Taking on Critical Limb Ischemia

The prevalence of patients in the United States with critical limb ischemia (CLI) is estimated to be 50 to 100 per 100,000 yearly and is on the rise.¹ It is estimated that within 1 year after clinical diagnosis, 30% of patients will undergo a major amputation, and 25–30% will be deceased.² CLI is associated with the presence of rest pain, tissue loss, ulcerations and gangrene of the foot or toes. Traditionally, CLI has been categorized as Rutherford Classification Stages: 3 (severe claudication) 4 (ischemic rest pain); 5 (minor tissue loss); 6 (major tissue loss).³ Patients with CLI have severe disease involving most of the tibial pedal arterial tree. Early detection and treatment of CLI can prevent amputation and save lives. There are many associated risk factors contributing to the increasing number of patients with CLI — our aging population, obesity, diabetes and tobacco consumption being the most significant. Patients over 80 years of age are at a much higher risk for CLI due to an increased sedentary lifestyle. The continuation of tobacco consumption triples the risk of CLI, and diabetes mellitus (DM) is known to exacerbate the risk of CLI four-fold.⁴ Diabetic patients present a significant challenge for both surgical and endovascular therapy. These patients with CLI often have severe distal high-grade stenosis and chronic total occlusions (CTOs). It is well known that a diabetic patient with CLI is ten times more likely to undergo an amputation when compared to non-diabetics.⁵

Presentation

CLI presentation is becoming more widely recognized with its course of initial, predominantly nocturnal, ischemic rest pain involving the foot. Patients often complain of having to dangle their feet over the side of the bed to get pain relief. CLI often progresses to tissue loss from minor injury or trauma to the skin or nails. It is now well understood that this minor trauma can initiate a cascade of ischemic tissue loss. The tissue loss can progress into a non-healing ulcer. If the lack of blood supply continues and the tissue’s metabolic demands are not met, the ulcer progresses to gangrene. The ischemic area becomes susceptible to infection and sepsis, contributing to an increase in cardiac events and possibly death.

Diagnosis

Patient history and physical examination continue to play a pivotal role during the diagnostic work-up of CLI. Ankle-brachial pressure indices (ABI) are the standard for detection of peripheral vascular disease, but are not applicable for all patients. This is especially true in patients with DM and end-stage renal disease (ESRD) or in other patients prone to severely calcified arteries who are likely to have a falsely elevated ABI. The ABI in this subset of patients is less likely to detect occlusive tibio-pedal arterial disease, in which palpation for the pedal pulses provides accurate detection of pulsatile blood flow in the tibio-pedal arteries. Otherwise, an ABI of 6 Following physical examination, precise angiographic diagnostic evaluation is a crucial step in the therapeutic algorithm during the preintervention phase. A pig-tail catheter placed in the distal aorto-iliac junction followed by contrast injection and distal runoff evaluation has been the most common method of peripheral diagnostic angiography. In CLI patients who are undergoing revascularization, the anatomical visualization and description should be obtained from a catheter placed near the target lesion (selective angiography). When comparing the selective angiography to the standard aorto-iliac runoff, it is clear that significant data regarding the tibio-pedal anatomical description can be missed when utilizing the aorto-iliac pig-tail method alone. Selective angiography is far more accurate, especially in the presence of tibio-pedal occlusive disease.

Pathophysiology

Atherosclerosis involves several highly interrelated processes including lipid disturbances, platelet activation, thrombosis, endothelial dysfunction, inflammation, oxidative stress, vascular smooth cell activation, altered matrix metabolism, remodeling and genetic factors.⁷ In early atherogenesis, recruitment of inflammatory cells and the accumulation of lipids lead to the formation of a lipid-rich core. Oxidized low-density lipoprotein (LDL) stimulates the production of chemokines and growth factors, resulting in smooth muscle cell proliferation. Oxidized LDL also stimulates the production of osteopontin, resulting in calcification. The spectrum of lesion morphology can range from fibrotic to fibrocalcific. Heavily calcified vessels are associated with extremely complex intervention as well as a higher risk of complications and therapeutic failures.

Treatment

Treatment of CLI can include endovascular therapy, surgical grafting or amputation. A large meta-analysis performed by Romiti et al⁸ on infrapopliteal angioplasty for chronic CLI indicated that percutaneous transluminal angioplasty (PTA) has become an acceptable form of treatment for patients with CLI. This meta-analysis, which reviewed endovascular and vascular surgical interventional data from 1981 to 2006, showed a transitional evolution preferential for endovascular therapy to treat CLI. Early on, patients with below-the-knee (BTK) CLI received PTA only when short proximal non-CTO tibial disease was present. Over time, the analysis demonstrated that the course of therapy had changed significantly. Operators moved toward treating long tibial disease, including CTO segments, more regularly with endovascular techniques. The positive progress of evolving CLI therapy is a necessary adaptation to the increased complexity of CLI.

