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Management of chronic limb-threatening ischemia
INTRODUCTION
Management decisions in the patient with chronic limb-threatening ischemia (CLTI) are
derived from the clinical presentation, physical examination, and review of noninvasive
vascular studies, with consideration of risk factors that impact a decision for intervention or
conservative care.
The approach is tailored to each patient based upon numerous factors, including presence
and degree of tissue loss, patient-specific vascular anatomy, availability of vascular conduit
for revascularization, and comorbidities such as cardiac risk (may impact the magnitude of
intervention) and renal insufficiency (may impact options for contrast agents and likelihood
of procedural success) [1]. If intervention is pursued, the interaction of the limb status,
patient comorbidities, and the patient's vascular anatomy determine the best form of
revascularization. As revascularization options have evolved and improved, more patients
have become candidates. Unfortunately, for some patients, the most appropriate course of
treatment may be primary amputation or palliation.
The overall management of CLTI ischemia is reviewed. The clinical manifestations and
diagnosis of CLTI, the approach to revascularization, as well as techniques for surgical and
endovascular revascularization are reviewed separately. (See "Lower extremity peripheral
artery disease: Clinical features and diagnosis" and "Clinical features and diagnosis of acute
arterial occlusion of the lower extremities".)
CLINICAL FEATURES AND DIAGNOSIS
®
AUTHORS: David G Neschis, MD, Hasan H Dosluoglu, MD, FACS, Michael A Golden, MD
SECTION EDITORS: John F Eidt, MD, Joseph L Mills, Sr, MD
DEPUTY EDITOR: Kathryn A Collins, MD, PhD, FACS
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Feb 2025.
This topic last updated: Aug 15, 2023.
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Clinical presentations — Patients with CLTI may present with ischemic rest pain, which is
pain across the base of the metatarsal heads at rest relieved by dependency, or with tissue
loss, which can be ulceration, dry gangrene, or wet gangrene (infection) occurring in the
lower extremities due to atherosclerotic occlusive disease of the iliac, femoral, popliteal,
tibial, or pedal arteries [1]. The patient can present initially without an antecedent history of
peripheral artery disease (PAD). Such a primary presentation may be more likely in patients
with a history of diabetes, heart failure, stroke, or renal failure [2]. (See "Lower extremity
peripheral artery disease: Clinical features and diagnosis", section on 'Lower extremity pain'
and "Lower extremity peripheral artery disease: Clinical features and diagnosis", section on
'Nonhealing wound/ulcer' and "Lower extremity peripheral artery disease: Clinical features
and diagnosis", section on 'Skin discoloration/gangrene'.)
Ischemic pain and pain progression — Patients with PAD may provide a description of
extremity pain that progresses over time when questioned. The classic presentation is a
patient who initially experienced pain in the muscles of the lower extremity, most often the
calf, with walking that is relieved by rest (ie, claudication), which, over months or years,
progresses to ischemic rest pain (ie, CLTI). However, perhaps more often than not, patients
do not describe such a progression. For a variety of reasons (obesity, shortness of breath,
lumbar spine disease, diabetic sensory neuropathy, general frailty), many patients with
PAD are sedentary and do not experience claudication. In such patients, it is only when
PAD progresses to the point that perfusion at rest is insufficient to support tissue
metabolism that ischemic rest pain or signs of tissue loss reveal themselves. Sometimes a
relatively minor injury can uncover underlying PAD and initiate a cascade of deterioration.
A variety of conditions can mimic ischemic rest pain, including neuropathy, arthritis, and
gout. Here, experience, a careful history and physical examination including palpation of
peripheral pulses, and properly performed Doppler pressures and waveforms can help
make the proper diagnosis. Examination of peripheral pulses may be challenging due to
calcification, edema, or wounds, and there should be a very low threshold to obtaining
noninvasive vascular studies in patients with lower leg and foot wounds. (See "Noninvasive
diagnosis of upper and lower extremity arterial disease", section on 'Ankle-brachial index'
and "Noninvasive diagnosis of upper and lower extremity arterial disease", section on
'Physiologic testing'.)
Foot or toe pain in a patient with absent pulses and a significantly abnormal ankle-brachial
index (ABI) should be presumed to be ischemic pain. Further complicating the assessment,
diabetes adds an additional level of complexity. Individuals with diabetes may be insensate
due to neuropathy and may not be aware of developing wounds or ulcers. Associated tibial
artery calcification, which is common with diabetes, may lead to falsely elevated or even
noncompressible Doppler pressures. The complexities of the diabetic foot in association
with PAD are reviewed separately.
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after Revascularization. N Engl J Med 2020; 382:1994.
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GRAPHICS
Nonhealing toe amputation wound
This picture depicts an ischemic wound following amputation of the 2 , 3 , and 4 digits at the
metatarsal-phalangeal joint level. A fibrotic wound base remains with little to no evidence of healing.
There is no granulation tissue or epithelial ingrowth.
