Chronic critical limb ischemia (CLI) is the leading cause of nontraumatic major amputations on a worldwide basis. CLI is one of the most severe manifestations of obstructive peripheral arterial disease. Patients presenting with CLI often have comorbid conditions associated with high mortality rates. Its definition is typically clinical as patients presenting with true ischemic rest pain, nonhealing ischemic ulcers, or gangrene. It is much more prevalent in patients with diabetes and the elderly.1 Critical limb ischemia is emerging as a critical issue in world health as people are living longer and diabetes is epidemic.2 Great strides have been made in the interventional and surgical therapy of CLI with reported limb salvage rates of >90%.3-5 Despite these reports there remains great debate about how these patients should be treated. Many patients are still referred straight to major amputation without having vascular consultation or noninvasive imaging.6 Arguments about whether there should be an “intervention first” vs “direct surgical revascularization first” approach persist.
Major amputation is associated with significant mortality and morbidity risk as well as substantially increased medical cost as compared with limb salvage.7,8 Amputation at an inappropriate level may lead to need for additional amputations or may unduly impact morbidity if too aggressive.
In the past few years there have been many advancements in the definition, diagnosis, and treatment of CLI. In this editorial I will highlight those that I have regarded as monumental.
Editor's note: View video commentary accompanying this editorial.
We cannot achieve ideal therapeutic consensus unless we are comparing treatment strategies in patients with truly matched disease. Rest pain is not equivalent to advanced gangrene with concomitant infection, yet historical studies include both as CLI. Mills created the Wound, Ischemia, and foot Infection (WIfI) system of wound assessment to help stratify these patients more precisely.9 This classification should be incorporated into clinical studies to allow better outcome evaluation with different treatment strategies. This could lead to a more scientific treatment decision process. True ischemic rest pain must be clearly distinguished from neuropathic pain.
Another concept that is becoming more widely accepted is the “angiosome” concept in helping to guide therapies in CLI. Angiosomes are 3-dimensional blocks of tissue supplied with blood predominately by certain arteries. In CLI collateral arterial perfusion may be inadequate, therefore direct perfusion of the angiosome-related vessel by surgery or intervention may be paramount.10
A basic clinical history and thorough physical exam with baseline clinical laboratories is crucial in all patients presenting with CLI. The clinician needs to globally assess these patients first, then concentrate on the legs.
Use of noninvasive diagnostics such as ABI and vascular ultrasound are well-established. Measurements of skin perfusion pressure (SPP) and transcutaneous O2 (TCOM) are being used more widely to more precisely assess adequacy of tissue perfusion and likelihood of treatment success or need for additional therapy.
Great strides have been made in computerized tomographic angiography (CTA), magnetic resonance angiography (MRA), and diagnostic angiography in evaluating anatomy and guiding therapy. The greatest limitation of CTA and diagnostic angiography in the past was the necessity for iodinated contrast, which brought inherent risks of contrast-induced nephropathy (CIN) and allergic response. Dystrophic calcification often precludes accurate assessment by CTA and MRA. More widespread acceptance and utilization of CO2 (related to more user friendly and sterile devices) as a contrast agent as described by Caridi et al would allow more thorough angiographic assessment utilizing small catheters with no risk of allergic response or CIN.11
CO2 angiography and external duplex arterial ultrasound are being used more commonly as imaging modalities during interventional therapies. These modalities have expanded diagnostic and revascularization treatment options in CLI patients.
Access is a crucial part of any interventional procedure. Access affects risk of bleeding, ability to reach a lesion, ability to cross a lesion, the size of device that can be delivered, and the risk of vascular complications. Access complications can adversely affect outcomes. There has been more widespread use of radial artery access in subclavian, mesenteric, and renal artery interventions to lessen the risk of bleeding complications, but currently available devices do not allow interventionists to treat most cases of CLI via this approach. More widespread use of pedal12,13 and even digital artery access14 is resulting in successful intervention when crossing can’t be achieved in an antegrade manner. Pedal access is associated with less bleeding and may allow earlier ambulation. The “pedal loop” technique as described by Graziano et al allows treatment of patients with below-the-ankle disease.15 In this technique, a guidewire is passed either from the dorsal to plantar arch or vice versa, then the entire segment is treated with percutaneous transluminal angioplasty to establish outflow.
CLI may be caused by multilevel disease or may be the result of only infrapopliteal (IP) disease. Usually the IP disease is diffuse and long total occlusions common. Better guidewires, dedicated crossing tools, and re-entry tools are emerging as useful interventional tools to cross lesions.
