Patients with chronic limb-threatening ischemia (CLTI) are among the most complex that a podiatrist may treat. Here the authors share their experience and the latest research on effectively preventing, diagnosing, classifying and managing CLTI.
The integration of a multidisciplinary approach to diagnosing and treating patients with chronic limb-threatening ischemia (CLTI) provides optimal care that results in a better quality of life for many patients with peripheral arterial disease (PAD).1 Patients with CLTI, an advanced stage of PAD, may have rest pain, gangrene (see top photo above) and/or ulcerations of greater than two weeks in duration. The disease continues to be refractory to treatment in some patients. However, contemporary management of patients with CLTI fosters the focused expertise of diverse teams to elucidate emerging concepts in diagnosing and treating the complex nature of PAD.
The Global Vascular Guidelines, published in June 2019, reflected an initiative by the European Society for Vascular Surgery (ESVS), the Society for Vascular Surgery (SVS) and the World Federation of Vascular Societies (WFVS). These three major global vascular surgery organizations provided a consensus on the “definition, evaluation, and management of CLTI with the goals of improving evidence-based care and highlighting critical research needs.”2
The Latest Recommendations Regarding PAD And CLTI Prevention
Peripheral arterial disease is first and foremost not a surgically managed disease. It is a systemic disease with modifiable risk factors such as smoking, diabetes mellitus, obesity, hypertension and hyperlipidemia.3-5 Although limb loss is a justifiable concern for those with CLTI, the PAD that caused the CLTI affects other anatomic systems as well.6 Thus, patients with CLTI have a markedly increased incidence of cardiovascular and cerebrovascular morbidity. Without aggressive risk factor modification, the prognosis of patients with CLTI is poor with a mortality rate of approximately 25 percent within one year of diagnosis.7,8
Patients with CLTI who abuse tobacco have poorer outcomes due to a significantly higher rate of disease progression and higher revascularization failure.9 Frontline health care providers should offer smoking cessation interventions at every visit.10
Antiplatelet agents continue to be recommended for all patients with PAD and CLTI. Multiple studies show a significant reduction in major adverse cardiovascular events in the antiplatelet group.11,12 Most recently, the Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) trial found that low-dose rivaroxaban (Xarelto®, Janssen) with aspirin versus aspirin alone reduced major adverse cardiovascular events.13
Aggressive lipid-lowering therapy with diet and statins reduces mortality in patients with CLTI.14 Concurrently, optimal blood pressure control has not been defined for patients with CLTI but systolic blood pressure less than 140 mmHg and diastolic blood pressure less than 90 mmHg provides reduction of cardiovascular events in this population.15 Hemoglobin A1c of less than 7 percent further modifies mortality risk for patients with CLTI and diabetes.16
The Newest Algorithms For Diagnosing And Stratifying CLTI
A high index of clinical suspicion is the key to successful treatment of CLTI. Early diagnosis and accurate staging of disease severity and continued progression, using such tools as the Society for Vascular Surgery Threatened Limb Classification System or the Wounds, Ischemia and Foot Infection classification (WIfI), provides a detailed prognosis of limb threat and thus tailors the urgency of treatment.17
Objective testing such as the ankle brachial index (ABI)/toe brachial index (TBI) and arterial duplex are simple, inexpensive, quick and noninvasive diagnostic measures to guide treatment and surveillance. Ankle pressure less than 50 mmHg or a toe pressure less than 30 mmHg with rest pain is suggestive of longstanding decline in peripheral perfusion.18 Ankle pressure less than 70 mmHg and a toe pressure less than 50 mmHg with gangrene/ulceration may also be diagnostic of this decline. A high index of suspicion is necessary for patients with neuropathy as patients may not report rest pain despite having CLTI. If the patient with CLTI is a candidate for revascularization, an angiogram continues to be the gold standard imaging technique for surgical intervention. Due to improved availability and accuracy, computed tomography angiography (CTA) and magnetic resonance angiography (MRA) are also widely used for diagnosis.