Graphic 101201 Version 3.0
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Amputation stump wound breakdown
This picture depicts transmetatarsal amputation stump wound breakdown due to ischemia. Full-
thickness wound dehiscence is seen medial and lateral with a fibrotic wound base and there is
dependent rubor characteristic for ischemia of the dorsal and plantar amputation flaps.
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Ischemic wound lateral foot
The picture depicts the clinical appearance of an ischemic wound on the lateral forefoot, specifically
at the plantar aspect of the 5th metatarsal-phalangeal joint. Note the wound appearance of fibrotic
tissue mixed with eschar in an area of increased pressure near a bony prominence.
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Pressure-induced injury of the foot
The patient, who was non-ambulatory, had a right knee contracture and developed a pressure-
induced wound on the posterior plantar heel. The dorsal foot and medial metatarsal wounds likely
developed as a result of a bandage that was too tight. Inclusion of a layer of non-adherent dressing
adjacent the skin can help prevent injury when applying bandages to the foot. Non-ambulatory
patients with contractures are challenging to off-load; the use of typical devices (ie, protective boots)
are usually not effective.
Courtesy of Andrew J Meyr, DPM.
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Pathophysiologic assessment in chronic foot ulcers
The conceptual diagram illustrates the interaction between the main factors that contribute to tissue
loss. This scheme is appropriate for any patient with a chronic wound/tissue loss. The clinician should
ask, "Which factor or combination of factors contributes the most to the pathophysiology of the
wound? Ischemia? Infection? Wound extent?" Early assessment helps determine initial wound
management priorities, but frequent reassessment is important since the wound environment is
dynamic, and the balance toward one or another factor can change.
Adapted from:
1. Armstrong DG, Mills JL. Juggling risk to reduce amputations: The three-ring circus of infection, ischemia and tissue loss-
dominant conditions. Wound Medicine 2013; 1:13.
2. Zhan LX, Branco BC, Armstrong DG, et al. The Society for Vascular Surgery lower extremity threatened limb
classification system based on Wound, Ischemia, and foot Infection (WIfI) correlates with risk of major amputation and
time to wound healing. Journal of Vascular Surgery 2015; 61:939.
3. Mills JL Sr, Conte MS, Armstrong DG, et al. The Society for Vascular Surgery Lower Extremity Threatened Limb
Classification System: risk stratification based on wound, ischemia, and foot infection (WIfI). Journal of Vascular Surgery
2014; 59:220.
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Amputation risk based on Wound-Ischemia-foot Infection system
Wound
grade (0-3)
Ischemia
grade (0-3)
foot Infection grade (0-3)
0 1 2 3
0 0 VL VL L M
1 0 VL VL M M
0 1 VL L M H
1 1 VL L M H
0 2 L L M H
1 2 L M H H
0 3 L M M H
1 3 M M H H
20 L L M H
3 0 M M H H
2 1 M M H H
3 1 M M H H
2 2 M M H H
3 2 H H H H
2 3 H H H H
3 3 H H H H
The table shows the effect of worsening Wound, Ischemia, and foot Infection (WIfI) clinical stage and
the prognosis of chronic limb-threatening ischemia. The clinical stages 1, 2, 3, and 4 correspond to the
VL, L, M, and H amputation risk categories. As an example, a foot with WIfI grades 002 is clinical stage
1 and has a low risk for amputation at one year, whereas a foot with WIfI grades 223 is clinical stage 4
and is high risk.
VL: very low risk; L: low risk; M: moderate risk; H: high risk.
Adapted from: Mills JL, Conte MS, Armstrong DG, et al. The Society for Vascular Surgery Lower Extremity Threatened Limb
Classification System: Risk stratification based on Wound, Ischemia, and foot Infection. J Vasc Surg 2014; 59:220.
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GLASS classification system*
Femoropopliteal segment
0 Mild or no significant (2/3 (>20 cm) length; may include any flush occlusion 20 cm; popliteal disease >5 cm or extending into
trifurcation; any popliteal CTO
Infrapopliteal segment
0 Mild or no significant (2/3 length; CTO >1/3 (>10 cm) of length (may
include target artery origin); any CTO of TP trunk
Infrainguinal GLASS stage (I to III)
FP grade
IP grade
0 1 2 3 4
0 N/A I I II III
1 I I II II III
2 I II II II III
3 II II II III III
4 III III III III III
IP grading is applied only to the primary selected vessel in the TAP.
Severe calcification (eg, >50% of circumference; diffuse, bulky, or "coral reef" plaques) within the TAP
increases the within-segment grade by +1.
TP trunk disease is only included if the target vessel is the posterior tibial or peroneal artery.
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GLASS: Global Anatomic Staging System; SFA: superficial femoral artery; CTO: chronic total occlusion;
TP: tibioperoneal; IP: infrapopliteal; FP: femoropopliteal; TAP: target arterial path.
