetic foot syndrome (DFS) [21]. In this patient subgroup, the tissue defect is frequently provoked in nature, i.e., resulting from microtrauma (nail edge, ill-fitting footwear, foreign body such as a sewing needle, thermal injury, etc.), which goes unnoticed due to reduced tactile, pain, and temperature sensitivity of the foot secondary to diabetic neuropathy [22].

2. Diagnostics, medical indications and contraindications for diagnostic methods

Diagnostic criteria:

The diagnosis is established based on complaints, medical history, physical examination, and instrumental diagnostic methods (lower extremity arterial duplex ultrasonography, direct lower extremity angiography).

2.1 Complaints and Anamnesis

Comments: the main complaints in CLTI are pain and the presence of trophic changes in the distal parts of the limb, the characteristics of which are detailed above (Chapter V, Section 6). It is important to note that in the absence of timely qualified care, the time elapsed from the onset of initial CLTI symptoms to the initiation of surgical treatment typically does not exceed 6 months [23].

When taking the medical history and ascertaining complaints in vascular disease, it is important to pay attention to risk factors and comorbidities typical for CLTI (see Chapter V, Section 3), prior arterial reconstructions (arterial bypass), and concurrent pharmacotherapy, particularly antiplatelet agents and anticoagulants ( antithrombotic agents, ATC code: B01A).

In all other respects, patient assessment for CLTI is conducted according to the general principles of clinical medicine.

2.2 Physical Examination

Comments: there is a lack of high-quality scientific literature regarding the methodology of general clinical examination in patients with CLTI. Therefore, it is recommended to perform the examination (visual assessment for vascular pathology) and physical examination in accordance with general clinical principles.

Comments: assessment of the local status must include inspection and palpation of the limb (visual assessment for vascular pathology, palpation for vascular pathology). Inspection evaluates skin color, presence of trophic changes, positional hyperemia, and edema. Palpation determines limb temperature, arterial pulsation, and signs of purulent-necrotic foci [3, 12, 24-26].

2.3 Laboratory Diagnostics

Comments: there is a lack of high-quality scientific literature regarding the methodology of laboratory diagnostics in patients with CLTI. Therefore, it is recommended to formulate a laboratory diagnostic plan in accordance with general clinical principles and the individual characteristics of the patient with CLTI.

2.4 Instrumental Diagnostics

Comments: duplex scanning (duplex ultrasound of lower extremity vessels (arteries and veins), duplex scanning of lower extremity vessels (arteries and veins)) is a non-invasive and the most accessible of all existing methods for visualizing limb arteries in CLTI to identify hemodynamically significant changes [3]. To confirm the diagnosis of CLTI, it is advisable to measure ankle pressure [3, 10].

Comments: confirming the diagnosis of CLTI in doubtful cases is aided by toe blood pressure (TBP, peripheral arterial blood pressure measurement) and transcutaneous oximetry (TCO, determination of soft tissue oxygen partial pressure (oximetry)) [27]. Signs of ischemic pain include a TBP level below 30 mm Hg and a transcutaneous oxygen tension (TcPO2) also below 30 mm Hg [3]. In CLTI with trophic changes, even higher values of ankle blood pressure, TBP, and TcPO2 do not rule out the threat of limb loss [10].

Comments: existing vascular imaging methods in CLTI - duplex ultrasound (DUS), computed tomography angiography (CTA), direct contrast angiography (CA), and magnetic resonance angiography (MRA) (lower extremity arterial duplex ultrasound, duplex scanning of lower extremity vessels (arteries and veins), computed tomography angiography of lower extremity vessels, contrast-enhanced magnetic resonance angiography (one region)) - have high sensitivity and specificity [28-33].

• Before performing femoropopliteal bypass grafting (femoropopliteal bypass) using an autologous vein conduit, it is recommended to map the superficial veins (lower extremity venous duplex ultrasound) intended for use during surgery [3, 34, 35].

GRC BLEL 2Grade of Recommendation B (Level of Evidence – 2)

Comments: to assess the quality and diameter of superficial veins prior to bypass surgery (femoropopliteal bypass), the authors recommend performing ultrasound scanning (lower extremity venous duplex ultrasound) with skin marking of the vein course [3, 34]. According to the VQI registry, vein mapping prior to bypass reconstruction (femoropopliteal bypass) in CLTI was performed in 40-84% of cases [35].

• In patients with CLTI, it is recommended to determine indications for the evaluation of other arterial beds (coronary, cerebral), (A04.10.002.003 Stress echocardiography with pharmacological stress, A04.10.002.004 Stress echocardiography with exercise, A06.10.006 Coronary angiography, A06.12.004 Selective carotid angiography) for functional assessment of the cardiovascular system, as well as other organs and systems in accordance with general clinical principles, recommendations of professional societies, and taking into account the expert opinion of relevant specialists of the multidisciplinary vascular team [3, 44, 47].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

Comments: concomitant coronary artery disease is common in patients with CLTI [36, 37]. Preventive coronary revascularization (percutaneous transluminal coronary angioplasty and stenting, coronary artery bypass grafting with cardiopulmonary bypass, off-pump coronary artery bypass grafting) in patients with CLTI, according to some data, improves long-term survival, but does not affect the perioperative risk of major complications [36, 38, 39].

Comments: data on the frequency of erosive and ulcerative lesions of the upper gastrointestinal tract are limited. Their potential role in the development of perioperative hemorrhagic complications is not supported by studies [40, 41].

Comments: patients with CLTI are frequently found to have concomitant asymptomatic atherosclerotic carotid disease [42, 43]. There is a lack of data in the literature supporting the efficacy of preoperative screening for atherosclerosis (duplex scanning of extracranial brachiocephalic arteries) of the carotid arteries and the justification for preventive carotid revascularization (carotid endarterectomy, percutaneous transluminal angioplasty and stenting of the internal carotid artery) in this category of patients.

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

3.1. Surgical treatment

Surgical treatment of patients with CLTI should pursue one or more of the following goals:

1. Relief or gradual regression of the main clinical manifestations of CLTI – rest pain and tissue trophic defects of the limb;

2. Preservation of a maximally weight-bearing and functionally competent limb, taking into account the potential prosthetics of its segments;

3. Elimination of the life-threatening condition caused by the presence of an infectious-inflammatory focus in the tissues of the affected limb.

Surgical intervention remains the primary method of treatment for CLTI today [3, 44]. Depending on the clinical situation, this treatment may pursue one or more of the following goals:

1. Relief or gradual regression of the main clinical manifestations of CLTI: rest pain and tissue trophic defects of the limb.

2. Preservation of a maximally weight-bearing and functionally competent limb, taking into consideration potential prosthetic replacement of its segments;

3. Elimination of the life-threatening condition caused by an infectious and inflammatory focus in the tissues of the affected limb.

The range of surgical interventions aimed at achieving these goals can be divided into four groups:

1. Revascularization (thromboendarterectomy, femoropopliteal bypass, balloon angioplasty of the popliteal artery and main arteries of the lower leg, balloon angioplasty with stenting of the popliteal artery and main arteries of the lower leg, mechanical recanalization, balloon angioplasty with stenting of the popliteal artery and main arteries of the lower leg);

2. Surgical debridement of trophic and infectious-inflammatory changes in the ischemic segment of the limb (surgical debridement of a wound or infected tissue) — opening and drainage of a purulent-necrotic focus (opening of a foot (lower leg) phlegmon (abscess), necrectomy, minor amputation (toe disarticulation), wound toilet (debridement), foot offloading measures;

3. Reconstructive and plastic interventions aimed at closing limb tissue defects (autodermoplasty);

4. Major limb amputation (lower limb amputation).

Comments: in a significant proportion of patients with CLTI, an increase in the duration of the prehospital and in-hospital preoperative period may pose a threat of limb loss [45, 46]. Published studies do not establish any universal timeframe for providing surgical care in CLTI.

• The decision to perform a surgical intervention (thromboendarterectomy, femoropopliteal bypass, balloon angioplasty of the popliteal artery and main arteries of the lower leg, balloon angioplasty with stenting of the popliteal artery and main arteries of the lower leg, mechanical recanalization, balloon angioplasty with stenting of the popliteal artery and main arteries of the lower leg) in CLTI is recommended to be made individually, taking into account the clinical picture, existing limitations for various surgical manipulations, as well as the patient's preferences based on the concept of informed consent [3, 12, 44, 47].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comments: according to international consensus documents, the presence of clinical signs of CLTI or restenosis/reocclusion in the area of arterial reconstruction previously performed for CLTI is an indication for surgical treatment (thromboendarterectomy, femoropopliteal bypass, balloon angioplasty of the popliteal artery and main arteries of the lower leg, balloon angioplasty with stenting of the popliteal artery and main arteries of the lower leg, mechanical recanalization, balloon angioplasty with stenting of the popliteal artery and main arteries of the lower leg) [3]. International guidelines and consensus documents available in the literature regarding the treatment of CLTI do not define any potential contraindications for surgical intervention [3, 12, 44, 47].

• In patients with steno-occlusive lesions of the aorta and iliac arteries, it is recommended to perform aortoiliac arterial reconstruction using an open or endovascular method (thromboendarterectomy, femoropopliteal bypass, balloon angioplasty of the popliteal artery and main arteries of the lower leg, balloon angioplasty with stenting of the popliteal artery and main arteries of the lower leg, mechanical recanalization, balloon angioplasty with stenting of the popliteal artery and main arteries of the lower leg). The choice of intervention method is made taking into account the clinical stage of chronic lower limb ischemia according to the Fontaine, A.V. Pokrovsky, and Rutherford classifications (Appendix G1), as well as the anatomical nature of the lesion according to the TASC II (Appendix G2) and GLASS (Appendix G3) classifications [3, 12, 44].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comments: open aortoiliac reconstructions (thromboendarterectomy, femoropopliteal bypass) have been studied in the greatest detail and are characterized by high long-term postoperative patency with a low rate of perioperative mortality [48, 49]. Endovascular interventions provide lower perioperative mortality and optimal long-term outcomes in relatively short and non-occlusive lesions of this arterial bed area [50]. In international consensus documents, open reconstructions (thromboendarterectomy, femoropopliteal bypass) are considered the method of choice for extensive and occlusive lesions, including those involving the abdominal aorta and common femoral artery, whereas endovascular interventions (balloon angioplasty of the popliteal artery and main arteries of the lower leg, balloon angioplasty with stenting of the popliteal artery and main arteries of the lower leg, mechanical recanalization, balloon angioplasty with stenting of the popliteal artery and main arteries of the lower leg) are preferred for relatively localized, more often non-occlusive changes in this arterial segment (see TASC II and GLASS classifications in Appendix G2) [12]. Qualitative comparative studies of open and endovascular techniques (thromboendarterectomy, femoropopliteal bypass, balloon angioplasty of the popliteal artery and main arteries of the lower leg, balloon angioplasty with stenting of the popliteal artery and main arteries of the lower leg, mechanical recanalization, balloon angioplasty with stenting of the popliteal artery and main arteries of the lower leg) for aortoiliac reconstruction cannot be found in the literature [51-55].

• When performing endovascular aortoiliac reconstruction (balloon angioplasty of the popliteal artery and main arteries of the lower leg, balloon angioplasty with stenting of the popliteal artery and main arteries of the lower leg, mechanical recanalization, balloon angioplasty with stenting of the popliteal artery and main arteries of the lower leg) in patients with thrombotic occlusion of the iliac arteries, aortofemoral, iliofemoral, or extra-anatomic bypass graft, it is recommended to consider the use of mechanical rotational thrombectomy/atherectomy devices (embolectomy catheter / thrombectomy system) for effective revascularization of the affected segment [51-53].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Comments: according to retrospective cohort studies, mechanical rotational thrombectomy/atherectomy (mechanical recanalization, balloon angioplasty with stenting of the popliteal artery and main arteries of the lower leg) is an effective and safe method of intravascular revascularization of iliac artery occlusions in acute or subacute thrombosis. In most cases, it is used in combination with other endovascular techniques (balloon angioplasty, stenting) (iliac artery balloon angioplasty) [51-53].

