16 CLTI
Authors: Nedal Katib and Danielle Bajakian
Contributor: Eilidh Gunn
16.1 Guidelines
Much of the content here is adapted from the most recent Global vascular guidelines on the management of chronic limb-threatening ischemia(Conte et al. 2019).
In 2019 the SVS, the ESVS and the World federation of Vascular Societies (WFVS) joined forces to put together the structure and funding of the Global Vascular Guidelines Initiative (GVG). Importantly all sponsorship was directly from the societies and any direct industry sponsorship or external sources were excluded. They put together a steering committee responsible for recruiting a large and diverse writing group and outlined the scope and developed the section briefs of the guideline.
They determined that:
“The term”critical limb ischemia” (CLI) is outdated and fails to encompass the full spectrum of patients who are evaluated and treated for limb-threatening ischemia in modern practice.”
Chronic Limb Threatening Ischemai (CLTI) was promoted as the term of choice and was defined by the target population.
The target population were:
Ischemic Rest Pain with confirmatory hemodynamic studies.
Diabetic Foot Ulcer or any lower limb ulceration present for at least 2 weeks.
Gangrene involving any portion of the lower limb or foot.
Exclusion from the population:
Purely Venous Ulcers
Acute Limb Ischemia/acute trash foot/ischemia due to emboli
Acute Trauma or mangled extremity
Wounds secondary to non-atherosclerotic conditions
Methodology of the guidelines utilized the structure of the GRADE certainty of evidence system.
They highlighted particular important sections in the evaluation and management of patients with CLTI: Patient Risk stratification, Limb Assessment and Severity of Limb Threat and the development of a specific evidence-based revascularisation guideline in CLTI.
It is important to note that compared to most guidelines, unfortunately in the management of CLTI, particularly when it comes to revascularisation, the level of evidence is generally LOW. Again, it is important to highlight that the significance of these guidelines in developing a standard approach and appropriately stratifying patients in not only management but ongoing research.
16.2 Demographics
16.2.1 Etiology and Presentation
How does PAD pathologically progress clinically into Chronic Limb Threatening Ischemia (CLTI)?
The latter stages of both the Rutherford and Fontaine Classification systems highlight this progression, with the Rutherford classification of Stage 5 being specifically minor tissue loss with focal gangrene, and stage 6 as major tissue loss identified by spreading of gangrene beyond the Trans metatarsal level.
Rutherford et al. Ad Hoc Committee on Reporting Standards, SVS/North American Chapter ISCVS:
| Grade | Category | Clinical Description |
|---|---|---|
| 0 | 0 | Asymptomatic -no hemodynamic significant occlusive disease |
| I | 1 | Mild Claudication |
| I | 2 | Moderate Claudication |
| I | 3 | Severe Claudication |
| II | 4 | Ischemic Rest Pain |
| III | 5 | Minor Tissue Loss |
| III | 6 | Major Tissue Loss |
What is Chronic Limb Threatening Ischemia (CLTI), sometimes previously known as Critical Limb Ischemia (CLI)?
In the last decade leading up to the 2021 Global Vascular Guidelines (GVG), the term (Chronic Limb threatening Ischemia) CLTI has been gradually replacing CLI. The GVG mentions that their “promotion” of the term CLTI is partly due to terms such as “critical or severe limb ischemia” failing to “recognize the full spectrum and inter-relatedness of components beyond ischemia that contribute to major limb amputation…”
What was the original definition and threshold for CLI, and how can we make sure we elicit the right symptoms from the patient?
John Cranley back in his publication in 1969 defined Ischemic Rest Pain as,
“…pain that occurs in the toes or in the area of the metatarsal heads. Occasionally…in the foot proximal to the metatarsal heads. Elevation of the limb above or at the horizontal position aggravates the pain and pendency…brings relief…” (Cranley 1969)
Nocturnal Rest Pain: Worse due to horizontal positioning (no gravitational assistance) and systolic BP drop during sleep.