* The GLASS classification also includes aortoiliac (inflow) staging. Stage I: Stenosis of the common
and/or external iliac artery, chronic total occlusion of either common or external iliac artery (not both),
stenosis of the infrarenal aorta; any combination of these. Stage II: Chronic total occlusion of the
aorta; chronic total occlusion of common and external iliac arteries; severe diffuse disease and/or
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Wounds in a limb at risk — Marginal perfusion to the extremity may be adequate to
sustain healthy tissue at rest but can be insufficient to provide the increased energy
required for wound healing. Wounds may arise spontaneously or be the result of surgical
procedures ( picture 1) or minor trauma. A surgical wound may begin to appear to heal,
but healing stalls or the wound separates and breaks down ( picture 2).
Protection of the feet and toes in patients with known CLTI is paramount. Ill-fitting
footwear can cause pressure wounds from straps or simply by being too tight. Patients
need to be warned not to walk in bare feet or in the dark to avoid injury from objects or
furniture. Shoes should be checked for small objects such as pebbles or dropped insulin
needles before being worn. Patients also need to be warned about avoiding injury related
to nail clipping and should be instructed to share their history of PAD with other providers,
such as podiatrists. Patients with skin breakdown should be referred to a healthcare
provider with expertise in wound care.
Marginally perfused feet are at high risk in the hospital or nursing facility settings.
Potential sites of pressure (most often the heels) must be meticulously and continuously
off-loaded to prevent pressure-induced injuries, which in the face of ischemia are unlikely
to heal without revascularization. In addition, since CLTI is often relatively symmetric,
patients who are hospitalized for limb revascularization are at risk for developing a
pressure-induced injury on the "good" leg. The contralateral foot in a patient recovering
from lower extremity revascularization must not be ignored; it should be examined
regularly during the hospitalization and off-loaded.
Often patients in whom a diagnosis of PAD has not yet been made have wounds of the
lower legs and feet that have been attributed to nonarterial causes (eg, surgery, infection,
injury, pressure-induced injury, chronic venous disease). In this setting, undiagnosed PAD
can lead to nonhealing and progression of the wounds to the point that the limb may
become unsalvageable.
Vascular assessment — Signs of advanced CLTI on noninvasive testing may include an ABI
less than 0.4, toe pressure less than 30 to 40 mmHg, a flat metatarsal waveform on pulse
volume recording, and low or absent pedal flow on duplex ultrasonography [3]; however,
ischemia and limb threat are part of a spectrum, and less severe levels of hemodynamic
impairment may contribute to delayed wound healing and increased amputation risk [4].
(See 'Limb staging by severity of limb threat' below and "Lower extremity peripheral artery
disease: Clinical features and diagnosis", section on 'Diagnosis of lower extremity PAD'.)
INITIAL MANAGEMENT
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Once admitted, the patient with CLTI benefits from inpatient pain services; anticoagulation,
which may help relieve rest pain in the short term; off-loading of areas of tissue loss and the
heels from surfaces; optimal wound care; antimicrobial therapy (as indicated); and
importantly, expedited diagnostic imaging, cardiac risk assessment, perioperative
optimization, and revascularization.
General care
Pain control – Ischemic rest pain is often severe and may be unbearable. It is not unusual
for the patient to require admission to the hospital, not because revascularization is
immediately required, but because rest pain can be unmanageable in an outpatient
setting. (See "Approach to the management of chronic non-cancer pain in adults".)
●
Systemic anticoagulation – Systemic anticoagulation is initiated in some cases to limit
propagation of any areas of acute thrombosis. Acute occlusion of chronic atherosclerotic
lesions (or prior stented or bypassed region) is a common source and may contribute to
worsening ischemia limb pain.
●
Off-loading – Pressure is avoided at any area of tissue injury and areas at risk for injury (eg,
heels). Unlike trauma and other etiologies of arterial occlusion, atherosclerotic PAD is a
systemic disease, and therefore the contralateral limb is usually not spared and is at
increased risk of ischemic complications. So continued protection and monitoring of the
contralateral limb is indicated to mitigate against the development of contralateral limb
ischemic complications of injury or tissue loss. (See "Prevention of pressure-induced skin
and soft tissue injury".)
●
Wound care – Areas of skin breakdown or gangrene should be inspected regularly for any
signs of progression or infection. Management should focus on pressure off-loading and
avoidance of further injury, and perhaps even more importantly, the non-affected limb
should be carefully off-loaded as well. (See "Principles of acute wound management" and
"Overview of treatment of chronic wounds" and "Prevention of pressure-induced skin and
soft tissue injury".)
●
Skin ulceration – Clean ulcers in patients with ischemia should generally not be debrided
prior to revascularization and can be covered with a moist dressing and lightly wrapped.
Wound sites with necrotic material may need chemical or mechanical debridement.
•
Dry gangrene – For patients with dry gangrene ( picture 3), the wound can be lightly
wrapped with a bulky dry gauze. Avoid excessive pressure that could aggravate ischemia
and lead to additional wounds ( picture 4).
•
Wet gangrene – For patients with wet gangrene or abscess, urgent or emergency
surgery is necessary to debride the wound and drain any fluid collections.