• In patients with steno-occlusive lesions of the common femoral artery without hemodynamically significant changes in the iliac arteries, it is recommended to consider open endarterectomy as the preferred reconstruction method (thromboembolectomy from the iliac and femoral arteries) [56-62].

GRC BLEL 2Grade of Recommendation B (Level of Evidence – 2)

Comments: patients with CLTI frequently present with hemodynamically significant lesions of the common femoral artery (CFA) requiring reconstruction [54, 55]. Open endarterectomy (thromboembolectomy from the iliac and femoral arteries) of the CFA provides high long-term patency (over 90%) even at 5-7 years [56-58]. Long-term results of endovascular interventions on the CFA (balloon angioplasty with stenting of the superficial femoral artery) have been scarcely studied over such timeframes, while the vast majority of patients in published studies of endovascular interventions on this segment had stenotic rather than occlusive lesions [59-62].

• In the presence of contraindications or limitations to open reconstruction of the common femoral artery (thromboembolectomy from the iliac and femoral arteries), it is recommended to consider endovascular methods: balloon angioplasty (including drug-eluting balloon catheter), stenting, directional atherectomy (superficial femoral artery balloon angioplasty with stenting, including drug-coated balloon dilatation catheter for percutaneous transluminal angioplasty of peripheral vessels) [3, 12, 59–63].

GRC BLEL 2Grade of Recommendation B (Level of Evidence – 2)

Comments: endovascular correction of hemodynamically significant lesions of the common femoral artery (CFA) (superficial femoral artery balloon angioplasty with stenting) is actively used by many teams as an alternative to open reconstruction (iliac and femoral artery thromboembolectomy, femoropopliteal bypass) [63]. The vast majority of patients in published studies of endovascular interventions in this segment had stenotic rather than occlusive lesions [59–62]. The results of randomized comparative studies of endovascular and open interventions (superficial femoral artery balloon angioplasty with stenting, iliac and femoral artery thromboembolectomy, femoropopliteal bypass) on the CFA are contradictory, and the types of endovascular devices used in them are currently unavailable in clinical practice [61, 62]. In international consensus documents, preference is given to the endovascular method (superficial femoral artery balloon angioplasty with stenting) in the presence of contraindications or limitations to open reconstruction (iliac and femoral artery thromboembolectomy, femoropopliteal bypass) [3, 12].

• For lesions of the femoropopliteal segment, it is recommended to perform open or endovascular reconstructions (iliac and femoral artery thromboembolectomy, femoropopliteal bypass, or superficial femoral artery balloon angioplasty with stenting) with the type of revascularization chosen by members of the vascular team depending on the clinical situation according to the TASC II classification of lower extremity arterial lesions (see Appendix G2) [35, 63–78].

GRC BLEL 2Grade of Recommendation B (Level of Evidence – 2)

Comment: open reconstructions (thromboendarterectomy, femoropopliteal bypass) are more frequently used for long and occlusive lesions of the femoropopliteal segment (FPS), while endovascular ones (superficial femoral artery balloon angioplasty with stenting) are used for relatively short, mostly non-occlusive changes [35, 63–66]. The main factors negatively affecting the long-term outcome of endovascular interventions (superficial femoral artery balloon angioplasty with stenting) in this zone include impaired outflow pathways, lesion type (results are worse for occlusions and diffuse lesions than for focal stenosis), degree of arterial calcification, and stage of ischemia (CLTI or IC) [67–72]. In international consensus documents, open reconstructions (thromboendarterectomy, femoropopliteal bypass) are considered the method of choice for long and occlusive lesions, including those involving the popliteal artery trifurcation, whereas endovascular interventions (superficial femoral artery balloon angioplasty with stenting) are preferred for relatively short, localized, mostly non-occlusive changes of this arterial segment (see TASC II classification in appendix G2). Data from randomized comparative studies of open and endovascular interventions (thromboendarterectomy, femoropopliteal bypass, superficial femoral artery balloon angioplasty with stenting) in patients with hemodynamically significant changes of the FPS are contradictory, the proportion of patients with CLTI in them is heterogeneous, and criteria for choosing one or another revascularization approach have not been defined [73–78].

• When choosing a conduit for a bypass procedure (femoropopliteal bypass) on the femoropopliteal segment, it is recommended to give preference to an autogenous great saphenous vein graft; if it is absent or unsuitable for use as a conduit, it is recommended to use alternative autologous saphenous veins (small saphenous vein, upper extremity veins), a synthetic vascular graft (synthetic blood vessel prosthesis***), semi-closed endarterectomy (endarterectomy with plastic reconstruction of great vessels), or a vascular allograft [35, 64, 76–78].

GCR BLoE 3Level of Evidence B (Level of Confidence of Evidence – 3)

Comments: results of high-quality comparative studies indicate that the long-term patency of autogenous femoropopliteal bypass grafts is higher than that of synthetic ones (synthetic blood vessel prosthesis***) [79, 80]. If the patient lacks a great saphenous vein, alternative autogenous conduits are used—the small saphenous vein, upper extremity veins, including the creation of a bypass graft from several—two, three, and sometimes four—autogenous fragments [81–85]. According to the BEST-CLI randomized trial, an adequate-diameter great saphenous vein is a more preferable conduit for infrainguinal bypass (femoropopliteal bypass) in CLTI than alternative conduits (autogenous or synthetic (synthetic blood vessel prosthesis***)) [78]. Several authors successfully use vascular allografts as an alternative to autologous venous conduits [86, 87].

In the absence of autologous venous material, some authors perform SFA reconstruction using semi-closed endarterectomy (thromboendarterectomy) (SEAE). In a randomized study involving a mixed patient cohort (23% CLTI, 77% IC), thromboendarterectomy was comparable in long-term outcomes to bypass grafting (femoropopliteal bypass). Subgroup analysis for CLTI was not performed [88]. According to a randomized study by Saaya et al., SEAE (thromboendarterectomy) and stenting (balloon angioplasty with superficial femoral artery stenting) for SFA occlusions provided virtually identical patency rates at 1 year post-intervention (82% and 83%, p>0.05); however, at 4 years, this rate was significantly higher in the SEAE (thromboendarterectomy) group (46% and 28%, p=0.04) [89].

• During endovascular reconstruction of the femoropopliteal segment (superficial femoral artery balloon angioplasty with stenting), it is recommended to consider performing balloon angioplasty (peripheral artery balloon angioplasty) with or without stent implantation, using drug-eluting balloons and/or stents (drug-coated balloon dilatation catheter for percutaneous transluminal angioplasty of peripheral vessels, drug-coated peripheral stents), stent-grafts (vascular stent-grafts), and endovascular atherothrombectomy (mechanical recanalization, popliteal artery and crural major artery balloon angioplasty with stenting) [55, 65, 90, 91, 92, 93].

For superficial femoral artery balloon angioplasty with stenting, peripheral artery balloon angioplasty: Recommendation Grade B (level of evidence – 2)

For mechanical recanalization, popliteal artery and crural major artery balloon angioplasty with stenting: Recommendation Grade C (level of evidence – 4)

Comments: balloon angioplasty (peripheral artery balloon angioplasty) for FPS lesions is effectively used both as an isolated revascularization method and in combination with the implantation of intravascular devices—stents, stent-grafts (drug-coated peripheral stents, vascular stent-grafts) [35, 55, 65, 90]. For relatively short stenoses and occlusions of the SFA and PopA, the long-term results of balloon angioplasty (superficial femoral artery balloon angioplasty with stenting, popliteal artery and crural major artery balloon angioplasty with stenting) are not inferior to the results of stenting (superficial femoral artery balloon angioplasty with stenting, popliteal artery and crural major artery balloon angioplasty with stenting), provided a satisfactory angiographic result is obtained [91, 92]. For long FPS lesions, the use of stent-grafts (vascular stent-grafts) provides higher reconstruction patency compared to conventional stenting (drug-coated peripheral stents) [93].

Balloon catheters and drug-eluting stents (cytostatic-eluting) (drug-coated balloon dilatation catheters, drug-eluting peripheral stents) are widely used in endovascular interventions and angioplasty (balloon angioplasty with stenting of the superficial femoral artery, balloon angioplasty with stenting of the popliteal artery and major arteries of the leg) of the femoropopliteal segment, providing superior long-term

patency compared to uncoated balloons (balloon dilatation catheters for percutaneous transluminal angioplasty) for relatively short lesions [90, 94-98]. Mechanical or laser atherothrombectomy (mechanical recanalization, balloon angioplasty with stenting of the popliteal artery and major arteries of the leg) is used in the treatment of femoropopliteal segment lesions either as a standalone method or in combination with balloon angioplasty and stenting (balloon angioplasty with stenting of the superficial femoral artery, balloon angioplasty with stenting of the popliteal artery and major arteries of the leg). According to high-quality comparative studies, this technique improves long-term outcomes of endovascular interventions on the superficial femoral artery and popliteal artery [99, 100].

• During endovascular reconstruction of the popliteal artery (balloon angioplasty with stenting of the popliteal artery and major arteries of the leg), stent implantation (drug-eluting peripheral stents) is recommended only in cases of suboptimal results from balloon angioplasty (peripheral artery balloon angioplasty) [44, 47].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comments: according to the randomized ETAP study, omitting stent implantation (drug-eluting peripheral stents) in the popliteal artery when a satisfactory result is achieved with balloon angioplasty (peripheral artery balloon angioplasty) does not lead to worse long-term patency compared to primary stenting (balloon angioplasty with stenting of the superficial femoral artery, balloon angioplasty with stenting of the popliteal artery and major arteries of the leg) [91].

• For lesions of the tibioperoneal (infrapopliteal) segment, it is recommended to perform open or endovascular reconstructions (thromboendarterectomy, femoropopliteal bypass, balloon angioplasty with stenting of the superficial femoral artery, balloon angioplasty with stenting of the popliteal artery and major arteries of the leg), with the revascularization modality chosen by the vascular team based on the clinical situation and according to the Global Limb Anatomic Staging System (GLASS) (see Appendix G3) [13, 35, 63, 65, 101-107].

GCR ALEL 1Grade of Recommendations A (Level of Evidence – 1)

Comments: revascularization of steno-occlusive lesions of the infrapopliteal segment (thromboendarterectomy, femoropopliteal bypass, balloon angioplasty with stenting of the superficial femoral artery, balloon angioplasty with stenting of the popliteal artery and major arteries of the leg) in chronic limb-threatening ischemia (CLTI) is performed via open and endovascular approaches [13, 35, 63, 65, 101-106]. According to a meta-analysis of retrospective cohort studies, endovascular interventions are inferior to open bypass reconstructions (open: thromboendarterectomy, femoropopliteal bypass; endovascular: balloon angioplasty with stenting of the superficial femoral artery, balloon angioplasty with stenting of the popliteal artery and major arteries of the leg) of the infrapopliteal segment in terms of long-term patency, while effectively ensuring a high limb salvage rate [105]. In the randomized BASIL-2 trial, the 2-year composite endpoint of major amputation or death was 63% after autogenous vein bypass (femoropopliteal bypass) and 53% after endovascular intervention (balloon angioplasty with stenting of the superficial femoral artery, balloon angioplasty with stenting of the popliteal artery and major arteries of the leg) (RR 1.35; 95% CI 1.02-1.80; p=0.037). Stratification by the complexity of infrapopliteal steno-occlusive lesions was not performed [107].

