DO NOT DUPLICATE. Critical limb ischemia (CLI) has been defined as patients with chronic. Endovascular Interventions for Limb Salvage REVIEW

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1 REVIEW WOUNDS 2011;23(12): From the 1 Chief of Division, Vascular/Endovascular Surgery, St. Luke s-roosevelt Hospital and Associate Clinical Professor of Surgery, Columbia University, New York, NY; 2 Department of Surgery, Division of Vascular Clinical Research, St. Luke s-roosevelt Hospital, New York, NY Address correspondence to: John C. Lantis II, MD 1090 Amsterdam Ave, Suite 7A New York, NY JLantis@chpnet.org Endovascular Interventions for Limb Salvage John C. Lantis II, MD; 1 J.A. Schwartz, MD 2 Abstract: Although operative bypass is still considered the gold standard for treating peripheral arterial disease, over the last decade endovascular interventions have become more popular and now represent the vast majority of peripheral arterial treatments being performed. Open bypass is associated with an unacceptable morbidity and mortality that is not encountered to the same extent with endovascular techniques. However, outcomes of endovascular intervention are dependent upon the location and nature of the lesion, as well as possibly the technologies available to treat the lesion and the experience of the interventionalist. In correctly selected patients, endovascular techniques should be the primary management employed for critical limb ischemia. The group of patients that would benefit from endovascular techniques continues to expand with new data constantly emerging. This article will review the current endovascular techniques currently being employed, focusing on the indication for specific intervention. Critical limb ischemia (CLI) has been defined as patients with chronic ischemic rest pain, ulcers, or gangrene attributable to objectively proven arterial occlusive disease. 1 CLI is a serious threat to life, and is associated with great morbidity and premature mortality. Within 3 months of presentation, 9% of patients will die, 1% will have a myocardial infarction, 1% will suffer from stroke, 12% will have an amputation, and 18% will have persistent CLI. CLI is a marker of premature death. Mortality rates are 21% at 1 year and 31.6% at 2 years. 1,2 Patients have chronic ischemic rest pain or gangrene due to arterial disease. Unfortunately, most of these patients will Endovascular intervention in arterial disease is less invasive [than surgery], and therefore, carries a lower risk profile. Endovascular approaches to limb salvage currently represent 70% of total interventions. Patients with CLI have abundant medical comorbidities that make them poor operative candidates. Therefore, endovascular therapy may be the only option for these patients who would otherwise not be amenable to surgical bypass. Vol. 23, No. 12 December

2 require a major amputation within 6 months to 1 year without undergoing hemodynamic improvement in their affected limb. Patients with CLI require life-prolonging intervention WOUNDS Indication for Endovascular Intervention Surgical intervention in CLI has long been the gold standard of improving hemodynamics, and ultimately, wound healing. Surgery is associated with significant morbidity and mortality. A randomized control trial comparing surgical bypass and angioplasty published in 2003 concluded that surgery is associated with a significantly higher rate of morbidity at 30 days (57% vs. 41%); however, after 2 years, surgery is associated with a reduced risk of future amputation, death, or both. 3 Endovascular intervention in arterial disease is less invasive and therefore carries a lower risk profile. Endovascular approaches to limb salvage currently represent 70% of total interventions. 4,5 Endovascular treatment has multiple benefits. Patients with CLI may not have appropriate bypass targets due to the nature of their disease, or they may not have adequate saphenous vein to provide as a bypass conduit. Additionally, patients with CLI have abundant medical comorbidities that make them poor operative candidates. Therefore, endovascular therapy may be the only option for these patients who would otherwise not be amenable to surgical bypass. Most current endovascular therapies are designed for aortoiliac and superficial fermoral artery (SFA) segment disease. The role of endovascular intervention depends on the TransAtlantic Inter-Society Consensus (TASC) classification of lower extremity arterial lesions. TASC classification of lesions is based upon a review of the world literature, in regards to the quality