•
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Clinical scenarios
For patients who are not candidates for revascularization (inadequate anatomy or prohibitive
medical risk), primary amputation may be a better option. Palliative measures can be
considered for those who do not desire amputation. (See 'Counseling the high-risk patient'
below.)
APPROACH TO THE PATIENT
Overall, most patients with CLTI had average perioperative risk and were predicted to survive
beyond two years in one large database review, and thus, most can be considered
candidates for limb salvage [5]. Although decisions regarding revascularization are often
Antimicrobial therapy – Empiric antimicrobial therapy is initiated to treat soft tissue
infection or osteomyelitis. Definitive therapy is directed toward organisms cultured from
tissue and bone biopsy specimens obtained during surgical debridement procedures. (See
'Limb staging by severity of limb threat' below and "Acute cellulitis and erysipelas in adults:
Treatment" and "Diabetic foot infection, including osteomyelitis: Clinical manifestations
and diagnosis".)
●
Ischemia without tissue loss or infection – Patients with minimal ischemia (ie, mild rest
pain) without tissue loss or infection can often be initially managed conservatively,
controlling pain and providing treatments to reduce the risk of future cardiovascular
events. (See 'Ongoing medical therapy and follow-up' below.)
●
Severe rest pain requires revascularization, provided it can be accomplished with
acceptable risks. (See 'Approach to the patient' below and 'Revascularization' below.)
Ischemia with ulceration or tissue loss – Appropriately selected patients with tissue loss
will require revascularization to achieve wound healing, provided it can be accomplished
with acceptable risks. (See 'Approach to the patient' below and 'Revascularization' below.)
●
With infection – Patients with ischemia and ulceration or tissue loss with infection
require expeditious management. The patient will require aggressive antibiotic therapy,
drainage, and/or debridement in addition to urgent vascular evaluation and
revascularization. The necessary procedures are typically staged. Active infection must
be controlled and necrotic infected tissue removed, but further tissue necrosis will
usually occur if restoration of adequate blood flow is not achieved soon thereafter.
Without infection – Patients with ischemia or ulceration or tissue loss without infection
can undergo less urgent evaluation, optimization, and revascularization. The wound is
likely to be more stable compared with one that is actively infected.
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complex, a three-step approach that takes into account limb staging, the anatomic pattern of
disease, and patient risk has been recommended [6].
Limb staging by severity of limb threat — Several clinical classifications can be used to
stratify the clinical severity of disease. CLTI represents stages 4 to 6 in the Rutherford
classification and stages 3 or 4 in the Fontaine classification. The Rutherford and Fontaine
classifications, which are decades old, were designed to classify chronic limb-threatening
ischemia (formerly termed critical limb ischemia) among patients with pure ischemia due to
peripheral artery disease (PAD); however, due to marked demographic shifts, particularly a
dramatic rise in diabetes prevalence, these classifications are less useful for appropriately
classifying patients with diabetes, neuropathy, or patient with an index wound with or
without infection, across a broader spectrum of PAD severity. In such patients, limb
perfusion is only one determinant of outcome. Wound extent and infection also significantly
impact the threat to a limb.
The Society for Vascular Surgery (SVS) Lower Extremity Threatened Limb Classification
System to Stratify Amputation Risk, Wound, Ischemia, and foot Infection (WIfI) is an updated
system for classifying the severity of limb threat that is intended to more accurately reflect
important clinical considerations, such as the presence and extent of ischemia, wounds, and
infection, which impacts management and amputation risk [7]. The classification can be
visualized as three intersecting rings of risk ( figure 1) [4,8]. WIfI also helps identify which
of these risks is "dominant" during a given time period throughout the patient's life. The
wound, ischemia, and infection grades are described in detail in the linked topic. (See
"Classification of acute and chronic lower extremity ischemia".)
The Global Vascular Guidelines for the management of CLTI recommend staging the limb
using WIfI [6]. WIfI grades three factors: the wound, the severity of ischemia, and the
presence of foot infection. The combinations of grades correspond to one of four clinical
limb stages (1 through 4) that correlate with the potential for wound healing and one-year
risk of amputation ( table 1). The staging system is not intended to dictate treatment but
rather to more precisely stratify patients according to their initial disease burden in a manner
that is analogous to Tumor-Nodes-Metastasis staging for cancer. Patients with clinical stage
1 limbs rarely require revascularization and can usually heal with simple wound care and
offloading. By contrast, patients with clinical stage 4 limbs have a very high amputation risk.
Clinical stages 2 and 3 are intermediate in threat to the limb. It is important to remember
that the stage of limb threat, not the individual grades of wound, ischemia, or infection,
drive urgency and potential need for admission and revascularization. WIfI also allows
comparison of therapeutic alternatives among patients with threatened limbs who have a
similar risk for amputation. The complete classification is available as an open access
document from the SVS on the Journal of Vascular Surgery website [9], and as an Interactive
Practice Guideline (iPG) app [10].
