Critical limb ischemia (CLI) has only recently been characterized in the clinical literature; therefore knowledge of the clinical impact of CLI is still rudimentary at best. The TransAtlantic Inter-Societal Consensus (TASC) committee and document on the management of peripheral arterial occlusive disease (PAOD) have recently attempted to unify and clarify CLI with the following recommendations:1 1. Recommendation 73: Clinical definition of critical limb ischemia: The term critical limb ischemia should be used for all patients with chronic ischemic rest pain, ulcers, or gangrene attributable to objectively proven arterial occlusive disease. The term critical limb ischemia implies chronicity and is to be distinguished from acute limb ischemia. 2. Recommendation 74: Trials and reporting standards definition of critical limb ischemia: A relatively inclusive entry criterion is favored, the aim being to ensure that the ulceration, gangrene, or rest pain is indeed caused by peripheral arterial disease and that most would be expected to require a major amputation within the next 6-months to a year in the absence of a significant hemodynamic improvement. To achieve this, it is suggested to use absolute pressures of either ankle pressure 40mmHg) and a high-risk cohort of 2029 patients (rest pain and tissue loss with or without ankle pressure 2 At 1 year, 95% of the high-risk group and 73% of the low-risk group required a major amputation without revascularization. A 75% limb salvage rate was achieved at 1 year in the high-risk group with revascularization. The cumulative probability of survival for the entire group was 74% at 1 year, 58% at 2 years, 56% at 3 years, 48% at 4 years, and 44% at 5 years. It is estimated that between 150,000 – 200,000 major and minor lower extremity amputations are performed in the United States (US) and Europe yearly for CLI.3-4 In the US, the amputation rate has increased from 19 to 30 per 100,000 persons over the last two decades primarily due to an increase in diabetes and an advancing age population.5-6 Despite advances in cardiovascular treatment and revascularization technology, in patients over 85 years of age, an amputation rate of 140 per 100,000 persons/year has been reported, with a primary amputation (PA) still carrying an excessively high mortality rate of 13-17%.6-8 Successful rehabilitation after below-knee amputation (BKA) is achieved in less than two-thirds of patients and in less than one half of patients after above-the-knee amputations (AKA).9-11 Multiple reports have repeatedly documented the poor overall prognosis for the CLI patient, but recent reports by Panayiotopoulos et al and Kalra et al have shown significantly improved long-term survival after revascularization and limb salvage as compared to CLI patients following revascularization failure and amputation.6,12 Kalra et al reported the long-term survival after infrainguinal bypass surgery (IBS) (pedal bypass) in 256 CLI patients. Amputation and ESRD predicted higher mortality (p = 0.014, p = 0.0001, respectively) and overall 5-year survival rates were 60%.6 The 5-year survival rate after an amputation was 26%, therefore documenting significantly worse long-term survival for patients suffering an amputation versus those CLI patients achieving limb salvage.6 Clearly, the clinical costs to the CLI patient are extremely high, underscoring the need for a better understanding of the entire scope of this major problem as well as the development of new technologies involved in treating this CLI patient population in which the incidence is expected to increase yearly. Therefore, any treatment strategy aimed at decreasing amputations would have a significant impact on both short- and long-term clinical outcomes. Laird et al in 2003 reported the encouraging results of the Laser Angioplasty for Critical Ischemia (LACI) phase II pivotal trial results. 