of the literature (Grade A C), and the success rates for types of procedures in various lower extremity vascular beds. Femoral-popliteal lesions that are TASC A (either a single stenosis < 10 cm in length, or a short stenosis of < 5 cm in length) have proven success with endovascular intervention, and therefore, endovascular treatment is now the treatment of choice over surgical bypass. TASC B lesions are characterized as multiple lesions (stenoses or occlusion) each less than 5 cm, a single stenosis or occlusion < 15 cm not involving the infrageniculate popliteal artery, a single or multiple lesions in the absence of continuous tibial vessels to support a bypass, heavily calcified occlusion < 5 cm in length, or a single popliteal stenosis. Patients with TASC B lesions should also undergo endovascular intervention rather than operative intervention, as there are data proving response to endovascular treatment. TASC C lesions (multiple stenoses or occlusions totaling > 15 cm with or without heavy calcification or recurrent stenoses or occlusions that need treatment after two endovascular interventions), and TASC D lesions (chronic total occlusions of CFA or SFA > 20 cm involving the popliteal artery, or chronic total occlusion of popliteal artery and proximal trifurcation vessels) are more extensive and have less success with endovascular repair. It is recommended that patients with TASC C and D lesions undergo surgical management if they are adequate operative candidates. As more research is being undertaken, the indication for endovascular treatment is being expanded to include infrapopliteal disease. 6 Endovascular interventions can be separated into primary techniques, such as angioplasty and stenting, or secondary techniques, including drug-eluting stents, drug-eluting angioplasty balloons, atherectomy, and cryotherapy. Primary Technologies Angioplasty and stenting are primary technologies that have been employed in endovascular treatments. Angioplasty is based upon fracturing arteriosclerotic plaque and stretching that plaque. Stenting adds a metal mesh structure to hold the plaque open, these stents are made out of alloys or stainless steel. The success of angioplasty and stenting is based upon the location and extent of the lesion(s). The TASC classification of the lesion needs to be determined in order to predict the outcome of the intervention. Achieving endovascular treatment success is a different concept than operative bypass success. Each patient needs individual consideration when balancing the risks of surgical repair with the potential decreased success of endovascular treatments for longer TASC lesions. Angioplasty can be further divided into subintimal and intraluminal. Subintimal angioplasty is a technique that can be employed for heavily diseased arteries. In this procedure the wire is placed behind the plaque. A subintimal channel is created by dissection and angioplasty. Stents were commonly used following a subintimal angioplasty if the result of the subintimal angioplasty alone was suboptimal. Many authors would state that stents are used routinely following subintimal angioplasty to improve the final outcome above the knee while they are not used below the knee. 7,8 Angioplasty combined with stenting is another primary technology. The stent may be bare metal or drug eluting. There are two main drug eluting stents being used for peripheral arterial lesions. Sirolimus is a drug that inhibits IL-2 and has been shown to block activation of T and B

3 Table 1. Patency rates over time for stenosis versus occlusion by treatment type. 1-year patency (%) 3-year patency (%) 5-year patency (%) PTA: stenosis 77 (78 80) 61 (55 68) 55 (52 62) PTA: occlusion 65 (55 71) 48 (40 55) 42 (33 51) PTA + stent: stenosis PTA + stent: occlusion 75 (73 79) 66 (64 70) (69 75) 64 (59 67) -- cells. Sirolimus eluting stents provide a local application of an antineointimal hyperplasia agent. The SIRROCCO 1 trial included 36 patients who received either a bare metal stent or a Sirolimus eluting stent. At 6 months, none of the patients in the Sirolimus group had restenosis, while 23.5% of patients in the bare metal stent group had restenosis. At 18 months post-stenting, slow eluting stents investigated had no restenosis, fast eluting stents had 33% restenosis, and those with bare metal stents had 29% restenosis. 