• When selecting a conduit for bypass surgery (femoropopliteal bypass) in the infrapopliteal segment, it is recommended to give preference to the great saphenous vein autograft; if it is absent or unsuitable for use as a conduit, the use of alternative autologous saphenous veins (small saphenous vein, upper extremity veins) is recommended; if these are absent or unsuitable, a synthetic vascular graft (synthetic blood vessel prosthesis***) or vascular allograft should be used [44, 47, 78, 108].

GRC BLEL 2Grade of Recommendation B (Level of Evidence – 2)

Comments: according to the randomized BEST-CLI trial, an adequate-diameter great saphenous vein is a preferred conduit for infrainguinal (including infrapopliteal) bypass surgery (femoropopliteal bypass) in CLTI compared to alternative conduits (autogenous or synthetic (synthetic blood vessel prosthesis***)) [78]. A retrospective analysis of the VQI vascular registry demonstrated that the highest patency of infrapopliteal bypass reconstructions (femoropopliteal bypass) is achieved when using a great saphenous vein conduit [108]. Alternative conduits also include spliced autogenous vein grafts composed of multiple venous segments, including alternative saphenous veins (small saphenous vein, upper extremity veins), synthetic vascular grafts (synthetic blood vessel prosthesis***), composite conduits (synthetic blood vessel prosthesis*** combined with an autogenous vein), and vascular allografting [86, 108-110].

• During endovascular reconstruction of the infrapopliteal segment, it is recommended to consider balloon angioplasty without stenting (peripheral artery balloon angioplasty) or balloon angioplasty with stent implantation (balloon angioplasty with stenting of the popliteal artery and major arteries of the leg utilizing a bare-metal peripheral stent***) [65, 105, 111].

GGR BLOE 1Grade of Recommendation B (Level of Evidence – 1)

Comments: among endovascular techniques for treating steno-occlusive lesions of crural arteries, balloon angioplasty without stenting (peripheral artery balloon angioplasty) is the most common [65, 105]. Patency and limb salvage rates following crural artery balloon angioplasty (peripheral artery balloon angioplasty) are lower in patients with long and occlusive lesions compared to those treated for short infrapopliteal stenoses [111]. In the long term, arterial balloon angioplasty (peripheral artery balloon angioplasty) provides a primary patency rate of 48.6% at 3 years [105].

Crural artery stenting (balloon angioplasty with stenting of the popliteal artery and major arteries of the leg) is performed in cases of unsatisfactory balloon dilation results. According to the VQI registry, the proportion of

stenting procedures (balloon angioplasty with stenting of the popliteal artery and major arteries of the leg) among all endovascular interventions on crural arteries is 9% [65]. A meta-analysis of seven randomized trials revealed no advantages of infrapopliteal stenting (balloon angioplasty with stenting of the superficial femoral artery, balloon angioplasty with stenting of the popliteal artery and major arteries of the leg) over balloon angioplasty (peripheral artery balloon angioplasty) regarding perioperative complications, 6-month primary patency, major amputations (lower extremity amputations), and 12-month mortality [112].

• During endovascular reconstruction of the infrapopliteal segment (balloon angioplasty with stenting of the popliteal artery and major arteries of the leg), it is recommended to consider the use of drug-eluting balloon catheters (drug-coated balloon dilatation catheter) [113-115].

GGR BLOE 1Grade of Recommendation B (Level of Evidence – 1)

Comments: according to a meta-analysis of 9 randomized studies involving patients with CLTI, angioplasty using a drug-eluting balloon catheter (peripheral artery balloon angioplasty, drug-coated balloon dilatation catheter) did not differ from conventional balloon angioplasty (peripheral artery balloon angioplasty) in terms of repeat revascularization rates (14.6% vs. 22.1%; p=0.15), risk of restenosis (33.3% vs. 62.9%; p=0.42), and major adverse events (29.0% vs. 38.8%; p=0.48) [113].

There is some clinical experience with endovascular mechanical atherectomy (MA) (aspiration endovascular thrombectomy, mechanical recanalization, balloon angioplasty with stenting of the popliteal artery and major crural arteries) for atherosclerotic lesions of the crural arteries. According to a retrospective study, no statistically significant differences were found between MA and balloon angioplasty (mechanical recanalization, balloon angioplasty with stenting of the popliteal artery and major crural arteries) in the 30-day complication rate, primary patency up to 18 months, overall mortality, lower extremity amputation rate, and epithelialization rate of trophic defects at 1 year [114].

A retrospective, propensity score-matched, single-center study evaluated the outcomes of laser atherectomy (aspiration endovascular thrombectomy, mechanical recanalization, balloon angioplasty with stenting of the popliteal artery and major crural arteries) compared to conventional balloon angioplasty (peripheral artery balloon angioplasty) in patients with CLTI. The authors found no statistically significant differences between the groups regarding the rate of reinterventions, major amputations (lower extremity amputation), and major adverse events at 1 and 2 years [115].

• In critical limb ischemia caused by lesions of the popliteal artery and crural arteries, following balloon dilation of the tibioperoneal segment (peripheral artery balloon angioplasty), it is recommended to consider the use of drug-eluting stents (peripheral artery stent, bare metal***, drug-eluting peripheral stents), including stents used for coronary artery disease (coronary stents with accessories) [65, 116].

GRC BLEL 2Grade of Recommendation B (Level of Evidence – 2)

Comments: according to the VQI registry, the proportion of stenting (balloon angioplasty with stenting of the popliteal artery and major crural arteries) among all endovascular interventions on crural arteries is 9% [65]. Based on a meta-analysis of 9 randomized trials, the use of drug-eluting stents (drug-eluting peripheral stents) within one year after revascularization (balloon angioplasty with stenting of the popliteal artery and major crural arteries) resulted in a significant reduction in the rate of reinterventions, restenoses, and major amputations (lower extremity amputations) compared to balloon angioplasty or conventional balloon stenting (peripheral artery balloon angioplasty) and bare metal stents (peripheral artery stent, bare metal***). These studies utilized stents certified for the treatment of coronary atherosclerosis (coronary stents with accessories***) [116].

• In cases of critical limb ischemia with involvement of the foot arteries, revascularization of the inframalleolar segment is recommended to be performed via an open or endovascular approach to the major branches of these vessels in the metatarsal or ankle region—plantar arteries, malleolar branches of the peroneal artery, tarsal branches of the dorsalis pedis artery, plantar arterial arch (bypass surgery, balloon angioplasty with stenting of the popliteal artery and major crural arteries), with the type of reconstruction selected by a specialist physician (cardiovascular surgeon) or members of the vascular team based on the clinical situation according to the Global Limb Anatomic Staging System (GLASS) (Appendix G3) [117-123].

For balloon angioplasty with stenting of the popliteal artery and major crural arteries, the Level of Evidence is B (level of certainty of evidence – 3)

For bypass surgery to major branches of vessels in the metatarsal or ankle region, the Level of Evidence is C (level of certainty of evidence – 4)

Comments: an option for open limb revascularization in significant lesions of inframalleolar main arteries is bypass surgery to the major branches of these vessels in the metatarsal or ankle region—the plantar arteries, malleolar branches of the peroneal artery, tarsal branches of the dorsalis pedis artery, and the plantar arterial arch [117-119]. According to Hughes et al., the 30-day graft occlusion rate (autogenous vein graft) is 11%, with a mortality rate of 1%. Primary patency and limb salvage rates reach 67% and 75% at 1 year, and 41% and 69% at 5 years, respectively [118].

According to retrospective studies, endovascular interventions on the foot arteries (peripheral artery balloon angioplasty) are not inferior in their immediate and long-term outcomes to balloon angioplasty of the crural arteries (peripheral artery balloon angioplasty) [120-123]. The impact of inframalleolar angioplasty (peripheral artery balloon angioplasty) on the rate and frequency of epithelialization of foot trophic lesions was evaluated in a retrospective comparative study, where this method provided a statistically significant increase in the healing rate (59.3% vs 38.1%, p <0.05) and a reduction in healing time (211 days vs 365 days, p=0.008) compared to balloon angioplasty at the crural artery level (peripheral artery balloon angioplasty) [123].

• In patients with critical limb ischemia caused by foot artery disease, when choosing a conduit for inframalleolar bypass surgery (femoropopliteal bypass), it is recommended to prioritize an autogenous great saphenous vein graft; if it is absent or unsuitable as a conduit, alternative autogenous veins (small saphenous vein, upper extremity veins) should be used [118].

GCR BLoE 3Level of Evidence B (Level of Confidence of Evidence – 3)

Comments: in the largest retrospective study of ultradistal bypass grafts (autogenous vein graft) to branches of the plantar main arteries, the outcomes of 98 procedures performed in 90 patients were analyzed. In 98% of cases, the indication for surgery was CLTI, and in another 2%, restenosis in a previously performed open reconstruction zone. An autogenous conduit was used in all observations except one. Within 30 days, graft thrombosis (autogenous vein graft) developed in 11%, and one death (1%) was recorded. Primary patency and limb salvage rates at 1 year were 67% and 75%, and at 5 years, 41% and 69%, respectively [118].

• In patients with total occlusion of the main arterial bed of the foot or following failed attempts at inframalleolar revascularization (thromboendarterectomy, femoropopliteal bypass), it is recommended to consider performing foot vein arterialization via an open, hybrid, or endovascular approach [124-128].

GRC BLEL 2Grade of Recommendation B (Level of Evidence – 2)

Comments: when blood flow in the main arteries at the inframalleolar level cannot be restored due to their total occlusion or following a technically unsuccessful recanalization attempt (the so-called "empty foot syndrome" or "no-option" CLTI), some authors utilize open, endovascular, or hybrid arterialization of the foot venous bed [124-128]. According to a meta-analysis published by Schreve et al. in 2017, foot vein arterialization achieved limb salvage in 75% of patients (95% CI 0.70-0.81) at 1 year. Early or 30-day mortality ranged from 0 to 10%, with an overall survival of 54-100% at a mean follow-up of 5-60 months. Primary patency of the reconstruction at 12 months ranged from 59 to 71% [127].

• In patients with critical limb ischemia caused by disease of the popliteal-crural-malleolar segments, during endovascular interventions on the popliteal-crural and foot segments (peripheral artery balloon angioplasty, balloon angioplasty with stenting of the popliteal artery and major crural arteries), including as part of multi-level disease correction, it is recommended to consider direct revascularization of the affected angiosome, especially in the presence of deep trophic lesions located in the middle or hindfoot, as well as when multiple angiosomes are affected, with the aim of improving the healing rates of the limb trophic lesion [116, 129-136].

GCR BLoE 3Level of Evidence B (Level of Confidence of Evidence – 3)

Comments: data on the impact of direct (ariosomal) revascularization on long-term outcomes of endovascular treatment for CLTI are derived from low- and medium-quality retrospective studies [116, 129-136]. Overall, in a significant portion of studies, angiosomal revascularization resulted in a reduced time to epithelialization of trophic defects [130, 132-135, 137]. Some authors also reported a lower incidence of major amputations (lower extremity amputation) with this approach [130, 133]. The Global Vascular Guidelines on the Management of Chronic Limb-Threatening Ischemia, published by Conte et al., recommend considering direct revascularization of the affected angiosome, especially for deep trophic defects located in the midfoot or hindfoot [3].

• In multilevel arterial disease of the limb, including aortoiliac disease with common femoral artery involvement, it is recommended to consider hybrid revascularization [138, 140-142].