The YUKON, DESTINY, and ACHILLES trials (utilizing “olimus” drugs on balloon-expandable stent platforms) have all shown encouraging patency results in short proximal IP lesions, but no major improvement in limb salvage.16-18 Several single-center trials had shown patency benefit (of IP vessels) with drug-eluting balloons19 (DEB) in long segment IP disease, but the premature cessation of the IN.PACT DEEP DEB trial secondary to safety and lack of efficacy have dampened initial clinical enthusiasm. Ongoing IP drug-eluting balloon clinical trials may provide additional answers.20
Use of both drug-eluting balloons above the knee and drug-eluting stents (DES) above the knee has shown patency benefit21-23 and is likely to be helpful in CLI patients with multilevel disease. Drug-eluting stents such as Zilver PTX (Cook Medical) and drug-eluting balloons such as Lutonix (Bard) have received FDA approval for above-the-knee applications and are currently being utilized by clinicians.
Atherectomy has had two clinical trials suggesting benefit. The randomized controlled EXCITE trial24 utilizing laser atherectomy to treat diffuse SFA in-stent restenosis showed a safety and efficacy benefit in the therapy of diffuse SFA in-stent restenosis and occlusion vs percutaneous translimunal angioplasty. The DEFINITIVE LE25 trial utilizing TurboHawk (Covidien) is the largest atherectomy registry to date. It showed similar outcomes in diabetic and nondiabetic patients and demonstrated excellent safety and efficacy profile in a wide spectrum of atherosclerotic peripheral artery disease.
Most patients presenting with CLI have options other than major amputation as first-line approach. Angiography and intervention can be safely attempted in the overwhelming majority of patients with less risk and cost than direct amputation. The use of ultrasound guidance and CO2 angiographic imaging allow evaluation and therapy even in patients with profound renal dysfunction and severe iodinated contrast allergy. Even patients with no obvious outflow vessels can have successful intervention with techniques such as “pedal loop” which create outflow. It is imperative that interventional therapy not preclude further surgical options and that surgical options not preclude subsequent interventional therapy which may be required later as this is progressive disease. Restoration of arterial blood supply is crucial, but is only part of required therapy.
A more standardized approach to treating patients with CLI is needed. Successful therapy requires better prevention and earlier diagnosis, restoration of blood flow, wound healing (multifactorial), medical therapy including antiplatelet therapies and lipid-lowering drugs, mechanical unloading, lifestyle modifications, and long-term preventive therapies. If we are to achieve a more standardized approach we need randomized clinical trials, more precise definitions including arterial disease patterns, concomitant infection, and degree of tissue damage. We need continued training to ensure that assessed outcomes are indicative of treatment effectiveness and not tainted by operator inexperience. We need better understanding of what percentage of patients are surgical candidates as estimates vary widely. We need to assess cost of therapies, long-term effectiveness, morbidity, and rates of limb salvage. We need better screening, prevention, and technology breakthroughs to improve overall outcomes. We must follow these patients closely as there is a high associated cardiovascular mortality risk with dramatically shortened life expectancy.
Editor’s note: Disclosure: Dr. Walker reports no financial relationships or conflicts of interest regarding the content herein.
- Allie DE, Hebert CJ, Ingraldi A, Patlola RR, Walker CM. “24-carat gold, 14-carat gold, or platinum standards in the treatment of critical limb ischemia: bypass surgery or endovascular intervention?” J Endovasc Ther. 2009;16 Suppl 1:I134-I146.
- Yost ML. Peripheral Arterial Disease Underestimated, Underdiagnosed and Undertreated. Volume I: A Significant Opportunity for Interventional Therapies. Atlanta: THE SAGE GROUP; 2000.
- Laird JR, Zeller T, Gray BH, et al. Limb salvage following laser-assisted angioplasty for critical limb ischemia: results of the LACI multicenter trial. J Endovasc Ther. 2006;13(1):1-11.
- Allie D, Hebert C, Walker C. Excimer laser-assisted angioplasty in severe infrapopliteal disease and CLI: the CIS “LACI equivalent” experience. Vasc Dis Manag. 2008;5(5). http://vasculardiseasemanagement.com/article/3248.
- Faglia E, Dalla Paola L, Clerici G, et al. Peripheral angioplasty as the first-choice revascularization procedure in diabetic patients with critical limb ischemia: prospective study of 993 consecutive patients hospitalized and followed between 1999 and 2003. Eur J Vasc Endovasc Surg. 2005;29(6):620-627.
- Allie DE, Hebert CJ, Lirtzman MD, et al. Critical limb ischemia: a global epidemic. A critical analysis of current treatment unmasks the clinical and economic costs of CLI. EuroIntervention. 2005;1(1):75-84.