16.2.2 Natural History
What is the natural history of CLTI and what do we know about its prognosis?
Fortunately, only a small portion of patients with Intermittent Claudication will go on to develop rest pain or tissue loss. Its estimated that anywhere between 5% -29% of patients with PAD or IC go on to develop CLTI over 5 years.
However, those that do develop CLTI, have a high risk of limb loss (greater than 20% annual risk).
Patients with CLTI have a high mortality risk (10-15% annual risk), the majority of terminal events being related to cardiovascular events. Limb loss or mortality may reach as high as 50% in 1 year. (Adam et al. 2005; Norgren et al. 2007)
What has changed in the last few decades?
Etiologically the prevalence of smokers(Ex and Current) in the population has decreased and the prevalence of diabetes has increased. For more details on the relationship between diabetes and pad, see Section 15.1.1
16.2.3 WIFi Classification
What is the WIFI Classification?
Interestingly in the original article by Bob Rutherford regarding Diabetes and PAD:
- “It was generally agreed that diabetic patients who have a varied clinical picture of neuropathy, ischemia and sepsis make the definition even more difficult and it is desirable that these patients be excluded…diabetic patients should be clearly defined as a separate category or should be clearly defined as a separate category.”
Since then, the SVS, while acknowledging that we can no longer exclude these patients and treat them separately given the overlap, have decided that a new classification system is necessary, as one of the key authors (Joseph Mills) states:
- “We classify things into groups to differentiate, remember and compare, observe and predict their behavior over time.” –Joseph Mills
WIfI stands for: Wound, Ischemia and foot Infection. Most of the existing Vascular and non-Vascular classification systems don’t include all three components or fail to stratify the degree of ischemia and presence of gangrene.(Mills et al. 2014)
Principles of WIfI:
Grades, Classes and Stages – Each of the three categories (WIfI) have Grades 0,1,2,3: Resulting in 64 Classes.
Delphi Consensus – Clinical Stages 1 (Very Low),2 (Low), 3 (Moderate), 4 (High Risk/Benefit).
What is the one-year risk of amputation with medical therapy alone?
What is the potential benefit from successful revascularization?
Analogous to TNM Staging
“It is intended to be an iterative process with the goal of more precisely stratifying patients according to their initial disease burden, analogous to TNM cancer staging, but not to dictate therapy.”
Get the App!
Check out the SVS iPG App for help using the WIfi classification during your day-to-day care of CLTI patients. The best way to understand the WIfi score is to use it on a few patients and see what recommendations are provided.
16.2.4 Differential Diagnosis
What about a differential diagnosis or other causes of similar pain as rest pain?
Acute lower limb ischemia has a different clinical presentation, but there may be some overlap with Acute on Chronic disease such as in the case of in situ thrombosis in the lower limb arterial system.
Other causes of ischemic pain include:
Buergers Disease, or Thromboangiitis Obliterans - for more see Section 3.3.4
Scleroderma
Fibromuscular Dysplasia - for more see Section 12.2
Popliteal Artery Entrapment - for more see Section 17.4.1
Cystic Adventitial Disease - for more see Section 17.4.2
Persistent Sciatic Artery Disease
Neurogenic pain
What is the Rutherford Acute Ischemia Grading System?
Although acute ischemia is very different from chronic ischemia, patients with progressive chronic PAD can develop an acute picture whether from embolism or in-situ thrombosis secondary to plaque rupture. See Chapter 17 for more.
16.3 Evaluation
What aspects of the clinical assessment is important?
Clinical Assessment involves a full history (the differential mentioned in Intermittent Claudication) and examination.
Clinical Examination:
Buergers Test (Buerger 1908) / AKA Ratschows Test (Max-Ratschow-Klinic) identifies when there is critical ischemia without necrosis yet or gangrene, and is characterized by pallor when the leg is elevated above the level of the heart, which then turns red when hanging down over the edge of the bed. This redness is referred to as “Sunset appearance” and its due to abnormal autoregulation. Its been described that normally only a third of the capillary bed is open at any time but in a state of critical ischemia because of the autoregulation being paralyzed a significantly higher portion of the capillaries open up.