Access

In a limb salvage procedure, access is a very important first step to ensure visualization of the target lesion. The appropriate access site is also crucial for the delivery of interventional devices to the diseased segment. There are three common access sites for the treatment of CLI. The most common is contralateral access, which is sufficient for proximal to mid-tibial interventions in the majority of limb salvage procedures. Antegrade access is utilized for mid-to-distal tibial and pedal interventions. And finally, the antegrade/retrograde approach is necessary when the takeoff of the target tibial vessel is not visualized (Figures 2 a–c). This approach involves a combination of obtaining access via the ipsilateral common femoral artery in an antegrade fashion and obtaining a retrograde access of the ipsilateral target tibial vessel.

Tibial CTO Crossing

Central lumen crossing is the preferred approach for tibial CTOs. In tibial limb salvage CTO procedures, subintimal recanalization is unforgiving and should be avoided, especially from mid-to-distal sections of the target vessel. As shown in Figures 3a and 3b, the subintimal track and hematoma created by wires and crossing devices could lead to patent vessel luminal loss and, subsequently, procedural failure.

Common CTO Crossing Devices

Guidewires. A wide range of interventional wires are available. The choice of wire type is typically based on operator preference. The workhorse wire post crossing should be 0.014 inches, especially when the intervention involves the distal tibial and pedal vessels. The Asahi wire family (Cardiovascular Systems, Inc., St. Paul, Minnesota) provides reasonable choices, with sizes starting at 0.014 and 0.018 inches. Out of this family of wires, the Treasure 12 wire provides excellent one-to-one torque and precise tactile and force delivery to the CTO cap. Crosser® Catheter. The Crosser Catheter (FlowCardia/Bard Peripheral Vascular) is a device that uses high-frequency mechanical vibration to facilitate central lumen guidewire crossing of the occlusion, allowing for subsequent plaque debulking (removal), balloon angioplasty or stent placement. For many patients, this minimally invasive approach to CTO recanalization can eliminate the need for long-vessel stenting by assisting in finding the hibernating vessel lumen between the proximal and distal CTO caps. In many CLI cases, it is not unusual to see the proximal tibial CTO cap and not the distal vessel reconstitution or cap. In these cases, the Crosser device has been extremely effective in traversing the proximal cap and continuing on to identify the distal hibernating reconstitutional vessel segment. Frontrunner™ XP. The Frontrunner XP (Cordis Corp., Miami Lakes, Florida) is a unique device with several assets that aid the operator in Crossing CTOs. It has a handle assembly with a proximal braided shaft for push and torque control. The distal shaft is flexible and can be manually shaped. It has a radiopaque, blunt, shapeable distal actuating tip. The Frontrunner does not have a guidewire lumen.

Atherectomy Devices

Atherectomy has evolved into four different treatment modalities. Each device performs a unique task and fills a unique need in treating patients with CLI. Rotational atherectomy devices. The Diamondback 360® orbital rotational atherectomy device (Cardiovascular Systems, Inc., St. Paul, Minnesota) is another option for the restoration of blood flow to patients with CLI. The Diamondback gives patients a treatment option to restore blood flow in the tibial and pedal arteries. It is an excellent tool for debulking calcified plaque in long, asymmetrically diseased tibio-pedal arteries, which is a common finding in CLI patients. Given the unique mechanism of orbital atherectomy provided by the Diamondback, the risk of dissection is less than that in plain-old balloon angioplasty.⁸ The Diamondback also changes the compliance of the vessel wall and therefore may occasionally achieve acceptable results as a standalone approach. Adjunctive balloon angioplasty post Diamondback intervention typically requires less atmospheric pressure, which may spare the vessel wall from barotraumas and reduce the risk of dissection. Directional atherectomy devices. The SilverHawk device uses a rotational carbide blade to shave plaque from the arterial wall. It stores the removed plaque in its nosecone, which has to be removed outside the vessel to be emptied. The SilverHawk removes the plaque by directional cutting atherectomy that is mechanically and manually operated. The device is rotated at multiple 10-degree angles until the plaque burden is reduced to an acceptable percent stenosis. The SilverHawk device effectively debulks CTOs and high-grade stenoses containing fibrotic plaque. The TurboHawk device is effective in debulking CTOs and high-grade stenoses containing calcified plaque. Laser tissue ablation devices. The laser guide catheters Turbo-Elite® and Turbo-Booster® (Spectranetics, Inc., Colorado Springs, Colorado) use laser energy to ablate tissue. Laser energy in the form of ultraviolet light is delivered in pulses through a catheter tip that vaporizes organic material. These devices can cross and treat both short and long lesions. They are also effective in treating CTOs and high-grade stenoses. One advantage of the Turbo-Elite catheter is its ability to be advanced without a guidewire, therefore providing another option for CTO crossing. Revascularization catheters. The first-generation Pathway device is the Jetstream G3™ (Pathway Medical Technologies, Inc., Kirkland, Washington), which has a front-cutting blade that is able to create a channel between 2.5–2.75 mm. With its blades fully deployed, the Jetstream G3 can create a channel up to 4 mm. The second and recently released device is the Jetstream G3SF (small fixed), which is a more flexible catheter with a 1.85 mm front-end cutting tip. Both devices have the ability to aspirate while performing atherectomy.