GCR BLoE 3Level of Evidence B (Level of Confidence of Evidence – 3)

Comments: according to the US Nationwide Inpatient Sample (NIS), between 2000 and 2004, the number of hybrid interventions annually performed for multilevel steno-occlusive lower extremity arterial disease ranged from 2,312 to 2,655, of which 28.3–29.8% were staged procedures (open and endovascular stages performed >1 day apart); (open stage: thromboendarterectomy, femoropopliteal bypass; endovascular stage: balloon angioplasty with stenting of the superficial femoral artery, balloon angioplasty with stenting of the popliteal artery and crural arteries) [138]. According to the VQI registry, between 2010 and 2017, the proportion of hybrid reconstructions for femoropopliteal disease increased from 6.1% to 32% [139]. When steno-occlusive lesions of the aortoiliac segment extend to the common femoral artery (CFA), hybrid interventions—a combination of open endarterectomy (thromboendarterectomy) of the CFA and endovascular correction of the arterial segment (lower extremity artery stenting) above the inguinal ligament—are effective [140-142]. In a large retrospective study by Zavatta et al., 30-day mortality after hybrid iliofemoral reconstructions was significantly lower than after open revascularization (thromboendarterectomy, femoropopliteal bypass) [142]. In a randomized trial by Starodoubtsev et al. in patients with iliac artery and CFA lesions, the rate of early postoperative complications was significantly lower with hybrid reconstruction compared to open revascularization (thromboendarterectomy, femoropopliteal bypass) (8.8% and 21%, respectively; p=0.03). At the same time, primary patency and limb salvage rates in the long-term follow-up did not differ between the groups [143].

• In combined aortoiliac and femoropopliteal lesions in patients with CLTI without trophic changes, it is recommended to consider aortoiliac reconstruction restoring direct inline flow (aortofemoral/aortoprofundaplasty bypass) to the deep femoral artery basin, followed by an evaluation of the need for further limb revascularization (femoropopliteal bypass) [144-147].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Comments: in patients with CLTI and combined steno-occlusive disease of the aortoiliac and femoropopliteal segments, deep femoral artery (DFA) basin revascularization (aortoprofundaplasty/aortofemoral bypass) without restoring direct blood flow to the downstream arterial bed is effective in some cases [144-147]. Risk factors for insufficient efficacy of isolated DFA reconstruction (profundaplasty) included: hemodynamically significant lesions of the DFA or popliteal artery, and the presence of no more than one single runoff crural vessel [147].

• In the absence of an autologous vein conduit of sufficient length in patients with CLTI and multilevel infrapopliteal lesions, it is recommended to consider bypass grafting (femoropopliteal bypass) to non-mainstream branches of the superficial femoral or popliteal arteries to relieve CLTI [119, 148-150].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Comments: in patients with extensive superficial femoral artery occlusions and no adequate autologous vein conduit, some authors perform bypass grafting (femoropopliteal bypass) to non-mainstream branches of the superficial femoral and popliteal arteries around the knee joint. The distal anastomosis is typically formed with the descending genicular artery or one of the sural arteries; an autologous vein is used as the conduit in most cases. According to retrospective studies without a control group, the rate of early graft thrombosis (autogenous vein graft) is 0–9%, primary patency at 3 years is 56–77%, 1-year limb salvage is 77%, and 3-year limb salvage is 73.5–90% [119, 148-150].

For peripheral artery balloon angioplasty: Recommendation Grade B (Level of Evidence – 1)

For thromboendarterectomy, aorto-profundal bypass, femoropopliteal bypass, lower extremity artery stenting: Recommendation Grade B (Level of Evidence – 3)

Comments: one of the indications for reconstructive limb artery surgery (thromboendarterectomy, aorto-profundal bypass, femoropopliteal bypass, lower extremity artery stenting, peripheral artery balloon angioplasty) is the detection of restenosis following previous revascularization (thromboendarterectomy, aorto-profundal bypass, lower extremity artery stenting, peripheral artery balloon angioplasty) [3]. According to retrospective and randomized trials, for the treatment of hemodynamically significant restenoses after aortoiliac and infrainguinal reconstructions (thromboendarterectomy, aorto-profundal bypass, femoropopliteal bypass, lower extremity artery stenting, peripheral artery balloon angioplasty), in addition to traditional open methods, balloon angioplasty (peripheral artery balloon angioplasty) is used, including the use of cutting balloon catheters and drug-coated balloon catheters (percutaneous transluminal angioplasty dilation catheter, drug-coated balloon dilation catheter) [151-156].

Comments: the proportion of patients with Charcot neuroarthropathy who are found to have hemodynamically significant main artery disease of the limb upon examination reaches 40–66.1% according to some data [157, 158]. As a rule, these lesions are asymptomatic, and the detection rate of CLTI in this clinical group is 82% lower than in diabetic foot syndrome with trophic lesions [158, 159]. However, during orthopedic foot reconstruction (foot tendon and ligament repair), surgical trauma contributes to the progression of baseline limb ischemia into critical ischemia. According to a retrospective study by Elmarsafi et al., the presence of steno-occlusive arterial disease in such patients increases the risk of postoperative major limb amputation (lower extremity amputation) by 4.3-fold (95% CI 1.7–11.0; p=0.002). Therefore, some authors consider preemptive limb revascularization (thromboendarterectomy, aorto-profundal bypass, femoropopliteal bypass, lower extremity artery stenting, peripheral artery balloon angioplasty) justified for "background" foot ischemia in patients with Charcot neuroarthropathy [159, 160].

• In patients with thrombotic occlusion of the native arterial bed or a previously reconstructed area (thromboendarterectomy, aortofemoral bypass, femoropopliteal bypass, lower limb artery stenting, peripheral artery balloon angioplasty) at the aortoiliac or infrainguinal segment of the limb, it is recommended to consider catheter-directed thrombolysis (local endovascular transarterial thrombolysis) [161-166].

GRC BLEL 2Grade of Recommendation B (Level of Evidence – 2)

Comments: when treating CLTI caused by thrombotic occlusion of native lower limb arteries or a previously reconstructed area (endovascular vessel wall reconstruction), catheter-directed thrombolysis (local endovascular transarterial thrombolysis) is also used [161-166]. Recombinant tissue plasminogen activator (rtPA) (enzyme preparations, ATC code B01AD) is most commonly used as the thrombolytic agent (antithrombotic agents B01A) [167, 168].

• In patients with CLTI, it is recommended to consider intraoperative instrumental visualization of the open arterial reconstruction area (direct lower limb artery angiography) of the lower limb arterial bed to identify potential hemodynamically significant changes and their subsequent correction [169, 170].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Comments: intraoperative visualization (ultrasound scanning, angiography, or both methods simultaneously) (duplex scanning of lower limb vessels (arteries and veins), direct lower limb artery angiography) is widely used when performing bypass procedures on lower limb arteries (aortofemoral bypass, femoropopliteal bypass) [169, 170]. At the same time, defects requiring revision of the reconstruction are found in 10-27% of cases [171].

Comments: literature data and international consensus documents recommend considering urgent conditionally radical surgical debridement (surgical debridement of the wound or infected tissue) for severe foot infection with signs of systemic inflammatory response (so-called "foot attack") as the first stage of surgical treatment for CLTI with trophic changes [46, 172, 173]. In retrospective studies involving patients with pronounced infectious-necrotic foot changes, early conditionally radical surgical debridement (surgical debridement of the wound or infected tissue) (performed on the day of admission or within 72 hours) was statistically associated with a higher limb salvage rate compared to delayed debridement [174, 175].

• In a patient with CLTI and diabetic foot syndrome without convincing signs of systemic inflammatory response (IDSA infection grade 4, WIfI grade 3), to improve revascularization outcomes, it is recommended that the cardiovascular surgeon or vascular team responsible for the patient's care decides on the urgency and frequency of conditionally radical surgical debridement (surgical debridement of the wound or infected tissue) of the trophic and infectious-inflammatory changes in the ischemic limb segment, as well as its staging relative to revascularization (aortofemoral bypass, femoropopliteal bypass, lower limb artery stenting, peripheral artery balloon angioplasty), based on clinical experience and general principles of clinical medicine systematized in the WIfI limb threat classification (Appendix G4) [176].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Comments: according to a retrospective study from the ACS-NSQIP registry, performing surgical debridement (surgical debridement of the wound or infected tissue) simultaneously with limb revascularization (aortofemoral bypass, femoropopliteal bypass, lower limb artery stenting, peripheral artery balloon angioplasty) for CLTI did not lead to an increase in perioperative mortality and the rate of early complications (including major amputation) (lower limb amputation) compared to two-stage treatment where debridement was performed after arterial reconstruction (aortofemoral bypass, femoropopliteal bypass, lower limb artery stenting, peripheral artery balloon angioplasty). The severity of infectious inflammation was not assessed in this study [176].

Comments: the healing time of a trophic defect after limb revascularization (aortofemoral bypass, femoropopliteal bypass, lower limb artery stenting, peripheral artery balloon angioplasty) often exceeds 6 months [177]. Transferring the surgical debridement stage (surgical debridement of the wound or infected tissue) of the trophic defect to another unit, provided continuity of care is maintained, can significantly increase the efficacy of limb salvage in patients with CLTI [178].

• In patients with CLTI and diabetic foot syndrome, following adequate surgical debridement (surgical debridement of the wound or infected tissue) of infectious-inflammatory and necrotic areas, it is recommended to consider closing the limb tissue defect (autodermoplasty) using flap transposition with an autograft and/or, in the case of complicated surgical wound healing, negative pressure wound therapy (vacuum therapy, vacuum application) [179-183, 237].

For autodermoplasty: Grade of Recommendation C (Level of Evidence – 4)

For negative pressure wound therapy (vacuum application) in the management of complicated surgical wound healing in patients with CLTI: Grade of Recommendation B (Level of Evidence – 2)

Comments: flap plastics for trophic defects using a free vascularized autograft (autodermoplasty) is widely used after limb revascularization (aortofemoral bypass, femoropopliteal bypass, lower limb artery stenting, peripheral artery balloon angioplasty) in patients with CLTI [179]. This technique provides high rates of defect epithelization and long-term amputation-free survival (lower limb amputation) [180-182]. Negative pressure wound therapy (vacuum therapy, vacuum application) as an independent method of closing a limb trophic defect, according to retrospective studies, provides a statistically significant reduction in major amputation rates (lower limb amputation) and an increased probability of trophic defect healing compared to hydrogel and alginate dressings (textile-based gel dressings for the treatment of burns and infected wounds) [183].

• The choice of the method for closing the limb tissue defect, the duration and frequency of its application, and its staging relative to revascularization (aortofemoral bypass, femoropopliteal bypass, lower limb artery stenting, peripheral artery balloon angioplasty) is recommended to be determined by the specialist physician (cardiovascular surgeon) or the vascular team responsible for the treatment of the patient with CLTI [180, 182, 184-191].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Comments: the body of literature on the choice of method for closing limb tissue defects following revascularization (aortofemoral bypass, femoropopliteal bypass, lower extremity artery stenting, peripheral artery balloon angioplasty) for CLTI is mainly represented by small retrospective studies without a control group or low-quality randomized studies that predominantly include patients with non-ischemic limb tissue defects [180, 182, 184-191].

• In patients with CLTI, an initial appointment (examination, consultation) with a cardiovascular surgeon is recommended to determine indications for major lower extremity amputation after considering all possible options for open and endovascular revascularization (aortofemoral bypass, femoropopliteal bypass, lower extremity artery stenting, peripheral artery balloon angioplasty) according to the WIfI limb threat classification system (Appendix G4) [3].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

• In patients with CLTI, an initial appointment (examination, consultation) with a surgeon is recommended to consider the feasibility of major lower extremity amputation in the presence of severe infectious and inflammatory changes requiring emergency or urgent radical surgical debridement (surgical debridement of a wound or infected tissue) with bone resection proximal to or in close proximity to the ankle joint [3].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comments: one of the surgical treatment methods for CLTI is major limb amputation (lower extremity amputation), which is performed in the following situations [3].