The Global Limb Anatomic Staging System (GLASS) is a newly proposed, clinically-oriented classification system to stratify CLTI.2 The stratification system incorporates the complex, multilevel and often tibial/pedal disease patterns typical to patients with CLTI. Use of the GLASS system involves identifying the target arterial path and determining the femoral popliteal GLASS grade, infrapopliteal GLASS grade, degree of calcification and the severity of pedal disease.
The GLASS system correlates primarily with endovascular outcomes and namely targets the inline arterial path providing runoff into the foot. It does not incorporate open bypass revascularization factors such as conduit availability. Accordingly, although the GLASS system facilitates a more complex and comprehensive anatomic staging system to guide clinical practice guidelines, it does require prospective validation.
Revascularization: When Is It Appropriate And What Is The Best Strategy?
The Global Vascular Guidelines on the management of CLTI propose a three-step integrated “PLAN” approach to deciding on revascularization treatment.2 These steps include: patient risk estimation; limb staging; and defining the anatomic pattern of disease.2
Patient risk estimation includes consideration of operative risk and life expectancy. One may still consider amputation before revascularization in patients with CLTI who have limited life expectancy and are non-ambulatory. The Global Vascular Guidelines recommend limb staging with the WIfI classification system (wound severity, ischemia, and infection), which guides intervention strategies and predicts expected outcomes. The GLASS classification system categorizes the anatomic pattern of disease to additionally aid in optimal revascularization strategies.2
In the era of minimally-invasive surgery gaining popularity, patients and proceduralists advocate for the “endovascular first” approach. This non-selective approach carries seldomly discussed risks. Ineffective endovascular revascularization may lead to progression of tissue loss. Furthermore, several studies suggest that patients with CLTI who undergo bypass after endovascular failures fare worse than those patients who undergo primary bypass surgery.19
Studies continue to argue for selective revascularization strategies that include open bypass options for appropriate disease anatomy in patients with low operative risk. The Bypass versus Angioplasty in Severe Ischemia of the Leg (BASIL) trial continues to be the only multicenter randomized control trial to compare endovascular and bypass revascularization outcomes.20 For patients with CLTI who lived more than two years, those initially treated with bypass surgery had better overall and amputation-free survival.
Comparative reviews of studies comparing open and endovascular treatments for patients with CLTI suggest similar mortality and amputation outcomes, but better patency for bypass intervention.21,22 Limitations to conclusions, however, include heterogeneity of patients, mixed disease processes and non-randomization. Thus, when one is assessing revascularization strategies in patients with CLTI, key considerations include patient risk, limb-threat severity and anatomic pattern of disease to determine revascularization feasibility. In standard risk patients, the treating physician may consider conduit status for possible open bypass surgery.
Regardless of technique, revascularization should target the appropriate angiosome. There has been wide discussion and review of the angiosome concept in the literature with consistent demonstration of improved outcomes.23 The clinical implications of targeted revascularization increase limb salvage through the restoration of direct inline blood flow to the wound area.24,25 In comparison to indirect revascularization, multiple systematic reviews demonstrate that direct revascularization of the feeding artery of the affected angiosome significantly improves both wound healing and limb salvage rates.26 Additionally, angiographosome-directed revascularization is an emerging concept gaining attention in recent years in the setting of CLTI with slow- or non-healing wounds. The angiographosome principle targets restoration of arterial flow based on real-time, observed visual patterns of wound perfusion at the time of the intervention.27
In patients with CLTI who are not appropriate for open bypass surgery, advanced endovascular technique allows an increased limb salvage rate in treatment of complex tibial disease. Pedal-plantar loop techniques to revascularize the foot, direct pedal puncture (see bottom two images above), and transcollateral angioplasty with antegrade and retrograde snaring are advanced endovascular techniques to treat tibial and plantar disease in appropriate patients with CLTI. These alternative techniques increase revascularization options with improved amputation rates in patients with CLTI who otherwise have limited options.28
Long calcified lesions in the tibial arteries and plantar arch often prevent revascularization, especially in patients with CLTI and diabetes. The deep plantar venous arch accompanies the deep plantar arterial arch. Thus, historically, arterialization of the venous circulation through creation of a percutaneous arteriovenous fistula provides an additional circulatory network to provide perfusion.29 While this is not yet a widely adopted practice due to surgical complexity and higher risk of surgical morbidity, novel approaches to percutaneous deep vein arterialization (pDVA) are a current focus of CLTI treatment research.