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The WIfI threatened limb classification has been validated in multiple studies and provides a
pragmatic means to assess the likelihood of wound healing and amputation risk in patients
with a spectrum of CLTI ischemia [4,11-15]. WIfI stages at presentation have correlated
strongly with wound healing time and wound healing rate at one year [16-20]. The use of
WIfI to stratify amputation risk has been reported from multiple centers across the United
States and from France, Italy, Germany, Spain, and Japan [16,21-23]. In a systematic review,
the one-year major amputation rate (four studies, 569 patients) was 0 percent, 8 percent, 11
percent, and 38 percent, for WIfI stages I, II, III, and IV, respectively [24]. The likelihood of
amputation after one year was also increased for patients with CLTI and higher WIfI stages,
providing important prognostic information. Two publications suggest that WIfI clinical stage
4 patients have a very low wound healing rate (44 percent) and high reintervention rate (46
percent) after endovascular therapy [17].
Anatomic pattern of disease — Computed tomographic angiography aids the diagnosis
and treatment planning for CLTI; however, most patients with CLTI will undergo conventional
catheter-based digital subtraction arteriography to identify the anatomic pattern of disease
and to identify target lesions for revascularization and possible inflow and outflow vessels for
bypass surgery. (See "Advanced vascular imaging for lower extremity peripheral artery
disease", section on 'Digital subtraction angiography'.)
The Global Limb Anatomic Staging System (GLASS) is an anatomic scheme proposed in the
2019 global vascular guidelines on the management of CLTI [6]. The GLASS classification
stratifies anatomic severity of infrainguinal occlusive disease and provides a framework for
evidence-based lower extremity revascularization for CLTI. GLASS involves grading the level
of disease in the femoropopliteal and infrapopliteal segments of the preferred target arterial
path for revascularization ( table 2). These are combined to provide a grade of overall
complexity that is intended to estimate limb-based patency of lower extremity interventions
for CLTI.
GLASS is predictive of limb outcomes following revascularization, but its predictability differs
for endovascular intervention compared with surgical bypass. A systematic review pooled
outcomes for 2204 patients with CLTI (2483 limbs) stratified by GLASS from eight studies
(seven retrospective cohort studies, one randomized trial) [25].
Following endovascular intervention, the pooled estimates for amputation-free survival
and limb salvage were worse for GLASS 3 compared with GLASS 1/2, and major adverse
limb events were increased for higher GLASS stages. Immediate technical failure also
increased with higher GLASS stage (GLASS 1: 3.9 percent; GLASS 2: 5.3 percent; GLASS 3:
27.9 percent).
●
Following bypass surgery, observed differences in amputation-free survival, limb salvage
rate, and major adverse limb events for GLASS 3 versus GLASS 1/2 were not significant.
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Procedural risk assessment — Candidates for revascularization should undergo procedural
risk assessment, which helps to determine candidacy for and approach to revascularization.
(See 'Approach to revascularization' below.)
Risk assessment typically focuses on the risk of major adverse cardiac events for which risk
assessment tools are available. (See "Evaluation of cardiac risk prior to noncardiac surgery".)
Although more difficult to assess, long-term survival should also be evaluated. In a review of
the Vascular Quality Initiative (VQI) database, over 38,000 patients with CLTI who underwent
revascularization were identified [5]. Subjects were stratified according to the following risk
categories:
The proportion of patients in the low-, medium-, and high-risk groups was 84, 10, and 6.5
percent, respectively. Patients in the high-risk group were significantly more likely to
undergo endovascular intervention compared with those in the low-risk group (75 versus 59
percent). Independent predictors of death included age >80 years, oxygen-dependent
chronic obstructive pulmonary disease, stage 5 chronic kidney disease, and bedbound
status; these were similar for all three models.
It is important to remember that the risk assessment tools including VQI risk assessment
tool have been developed using retrospectively collected data from patients who have
undergone revascularization and have excluded conservatively managed patients or those
who underwent primary amputation, and none have been prospectively tested and
validated.
COUNSELING THE HIGH-RISK PATIENT
When to consider palliative care — A subset of patients with CLTI are poor candidates for
revascularization because of comorbidities or unfavorable arterial anatomy. These patients
can often be managed with conservative therapy consisting of medical optimization, pain
control, aggressive wound care, and possibly pharmacologic therapies aimed at improving
wound healing. The goal is to get the patient into a manageable, stable state. If pain is
absent or not severe, a stable, chronic, nonhealing wound may be an acceptable situation
For GLASS 2 or GLASS 3, but not GLASS 1, the pooled rate of major adverse limb events
was significantly better for bypass surgery compared with endovascular therapy.
●
High risk was defined as 30-day survival97 percent or two-year survival >70 percent.●
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(so-called "wound hospice"). This may also be incorporated into a revascularization plan. As
an example, if the patient has multilevel lower extremity peripheral artery disease (PAD), a
simpler intervention or procedure that improves flow proximally may improve perfusion
sufficiently to stabilize the wound. However, if the patient has unremitting pain, primary
amputation may be required as a component of a palliative care plan, since narcotics for
ischemic limb pain is usually an untenable long-term option. (See 'Primary amputation
versus revascularization' below.)