The ischemic Angle: A refinement to Berger’s Test: The angle of elevation from the horizontal at which the Doppler Signal of the PT or DP disappears. This is also referred to as the ‘pole test’, whereby the foot is raised alongside a calibrated pole marked in mmHg.
Tissue Loss:
Gangrene Dry or Wet (infection)
Level of tissue Loss
Probing To Bone/ Exposed structures: Tendons, Soft Tissue, bone, Joint Capsule.
Examination of an Ulcer (may have many etiologies) – important not only to identify extent of disease but also to exclude other etiologies:
- Such as venous, mixed, infective, autoimmune, inflammatory, malignancy or trauma.
Foot Infection - Signs of infection, erythema, rubor, cellulitis, tenderness or unexplained hyperglycemia in diabetic patients should prompt urgent referral.(Kalish and Hamdan 2010)
16.3.1 Physiologic Testing
What other clinical evaluation is necessary for the patient with CLTI?
In addition to history, examination, and WIfI assessment mentioned above, for patients with diabetes and an ulcer a full assessment of neuropathy and a “probe to bone” test for any open ulcers is recommended as part of good practice.
In the PAD and intermittent claudication sub chapters the non-invasive methods of assessment for these patients have been discussed. In addition it is important to emphasize the role of Toe Pressures (TP) and Toe Pressure Index (TPI) in this cohort of patients.
CLTI measurements most predictive of non-healing are ankle pressure <50mmHg, ABI <0.4, TcPO2 <20mmHg, and TP <20mmHg.(Gerhard-Herman et al. 2017; Wickström et al. 2017). Healing of an ulcer or tissue loss is unlikely if a patient’s toe pressures are less than 55mmHg. And Toe Pressures have been validated in multiple studies to correlate with Amputation free survival and wound healing: Amputation Free Survival TP <30mmHg 2.13 HR (1.52-2.98). (Wickström et al. 2017; Hicks et al. 2018)
Patients with ESRD or DM develop medial calcification and often have elevated ABPI (>1.3) - which is associated with an elevated risk of cardiovascular mortality. Outcomes in patients with ESRD are worse in relation to amputation free survival and amputation rates, regardless of revascularization strategy.(Meyer et al. 2018) Toe pressures are particularly important in this scenario. (Resnick et al. 2004; Vitti et al. 1994)
Regarding non-invasive assessment for wound healing, a TcPO2 greater than 40mmHg has the greatest correlation with amputation stump healing.(Malone et al. 1987)
16.3.2 Imaging
What imaging assessment is required?
The CLTI Guidelines outline an algorithm of attaining Arterial Anatomical Imaging. Starting with US and then depending on the information required, CTA, MRA, or eventually digital subtraction angiography. They emphasize the importance of obtaining good quality imaging to appropriately stage and be able to compare the level and degree of disease.
For wounds with concern for underlying osteomyelitis - initial workup is with plain radiography, which can identify soft tissue emphysema, evidence of osteomyelitis, or presence of a foreign body. High suspicion of early osteomyelitis with negative x-ray may warrant an MRI.(Giurato et al. 2017)
The most recently published RCT in CLTI, BEST-CLI, highlights the good outcomes of surgical bypass with saphenous vein, suggesting that vein mapping also be considered a routine imaging study during the workup of patients. This will help to clearly understand revascularization options before attempting endovascular diagnostic or therapeutic interventions.(Farber et al. 2022)
Take a Listen
Check out our episode with BEST-CLI Principle Investigators Dr. Alik Farber and Dr. Matthew Menard as they discuss the development of this trial. This episode was created as they were completing enrollment and prior to the release of the results of their study.