The LimFlow Stent Graft System (LimFlow) is currently undergoing clinical trials with no-option CLI patients. The interim results of the PROMISE I trial investigating the LimFlow system demonstrated a 100 percent technical success rate of revascularization in the foot and limb salvage at six months with progressive wound healing.30 Preliminary outcomes are promising for LimFlow feasibility and safety for no-option CLI patients.30 However, patient follow up is currently ongoing and a larger scale trial is warranted.
What About Non-Revascularization Options?
Spinal cord stimulation activates cell signaling pathways to vasodilate and improve microcirculatory status to reduce amputation rates in addition to treating chronic CLTI pain.31 There is also evidence that lumbar sympathectomy increases vasodilation and reduces sympathetic tone, improving oxygenation to tissues.32 Furthermore, intermittent pneumatic compression increases arterial blood flow by increasing the arteriovenous pressure gradient and stimulating vasodilation.33 When surgical revascularization is not feasible in patients with CLTI, spinal cord stimulation, lumbar sympathectomy and intermittent pneumatic compression in selected patients can improve amputation rates and improve rest pain.31-33
Pharmacotherapy adjuncts such as prostanoids, vasoactive drugs and hyperbaric oxygen therapy continue to show promise anecdotally for patients with CLTI who lack revascularization options. However, the lack of evidence-based research of these pharmacotherapy options warrants further research.34,35 Gene (i.e. fibroblast growth factor 1, vascular endothelial growth factor, hepatocyte growth factor, etc.) and stem cell therapy (i.e. bone marrow-derived mononuclear cells, mesenchymal stromal cells, etc.) are under investigation for their potential in inducing therapeutic neovascularization.36-38
Researchers are evaluating various dietary and nutritional supplements known to increase nitric oxide release and restore endothelial function (sodium nitrate, cocoa, L-arginine, L-citrulline precursor) in ongoing clinical studies. However, the current data suggests that routine use of these supplements is most beneficial in patients with stable PAD as opposed to those with CLTI and tissue loss.39
Patients with CLTI continue to actively enroll in clinical trials, but given the overall comorbid and heterogenous patient population and discrepancy of results between preclinical and clinical results, completion of these clinical trials is slow and thus, use of these biologics is still investigational.
Final Thoughts: A Comprehensive Approach To A Complex Issue
The success of revascularization in the patient with CLTI lies within a collaborative team approach. Debridement to viable tissue, control of infection, offloading and revascularization surveillance necessitate the expertise of podiatric surgeons, vascular surgeons, infectious disease consultants and prostheticians. Despite best efforts, CLTI is a chronic and progressive disease. Therefore, efforts to develop novel therapeutic options are necessary to continuously improve the prognosis for those with CLTI.
Dr. Kiguchi is a vascular surgeon with the MedStar Heart and Vascular Institute and Director of MedStar Health Vein Centers in Washington, D.C. with offices in Chevy Chase, Md. and Mclean, Va. She is board certified in Vascular Surgery by the American Board of Surgery. Dr. Kiguchi discloses that she is a member of the Speaker’s Bureau for Medtronic, Inc.
Ms. Cutler is a vascular surgery nurse practitioner with the MedStar Heart and Vascular Institute. She practices at multiple MedStar Heath Vein Centers with offices in Washington, D.C., Chevy Chase, Md. and McLean, Va.
1. Diaz-Sandoval L. Critical limb threatening ischemia: the time has come for a multidisciplinary approach. J Vasc Endovasc Ther. 2019;4(1):9.
2. Conte MS, Bradbury AW, Kolh P, et al. Global vascular guidelines on the management of chronic limb-threatening ischemia. J Vasc Surg. 2019;69(6S):3S-125S.
3. Moss SE, Klein R, Klein BE. The 14-year incidence of lower extremity amputations in a diabetic population. The Wisconsin epidemiologic study of diabetic retinopathy. Diabetes Care. 1999;22(6):951-959.