9 Paclitaxel (PTX), another drug eluting stent, is a mitotic inhibitor that affects microtubule growth during cell division. This drug is commonly used in various chemotherapy protocols. Paclitaxel SFA stents have been investigated in comparison to angioplasty alone, paclitaxel stent plus angioplasty, and bare metal stent plus angioplasty. Two years after study commencement 278 patients were analyzed. Seventy five percent of patients who had a drug eluting stent placed had their artery open 2 years after the procedure, whereas only 32.8% of those patients that had angioplasty alone had their artery open at the same time point. For those patients who were treated with a drug eluting stent they were almost 20% more likely (81.2%) to have their artery open at 2 years than those treated with a bare metal stent (62.7%). 10 Due to these outcomes this stent will soon be available in the United States. Drug eluting angioplasty balloons (DEB) are another adjunctive device to aid in arterial patency. The balloons are coated with urea (paclitaxel). There is a short burst of drug release over seconds, after which paclitaxel stays in the arterial wall for 28 days after treatment. The IN.PACT trial evaluated DEB in SFA lesions. DEB plus stent was compared to stent alone, and to atherectomy 11 Table 2. Meta analysis of PTA alone versus stenting. 1-year patency (%) 2-year patency (%) Angioplasty Angioplasty and stenting (atherectomy, in most cases, refers to the remote removal of plaque using some form of remote cutting blade or grinding device). The THUNDER trial also examined DEB. A 0.4-mm lumen loss was observed in patients that were treated with a DEB compared to a 1.7 mm late lumen loss in the patients treated with angioplasty alone. Binary restenosis was seen in 44% of the patients that underwent angioplasty versus 17% in the DEB group. 12 This new technology is currently being further investigated in the IN.PACT DEEP trial. The general consensus in the literature is that stenting in the above knee SFA and popliteal region adds some long-term patency to percutaneous outcomes. 13 However, some respected reviews, such as the Cochrane review, do not support this hypothesis. 14 According to Dormandy et al, 15 the 1-year patency of above the knee angioplasty with and without is 67% and 61%, respectively, while the 3-year patency with and without stenting is 58% and 51%, respectively. The major complications reported are fairly low with 4% in the angioplasty arm and 7% in the angioplasty plus stent arm. 15 The TASC II data also evaluated femoral-popliteal lesions, comparing angioplasty alone for stenotic lesions versus occlusions, as well as angioplasty plus stenting of stenotic lesions versus occlusive disease. The endovascular results showed a 1-year patency of 77% for those that had angioplasty alone for a stenotic lesion compared to a 1-year patency of 65% for the patients that had occlusive disease (Table 1). As one might expect, patients who had stenosis instead of complete occlusions did somewhat better, and stents did better in occlusions and appeared to show more benefit over time as well. The corresponding 3-year patency was 61% for the former and 48% for the latter. Patients who received stents in addition to angioplasty were found to have a 75% 1-year patency of those who had a stenotic lesion, and a 1-year patency of 73% for those with occlusive lesions. The corresponding 3-year patency for the angioplasty plus stent patients was 66% for those that had stenosis and 64% for Vol. 23, No. 12 December

4 The general consensus in the literature is that stenting in the above knee SFA and popliteal region adds some long-term patency to percutaneous outcomes. 13 However, some respected reviews, such as the Cochrane review, do not support this hypothesis. those with initial occlusive disease. 6 The question of tostent or not-to-stent is probably best summed up in the 2008 meta analysis, which evaluated high quality studies that compared angioplasty with angioplasty plus stenting in SFA lesions and found a wide range of results. A total of 934 patients were included in the study, with 452 patients undergoing balloon angioplasty alone, while 482 patients underwent stenting (Table 2). The 1-year primary patency following angioplasty ranged from 45% to 84.2%, and at 2 years, the primary patency ranged from 25% to 77.2%. The stenting results for 1-year primary patency were cited as 63% to 90% and the 2-year primary patency ranged from 46% to 87%. 