There are no data to support the routine use of primary pharmacologic therapy in patients
with CLTI; the best therapeutic option is revascularization (endovascular, open); however,
when revascularization is not possible, medical therapies may be considered. Therapies that
have been investigated include prostaglandins, therapeutic angiogenesis, stem cell therapy,
and spinal cord stimulation. These are reviewed separately. (See "Investigational therapies
for treating symptoms of lower extremity peripheral artery disease".)
At Veterans Health Care Administration Hospitals involved in their mandatory Prevention of
Amputation Care Team (PACT) programs, 49 patients were assigned to conservative
management [26]. Inclusion criteria included the presence of a nonhealing wound (ulcer,
gangrene, surgical wound) for at least six weeks, ankle-brachial indexhttps://www.uptodate.com/contents/management-of-chronic-limb-threatening-ischemia/abstract/31
transfer out of bed can significantly impact a patient's quality of life. In addition, even older
adult patients have strong biases with respect to efforts to attempt limb salvage versus
primary amputation. The majority treated in the study suffered from CLTI and likely faced
amputation (not without its own risks) if revascularization was withheld. Thus, as in most
cases in medicine and surgery, the treatment plan needs to be individualized according to
each patient's vascular condition, comorbidities, and wishes.
REVASCULARIZATION
Optimal treatment of patients with CLTI requires expertise in both endovascular and open
revascularization techniques to manage this heterogeneous population. Details of these
techniques are reviewed separately.
Indications for and goals of revascularization — Most patients with CLTI can be offered a
reasonable attempt at limb salvage; however, primary amputation may be more appropriate
for some patients. (See 'Primary amputation versus revascularization' above.)
The goals of revascularization are to:
Approach to revascularization — Patients with CLTI often have multilevel disease and the
extent of revascularization depends on the goals of revascularization. The Global Vascular
guidelines emphasize the importance of an approach that is tailored to the individual patient
based upon numerous factors including the presence and degree of tissue loss; patient-
specific vascular anatomy; availability of vascular conduit; comorbidities such as cardiac risk,
which impacts the magnitude of intervention; and presence of diabetes or chronic kidney
disease, which impacts options with respect to use of contrast agents and likelihood of
procedural success [6]. To alleviate ischemic rest pain, restoration of flow into the lower
Endovascular – Percutaneous intervention (angioplasty, stent) is a less invasive alternative
to surgery in patients with CLTI that is associated with improved periprocedural outcomes
but is less durable. However, given the often limited life-expectancy of patients with CLTI,
durability may not be the most important factor to consider. (See "Endovascular
techniques for lower extremity revascularization".)
●
Surgery – For patients expected to live longer than two years and who are good surgical
candidates with adequate autogenous vein, the reduced intervention rate and durability of
bypass surgery probably outweighs the short-term increase in morbidity. (See "Lower
extremity surgical bypass techniques".)
●
Alleviate rest pain●
Heal wounds●
Improve physical functioning●
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extremity (ie, inflow) by treating aortoiliac and/or common femoral artery disease may be
adequate. For patients with tissue loss, in-line flow to the region of ulceration or gangrene
on the distal extremity is generally necessary to permit wound healing. Achieving in-line flow
can be accomplished using endovascular or open surgical revascularization.
Assessment of available saphenous vein by duplex imaging is an important early step in
treating patients with infrainguinal disease, particularly those with CLTI, as saphenous vein
availability and suitability has a major impact on selection of an open versus endovascular
treatment approach. The Best Endovascular versus Best Surgical Therapy for Patients with
Critical Limb Ischemia trial was a two parallel-trial cohort design that included over 1800
patients with CLTI and infrainguinal peripheral artery disease, with the goal of determining
whether a surgery-first or endovascular-first approach is preferred for patients with CLTI
judged to be suitable candidates for either approach [33,34]. In the first cohort, all patients
had an available single segment of suitable great saphenous vein on preoperative
ultrasound, whereas in the second cohort, none of the patients had an identifiable single
segment of great saphenous vein. Initial procedural success was 98 and 100 percent in the
first and second surgical cohorts, respectively, and 85 and 80.6 percent in the first and
For aortoiliac disease, an endovascular-first approach is recommended. Surgical
revascularization (eg, aortoiliac, aortofemoral, or extra-anatomic bypass) may be
warranted following failed endovascular intervention. For common femoral artery disease,
common femoral endarterectomy with patch angioplasty ensuring adequate flow into the
deep femoral artery can be performed concomitantly with an inflow procedure (eg, iliac
stenting), lower extremity bypass procedure (eg, femoropopliteal bypass, femoral-tibial
bypass), or lower extremity stenting (eg, superficial femoral artery).