Following a specialist consultation (initial appointment (examination, consultation) with a cardiovascular surgeon, initial appointment (examination, consultation) with a surgeon) at a medical organization providing specialized care in cardiovascular surgery and X-ray endovascular diagnostics and treatment, after considering all possible options for open and endovascular revascularization:

1. When performed revascularization, surgical debridement, and measures aimed at epithelialization of the amputation/trophic defect (aortofemoral bypass, femoropopliteal bypass, lower extremity artery stenting, peripheral artery balloon angioplasty) (surgical debridement of a wound or infected tissue) (autodermoplasty) fail to preserve a functional and weight-bearing part of the foot due to an extensive and non-reconstructable tissue defect.

2. When there is no prospect of preserving a functional and weight-bearing part of the foot/leg due to extensive necrotic changes and/or the lack of technical capability to perform limb revascularization (aortofemoral bypass, femoropopliteal bypass, lower extremity artery stenting, peripheral artery balloon angioplasty) owing to the characteristics of the arterial bed disease.

3. In situations where the ischemic limb has irreversibly lost its weight-bearing capacity due to neurological disorders, neuromuscular, and osteoarticular diseases.

4. In cases of excessively high operative risk due to the patient's condition and the severity of comorbidities, as well as low life expectancy.

A two-stage approach to major lower extremity amputations in CLTI is used by many authors to improve stump healing (less commonly thigh) and preserve a longer and more functional limb segment, typically in patients with extensive necrosis without clear demarcation, severe infection, and signs of osteomyelitis [192-196]. In a randomized study by Fisher et al., the rate of wound complications in the primary major lower extremity amputation group was 21% versus 0% in the two-stage approach group (p=0.05) [195]. According to retrospective studies, two-stage major lower extremity amputation increased the rate of successful stump healing and reduced perioperative mortality compared to single-stage lower extremity amputation [192, 194].

• In patients with CLTI, when determining the level of major lower extremity amputation, it is recommended to consider preserving as functional a limb segment as possible to increase the likelihood of successful prosthetics [197].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Comments: according to retrospective studies, the functional status of the limb in patients after major limb amputations (lower extremity amputation) below the knee joint is significantly better compared to patients who underwent above-knee amputation (thigh amputation) [197, 198].

• In patients with CLTI, when determining the level of major lower extremity amputation, it is recommended to be guided by clinical signs and consider using transcutaneous oximetry (determination of tissue oxygen partial pressure — oximetry) to assess the likelihood of successful stump healing at the planned amputation level [199-201].

GCR BLoE 3Level of Evidence B (Level of Confidence of Evidence – 3)

Comments: when determining the level of amputation (lower extremity amputation), one should be guided by clinical signs (appearance of the limb at various segments, presence of edema, hyperemia, cyanosis, trophic changes, joint contracture). The degree of tissue bleeding at the amputation level (lower extremity amputation) is not a reliable predictor of stump healing [199]. Among instrumental methods for assessing the probability of successful limb stump healing, the most common is the measurement of transcutaneous oxygen tension (determination of tissue oxygen partial pressure — oximetry) at the level of the planned amputation (lower extremity amputation). According to several retrospective studies, a value of this parameter above 35-40 mmHg was statistically associated with a high probability of below-knee stump healing [199-201]. Notably, determining the level of major amputation (lower extremity amputation) based on the level of main artery occlusion has not been confirmed as effective in clinical studies and does not feature in recent scientific literature [199].

• In patients with CLTI, to increase the likelihood of successful limb stump healing, it is recommended to consider preemptive or delayed revascularization (aortofemoral bypass, femoropopliteal bypass, lower extremity artery stenting, peripheral artery balloon angioplasty) [202-205].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Comments: to increase the probability of healing or relief of tissue ischemia at the amputation level (lower extremity amputation), some teams resort to open or endovascular revascularization of the limb stump (aortofemoral bypass, femoropopliteal bypass, lower extremity artery stenting, peripheral artery balloon angioplasty) [202-205].

Comments: according to a systematic review by Sanni et al., the efficacy of lumbar sympathectomy (LS) in CLTI has been evaluated in two randomized studies, with only one of them using lumbar sympathectomy as a standalone treatment method. The authors failed to identify any significant advantages of lumbar sympathectomy over conservative treatment in terms of limb salvage rate, rate and time of trophic defect healing [206].

Comments: according to a meta-analysis of 6 randomized trials of spinal cord stimulation (SCS, implantation of temporary electrodes for spinal cord and peripheral nerve neurostimulation) in patients with CLTI and non-reconstructable arterial lesions, the rate of major lower limb amputations at 12 months after treatment initiation was significantly lower (RR 0.71; 95% CI 0.56–0.90), while the percentage of patients with a substantial reduction in rest pain was higher in the SCS group (implantation of temporary electrodes for spinal cord and peripheral nerve neurostimulation) compared to conservative treatment. The proportion of patients without trophic disorders ranged from 24% to 49%. Severe infection in the area of trophic changes was an exclusion criterion in 5 studies, and extensive or deep necrosis in 3 out of 6 studies [207].

3.2. Conservative treatment

• Prostanoid therapy (Prostaglandins G02AD) is not recommended for patients with CLTI [208].

GGR BLOE 1Grade of Recommendation B (Level of Evidence – 1)

Comments: according to a meta-analysis of 33 randomized trials of prostanoids (Prostaglandins G02AD) in CLTI, including 21 placebo-controlled trials, prostanoids (Prostaglandins G02AD) did not affect the rate of major amputations (lower limb amputation) but were more frequently associated with side effects (headache, nausea, vomiting, diarrhea, flushing, hypotension) compared to placebo [208].

• Pentoxifylline** therapy is not recommended for patients with CLTI [210, 213].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

Comments: a randomized study by Dawson et al. noted a statistically significant reduction in rest pain intensity during intravenous administration of the drug (pentoxifylline**) compared to the placebo group (28% and 15%, respectively; p=0.026). Meanwhile, the incidence of gastrointestinal side effects was significantly higher in patients receiving pentoxifylline** (37.6% and 11.5%; p <0.0001) [209]. The Norwegian study registered no statistically significant differences in rest pain intensity with a 7-day course of intravenous pentoxifylline** [210].

• Growth factor gene therapy (group C05XX Other vasoprotectives) is not recommended for patients with CLTI [211].

GGR BLOE 1Grade of Recommendation B (Level of Evidence – 1)

Comments: according to a meta-analysis of 17 high-quality randomized gene therapy trials, this type of treatment does not cause statistically significant changes in major amputation rates (lower limb amputation) and overall survival compared to placebo in patients with CLTI [211].

• If there are indications for planned major amputation (lower limb amputation) in patients with CLTI, it is recommended to consider palliative treatment and refrain from surgical treatment in cases of extremely high surgical risk due to severe comorbidities and/or a severe general condition of the patient, provided that the infectious process in the necrotic area of the limb is mild and non-progressive [212–214].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Comments: a significant portion of patients with CLTI have severe comorbidities that sharply increase the risk of perioperative complications and worsen long-term treatment outcomes. In patients with an extremely high operative risk who have indications for planned major amputation (lower limb amputation) for CLTI, a number of authors refrain from surgical treatment in favor of palliative care (pain management, infection control in the necrotic area, management of comorbidities), provided that the infectious process in the necrotic area of the limb is mild and non-progressive [212–214].

4. Medical Rehabilitation and Sanatorium-Resort Treatment

• When determining the level of major limb amputation (lower limb amputation) in patients with CLTI, it is recommended to take into account the prospects for subsequent prosthetic rehabilitation [197, 216].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

• Following a major amputation (lower limb amputation) for CLTI, it is recommended to consider referring the patient to a specialized limb prosthetic center [197, 215, 216].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Comments: literature data concerning the rehabilitation of patients with CLTI are represented by isolated studies on the long-term outcomes of lower limb prosthetics after major lower limb amputation. The goal of rehabilitation is therefore to ensure maximum mobility for patients in whom limb salvage failed.

The proportion of patients able to ambulate independently with a prosthesis is significantly higher following below-knee amputations compared to above-knee amputations [197, 215].

According to Webster et al., patient age over 55 years and the presence of severe comorbid conditions such as chronic obstructive pulmonary disease and hemodialysis reduced the efficacy of limb prosthetics [216].

5. Prevention and Dispensary Observation

Comments: in the randomized CLIPS trial, acetylsalicylic acid** (ASA) therapy in patients with asymptomatic chronic lower extremity artery disease over 2 years led to a significant reduction in the risk of reaching the combined

endpoint of CLTI or major adverse vascular events compared to placebo (58% risk reduction, p=0.014). The groups did not significantly differ in the incidence of CLTI as an isolated endpoint [217].

A sub-analysis of the randomized COMPASS trial included patients with asymptomatic or symptomatic lower extremity arterial disease (32% had a history of limb revascularization [aortobifemoral bypass, femoropopliteal bypass, lower extremity artery stenting, peripheral artery balloon angioplasty]). Patients received dual antithrombotic therapy with acetylsalicylic acid** (ASA) at a dose of 100 mg/day combined with rivaroxaban** (ATC code: B01AF, direct factor Xa inhibitors) at a dose of 2.5 mg twice daily. Compared with acetylsalicylic acid** monotherapy, dual antithrombotic therapy statistically significantly reduced the risk of the combined endpoint of cardiovascular death/myocardial infarction/stroke by 28%; the risk of major adverse limb events by 46%; the risk of major limb amputation (lower limb amputation) by 70%; and the risk of unplanned vascular interventions for limb ischemia by 43%. At the same time, the risk of major bleeding events according to the modified International Society on Thrombosis and Haemostasis (ISTH) criteria in the dual therapy group was significantly higher than with acetylsalicylic acid** monotherapy (3.1% vs 1.9%; p=0.0089). The groups did not significantly differ in the incidence of fatal, intracranial, or critical organ bleeding [218, 219].

Comments: the randomized, double-blind, multicenter VOYAGER PAD trial included patients after lower limb artery reconstructions (35% open surgery, 65% endovascular) who received postoperative dual antithrombotic therapy (rivaroxaban** 2.5 mg twice daily combined with acetylsalicylic acid** 100 mg/day) or acetylsalicylic acid** monotherapy 100 mg/day. Over 3 years, dual antithrombotic therapy resulted in a statistically significant 12% reduction in the incidence of repeat revascularizations (aortofemoral bypass, femoropopliteal bypass, lower limb artery stenting, peripheral artery balloon angioplasty), a 28% reduction in hospitalizations due to thrombotic events, and a 20% reduction in the risk of the composite endpoint of acute limb ischemia/lower limb amputation/myocardial infarction/ischemic stroke/coronary death. These benefits were preserved in the subgroup of patients with CLTI.

There were no significant differences between the dual antithrombotic therapy and acetylsalicylic acid** groups regarding the incidence of major bleeding events, intracranial bleeding, and fatal bleeding (assessed using the Thrombolysis in Myocardial Infarction [TIMI] scale). According to the stricter International Society on Thrombosis and Haemostasis (ISTH) criteria, the incidence of major bleeding events in the dual antithrombotic therapy group was 5.94% versus 4.06% in the acetylsalicylic acid** group (p=0.007) [219, 220].