Balloons

Adjunctive balloon angioplasty is used with atherectomy and standalone scoring balloons with devices such as the AngioSculpt® (AngioScore, Inc., Fremont, California) and cutting balloons with longitudinal microsurgical blades such as the Flextone® (Boston Scientific Corp., Natick, Massachusetts). Both balloons are limited by their ≤ 2 cm length, which makes these devices impractical to treat long, diffusely diseased or long occlusions. The Vascutract™ (Bard Peripheral Vascular, Inc., Tempe, Arizona) features a long, single 0.014 inch wire on the outer edge of a long balloon, which provides an acceptable alternative to scoring and cutting balloons in long, diffusely diseased vessels. The Vascutract is a unique balloon with a distal rapid-exchange exit port allowing a single wire on the outside of the balloon. When the balloon is inflated, the Vascutract wire and standalone guidewires are pushed against the plaque and the vessel wall. The wire trapped between the vessel wall and the balloon provides controlled dissection and changes the compliance of resistant plaque. Long, tapered balloons provide a unique therapeutic option for long, tapered tibio-pedal vessels. The tapered balloons differ by a 0.5 mm outer diameter from the distal to proximal ends. Multiple balloons provide large variations in length and strength to accommodate the variation in the complexity of CLI. The IN.PACT Amphirion™ paclitaxel-eluting PTA balloon (Invatec, Inc./Medtronic, Inc., Roncadelle, Italy) was recently launched in Europe. More data are needed to support the long-term benefits of drug-eluting balloons in the treatment of CLI.

Stents

Most bare-metal, balloon-expandable and self-expandable stents have not shown any long-term benefits, primarily due to the well-known phenomenon of intimal hyperplasia formation potentially leading to insufficient long-term patency rates.^2,8 Treating below-the-knee with drug-eluting stents is an effective means of relieving symptoms and preventing major amputation. Procedural complications and limb revascularization rates have been low. Limb salvage and survival rates in patients treated with drug-eluting stents exceed those of historic controls.^2,8

Conclusion

CLI is associated with significant morbidity and mortality. It is imperative that physicians maintain a high index of suspicion, which often requires a multidisciplinary approach including aggressive treatment of traditional risk factors, lifestyle modification and therapeutic intervention to restore antegrade blood flow. The availability of multiple interventional devices and techniques can offer patients options in diseased arterial territories, which have traditionally not been possible, particularly in tibial and pedal interventions. Endovascular therapy has emerged as a minimal morbidity and mortality procedure with significant improvement in distal extremity perfusion pressure. An understanding of the natural history of peripheral arterial disease, patient-related risk factors and lesion morphology and selection criteria, as well as an understanding and knowledge of various devices and techniques, are essential elements required to perform these procedures effectively and safely.

References

1. Adam DJ, Beard JD, Cleveland T, et al. Bypass versus angioplasty in severe ischaemia of the leg (BASIL): Multicentre, randomized controlled trial. Lancet 2005;366:1925–1934. 2. Feiring, AJ, Krahn, M, Nelson, L, et al. Preventing leg amputations in critical limb ischemia with below-the-knee drug-eluting stents: The PaRADISE (Preventing Amputations using Drug eluting StEnts) Trial. J Am Coll Cardiol 2010;55:1580–1589. 3. Schmieder FA, Comerota AJ. Intermittent claudication: Magnitude of the problem, patient evaluation, and therapeutic strategies. Am J Cardiol 2001;87:3D–13D. 4. Dormandy J, Verstraete M, Andreani D, et al. Second European consensus document on chronic critical leg ischemia. Circulation 1991;84(Suppl 4):1–26. 5. DeBakey ME, Crawford ES, Garrett E, et al. Occlusive disease of the lower extremities in patients 16 to 37 years of age. Ann Surg 1964;159:873–890. 6. Cohen D, Kassab E, Pupp G, et al. Peripheral arterial disease. Are we doing enough to diagnose and treat patients with PAD? Supplement to Endovascular Today. Summer 2008. 7. Faxon D, Creager MA, Smith SC, et al. Executive summary: Atherosclerotic vascular disease conference proceeding for healthcare professionals from a special writing group of the American Heart Association. Atherosclerotic Vascular Disease Conference. American Heart Association. Circulation 2004;109:2595–2604. 8. Romiti M, Albers M, Brochado-Neto FC, et al. Meta-analysis of infrapopliteal angioplasty for chronic critical limb ischemia. J Vasc Surg 2008;47:975–981.

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From the Department of Research and Endovascular Interventions, Metro-Health Hospital, Wyoming, Michigan. Disclosures: Dr. Mustapha has been a consultant for Bard, Cardiovascular Systems, Inc., Cordis Corp., and ev3, Inc. Address for correspondence: J.A. Mustapha, MD, FACC, FSCAI, Assistant Professor of Medicine, Michigan State University, Director of Research and Endovascular Interventions, Metro-Health Hospital, 5900 Byron Center Ave. S.W., Wyoming, MI 49519. E-mail: jihad.mustapha@metrogr.org