16 The vast variation in outcomes exhibit the difficulty one has in applying scientific rigor to this question. However, once again a general trend that patients with stents did better in the short term, as well as the long term. Secondary Technologies Percutaneous atherectomy, or atheroreductive therapy, has gained very widespread acceptance. The theory behind this therapy is based on the actual excision or ablation of the lesion and not solely on the application of radial force (eg, angioplasty and stenting). The therapies that are available include the excision of the plaque, or ones that increase the compliance of the artery while grinding or applying heat and laser ablative therapy to the lesions. Atherectomy can remove plaque disease and theoretically improve arterial inflow to distal wounds. Performing atherectomy does not induce barotrauma unlike angioplasty, and therefore has potentially less risk of neointimal hyperplasia and recurrence following the procedure. There are many instruments that can be utilized to perform an atherectomy. The Jetstream (Pathway Medical Technologies, Kirkland, WA), Diamondback Orbital Atherectomy (Cardiovascular Systems Inc, St Paul, MN), Silverhawk (ev3 Endovascular Inc, Plymouth, MN), and the Excimer laser (Spectranetics, Colorado Springs, CO) are the primary devices in this arena. The Jetstream device spins in a downward motion and can ablate a wide variety of plaque types. The primary clinical trial supporting this therapy investigated 172 patients with a wide range 360 WOUNDS of clinical severity of lower limb ischemia at 9 sites at 1 year the Ankle-Brachial Index (ABI) increased from 0.59 ± 0.21 at baseline to 0.82 ± 0.27 (P < 0.05). 17 The Diamondback Orbital Atherectomy device utilizes a diamondcoated abrasive crown which moves in a rotational path within the vessel while generating small particles. These particles are taken up by the capillaries and ultimately reach the reticuloendothelial system. The OASIS trial investigated this device and found a procedural success of 93% with an initial device success of 78%. 18 The excimer laser is a tool used to debulk lesions and may be indicated in cases of occlusion or severe stenosis prior to performing angioplasty of the lesion. The 308 nm excimer laser utilizes flexible fiber optic catheters to deliver intense bursts of UV energy in short pulse durations. This UVB light has a short penetration depth of 50 µm and breaks molecular bonds directly by a photochemical process. One unique feature of using UV light is this direct lytic action. This works intravascularly, in theory, by removing a tissue layer of about 10 µm with each energy pulse. The excimer laser was investigated in one single-center study that looked at patients with Rutherford Class 4-6 critical limb ischemia (CLI) at 1 year out after having either percutaneous angioplasty, percutaneous angioplasty plus stent, or the excimer laser. The excimer laser was shown to have a primary patency of 75% at 1 year, which equaled that of the group that had percutaneous angioplasty plus stenting performed. The angioplasty alone group had a decreased 1-year primary patency of 68%. 19 The Limb Salvage Following Laser Assisted Angioplasty for Critical Limb Ischemia (LACI) study, which also evaluated the Excimer laser, quoted an 86% procedural success when the laser was employed versus a 70% procedural success without the laser utilizing angioplasty alone. Forty one percent (41%) of the lesions treated were in the SFA and 41% were in the infrapopliteal arteries; a significant number of these lesions also underwent stenting (45%). 20 The TALON trial is the most cited clinical data to support the use of the Silverhawk device. 21 This is fundamentally a registry with 601 patients representing 748 limbs at 19 centers being treated. The target lesion revascularization rates were 90% at 6 months and 80% at 1 year. However, the patients/lesions did worse if the lesion was greater than 10 cm in length or the patient had a Rutherford classification greater than Cryotherapy (Boston Scientific, Natick, MA), while not truly atheroreductive, may be best placed into this category. Cryotherapy cools vessels with nitrous oxide, which is thought to improve long-term patency due to inducing