13 This prompted a retrospective analysis of our group’s (the Cardiovascular Institute of the South [CIS]) 24-month excimer laser atherectomy (ELA) experience in a similar patient population; therefore, we report our CIS “LACI Equivalent” results. LACI Pivotal Trial The LACI pivotal multi-center trial (15 US and German sites) enrolled 145 CLI patients with 155 ischemic limbs with Rutherford Class 4-6 (rest pain and early tissue loss-ulceration) who were poor or nonsurgical bypass candidates. These patients were considered very fragile with significant cardiopulmonary comorbidities and at high-risk for major amputation. ELA was delivered in 96% of the cases, including 8% who had failed guidewire crossing and required the “step-by-step” technique developed and championed by Professor Giancarlo Biamino. This technique utilizes methodical laser advancements through chronic total occlusions (CTO) uncrossable by traditional guidewire techniques. Of the 423 lesions treated, 41% were superficial femoral artery (SFA), 15% were popliteal artery (PA), and 41% were infrapopliteal arteries (IA). Forty-five percent of the overall lesions treated with ELA required a stent with 61% in the SFA, 38% in the PA, and 16% in the IA.13 The LACI results achieved an excellent 93% 6-month limb salvage rate with only 2 patients requiring IBS during follow-up. The in-hospital serious adverse event rate was extremely low, with a mean hospital stay of 3 days. “Straight line flow” to the foot was achieved in 89% of patients and at 6 months, only 16% required a secondary reintervention, with 69% achieving improvement in Rutherford category. The LACI trial is one of the only scientific-based attempts at evaluating any treatment in this CLI patient population at high-risk for amputation. CIS “LACI Equivalent” Patients: Between October 2001 — October 2003, 62 patients (62 limbs) with Rutherford Class 5-6 symptoms and CLI presented with severe infrainguinal disease without single vessel “straight line flow” to the foot. Seventy IA were treated, including posterior tibial (PTA) 21/70 (30%), peroneal 16/70 (23%), anterior tibial (ATA) 8/70 (11%), tibioperoneal trunk 14/70 (20%), and multiple 11/70 (16%). 28/62 (45.1%) and 19/62 (30.6%) of the CLI cases required SFA and PA ELA respectively. 5/62 (8%) patients required the “step-by-step” technique. Significant cardiopulmonary co-morbidities included coronary artery disease 56/62 (90.3%), congestive heart failure 38/62 (61.2%), chronic obstructive pulmonary disease 29/62 (46.7%), chronic renal insufficiency 24/62 (38.7%), and diabetes 51/62 (82.2%). The treatment group included 42 men and 20 women with a mean age of 73.4 years. Technique: The contralateral common femoral artery is always our access of choice unless contraindicated, and standard guidewire techniques were used to place a 7 or 8-French sheath over the aortic bifurcation. Excimer laser atherectomy, using a variety of laser catheters ranging from 0.9 mm to 2.0 mm in diameter (CVX-300, Spectranetics Corporation, Colorado Springs, CO) was used to laser debulk the lesions as previously described.14 The concentric Extreme 0.9 mm (0.014-inch and 0.018-inch wire, over-the-wire) catheter is the most frequently used catheter to begin laser atherectomy, especially in the IA, and we recommend starting with smaller size catheters. Excimer laser therapeutic energy density (fluence) is between 30 mJ/mm2 and 80 mJ/mm2, with 45 mJ/mm2 being a common starting level. Pulse repetition rates are from 25 pulses/s to 40 pulses/s, with calcium-cutting, 0.9 mm catheters being able to deliver 80 mJ/mm2 and 80 pulse repetitions/s. Adjuvant percutaneous transluminal balloon angioplasty (BA) was used post ELA frequently in the first 12 months of our experience, but less frequently in the second 12 months, as we learned to accept post laser atherectomy-only angiographic results in an effort to avoid barotrauma and stent deployment, especially in an IA. Optional stenting was reserved for flow-limiting residual stenosis or significant dissections. The goal was to achieve “straight line flow” to the foot in at least one IA. Anticoagulation was provided by direct thrombin inhibition with bivalirudin (Angiomax, The Medicines Company, Parsippany, NJ) with the recommended coronary dose of 0.75 mg/kg bolus with 1.75 µg/kg/hour periprocedural infusion. Further platelet inhibition was provided by glycoprotein IIb/IIIa inhibition with tirofiban (Aggrastat, Guilford Pharmaceuticals, Baltimore, MD) with a 0.4 ug/kg/min 30-minute bolus with 8-12 hour peri and postprocedural 0.1 µg/kg/min continuous infusion in every case. The recognition of severe heparin limitations has prompted the adoption of direct thrombin inhibition on all of our PVD cases since bivalirudin became available. We believe this has significantly decreased our bleeding complications and optimized anticoagulation