What is the Global Limb Anatomic Staging System (GLASS)? (Conte et al. 2019)
Because the existing arterial anatomical staging of disease is vague, “lesion focused”, and not all encompassing (beyond the concept of ‘in-line pulsatile flow to the foot’), GLASS focuses on infrainguinal disease, and attempts to incorporate all aspects in its staging to improve vascular care and evidence-based revascularisation (EBR) outcomes.
GLASS is a grading system based on anatomical and subjective assessment of calcification and incorporates two novel and important concepts:
The Target Arterial Path (TAP)
Estimated Limb-Based Patency (LBP)
As GLASS focuses on Infrainguinal disease, with the aortoiliac (AI) segment considered the inflow disease which includes the Common Femoral Artery and the Profunda Artery. Therefore, the GLASS grades assume the inflow vessels are treated and adequately ‘dealt with’.
Infrainguinal disease assessment for Femoropoliteal (FP) and Infrapopliteal (IP) is based on length of disease and the extent of CTOs. The FP and IP GLASS Grades are then combined into Stages 1-3.
The calcification scale is a dichotomous subjective assessment of the degree of calcification and if there is >50% circumference of calcification, diffuse or bulky calcification or “coral reef” plaques, then there is an increase in the within-segment grade by one numerical value.
There is also mention of the Inframaleolar (IM) degree of disease (PO, P1-absent arch, P2-no target artery crossing into foot) which is not included in the GLASS staging given little evidence on the outcomes this difference makes on overall patency and limb salvage.
Once the GRADES (0-4) of FP and IP disease are determined then staging (1-3) can be performed based on the matrix or grid that is provided. Staging then allows for est imated Peripheral endoVascular Intervention outcomes (PVI) to be predicted, Immediate Technical Failure (ITF - <10% or < 20% or > 20%)) and 1-year Limb Based Patency (LBP - >70%, 50-75% or <50%).
What is the Target Arterial Path (TAP)?
“The selected continuous route of in-line flow from groin to ankle. The TAP typically involves the least diseased IP artery but may be angiosome based.”
Again, Get the App!
Check out the SVS iPG App for help with also the GLASS Criteria during your day-to-day care of CLTI patients. The best way to understand the GLASS Criteria is to use it on a few patients and see what recommendations are provided.
16.4 Management
16.4.1 Medical Managment
What are the recommendations for patients with CLTI when it comes to Medical Therapy and Risk Factor Modification?
Treat all patients with CLTI with an antiplatelet agent (Grade 1 Level A). Consider Clopidogrel as the single agent (Grade 2 Level B) – CAPRIE(Committee 1996)
High-intensity statin therapy to reduce all-cause and cardiovascular mortality - Atorvastatin 80mg or Rosuvastatin 40mg. These can be titrated down to atorvastatin 40mg or rosuvastatin 20mg if unable to tolerate. (Grade 1 Level A) (Arya et al. 2018; Grundy et al. 2019)
Control Hypertension to BP target <140mm Hg systolic and <90mm Hg diastolic in patients with CLTI (Grade 1 Level B)
Offer Smoking Cessation interventions and ask all smokers or former smokers about status of tobacco use every visit (Grade 1 Level A)
Diabetic foot wounds with signs of infection, erythema, swelling, pain and foul smelling drainage should be investigated with plain radiography, ESR, CRP, cultures and, managed with iv antibiotics. Signs of systemic sepsis, such as fevers, tachycardia or shock, such as hypotension, should warrant urgent debridement and drainage, regardless of vascular status.
For more details, see Section 15.2.2.1
16.4.2 Endovascular and Surgical Management
Which revascularisation management strategies exist for CLTI?
The mainstay of management for patients with CLTI have always been based on the fundamental principle of limb salvage. Given the high risk of limb loss in these patients there is a low threshold to revascularize these patients if they have occlusive disease that is treatable. But strategy has varied significantly.(Conte et al. 2019)
The CLTI Guidelines provide an approach to dealing with this complex condition on planning three aspects to each case:
Patient Risk Estimation
Limb Staging
Anatomic Pattern of Disease
What is involved with the Patient Risk Estimation?