5 Atherectomy can remove plaque disease and theoretically improve arterial inflow to distal wounds. Performing atherectomy does not induce barotrauma unlike angioplasty, and therefore has potentially less risk of neointimal hyperplasia and recurrence following the procedure. apoptosis. This modality can be used in conjunction with other endovascular treatments for arterial disease. Cryotherapy has been shown to limit restenosis, vessel recoil, and dissection. 22 In the one multicenter trial involving this technology 102 patients were treated for TASC B lesions, there was a 15% 9-month reintervention rate with a primary 9-month patency of 70%, but a 3-year overall patency rate of 75%. 23 Another study looked at the restenosis rates of patients with diabetes treated with a stent and cryoplasty versus those treated with stenting alone. Patients who were treated with cryoplasty had almost half the restenosis rate at 1 year (29.3%) versus those treated with stenting alone (55.8%). 24 This technique has been shown to have most success for restenosis, and usually has to be repeated due to limited success over time. The wide variety of disease types, locations, and emerging technologies make specific standardization of algorithms especially difficult. Therefore, a comprehensive understanding of the technologies available, with the ultimate goal of limb salvage, is necessary to treat these patients. Augmentative Devices There are many specialized instruments and tools on the market that have been designed to aid in performing endovascular procedures for difficult to access arterial lesions. Quickcross (Spectranetics, Colorado Springs, CO) catheters are employed in crossing chronic total occlusions or difficult lesions. This catheter provides a seamless transition from guidewire to catheter. It lends to smooth tracking through tortuous anatomy and diffuse disease. The lack of any significant technology and the low cost of this device make it very attractive. The Crosser (Bard Peripheral Vascular Inc, Tempe, AZ) is an instrument that provides high frequency mechanical vibrations to recanalize total occlusions that are unable to be bypassed using conventional guidewires. The PATRIOT trial evaluated the success and risk profile of the Crosser and found an 84% recanalization success rate with no arterial perforation complications. 25 Additionally, surgeons were able to achieve very quick crossing times. 25 However, this device adds significant costs to the overall crossing time. A new player to this market will be the True-Path (Boston Scientific, Natick, MA) intraluminal cannulation device, which is just coming to market. Significant clinical utilization is pending. Future Therapies Endovascular techniques are the best option for treating TASC A and TASC B lesions. The indication for performing endovascular treatment for CLI is constantly expanding as more research is coming forth. The modification of the TASC data to the TASC II data indicates that we continue to push the boundaries of what lesions may respond favorably to percutaneous intervention. Many of us believe that with endovascular intervention we rarely burn bridges while providing revascularization with minimal morbidity. Continued endovascular innovations help us push these boundaries but sometimes at exponential expense. In the future, medical therapies may play a greater role in critical limb ischemia. High dose HDL has been shown to have some success in patients with coronary artery disease in reducing a significant amount of plaques from coronary arteries. This may eventually be applied to peripheral arterial disease. Gene therapy is also currently being investigated in improving arterial disease. Preliminary trials utilizing intramuscular injection of autologous bone marrow mononuclear cells may decrease peripheral arterial plaque formation. Conclusion It is well known that wounds cannot heal without adequate blood supply. Physiologic testing is the first step in treating a patient with CLI, followed by imaging and classification of their arterial disease, and finally counseling with a vascular surgeon before deciding which vascular intervention would provide the most success and least risk for the individual patient (Figure 1 A C). Correct endovascular therapy is less invasive than an operative bypass revascularization and has proven success on TASC A and TASC B lesions, and can result in successful limb salvage (Figure 2 A C). Endovascular therapy encompasses many different techniques and is continuously evolving. The wide variety of disease types, locations, and emerging technologies make specific standardization of algorithms especially difficult. Therefore, a comprehensive understanding of the technologies available, with the ultimate Vol. 23, No. 12 December

6 Lantis and Schwartz IC A TE Figure 1B. Tibioperoneal trunk prior to atherectomy and angioplasty. U PL Figure 1C. Open toe amputation prior to revascularization. Figure 2B. Tibioperoneal trunk after atherectomy and angioplasty. Figure 2C. Open toe amputation 3 months after revascularization. D O N O T D Figure 1A. Pre-atherectomy and angioplasty ABI and pulse volume recordings. Figure 2A.Post-atherectomy and angioplasty ABI and pulse volume recordings. 362 Lantis.indd 362 WOUNDS 12/7/11 5:24 PM