in this patient population at high risk for both bleeding and thrombotic complications.15 Definitions and Follow-Up: Procedural success was defined as a patent vessel with Results: We obtained procedural success in 59/62 (95.2%), with all successful cases resulting in “straight-line flow” to the foot. 9/62 (14.5%) required a secondary reintervention [bypass 2/62 (3.2%) and repeat ELA 7/62 (11.2%)] at mean 7 months (range 1-21 months). There were no periprocedural deaths or major vascular or bleeding complications requiring surgery. There were 4/62 (6.4%) minor (Case Examples Case #1: A 69-year-old diabetic male presented with an ischemic left foot with a black ischemic eschar of the left ankle and heel after being told to “just soak your leg in betadine and it will get better” (Figure 1A, page 18). Angiography revealed a 100% occlusion of the ATA, peroneal artery, and subtotal occlusion of the proximal PTA and 100% occlusion of the mid-PTA with no flow to the foot (Figures 1B-C). A Glidewire and Glidecath (Terumo Medical, Somerset, NJ) were positioned to the mid-PTA and a 0.014” coronary wire was advanced to the tarsal vessel of the foot (Figure 1D). A 0.9 mm Extreme laser was advanced over the wire into the tarsal vessel (Figure 1E). Low-pressure coronary balloons were used for BA with excellent “straight-line flow” provided to the foot (Figures 1F-H). Twenty-four hours later, the eschar was debrided and several Apligraf (Organogenesis, Boston, MA) were applied, all under local anesthesia, in an attempt to provide optimized wound healing (Figures 1I-K). Bioengineered graftskin or Apligraf, is a new bilayered tissue-engineered skin, equivalent FDA-approved for treatment in venous and diabetic ulcers. It is reported to improve wound healing and epithelization by multiple mechanisms, including increasing matrix proteins, cytokines, and growth factors and promoting angiogenesis.16-17 Apligraf has been recently reported in the Annals of Thoracic Surgery to decrease the time to healing in patients with sternal and leg wound complications following coronary artery bypass surgery (CABG). It is reportedly showing promise as an adjuvant in wound healing after revascularization in patients with CLI.18 The patient achieved complete wound healing at 48 days (1L-M). Case #2 A 72-year-old black diabetic male presented with left foot rest pain and early gangrenous changes of digits 1-3 (Figure 2A, page 20). Angiography revealed a 100% SFA occlusion and a 100% PTA occlusion with > 90% ATA and peroneal stenosis (Figures 2B-C). ELA with low-pressure BA was performed at the same setting in the SFA, ATA, and peroneal artery with excellent results (Figures 2D-F). A 0.018” coronary wire was utilized in all areas with “kissing BA” performed in the IAs (Figures 2 G-H). Limb salvage was achieved and the patient remains asymptomatic at 18 months post procedure (Figure 2I). Discussion The overall prognosis of the CLI patient remains dismal despite advances in the treatment of many other cardiovascular diseases. As noted earlier, Wolfe et al identified a > 90% 12-month amputation rate in a high-risk CLI patient population if not revascularized and > 25% even if revascularization was provided.2 CLI is a marker for premature death with mortalities of 21% and 31.6% at 1 and 2 years respectively, after a diagnosis of CLI is made.19 Within 3 months of diagnosis of CLI, there is a 9% mortality, 1-2% will have a MI or stroke, and 12% will require a major amputation clearly defining this poor prognosis. To confound the problem even more, there occurs no universal consensus and sparse data exists regarding the treatment of CLI. The LACI trial Phase II data provides one of the few published multi-center series regarding the treatment of CLI. The CIS “LACI Equivalent” results very closely mirror the excellent results of the LACI trial. This is important, considering the overall dismal results of medical therapy (non-revascularizations) once the patient reaches the advanced Rutherford classifications for CLI. No pharmacologic clinical trials have been published demonstrating improved outcome as a sole therapy in patients with CLI without revascularization. Prostanoids (PGE1 and PGE2) have had the most investigations, but the data is inconclusive and failure rates of > 80% have been reported.1, 20-22 The general TASC recommendations for prostanoids and all other