●
For femoropopliteal artery disease, the selection of open surgical or endovascular
revascularization depends on the length of the lesion. Surgical bypass is overall more
durable for longer lesions compared with stenting [32]. For tibial vessel disease, the
selection of open surgical or endovascular revascularization is complex and based on the
combination of severity of limb threat, vascular anatomy, availability of suitable saphenous
vein, the life expectancy of the patient, and shared surgeon-patient decision making. For
patients who are judged to be suitable candidates for either open surgical bypass or
endovascular revascularization and who have a suitable single segment of great
saphenous vein, a bypass-first strategy is associated with less major adverse limb events
or deaths, although some patients may still prefer an endovascular-first approach. For
patients requiring infrapopliteal level bypass with or without additional infrainguinal
intervention, endovascular-first strategy may be associated with better amputation-free
survival. For those without an adequate single segment great saphenous vein, either
surgical bypass or endovascular revascularization may be selected after fully informed,
shared decision making.
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second endovascular cohorts, respectively. Following randomization to surgical bypass or
endovascular revascularization, the technique used was at the discretion of the operator. The
rates of adverse cardiovascular events and death were similar between the cohorts and were
also similar between the groups within each cohort.
The BASIL-2 trial randomized 345 patients with CLTI requiring infrapopliteal revascularization
to a vein bypass first (VB; 172 participants) or best endovascular treatment first strategy (BET;
173 participants) with or without proximal infrainguinal revascularization [35]. Most vein
bypasses used the great saphenous vein and originated from the common or superficial
femoral arteries. Most endovascular interventions were plain balloon angioplasty; plain or
drug eluting stents were used selectively. The rate of major amputation or death was lower
in the BET group compared with the vein bypass group (53 versus 63 percent; adjustedhazard ratio [aHR] 1.35, 95% CI 1.02-1.80). This outcome was driven primarily by lower
mortality in the BET group (45 versus 53 percent; aHR 1.37, 95% CI 1.00-1.87). Overall,
median amputation-free survival was 3.8 years, 3.3 years in the VB group and 4.4 years in the
BET group; these results are similar to those reported in the BASIL-1 trial [36].
The BASIL-2 trial differed from BASIL-1 trial, which showed better amputation-free survival
with a surgery-first approach. However, in the BASIL-1 trial, approximately 25 percent of
patients had infrapopliteal interventions, with a significant number of patients with bypass
In the first cohort, all patients had a suitable single segment of great saphenous vein and
were randomly assigned to either surgical bypass (n = 718) or endovascular
revascularization (n = 716). After a mean 2.7 years, the composite outcome of a major
adverse limb event or death from any cause was significantly lower in the surgical bypass
group (42.6 versus 57.4 percent; hazard ratio [HR] 0.68, 95% CI 0.59-0.79). Among the early
failures in the endovascular group, 66 of 108 (61 percent) subsequently underwent surgical
bypass. The rate of major reintervention was also lower in the surgical group (9.2 versus
23.5 percent; HR 0.35, 95% CI 0.27-0.47). The incidence of above-ankle amputation of the
index limb was also lower in the surgical group (10.4 versus 14.9 percent; HR 0.73, 95% CI
0.54-0.98).
●
In the second cohort, patients did not have a single segment of great saphenous vein and
were randomly assigned to surgical bypass (48 alternative autogenous vein, 119 prosthetic
grafts, 30 great saphenous vein identified on exploration) or endovascular
revascularization (n = 199). After a mean 1.6 years follow-up, the composite primary
outcome was also lower in the bypass cohort but was not statistically significant (42.8
versus 47.7 percent; 95% CI 0.58-1.06). Among the early failures in the endovascular group,
26 of 37 subsequently underwent surgical bypass. The rates of re-intervention and time to
re-intervention were similar. The rate of above-ankle amputation was also similar between
the groups.
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procedures that used nonautologous grafts, which could explain the different outcomes. The
BASIL-2 trial also seemed to conflict with the results of the BEST-CLI trial. Over half of those
in the BEST-CLI had infrapopliteal level revascularizations; however, the primary endpoints of
the two studies differed. Although BASIL II and the BEST-CLI trial were developed, run, and
analyzed entirely independently, the two groups of investigators have collaborated closely
and entered into a data-sharing agreement before either trial was analyzed. Until an in-
depth comparison of the two trials is made using individual, patient-level data meta-analysis,
it will not be possible to make strong recommendations for patients with CLTI who need
infrapopliteal revascularization.
ONGOING MEDICAL THERAPY AND FOLLOW-UP
Following revascularization for CLTI, regular follow-up is important [3]. Regardless of
revascularization type, follow-up consists of periodic clinical evaluations that should note any
return or progression of symptoms, the presence of pulses, and measurement of the ankle-
brachial pressure index and toe systolic pressure. Duplex imaging of the revascularized limb
(with bypass or endovascular means) with measurement of peak systolic velocity and
calculation of velocity ratio across all lesions also plays an important role. (See "Noninvasive
diagnosis of upper and lower extremity arterial disease", section on 'Ankle-brachial index'.)
Surveillance ultrasound – Surveillance ultrasound is typically obtained following
revascularization. Patients with autologous bypass are likely to benefit from routine
surveillance. (See "Lower extremity surgical bypass techniques", section on 'Graft
surveillance'.)