4. Ix JH, Biggs ML, Kizer JR, et al. Association of body mass index with peripheral arterial disease in older adults: the cardiovascular health study. Am J Epidemiol. 2011;174(9):1036- 1043.
5. Ridker PM, Stampfer MJ, Rifai N. Novel risk factors for systemic atherosclerosis: a comparison of C-reactive protein, fibrinogen, homocysteine, lipoprotein(a), and standard cholesterol screening as predictors of peripheral arterial disease. JAMA. 2001;285(19):2481- 2485.
6. Abu Dabrh AM, Steffen MW, Undavalli C, et al. The natural history of untreated severe or critical limb ischemia. J Vasc Surg. 2015;62(6):1642-1651.
7. Sigvant B, Lundin F, Wahlberg E. The risk of disease progression in peripheral arterial disease is higher than expected: a meta-analysis of mortality and disease progression in peripheral arterial disease. Eur J Vasc Endovasc Surg. 2016;51(3):395-403.
8. van Haelst ST, Koopman C, den Ruijter HM, et al. Cardiovascular and all-cause mortality in patients with intermittent claudication and critical limb ischaemia. Br J Surg. 2018;105:252-261.
9. Willigendael EM, Teijink JA, Bartelink ML, Peters RJ, Buller HR, Prins MH. Smoking and the patency of lower extremity bypass grafts: a meta-analysis. J Vasc Surg. 2005;42(1):67–74.
10. Blomster JI, Woodward M, Zoungas S, et al. The harms of smoking and benefits of smoking cessation in women compared with men with type 2 diabetes: an observational analysis of the ADVANCE (action in diabetes and vascular disease: preterax and diamicron modified release controlled evaluation) trial. BMJ Open. 2016;6:e009668.
11. Antithrombotic Trialists’ Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ. 2002;324(7329):71- 86.
12. CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet. 1996;348(9038)1329- 1339.
13. Anand SS, Bosch J, Eikelboom JW, et al. Rivaroxaban with or without aspirin in patients with stable peripheral or carotid artery disease: an international, randomised, double-blind, placebo-controlled trial. Lancet. 2018;391(10117):219-229.
14. Rodriguez F, Maron DJ, Knowles JW, Virani SS, Lin S, Heidenreich PA. Association between intensity of statin therapy and mortality in patients with atherosclerotic cardiovascular disease. JAMA Cardiol. 2017;2:47-54.
15. Moise N, Huang C, Rodgers A, et al. Comparative cost-effectiveness of conservative or intensive blood pressure treatment guidelines in adults aged 35-74 years: the Cardiovascular Disease Policy Model. Hypertension. 2016;68:88-96.
16. American Diabetes Association. Glycemic targets: standards of medical care in diabetes—2018. Diabetes Care. 2018;41:S55-S64.
17. Mills Sr 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 (WIfI). J Vasc Surg. 2014;59:220-234.
18. Norgren L, Hiatt WR, Dormandy JA, Nehler MR, Harris KA, Fowkes FG. Intersociety consensus for the management of peripheral arterial disease (TASC II). J Vasc Surg. 2007;45(suppl S):S5–S67.
19. Nolan BW, De Martino RR, Stone DH, et al. Prior failed ipsilateral percutaneous endovascular intervention in patients with critical limb ischemia predicts poor outcome after lower extremity bypass. J Vasc Surg. 2011;54:730e5.
20. Bradbury AW, Adam DJ, Bell J, et al. Bypass versus angioplasty in severe ischaemia of the Leg (BASIL) trial: analysis of amputation free and overall survival by treatment received. J Vasc Surg. 2010;5(Suppl):18Se31S.
21. Korhonen M, Biancari F, Söderström M, et al. Femoropopliteal balloon angioplasty vs. bypass surgery for CLI: a propensity score analysis. Eur J Vasc Endovasc Surg. 2011;41:378e84.
22. Jones WS, Dolor RJ, Hasselblad V, et al. Comparative effectiveness of endovascular and
surgical revascularization for patients with peripheral artery disease and critical limb ischemia: systematic review of revascularization in critical limb ischemia. Am Heart J. 2014;167:489e498.