- Panayiotopoulos YP, Tyrrell MR, Owen SE, Reidy JF, Taylor PR. Outcome and cost analysis after femerocrural and femopopliteal grafting for critical limb ischemia. Br J Surg. 1997;84(2):207-212.
- Cheshire NJ, Wolfe JH, Noone MA, Davies L, Drummond M. The economics of femorocrural reconstruction for critical leg ischemia with and without autologous vein. J Vasc Surg. 1992;15(1):167-174; discussion 174-175.
- 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). J Vasc Surg. 2014;59(1):220-234.e1-2.
- Iida O1, Soga Y, Hirano K, et al. Long-term results of direct and indirect endovascular revascularization based on the angiosome concept in patients with critical limb ischemia presenting with isolated below-the-knee lesions. J Vasc Surg. 2012;55(2):363-370.
- Caridi JG, Cho KJ, Fauria C, Eghbalieh N. Carbon dioxide digital subtraction angiography (CO2 DSA): a comprehensive user guide for all operators. Vasc Dis Manag. 2014;11(10):E221-E256.
- Mustapha JA, Saab F, McGoff T, Heaney C. TAMI technique: tibiopedal arterial minimally invasive retrogade revascularization. Endovascular Today. 2013;January:E39-E47.
- Walker CM. Pedal access in critical limb ischemia. In RS Dieter, RA Dieter Jr., RA Dieter III, eds. Endovascular Interventions: A Case-Based Approach. New York: Springer; 2014:805-822.
- Manzi M, Palena LM. Extreme options after failed antegrade CLI treatments: A step-by-step look at retrograde distal metatarsal (digital) artery puncture and direct puncture of occluded calcified tracts. Endovascular Today. 2013;January:E48-E52.
- Graziani L, Silvestro A, Bertone V, et al. Vascular involvement in diabetic subjects with ischemic foot ulcer: a new morphologic categorization of disease severity. Eur J Vasc Endovasc Surg. 2007;33(4):453-460.
- Bosiers M, Scheinert D, Peeters P, et al. Randomized comparison of everolimus-eluting vs. bare metal stents in patients with critical limb ischemia and infrapopliteal arterial occlusive disease. J Vasc Surg. 2012;55(2):390-398.
- Rastan A, Tepe G, Krankenberg H, et al. Sirolimus-eluting stents vs. bare-metal stents for treatment of focal lesions in infrapopliteal arteries: a double-blind, multi-centre, randomized clinical trial. Eur Heart J. 2011;32(18):2274-2281.
- Scheinert D, Katsanos K, Zeller T, et al; ACHILLES Investigators. A prospective randomized multicenter comparison of balloon angioplasty and infrapopliteal stenting with the sirolimus-eluting stent in patients with ischemic peripheral arterial disease:1-year results from the ACHILLES trial. J Am Coll Cardiol. 2012;60(22):2290-2295.
- Schmidt A. DEB in below the knee: results from the Leipzig registry. Presented at Leipzig Interventional Course, Leipzig, Germany, January 19, 2011.
- Zeller T, Baumgartner I, Scheinert D, et al. Drug-eluting balloon vs standard balloon angioplasty for infrapopliteal arterial revascularization in critical limb ischemia: 12-month results from the IN.PACT DEEP randomized trial. J Am Coll Cardiol. 2014;64(15):1568-1576.
- Zilver PTX drug-eluting stent study data show continued patency at 5 years [press release]. Cook Medical; November 4, 2014.
- Scheinert D. Drug-eluting balloons in the SFA. Endovascular Today. 2010;March:E42-E44.
- Scheinert D, Duda S, Zeller T, et al. The LEVANT I (Lutonix paclitaxel-coated balloon for the prevention of femoropopliteal restenosis) trial for femoropopliteal revascularization: first-in-human randomized trial of low-dose drug-coated balloon versus uncoated balloon angioplasty. JACC Cardiovasc Interv. 2014 Jan;7(1):10-19.
- Dippel E. EXCITE ISR: a prospective, randomized trial of excimer laser atherectomy versus balloon angioplasty for treatment of femoropopliteal in-stent restenosis. Presented at Transcatheter Cardiovascular Therapeutics, Washington, DC, September 16, 2014.
- McKinsey JF, Zeller T, Rocha-Singh KJ, Jaff MR, Garcia LA; DEFINITIVE LE Investigators. Lower extremity revascularization using directional atherectomy: 12-month prospective results of the DEFINITIVE LE study. JACC Cardiovasc Interv. 2014;7(8):923-933.