• In patients without a high bleeding risk, it is recommended to consider dual antithrombotic therapy with acetylsalicylic acid** at a dose of 100 mg/day (primary prevention of acute myocardial infarction) and rivaroxaban** 2.5 mg twice daily (prevention of stroke, myocardial infarction, and cardiovascular death, as well as prevention of acute limb ischemia and overall mortality in patients with coronary artery disease [CAD] or peripheral artery disease [PAD] in combination with acetylsalicylic acid) combined with short-term clopidogrel** for up to 1 month in patients after lower limb endovascular revascularization (superficial femoral artery balloon angioplasty with stenting, popliteal artery and crural artery balloon angioplasty with stenting) for CLTI [221].

GRC BLEL 2Grade of Recommendation B (Level of Evidence – 2)

Comments: about half of the patients in the trial additionally received clopidogrel** (ATC code: B01AC, Platelet aggregation inhibitors excluding heparin), i.e., they received triple antithrombotic therapy. The median duration of triple therapy was 30 days. When the duration of concomitant clopidogrel** use was ≤ 30 days, the incidence of ISTH major bleeding events in the dual antithrombotic therapy group did not differ from that in the control group. When the duration of concomitant clopidogrel** use exceeded 30 days, a 2.71% increase in the incidence of ISTH major bleeding events was observed in the triple antithrombotic therapy group compared with dual therapy with rivaroxaban** + acetylsalicylic acid** (RR 3.20; 95% CI 1.44-7.13). At the same time, the benefits of dual antithrombotic therapy in achieving the primary endpoint compared with acetylsalicylic acid** + placebo did not depend on concomitant clopidogrel** use (p for interaction 0.92) [221].

Comments: there is a lack of high-quality literature data on the comparative efficacy of various intraoperative antithrombotic prophylaxis strategies during arterial reconstructions (aortofemoral bypass, femoropopliteal bypass, lower limb artery stenting, peripheral artery balloon angioplasty) in patients with CLTI [210, 212-224].

Comments: the randomized MIRROR trial included patients after endovascular interventions (superficial femoral artery balloon angioplasty with stenting, popliteal artery and crural artery balloon angioplasty with stenting) on the femoropopliteal segment who received DAPT or acetylsalicylic acid** monotherapy for 6 months. The procedure (superficial femoral artery balloon angioplasty with stenting, popliteal artery and crural artery balloon angioplasty with stenting) was performed for CLTI in 33.8% of patients. The primary endpoint of the study was platelet activation marker activity. By the end of the follow-up period, the incidence of repeat revascularizations (superficial femoral artery balloon angioplasty with stenting, popliteal artery and crural artery balloon angioplasty with stenting) of the operated segment (secondary endpoint) for clinical indications was significantly lower with DAPT compared with acetylsalicylic acid**. In the DAPT group, 30% of patients exhibited resistance to clopidogrel** due to high residual platelet reactivity [222]. The main purpose of prescribing these drugs is to reduce the risk of repeat revascularization (aortofemoral bypass, femoropopliteal bypass, lower limb artery stenting, peripheral artery balloon angioplasty).

Comments: in the double-blind, randomized CASPAR trial, patients after infrainguinal bypass reconstructions (femoropopliteal bypass) received DAPT or acetylsalicylic acid** monotherapy. A significant statistical interaction was observed between the treatment effect and the graft type (P = 0.008) (autogenous vein graft, synthetic blood vessel prosthesis***). In the subgroup of synthetic conduits (synthetic blood vessel prosthesis***), the risk of graft occlusion (synthetic blood vessel prosthesis***) throughout the entire follow-up period was significantly lower with DAPT compared with acetylsalicylic acid** (HR 0.65; 95% CI 0.45-0.95) [223].

Comments: high-quality scientific data on the efficacy of vitamin K antagonists (VKAs) after open reconstructive surgery (aortofemoral bypass, femoropopliteal bypass, thrombendarterectomy) for CLTI are presented by three open-label randomized trials. In two of them, vitamin K antagonists were used as monotherapy, and target INR values differed significantly from those currently accepted in clinical practice. The analysis of bleeding complications is incomplete. These circumstances make unambiguous interpretation of these studies in terms of clinical practice guidelines difficult [224-226].

Comments: according to a meta-analysis of 29 studies (including 4 randomized ones), smoking cessation after lower extremity arterial bypass surgery (aortofemoral bypass, femoropopliteal bypass) resulted in a 3.09-fold reduction in the long-term risk of graft occlusion (95% CI 2.34–4.08; p < 0.00001) [227].

Comments: according to retrospective studies, statin therapy (HMG-CoA reductase inhibitors) contributed to an increased patency rate of the reconstruction zone, a decreased rate of repeated revascularizations (aortofemoral bypass, femoropopliteal bypass), and lower overall mortality in patients after lower limb revascularization (aortofemoral bypass, femoropopliteal bypass) [198, 228–230].

5.1 Follow-up care

• Patients after surgical treatment for CLTI are recommended to undergo periodic clinical (visual assessment for vascular pathology, palpation for vascular pathology) and/or ultrasound examination (lower extremity arterial Doppler ultrasound, duplex scanning of lower extremity vessels (arteries and veins)) to monitor limb status, assess the function of the performed arterial reconstruction, and detect signs of restenosis and clinical recurrence of CLTI [231–234].

Leveled of Evidence CLevel of Data Reliability 2Level of evidence C (level of data reliability – 2)

Comments: according to qualitative comparative studies, postoperative follow-up, including periodic clinical examination (visual assessment for vascular pathology, palpation for vascular pathology) and/or ultrasound examination (lower extremity arterial Doppler ultrasound, duplex scanning of lower extremity vessels (arteries and veins)), effectively detects signs of restenosis in the reconstruction zone and recurrence of limb ischemia [231–234]. During the first year after limb revascularization (aortofemoral bypass, femoropopliteal bypass, lower extremity artery stenting, peripheral artery balloon angioplasty), more frequent follow-up examinations increase the effectiveness of health screening [232].

6. Organization of Medical Care

The goal of medical care for CLTI is to reduce the specified population rate of major lower limb amputations (number of major lower limb amputations per 100,000 population per year).

The primary type of medical care for CLTI is specialized, including high-tech, medical care (surgical care) in an inpatient setting. The types of surgical interventions performed for CLTI are listed in Section 3.1 of these guidelines.

The stages of medical care for CLTI include skilled and specialized care in an inpatient setting or an outpatient medical facility (primary health care).

Possible indications for hospitalization of CLTI patients include:

– the need to provide specialized, including high-tech, medical care - surgical care (see Section 3.1);

– development of a severe comorbid condition in a CLTI patient in the absence of indications or the presence of contraindications for surgical treatment of CLTI.

The grounds for discharge from the hospital are:

– stable and satisfactory condition of the patient:

a. after surgical treatment;

b. when contraindications to surgical treatment are identified;

c. if the patient refuses the proposed surgical treatment;

d. if it is technically impossible to perform the surgical intervention in the given hospital;

– other legitimate grounds provided for by federal and regional regulations, as well as the internal regulations of the medical institution.

Key principles of organizing medical care for CLTI include:

– reducing the duration of the pre-hospital stage (time from the onset of CLTI symptoms to patient admission to the hospital for specialized, including high-tech, medical care - surgical care);

– reducing the duration of preoperative preparation and examination in an inpatient setting;

– ensuring a multidisciplinary approach to patient management in the hospital;

– ensuring continuity of patient care between inpatient departments and at the outpatient stage after discharge from a specialized hospital.

In order to reduce the duration of the pre-hospital stage during a patient's initial visit for consultative care at an outpatient healthcare facility, the examination algorithm should be shortened as much as possible. If there are clinically justified suspicions of CLTI, even if instrumental data on steno-occlusive changes in the limb arteries (lower extremity arterial Doppler ultrasound, duplex scanning of lower extremity vessels (arteries and veins)) are absent at the time of examination, the patient should be referred to a specialized hospital as soon as possible to resolve the issue of the necessity and urgency of surgical intervention. It is not recommended to initiate any therapeutic measures in CLTI patients in an outpatient care setting without a prior examination by a specialist physician (cardiovascular surgeon) in a specialized hospital.

Upon admission to a specialized hospital (by referral from an outpatient facility, on an emergency basis from home, or by transfer from another hospital), an accelerated preoperative examination of the patient is performed to determine the need and feasibility of surgical care, define the range of planned interventions and the sequence of their performance, and establish the scope of preoperative preparation. All irrelevant studies whose results do not affect the choice of surgical treatment tactics for CLTI should be excluded from the preoperative diagnostic algorithm (see Section 2). If necessary, additional examination related to the patient's existing chronic comorbidities can be performed in the postoperative period.

The implementation of a multidisciplinary approach to the treatment of CLTI in a hospital involves the participation of specialists from various fields in decision-making regarding patient management tactics and a rational distribution of treatment stages among these specialists, which increases the effectiveness of the measures taken and reduces the risk of failure (in particular, the risk of major lower limb amputation). In international consensus documents, this group of specialists is referred to as a vascular team. It may include a surgeon, a cardiovascular surgeon, an endovascular surgeon (endovascular diagnostics and treatment physician), an anesthesiologist-reanimatologist, a cardiologist, an orthopedic trauma surgeon, and an endocrinologist. In actual practice, the vascular team may be represented by various combinations of these specialists depending on the organizational and staffing structure of the hospital. If the hospital lacks a vascular team or lacks a specialist of the appropriate profile within the vascular team, consultative care can be organized using telemedicine technologies. If the hospital lacks the conditions to perform the intervention, it is recommended to discuss the possibility of transferring the patient to another hospital with the necessary specialists and technical resources.

Ensuring continuity in the care of a CLTI patient after discharge from the hospital is facilitated by:

– active use of telemedicine technologies;

– creation of a unified registry of CLTI patients;

– development of documents regulating the procedure for providing care to CLTI patients, taking into account the organizational and staffing structure of cardiovascular and endovascular surgery departments in each region;

– integration of outpatient and inpatient departments involved in the treatment of this category of patients into an organizationally unified structure;

– development of new tariffs within the framework of the compulsory medical insurance system that ensure the performance of surgical debridement of trophic limb changes and reconstructive plastic interventions (wound or infected tissue debridement, skin autografting) on the foot in outpatient facilities and day hospitals.

7. Additional Information

No.