●
However, there is no consensus whether or when to obtain surveillance ultrasound
following endovascular intervention or how best to manage asymptomatic restenosis
when identified. The Global Vascular Guidelines note that data demonstrating a clinical
benefit for surveillance after endovascular intervention are inadequate [6]. (See
"Endovascular techniques for lower extremity revascularization", section on 'Surveillance
after endovascular interventions'.)
Subgroups who may benefit more than others from close surveillance and early
reintervention following endovascular intervention may include those with:
Multiple failed angioplasties•
Previously failed bypasses or for whom conduits are unavailable•
Severe ischemia (eg, WIfI ischemia grade 3), unresolved tissue loss, or appearance of
new inflow lesions
•
Known poor runoff or long target vessel occlusion•
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Wound evaluation and surveillance – Patients who have been successfully treated for CLTI
are at relatively high risk for recurrence. Immediately following revascularization, wounds
are followed to complete healing. Thereafter, the patient should be evaluated at least twice
yearly by a vascular specialist and should be provided with verbal and written instructions
for self-surveillance. Breakdown of the wound or appearance of new wounds may be
indicative of a failing revascularization, and repeat intervention may be needed.
●
Cardiovascular risk reduction – Antiplatelet therapy (aspirin 75 to 325 mg) is recommended
to reduce the risk of myocardial infarction, stroke, and vascular death in individuals with
symptomatic peripheral artery disease, including those with CLTI [27]. Clopidogrel is an
effective alternative to aspirin in those who cannot take aspirin. Risk factor reduction
strategies, including control of hypertension, hyperlipidemia, and blood sugar, as well as
smoking cessation, are essential. Intensive-dose statin therapy (eg, rosuvastatin 20 to 40
mg daily, atorvastatin 40 to 80 mg daily) reduces cardiovascular events, mortality, and
amputation rates in patients with PAD [37-39]. (See "Peripheral artery disease: Prevalence
and risk factors".)
●
Antithrombotic therapy — Following lower extremity revascularization, thebenefits of the
long-term antithrombotic therapy remain unclear. Antiplatelet agents or anticoagulants
are often used to prevent graft occlusion, although data about their efficacy are limited
[40]. There may be a benefit of direct oral anticoagulants for long-term use in patients with
peripheral artery disease (PAD). (See "Overview of lower extremity peripheral artery
disease" and "Endovascular techniques for lower extremity revascularization", section on
'Antiplatelet therapy' and "Lower extremity surgical bypass techniques", section on
'Antithrombotic therapy'.)
●
The Cardiovascular Outcomes for People Using Anticoagulation Strategies trial, a
multicenter randomized trial of 7470 individuals with stable, mild to moderate PAD
reported reduced major adverse cardiovascular events (death, myocardial infarction, or
stroke) and major adverse limb events in patients who received low-dose rivaroxaban
(an oral factor Xa inhibitor) in combination with aspirin compared with aspirin alone.
However, in this study, only 8.5 percent of patients had an ankle-brachial index ofand increased amputation risk. Marginal perfusion to
the extremity may be adequate to sustain healthy tissue at rest but can be insufficient to
provide the increased energy required for wound healing. (See 'Vascular assessment'
above.)
●
Initial management – The initial care of the patient with CLTI includes control of pain,
which can be severe, anticoagulation to limit thrombus propagation in some cases,
appropriate wound care, pressure off-loading, and treatment of infection, if present. (See
'Initial management' above.)
●
Approach to the patient – The approach is tailored to the individual and involves a three-
step approach that takes into account limb staging using the Society for Vascular Surgery
Lower Extremity Threatened Limb Classification System, the anatomic pattern of disease,
and assessment of the patient's procedural risk. (See 'Approach to the patient' above and
'Revascularization' above.)
●
The Wound, Ischemia, and foot Infection classification grades the wound, the severity of
ischemia, and the presence of foot infection ( figure 1). The combinations of these
grades correspond to one of four clinical stages (1 through 4) that correlate with the
potential for wound healing and risk of amputation ( table 1). The stage of limb threat
drives the urgency and potential need for hospital admission and revascularization. (See
'Limb staging by severity of limb threat' above.)
•
Angiography identifies the anatomic pattern of disease, possible target lesions for
revascularization, and possible inflow and outflow vessels for bypass surgery. The Global
Limb Anatomic Staging System (GLASS) ( table 2) is a classification that stratifies
anatomic severity by grading the level of disease along the potential target arterial path
for revascularization. (See 'Anatomic pattern of disease' above.)
•
Assessment of procedural risk helps determine candidacy for, approach to
(endovascular, open surgical), and extent of revascularization. For a patient with high
procedural risk, a limited revascularization may accomplish the intended goal. (See
'Procedural risk assessment' above.)
•
Revascularization – Most patients with CLTI can be offered a reasonable attempt at limb
salvage to alleviate rest pain, heal wounds, and improve physical functioning. Informed,
shared decision making is important in making decisions regarding choice of
revascularization. (See 'Revascularization' above.)
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●
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