Good Practice Statements (Recommendations section 6)
“Refer all patients with suspected CLTI to a vascular specialist for consideration of limb salvage, unless major amputation is considered medically urgent.”
“Offer primary amputation or palliation to patients with limited life expectancy, poor functional status (e.g. non ambulatory), or an unsalvageable limb after shared decision-making.”
Recommendation 6.3:
Estimate periprocedural risk and life expectancy in patients with CLTI who are candidates for revascularization. Grade 1 (Strong) Level of Evidence C (Low)
Average Surgical Risk: <5% operative mortality and 2-year survival >50%
Severe Surgical Risk: >/= 5% operative mortality and 2-year survival </=50%
Understanding disparities is important when interpreting risk for amputation. Observational studies have found certain populations to be at higher risk of amputation regardless of disease severity. These groups include African Americans, lowest median income, medicaid insurance, uninsured, or those from regions with less access to vascular surgeons.(Hughes et al. 2019; Ho et al. 2005; Eslami, Zayaruzny, and Fitzgerald 2007)
What is involved and recommended with the Limb Staging and recommendation for Management?
Use an integrated threatened limb classification system (such as WIfI) to stage all CLTI patients who are candidates for limb salvage. Grade 1 (Strong) Level of Evidence C (Low)
Perform urgent surgical drainage and debridement (including minor amputation if needed) and commence antibiotic treatment in all patients with suspected CLTI who present with deep space foot infection or wet gangrene. (Good Practice Statement)
Offer Revascularisation to all “average surgical risk patients” (\<5% operative mortality and 2-year survival >50%) with advanced limb-threatening conditions (e.g. WIfI stage 4) and significant perfusion deficits (e.g. ischemia grades 2 and 3). Particularly if they have good saphenous vein. Grade 1 (Strong) Level of Evidence C (Low) (Adam et al. 2005; Norgren et al. 2007)
What is involved in the Planning of the Anatomic pattern of disease and its effects of revascularisation strategy?
The overall pattern of arterial occlusive disease is a dominant factor in guiding type of revascularisation and timing of such.
Do all patients require direct in-line flow to the foot as a primary technical outcome with revascularisation?
Patients with rest pain do not necessarily require direct in line flow are those with rest pain “for which correction of inflow disease alone or treatment of FP disease even without continuous tibial runoff to the foot may provide relief of symptoms. This may also be the case in patients presenting with minor degrees of tissue loss.”
Profunda-popliteal collateral index (Segmental pressures AK-BK/AK) of less than 0.25 may suggest that there is sufficient collateral network between profunda and popliteal that SFA treatment may not be necessary. (Boren et al. 1980; Mawatari et al. 2000)
What are some essential Key Factors to consider before deciding Open versus Endovascular according to the CLTI guidelines?
The “availability of and quality of autogenous vein conduit”
Single segment GSV best conduit for infrageniculate bypass. (Arvela et al. 2010; Avgerinos et al. 2015; Moreira et al. 2016).
Fem-AK pop bypass with prosthetic may be preferred to contralateral GSV. (Moreira et al. 2016)
If the target is below the knee, then all autogenous conduits–contralateral GSV, SSV, and spliced arm vein–are preferred over prosthetic grafts.(Brochado Neto et al. 2014; Faries et al. 2000; Taylor et al. 1987)
Patient overall risk (as mentioned above) and Limb Staging
Planning distal bypasses should take into account the angiosome of the wound and the most distal healthy inflow vessel to result in the shortest bypass possible.(Hingorani et al. 2016; Jongsma et al. 2017)
Intensified anti-thrombotic therapy may be needed in patients with “high risk” infrainguinal bypasses–prosthetic conduit, below the knee target, suboptimal conduit, poor arterial runoff, extensive lesions or tissue loss. Single anti-platelet may not be sufficient, and should be intensified to asa/rivaroxaban, dual antiplatelet, or anticoagulation with Vit K antagonist.(Conte et al. 2015; Hussain et al. 2018; Strobl et al. 2013; Tepe et al. 2012)
The Target EndoVascular Intervention (TVI) outcomes
What evidence do we have for deciding between Endo and Open management? What is the BASIL trial?