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

Akchurin R.S. – Academician of the RAS, Head of the Department of Cardiovascular Surgery, Deputy Director General for Surgery at the National Medical Research Center for Cardiology, Honorary President of the Russian Society of Angiologists and Vascular Surgeons;

Abugov S.A. – MD, PhD, Professor, Head of the Department of X-ray Endovascular Diagnostics and Treatment at the Petrovsky National Research Centre of Surgery;

Aleykan B.G. – Academician of the RAS, MD, PhD, Professor, Deputy Director for Science at the Vishnevsky National Medical Research Center of Surgery; Chairman of the Russian Scientific Society of Specialists in X-ray Endovascular Diagnostics and Treatment;

Arakelyan V.S. – MD, PhD, Professor, Head of the Department of Vascular Surgery and Angiology at the Bakulev National Medical Research Center for Cardiovascular Surgery; Member of the Russian Society of Angiologists and Vascular Surgeons;

Vachev A.N. – MD, PhD, Professor, Head of the Department of Faculty Surgery at Samara State Medical University; Member of the Board of the Russian Society of Angiologists and Vascular Surgeons;

Baryshnikov A.A. – Head of the Departments of Vascular Surgery and X-ray Endovascular Diagnostics and Treatment at the SUSMU Clinic, Chief Vascular Surgeon of the Chelyabinsk Region;

Belov Yu.V. – Academician of the RAS, MD, PhD, Professor, Russian Society of Angiologists and Vascular Surgeons;

Borodulin A.V. – PhD, Head of Department at the St. Elizabeth Hospital, Saint Petersburg;

Bredikhin R.A. – MD, PhD, Leading Researcher at the Department of Vascular Surgery, Interregional Clinical Diagnostic Center (MKDC), Kazan, Member of the Board of the Russian Society of Angiologists and Vascular Surgeons;

Varava A.B. – Vishnevsky National Medical Research Center of Surgery of the Russian Ministry of Health; X-ray endovascular surgeon;

Vinogradov R.A. – MD, PhD, Head of the Department of Vascular Surgery at the Ochapovsky Research Institute – Regional Clinical Hospital No. 1. Member of the Board of the Russian Society of Angiologists and Vascular Surgeons;

Gavrilenko A.V. – Academician of the RAS, MD, PhD, Professor, Head of the Department of Vascular Surgery at the Petrovsky National Research Centre of Surgery; Member of the Board of the Russian Society of Angiologists and Vascular Surgeons;

Galstyan G.R. – MD, PhD, Professor, Head of the Diabetic Foot Department, Chief Researcher at the Dedov National Medical Research Center for Endocrinology of the Ministry of Health of the Russian Federation;

Zholkovsky A.V. – Head of the Department of Vascular Surgery at the Rostov Clinical Hospital of the Southern District Medical Center of the FMBA of Russia;

Zavatsky V.V. – PhD, Head of the Department of Vascular Surgery at the St. Petersburg City Aleksandrovsky Hospital;

Zatevakhin I.I. – President of the Russian Society of Surgeons (ROH), Academician of the RAS, Head of the Department of Faculty Surgery of the Pediatric Faculty at the Pirogov Russian National Research Medical University;

Eroshenko A.V. – PhD, Head of Endovascular Interventions at the K+31 Clinic; Member of the Board of the Russian Society of Angiologists and Vascular Surgeons;

Eroshkin I.A. – MD, PhD, Head of the Scientific Department of X-ray Surgical Methods of Diagnostics and Treatment at the Sklifosovsky Research Institute for Emergency Medicine of the Moscow Healthcare Department, Professor at the Department of Endovascular and Vascular Surgery of the Russian University of Medicine of the Ministry of Health of the Russian Federation; Member of the Russian Society of Angiologists and Vascular Surgeons;

Imaev T.E. – MD, PhD, Head of the Laboratory of Hybrid Methods for Treating Cardiovascular Diseases at the Chazov National Medical Research Center for Cardiology, Member of the Russian Society of Angiologists and Vascular Surgeons;

Kazakov Yu.I. – MD, PhD, Professor, Head of the Department of Cardiovascular Surgery at TSMU, Member of the Russian Society of Angiologists and Vascular Surgeons;

Kavteladze Z.A. – MD, PhD, Professor, Head of the Center for Cardiovascular and Endovascular Surgery at RGNKC, X-ray endovascular surgeon;

Kalashnikov V.Yu. – Corresponding Member of the RAS, MD, PhD, Professor, Head of the Department of Cardiology, Endovascular and Vascular Surgery at the Dedov National Medical Research Center for Endocrinology of the Ministry of Health of the Russian Federation;

Kalinin R.E. – MD, PhD, Professor, Rector, Head of the Department of Cardiovascular, X-ray Endovascular Surgery and Radiology at the Pavlov Ryazan State Medical University; Member of the Board of the Russian Society of Angiologists and Vascular Surgeons;

Kalitko I.M. – PhD, Leading Vascular Surgeon at the Clinic of Innovative Surgery LLC;

Karpenko A.A. – MD, PhD, Head of the Center for Vascular and Hybrid Surgery at the Meshalkin National Medical Research Center; Member of the Board of the Russian Society of Angiologists and Vascular Surgeons;

Kuryanov P.S. – PhD, Head of the Department of X-ray Endovascular Diagnostics and Treatment at St. George Hospital, Saint Petersburg, Member of the Russian Society of Angiologists and Vascular Surgeons;

Lepilin P.M. – PhD, Senior Researcher at the Laboratory of Hybrid Methods for Treating Cardiovascular Diseases at the Chazov National Medical Research Center for Cardiology, Member of the Russian Society of Angiologists and Vascular Surgeons;

Litvinyuk N.V. – Research Institute for Complex Issues of Cardiovascular Diseases, Kemerovo/Krasnoyarsk; X-ray endovascular surgeon;

Lipin A.N. – MD, PhD, Professor at the Department of Naval Surgery of the Kirov Military Medical Academy, Head of the Limb Salvage Center (St. Petersburg City Hospital No. 14);

Matyushkin A.V. – MD, PhD, Professor at the Department of Faculty Surgery of the Pediatric Faculty at the Pirogov Russian National Research Medical University, Head of the Department of Vascular Surgery; Member of the Board of the Russian Society of Angiologists and Vascular Surgeons;

Mukhamadeev I.S. – MD, PhD, Head of the Department of Cardiovascular Surgery at the Perm Regional Clinical Hospital;

Nokhrin S.P. – MD, PhD, Leading Researcher at the Department of Emergency Cardiovascular Surgery at the Dzhanelidze St. Petersburg Research Institute of Emergency Medicine;

Platonov S.A. – PhD, Head of the Department of Cardiovascular and Endovascular Surgery at the Dzhanelidze St. Petersburg Research Institute of Emergency Medicine, Member of the Russian Society of Angiologists and Vascular Surgeons;

Plotnikov M.V. – PhD, Associate Professor at the Department of Cardiology, X-ray Endovascular and Cardiovascular Surgery at KGMA;

Sapelkin S.V. – MD, PhD, Leading Researcher at the Department of Vascular Surgery at the Vishnevsky National Medical Research Center of Surgery; Member of the Russian Society of Angiologists and Vascular Surgeons;

Svetlikov A.V. – MD, PhD, Head of the Center for Vascular Surgery at Clinical Hospital No. 122, Saint Petersburg; Vice-President of the Russian Society of Angiologists and Vascular Surgeons;

Sitkin I.I. – MD, PhD, Leading Researcher at the Diabetic Foot Department at the Dedov National Medical Research Center for Endocrinology of the Ministry of Health of the Russian Federation;

Sokurenko G.Yu. – MD, PhD, Professor at the Department of Cardiovascular Surgery at the Mechnikov North-Western State Medical University; Member of the Board of the Russian Society of Angiologists and Vascular Surgeons;

Soroka V.V. – MD, PhD, Professor, Head of the Department of Emergency Cardiovascular Surgery at the Dzhanelidze St. Petersburg Research Institute of Emergency Medicine; Member of the Board of the Russian Society of Angiologists and Vascular Surgeons;

Suchkov I.A. – MD, PhD, Professor, Professor at the Department of Cardiovascular, X-ray Endovascular Surgery and Radiology at the Pavlov Ryazan State Medical University; Vice-President of the Russian Society of Angiologists and Vascular Surgeons, Member of the Board of the Russian Society of Surgeons;

Troitsky A.V. – MD, PhD, Professor, Head of the Center for Vascular Surgery and General Director, Federal Research and Clinical Center of the FMBA; Member of the Russian Society of Angiologists and Vascular Surgeons;

Fokin A.A. – MD, PhD, Professor, Head of the Department of Surgery at the Institute of Continuing Professional Education of SUSMU; Vice-President of the Russian Society of Angiologists and Vascular Surgeons;

Kharazov A.F. – PhD, Senior Researcher at the Department of Vascular Surgery at the Vishnevsky National Medical Research Center of Surgery; Member of the Russian Society of Angiologists and Vascular Surgeons;

Chernyavsky M.A. – MD, PhD, Head of the Research Department of Vascular and Interventional Surgery at the Almazov National Medical Research Centre; Member of the Russian Society of Angiologists and Vascular Surgeons;

Chupin A.V. – MD, PhD, Head of the Department of Vascular Surgery at the Vishnevsky National Medical Research Center of Surgery. Vice-President of the Russian Society of Angiologists and Vascular Surgeons.

All clinical guideline development group members declare no conflict of interest.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience of these clinical guidelines:

1. Cardiovascular Surgeon

2. Surgeon

3. Endovascular surgeon

4. Cardiologist

5. Ultrasound Diagnostics Physician

These guidelines are based on the fundamental principle of evidence-based medicine, according to which decision-making on the use of specific medical technologies must rely on a comprehensive analysis of all available scientific evidence regarding their efficacy and safety, rather than on expert opinion and doctors' personal clinical experience.

Assessment of the scientific validity of information included in clinical guidelines (CG) is carried out by assessing the levels of evidence (LE) and grades of recommendation (GR) of thesis recommendations (Tables 1, 2, 3).

Table 1. Scale for assessing levels of evidence (LE) for diagnostic methods (diagnostic interventions)

Table 2. Scale for assessing the levels of evidence (LE) for prevention, treatment, and medical rehabilitation methods, including those based on natural therapeutic factors (preventive, therapeutic, and rehabilitation interventions)

Table 3. Scale for assessing the grades of recommendation (GR) for prevention, diagnostic, treatment, and medical rehabilitation methods, including those based on natural therapeutic factors (preventive, diagnostic, therapeutic, and rehabilitation interventions)

For each recommendation statement, a systematic search and selection of publications is conducted by several members of the working group across multiple electronic bibliographic databases in accordance with predefined criteria.

The determination of the level of reliability of evidence (LRE) and level of убедительности recommendations (LUR) is carried out based on the clinical studies of the highest design (providing the most reliable evidence) identified through the systematic search.

Procedure for updating clinical guidelines.

The mechanism for updating clinical guidelines provides for their systematic revision at least once every three years, as well as upon the emergence of new evidence-based medicine data on the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

These guidelines were developed in accordance with:

• Order of the Russian Ministry of Health dated February 28, 2019, No. 103n "On Approval of the Procedure and Deadlines for the Development of Clinical Practice Guidelines, Their Revision, the Standard Template of Clinical Practice Guidelines, and Requirements for Their Structure, Composition, and Scientific Validity of Information Included in Clinical Practice Guidelines";

• Methodological Recommendations for Evaluating the Scientific Validity of Information Included in Clinical Practice Guidelines. FSBI "Center for Expertise and Quality Control of Medical Care" of the Russian Ministry of Health, 2019;

• Order of the Russian Ministry of Health No. 918n dated November 15, 2012, "On Approval of the Procedure for Providing Medical Care to Patients with Cardiovascular Diseases";

• Methodological Recommendations for the Development of Clinical Practice Guidelines (Treatment Protocols) for the Provision of Medical Care.

Appendix B. Physician Action Algorithms

Appendix B1. Decision-making algorithm for a patient with suspected critical lower limb ischemia

Appendix B2. Clinical algorithm for the differential diagnosis of ischemic and non-ischemic pain and trophic changes of the lower limb

Appendix C. Patient Information

Ischemia is a condition in which blood flow to a specific area of the body is sharply reduced, resulting in impaired cell function and, in severe cases, cell death. The cause of ischemia is the narrowing or occlusion of arteries carrying blood from the heart to organs.

Lower limb ischemia in early stages manifests as impaired function, specifically a restricted walking distance.

Critical ischemia is an extreme manifestation of impaired lower limb arterial patency, manifesting as intense pain or tissue necrosis of the limb resulting from a critical reduction in blood flow. Tissue necrosis may present as a long-healing ulcer or gangrene (in gangrene, the skin turns black).

The main risk factors that increase the likelihood of lower limb ischemia include smoking, diabetes mellitus, advanced age, lipid metabolism disorders, and hypertension.

Warning signs that may indicate the development of critical lower limb ischemia:

– abrasions or ulcers on the foot that do not heal or heal very slowly;

– severe pain or numbness in the limb at rest;

– gangrene (blackening of parts of the foot).

If any of these symptoms appear, seek medical attention immediately.