23. Broadmann M. The angiosome concept in clinical practice: implications for patient-specific recanalization procedures. J Cardiovasc Surg. 2013;54(5):567-571.
24. Attinger CE, Evans KK, Bulan E, Blume P, Cooper P. Angiosomes of the foot and ankle and clinical implications for limb salvage: reconstruction, incisions, and revascularization. Plast Reconstr Surg. 2006;117(suppl 7):261S– 293S.
25. Fossaceca R, Guzzardi G, Cerini P, et al. Endovascular treatment of diabetic foot in a selected population of patients with below-the-knee disease: is the angiosome model effective? Cardiovasc Intervent Radiol. 2013;36(3):637–644.
26. Jongsma H, Bekken J, Akkersdijk GP, Hoeks S, Verhagen H, Fioole B. Angiosome-directed revascularization in patients with critical limb ischemia. J Vasc Surg. 2017; 65(4):1208- 1219.
27. Shackles C, Herman K, Gallo V, Rundback J. Angiographosome-directed revascularization: extending the angiosome model to targeted, real-time, angiography-guided restoration of target tissue perfusion. Endovascular Today. 2018;17(5):52-58.
28. Palena LM, Manzi M. Extreme below-the-knee interventions: retrograde transmetatarsal or transplantar arch access for foot salvage in challenging cases of critical limb ischemia. J Endovasc Ther. 2012;19(6):805–811.
29. Francois-Franck M. Note a propos de la communication de M Raimond Petit sur la susture arterio-veneuse. Compt Rend Hebd Soc Biol. 1896;48:150.
30. Mustapha JA, Saab FA, Clair D, Schneider P. Interim results of the PROMISE I trial to investigate the LimFlow system of percutaneous deep vein arterialization for the treatment of critical limb ischemia. J Invasive Cardiol. 2019;31(3):57-63.
31. Ubbink DT, Vermeulen H. Spinal cord stimulation for nonreconstructable chronic critical leg ischaemia. Cochrane Database Syst Rev. 2013;2:CD004001.
32. Sanni A, Hamid A, Dunning J. Is sympathectomy of benefit in critical leg ischaemia not amenable to revascularisation? Interact Cardiovasc Thorac Surg. 2005;4:478e83.
33. Kavros SJ, Delis KT, Turner NS, et al. Improving limb salvage in critical ischemia with intermittent pneumatic compression: a controlled study with 18-month follow-up. J Vasc Surg. 2008;47:543-549.
34. Nikol S, Baumgartner I, Van Belle E, et al. Therapeutic angiogenesis with intramuscular NV1FGF improves amputation-free survival in patients with critical limb ischemia. Mol Ther. 2008;16:972-978.
35. Iafrati MD, Hallett JW, Geils G, et al. Early results and lessons learned from a multicenter, randomized, double-blind trial of bone marrow aspirate concentrate in critical limb ischemia. J Vasc Surg. 2011;54:1650-1658.
36. Tongers J, Roncalli JG, Losordo DW. Therapeutic angiogenesis for critical limb ischemia – microvascular therapies coming of age. Circulation. 2008;118(1):9–16.
37. Peeters Weem SM, Teraa M, de Borst GJ, Verhaar MC, Moll FL. Bone marrow derived cell therapy in critical limb ischemia: a meta-analysis of randomized placebo controlled trials. Eur J Vasc Endovasc Surg. 2015;50(6):775–783.
38. Teraa M, Sprengers RW, Schutgens RE, et al. Effect of repetitive intra-arterial infusion of bone marrow mononuclear cells in patients with no option limb ischemia: the randomized, double-blind, placebocontrolled rejuvenating endothelial progenitor cells via transcutaneous intra-arterial supplementation (JUVENTAS) trial. Circulation. 2015;131:851-860.
39. Sonnenschein K, Neuser J, Bauersachs J, Tongers J. New horizons in the treatment of lower extremity arterial disease. E-Journal of Cardiology Practice. 2018;16(10). Available at: https://www.escardio.org/Journals/E-Journal-of-Cardiology-Practice/Volume-16/ New-horizons-in-the-treatment-of-lower-extremity-arterial-disease . Accessed January 16, 2020.