In November of 2022, the first results of the BEST-CLI were published in the NEJM. BEST-CLI is the first international, open-label, multicenter, superiority trial of its scope and scale. The key results found that in patients with adequate great saphenous vein conduit, the surgical group demonstrated a lower incidence of major adverse limb events or death (the study’s primary endpoint) than the endovascular group. They found relatively equivalent outcomes in patients with inadequate autogenous conduit.(Farber et al. 2022) The full impact of the results of this study is yet to be determined, and there will likely be several additional analyses published from this study’s data. It is unlikely that this data will impact what is tested on this year’s exams. However, you should keep an eye out for future results!
Take a Listen
Check out our episode with BEST-CLI Principle Investigators Dr. Alik Farber and Dr. Matthew Menard as they discuss the development of this trial. This episode was created as they were completing enrollment and prior to the release of the results of their study.
Other than this most recent study, the evidence is largely of poor quality, and is retrospective, non-controlled, or industry sponsored. BASIL (Bypass versus Angioplasty in Severe Ischemia of the Leg) previously had been the only multicenter RCT (BASIL -2 and 3 underway) directly comparing an endo versus open management strategy for CLTI and Infra-inguinal occlusive disease.
BASIL compared POBA and Bypass across multiple centers (27 centers, n=452, 1999-2004) in the UK. Primary endpoint was Amputation-Free Survival (AFS). (Bradbury et al. 2005)
Major Findings:
At 6-months follow up: no difference in AFS.
Intention-To-Treat Analysis of overall follow up showed no significant difference in AFS and overall survival.
Among patients who survived >2 years, overall survival was better for those treated with Bypass as a first approach
Analysis to treat:
Prosthetic Bypass Patients did very poorly (even compared to POBA).
Patients who had bypass after failed POBA had significantly worse AFS compared to those treated with a bypass as initial treatment.
Criticism of BASIL:
Majority had POBA alone (not currently best endovascular option)
25 % of Open Bypass were Prosthetic
The technology and technical Skill with growing operator experience in Endovascular has improved.
For isolated tibial disease, first line endovascular treatment of choice is transluminal, or subintimal angioplasty. Atherectomy, stenting, and drug coated balloons are often used, but should currently not be considered first line, but this data is rapidly evolving. Patency is often poor but limb salvage is reasonable.(Popplewell and Bradbury 2019; Kayssi et al. 2016; Mustapha et al. 2016)
Optimal follow up for endovascular interventions of the lower extremity has not yet been established, but should at least include a pulse exam, ABPI and duplex to establish a new baseline after intervention.(Zierler et al. 2018; Mohler et al. 2012)
What are the BASIL 2, BASIL 3, and BEST-CLI Trials?
BASIL 2: Infrapopliteal Disease: Vein Bypass First vs. Best Endovascular Treatment first.
BASIL 3: PBA +/- BMS vs. DCB +/- BMS vs. DES
(Both Follow up 24-60 months, Primary Endpoint AFS)
BEST-CLI: Open Bypass versus Endovascular Intervention, Primary Endpoint: MALE-Free Survival. Major Above-the-Ankle Amputation, Major Bypass or Jump/interposition graft revision or the need for thrombectomy or thrombolysis (MALE).
16.4.3 Complications
What are some complications of lower extremity revascularization procedures?
For a comprehensive list of access complications after endovascular therapy, see Section 22.1
Femoral exploration carries high risk of infection or lymphatic leak. Lymphatic leaks often resolve spontaneously. Infected lymphatic leaks, particularly in the setting of prosthetic bypass require exploration. Should a lymph leak not resolve with conservative management, definitive therapy requires alcohol ablation or muscle flap coverage. The most important aspect of lymph leak is prevention with careful dissection and tissue management during femoral exploration.(Obara et al. 2014; Weaver et al. 2014)