7 goal of limb salvage, is necessary to treat these patients. However, the practitioner must keep in mind that while new technologies might be very exciting, they are outpacing our clinical documentation of need and efficacy. However, for many of us, in correctly selected patients endovascular limb salvage should be the first option. References 1) Norgren L, Hiatt WR, Dormandy JA, Nehler MR, Fowkes FG; TASC II Working Group. Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II). J Vasc Surg. 2007;45(Suppl S):S5A-S13A. 2) Golomb BA, Dang TT, Criqui MH. Peripheral arterial disease; morbidity and mortality implications. Circulation. 2006;114: ) Adam DJ, Beard JD, Cleveland T, et al. Bypass versus angioplasty in severe ischaemia of the leg (BASIL): multicentre, randomised controlled trial. Lancet. 2005;366(9501): ) Suding PN, McMaster W, Hansen E, Hatfield AW, Gordon IL, Wilson SE. Increased endovascular interventions decrease the rate of lower limb artery bypass operations without an increase in major amputation rate. Ann Vasc Surg. 2008;22(2): ) Cull DL, Langan EM, Gray BH, Johnson B, Taylor SM. Open versus endovascular intervention for critical limb ischemia: a population-based study. J Am Coll Surg. 2010;210(5): ) Norgren L, Hiatt WR, Dormandy JA, Nehler MR, Fowkes FG; TASC II Working Group. Inter-Society Consensus for the management of Peripheral Arterial Disease (TASC II). J Vasc Surg. 2007;45(Suppl S):S47-S58. 7) Schneider JR, Verta MJ, Alonzo MJ, Hahn D, Patel NH, Kim S. Results with Viabahn-assisted subintimal recanalization for TASC C and TASC D superficial femoral artery occlusive disease. Vasc Endovascular Surg. 2011;45(5): ) Zhu YQ, Zhao JG, Liu F, et al. Subintimal angioplasty for below-the-ankle arterial occlusions in diabetic patients with chronic critical limb ischemia. J Endovasc Ther. 2009;16(5): ) Duda SH, Bosiers M, Lammer J, et al. Sirolimus-eluting versus bare nitinol stent for obstructive superficial femoral artery disease: the SIROCCO II trial. J Vasc Interv Radiol. 2005;16(3): ) Dake M. Cook Medical s 2-Year Zilver PTX Trial Results. Presented at: The International Symposium on Endovascular Therapy (ISET); January 17, 2011; Miami Beach, FL. 11) Tepe G. IN.PACT SFA I study. Presented at: The EuroPCR 2011 conference; May 16, 2011; Paris, France. 12) Tepe G, Zeller T, Albrecht T, et al. Local delivery of paclitaxel to inhibit restenosis during angioplasty of the leg. N Engl J Med. 2008;358: ) Schillinger M, Sabeti S, Loewe C, Dick P, Amighi J, Mlekusch W, Schlager O, Cejna M, Lammer J, Minar E. Balloon Angioplasty versus Implantation of Nitinol Stents in the Superficial Femoral Artery. N Engl J Med. 2006;354: ) Twine CP, Coulston J, Shandall A, McLain AD. Angioplasty versus stenting for superficial femoral artery lesions. Cochrane Database Syst Rev. 2009;(2):CD ) Dormondy JA, Rutherford RB. Management of peripheral arterial disease. Trans-Atlantic Inter-Society Consensus (TASC). J Vasc Surg. 2000;31(1 Pt 2):S1-S ) Mwipatayi BP, Hockings A, Hofmann M, Garbowski M, Sieunarine K. Balloon angioplasty compared with stenting for treatment of femoropopliteal occlusive disease: a meta-analysis. J Vasc Surg. 2008;47(2): ) Sixt S, Rastan A, Scheinert D, et al. The 1-year clinical impact of rotational aspiration atherectomy of infrainguinal lesions. Angiology. 2011;62(8): ) Shrikhande GV, McKinsey JF. Use and abuse of atherectomy: where should it be used? Semin Vasc Surg. 2008;21(4): ) Feiring AJ, Wesolowski AA, Lade S. Primary stent-supported angioplasty for treatment of below-knee critical limb ischemia and severe claudication. Early and one-year outcomes. J Am Coll Cardiol. 2004;44(12): ) 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): ) Ramaiah V, Gammon R, Kiesz S, et al. Midterm outcomes from the TALON Registry: treating peripherals with SilverHawk: outcomes collection. J Endovasc Ther. 2006;13(5): ) Laird JR, Dawson DL. The role for cryoplasty in the treatment of infrainguinal artery disease: case studies. J Endovasc Ther. 2009;16(2 Suppl 2):II ) Laird JR, Biamino G, McNamara T, et al. Cryoplasty for the treatment of femoropopliteal arterial disease: extended follow-up results. Endovasc Ther. 2006;13(Suppl 2):II ) COBRA Clinical Trial Results. Presented at: The Transcatheter Cardiovascular Therapeutics Scientific Symposium; San Francisco, CA; November 11, ) Joyce JD. Patriot Evaluates Flowcardia s Crosser to Mediate CTO Recanalization. Presented at: The Vascular Interventional Advances Meeting; October 22, 2009; Las Vegas, NV. Vol. 23, No. 12 December