pharmacological therapies for CLI are as adjunctive treatments at best and these should be used as sole therapy only if no revascularization option is available.1 Ongoing trials with gene-induced therapeutic angiogenesis are promising, but likewise no definitive data exists that this therapy is ready for a primary treatment role in CLI at this time.1, 23-24 Tibial bypass surgery has a good proven track record in the CLI patient population and achieves limb salvage rates of > 80-90% at 5 years25-27 but the procedure has limitations, including: oftentimes requires general anesthesia, requires optimal vein as a conduit, small but not negligible perioperative cardiovascular mortality and morbidity (2-8%), moderate (10-30%) wound infection rate, requires intense graft surveillance with a 20-30% reintervention rate for optimal secondary patency outcomes, utilizes the vein that still remains the most frequently used conduit for CABG, and the surgery is a technically demanding operation not performed in every community. Substantial experience over the last decade has demonstrated the safety and, in general, excellent immediate and short-term results in the CLI patient population with infrainguinal BA.1,28-30 Therefore, the excellent results of the LACI trial and now our “LACI Equivalent” experience should underscore the appropriateness of aggressive endovascular strategies to provide “straight-lined” revascularization to the foot for limb salvage. Our “LACI Equivalent” results again confirm a very low overall complication rate ( 90% 6-month limb salvage rates in a patient population with > 90% risk for major amputation within 12 months. The concept of “straight line flow” to the foot was not only defined by the LACI trial experience. Bakal et al31 in 1990 reported an 80% limb salvage rate in patients with “straight line flow” to the foot in at least one tibial vessel after BA, versus 0% limb salvage when no flow to the foot could be obtained. The role of tibial stenting and the use of drug-eluting stents in the IA remain undefined, but a recent report by Biamino32 and a subset analysis of the IA stented cases in the LACI trial have shown improved results versus BA alone, further extending the potentials for improving endovascular outcomes in CLI. Our favorable experience with ELA in the CLI patient population has significantly improved our overall limb salvage rates, especially in those patients who are poor candidates for IBS or have no available conduit. Additionally, ELA has not taken away the surgical IBS option for the patient in those several patients who have required IBS for limb salvage after ELA was chosen as first line therapy. ELA has been shown to have “thromboablative” as well as “atheroablative” benefits in the treatment of coronary artery disease, AMI, and saphenous vein graft disease post CABG.33-35 Unquestionably, all phases of thrombus play a significant role in CLI and this is likely an added laser benefit in this patient population. This “thromboablative” effect may be responsible for our trend towards less BA and stenting post laser atherectomy, especially in the IAs. The often diffuse nature of IA disease makes avoiding the inevitable dissections created by higher pressure BA very attractive. We believe laser therapy has allowed us to avoid barotrauma and stenting in the IAs by creating an acceptable angiographic appearance with flow oftentimes to the foot with laser therapy alone. We are still concerned about placing stents in the infrapopliteal vessels. Conclusion In conclusion, our CIS “LACI Equivalent” experience confirms the safety and efficacy of excimer laser-assisted therapy in the treatment of severe infrapopliteal disease and CLI. Our 91.8% 6-month limb salvage rates closely mirror the excellent 93% 6-month limb salvage rate reported in the LACI pivotal multi-center trial, therefore further adding to the accumulating data that laser endovascular therapy is a vital tool when facing limb salvage in the CLI patient. Acknowledgement: We thank Mrs. Kelly Tilbe for her technical help with manuscript preparation. Dr. Allie, Chris Hebert, and Dr. Walker have disclosed that they have no significant financial relationship with any organization that could be perceived as a real or apparent conflict of interest in the contexts of the subject of this article. The authors can be contacted at David.Allie@cardio.com.