In addition to a specialist examination, the diagnosis of critical lower limb ischemia may include:

– ultrasound examination (duplex or triplex scanning of lower limb arteries) (ultrasound Dopplerography of lower limb arteries, duplex scanning of lower limb vessels (arteries and veins));

– magnetic resonance imaging, computed tomography (contrast-enhanced magnetic resonance angiography (one region), computed tomography angiography of one anatomical region);

– direct angiography (direct lower limb arterial angiography) (a procedure in which a special contrast agent is injected directly into the arterial system of the lower limbs).

Treatment of critical lower limb ischemia should be initiated as early as possible. Therefore, it is very important to consult a specialist (cardiovascular surgeon) at the first symptoms of the disease, or, if unavailable, a polyclinic surgeon.

The primary treatment method for critical ischemia is surgical. It most commonly consists of one or more of the following interventions:

– revascularization (thromboendarterectomy, aorto-bifemoral bypass, femoropopliteal bypass, lower limb artery stenting, peripheral artery balloon angioplasty) (improving or fully restoring blood flow to the limb);

– necrosectomy (surgical debridement of a wound or infected tissue) (removal of dead and/or infected tissue) or minor lower limb amputation (removal of dead and/or infected tissue with bone resection at the foot level);

– major lower limb amputation (removal of dead and/or infected tissue with bone resection at the leg or thigh level).

Following surgical treatment, medications that reduce the risk of blood clots (antithrombotic agents) must be taken. Their selection is determined by the attending physician based on clinical indications and contraindications.

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

Appendix G1: Classifications of chronic lower limb ischemia severity

Russian title: Classifications of severity of chronic lower limb ischemia.

Original title (if applicable): (none)

Source (official developer website, validation publication): 1. Pokrovsky A.V. Diseases of the aorta and its branches - M., “Meditsina”, 1979, pp. 199 – 234;

1. Fontaine R., Kim M., Kieny R. Die chirurgische Behandlung der peripheren Durchblutungsstörungen. // Helv Chir Acta. 1954. Vol. 21, № 5–6. P. 499–533.

2. Rutherford RB, Baker JD, Ernst C, Johnston KW, Porter JM Ahn S, et al. Recommended standards for reports dealing with lower extremity ischemia: revised version. J Vasc Surg 1997;26: 517-538.

3. European Society for Vascular Surgery (ESVS) 2020 Clinical Practice Guidelines on the Management of Acute Limb Ischaemia. Eur J Vasc Endovasc Surg. 2020; 59: , 173 – 218. https://doi.org/10.1016/j.ejvs.2019.09.006.

Type (underline):

- rating scale

- index

- questionnaire

- other (specify): Clinical classification.

Purpose: Determination of patient treatment tactics.

Content (template): A table reflecting the degree of lower limb ischemia by disease stage and the severity of ischemic soft tissue disorders of the lower limbs.

Key (interpretation): Point scoring scale.

Explanations: Indications for surgical treatment, wound debridement or infected tissue management, and lower limb amputation are determined based on the disease stage and degree of lower limb ischemia. Indications for surgical treatment are considered in Fontaine stages II-III, A.V. Pokrovsky stages IIa-III, and Rutherford categories 2-4. Revascularization with wound debridement or infected tissue management is indicated for the combination of stages III-IV with trophic disorders according to the Fontaine and A.V. Pokrovsky classifications and Rutherford categories 5-6. Indications for lower limb amputation are considered in Fontaine and A.V. Pokrovsky stage IV and Rutherford category 6.

Appendix G2: TASC II classification of lower extremity arterial lesions

Russian title: TASC II classification of lower limb arterial lesions.

Original title (if applicable): Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II).

Source (official developer website, validation publication): Norgren L, Hiatt WR, Dormandy JA, Nehler MR, Harris KA, Fowkes FGR. on behalf of the TASC II Working Group. Inter- society consensus for the management of peripheral arterial disease (TASC II). J Vasc Surg. 2007 Jan;45(1 Suppl):S5–S67.https://doi.org/10.1016/j.ejvs.2019.09.006.

Type (underline):

- rating scale

- index

- questionnaire

- other (specify): Clinical and anatomical classification.

Purpose: Determination of patient treatment tactics depending on the location and extent of the arterial lesion.

Content (template): A table classifying and reflecting the anatomical location of lower limb arterial lesions by degree and extent of the lesion.

Key (interpretation): Visual rating scale.

Explanations: Depending on the location and extent of the lesion, conclusions are drawn regarding indications for open reconstructive (thromboendarterectomy, aorto-bifemoral bypass, femoropopliteal bypass) or endovascular (lower limb artery stenting, peripheral artery balloon angioplasty) procedures. For lesion classes A and B, endovascular procedures (lower limb artery stenting, peripheral artery balloon angioplasty) are recommended; for lesion classes C and D, open procedures (thromboendarterectomy, aorto-bifemoral bypass, femoropopliteal bypass) are recommended.

Appendix G3: Global Limb Anatomic Staging System (GLASS)

Russian title: Global Limb Anatomic Staging System (GLASS).

Original title (if applicable): The Global Limb Anatomic Staging System (GLASS) for CLTI: Improving Inter-Observer Agreement.

Source (official developer website, validation publication): Wijnand JGJ, Zarkowsky D, Wu B, van Haelst STW, Vonken EPA, Sorrentino TA, Pallister Z, Chung J, Mills JL, Teraa M, Verhaar MC, de Borst GJ, Conte MS. The Global Limb Anatomic Staging System (GLASS) for CLTI: Improving Inter-Observer Agreement. J Clin Med. 2021 Aug 4;10(16):3454. doi: 10.3390/jcm10163454. PMID: 34441757; PMCID: PMC8396876.

Type (underline):

- rating scale

- index

- questionnaire

- other (specify): Clinical and anatomical classification.

Purpose: Determination of patient treatment tactics depending on the location, extent, and combined nature of lower limb arterial lesions.

Content (template): A table classifying and reflecting the anatomical location of lower limb arterial lesions by degree, extent, and combined nature of the lesions.

Key (interpretation): Point scoring scale.

Notes: Depending on the localization, extent, and combination of lower extremity arterial lesions, conclusions are drawn regarding the indications for open reconstructive (thromboendarterectomy, femoropopliteal bypass) or endovascular (lower extremity artery stenting, peripheral artery balloon angioplasty) procedures. Indications for a specific type of surgery involve comparing GLASS classification data with data obtained from the WIfI classification (detailed below).

Appendix G4: WIfI limb threat classification system

Russian name: WIfI limb threat classification system.

Original name (if available): WIfI classification: the Society for Vascular Surgery lower extremity threatened limb classification system, a literature review.

Source (official developers' website, validation publication): Cerqueira LO, Duarte EG, Barros ALS, Cerqueira JR, de Araújo WJB. WIfI classification: the Society for Vascular Surgery lower extremity threatened limb classification system, a literature review. J Vasc Bras. 2020 May 8;19:e20190070. doi: 10.1590/1677-5449.190070. PMID: 34178056; PMCID: PMC8202158.

Type (underline):

- scoring scale for the severity of ischemia, soft tissue infection severity, and degree of trophic disorders

- score

- questionnaire

- other (specify):

Purpose: Determination of patient treatment tactics depending on the severity of lower limb ischemia, severity of soft tissue infection processes, and degree of trophic disorders caused by lower limb ischemia.

Content (template): A table classifying and reflecting the assessment of wound severity, lower limb ischemia, and the severity of the infectious process in the soft tissues and bones of the lower extremities.

Key (interpretation): Point scoring scale.

Explanations: Depending on the localization, extent, and combination of lower limb arterial lesions, the severity of trophic disorders, characteristics of the tissue wound resulting from ischemia, and severity of soft tissue inflammation, conclusions are drawn regarding indications for open reconstructive (thromboendarterectomy, femoropopliteal bypass) or endovascular (lower limb artery stenting, peripheral artery balloon angioplasty) surgery combined with surgical

debridement of the wound or infected tissue, or lower limb amputation. According to this classification system, when stage I lower limb changes according to the WIfI classification are combined with any stage of GLASS lesions (I, II, or III), revascularization is not recommended. With stage II lower extremity arterial disease according to the GLASS classification, revascularization is not recommended regardless of the WIfI stage, except for WIfI-2, where endovascular interventions (lower limb artery stenting, peripheral artery balloon angioplasty) are recommended. When stages 2–4 according to WIfI are combined with stage 1 according to GLASS, endovascular surgery (lower limb artery stenting, peripheral artery balloon angioplasty) is recommended, while for stages 3–4 according to WIfI combined with stage 3 according to GLASS, open surgical treatment (thromboendarterectomy, femoropopliteal bypass) is recommended.

W – Wound severity assessment

I – Ischemia severity assessment*

*A flat or minimally pulsatile pulse-volume waveform corresponds to grade 3. Toe blood pressure (TBP, blood pressure measurement on peripheral arteries) or TcPO2 (transcutaneous oxygen pressure measurement/oximetry in soft tissues) should be measured if the ABI cannot be determined due to vessel non-compressibility (>1.3). TBP must be measured in diabetic patients. If arterial calcification prevents obtaining reliable ABI and TBP values, ischemia is documented based on TcPO2 (transcutaneous oxygen pressure measurement/oximetry) values, skin perfusion pressure, or pulse volume recordings. If TBP and ABI values indicate different grades of ischemia, the TBP value shall take precedence.

fI – Assessment of Infection Severity

^a Ischemia can complicate or increase the severity of any infection. Systemic infection may occasionally present alongside other clinical signs such as hypertension, confusion, vomiting, or metabolic disorders, e.g., acidosis, severe hyperglycemia, and newly diagnosed azotemia.

Risk of major limb amputation within 1 year

Probable benefit (necessity) of revascularization (after control of the infectious process)

VL – very low amputation risk / revascularization benefit; L – moderate amputation risk / revascularization benefit; M – intermediate amputation risk / revascularization benefit; H – high amputation risk / revascularization benefit.

Appendix G5: Classification System for the Presence and Severity of Foot Infection, Developed by the Infectious Diseases Society of America (IDSA) and the International Working Group on the Diabetic Foot (IWGDF)

Russian Title: Classification System for the Presence and Severity of Foot Infection, Developed by the Infectious Diseases Society of America (IDSA) and the International Working Group on the Diabetic Foot (IWGDF).

Original Title (if available): IWGDF/IDSA Guidelines on the Diagnosis and Treatment of Diabetes-related Foot Infections (IWGDF/IDSA 2023).

Source (official developer website, validation publication): Éric Senneville, Zaina Albalawi, Suzanne A van Asten, Zulfiqarali G Abbas, Geneve Allison, Javier Aragón-Sánchez, John M Embil, Lawrence A Lavery, Majdi Alhasan, Orhan Oz, Ilker Uçkay, Vilma Urbančič-Rovan, Zhang-Rong Xu, Edgar J G Peters, IWGDF/IDSA Guidelines on the Diagnosis and Treatment of Diabetes-related Foot Infections (IWGDF/IDSA 2023), Clinical Infectious Diseases, 2023;, ciad527, https://doi.org/10.1093/cid/ciad527

Type (underline):

- diabetic foot infection severity grading scale

- index

- questionnaire

- other (specify):

Purpose: Determining patient management tactics depending on the severity of inflammatory and infectious changes in the soft tissues and bones of the foot.

Content (Template): A table classifying and reflecting the assessment of wound infection severity in diabetic foot.

Key (interpretation): Point scoring scale.

Explanatory Notes: Depending on the severity of trophic disorders and the severity of existing infectious and inflammatory processes in the wound, indications are determined for surgical debridement of the wound or infected tissue (for mild and moderate severity) or lower limb amputation (for severe foot infection).

Note. *In any direction from the wound edge. The presence of clinically significant foot ischemia substantially complicates both the diagnosis and treatment of the infection.