Critical Limb Ischemia: Future Directions and New Modalities of Therapy

VASCULAR DISEASE MANAGEMENT 2010;7(10):E200–E202

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Introduction

As our population ages with an increasing prevalence of diabetes and metabolic syndrome, the United States and other developed nations are facing a significant growth in the number of patients presenting with critical limb ischemia (CLI). Patients who present with CLI are at significant risk for both cardiovascular mortality and disease-based morbidity. Multiple specialties are being integrated into the care of these patients and driving the development of less invasive, percutaneous techniques. Economically sensible and successful interventional treatments will need to become better defined.

Critical limb ischemia is defined as rest pain, ulcerations and gangrene. The basis of treatment centers around the fact that the amount of blood flow required to heal damaged tissue is significantly more than that required to maintain intact tissue. Conservative care outcomes are poor, with a short-term mortality rate of 10%. Other risks associated with CLI include myocardial infarction, stroke (2%), amputation (12%) and persistent CLI (18%).¹ Successful reperfusion techniques must provide improvement in “straight-line” blood flow to the foot for a sufficient time interval for wounds or surgical sites to heal. The long-term care costs significantly favor treatment paradigms that avoid amputation.

Before undertaking any interventional or surgical therapy, proper evaluation and documentation of the status of any infection must be completed. Multiple variables need to be evaluated including the vascular anatomy, patency of the plantar arch, the amount of tissue destruction that has occurred and the need for surgical debridement. The anatomic obstructions that are present in patients with CLI are usually multilevel, or in the case of the infrapopliteal area, multisegmental. The techniques for increasing perfusion to the threatened limb can be complex and may include open surgery, endovascular means or combined treatment in select populations. Because of the comorbidities that are often present in the population with CLI, the use of endovascular techniques is often considered the appropriate first treatment option. Infrainguinal endovascular procedures have not demonstrated the long-term patency associated with open surgical procedures. However, limb salvage appears to be similar and the endovascular procedures are usually easily repeatable. The BASIL trial,² which randomized patients with CLI to surgery and angioplasty, showed a cost benefit for angioplasty at 1 year with similar clinical outcomes.

Though plain balloon angioplasty certainly is the cornerstone for endovascular care, there are other niche techniques that are being utilized for successful outcomes.³ Cutting balloon angioplasty, cryoplasty, multiple types of atherectomy and excimer laser have been reported with good 6- to 12-month limb salvage.^4–7 The application of coronary stents certainly is feasible, and early hemodynamic and limb salvage have been excellent in a recent series.^8,9 However, most of the data on stents have involved short lesions and have little relevance to the majority of the patients with CLI and long total tibial artery occlusions. Long total occlusions have often been difficult to traverse with a guidewire. Industry has recently started to focus on developing wires and support catheters that appear to be improving success rates. Long endovascular techniques have started to take advantage of any patent pedal vessels for successful retrograde wire access, adding another avenue for success.¹⁰

The next significant revolution in revascularization for CLI in the near term of 2–5 years in the United States appears to be associated with drug-coated balloons and stents, while in the mid-term of 5–10 years, there will likely be increasing success in drug-eluting bioabsorbable stent technology. Recently, trials have demonstrated significant improvement of patency in simple femoropopliteal disease treated with drug-coated balloon technology.^11,12 With the recent development of long tibial balloons, early angiographic success, even in long tibial disease, has been improved. It would certainly seem simple to extrapolate these data to the tibial vessels. However, the regulatory agencies of the United States are historically more detail-oriented than their international counterparts. With drug-coated stents, especially those with polymers or release mechanisms, the amount of drug on the stent can be easily calculated, as can the elution parameters, and so forth. With drug-coated balloons, the answer to these questions may not be as simple. In the tibial vascular bed, another significant question may center on the question of how the release of the majority of the drug on the balloon into the distal vascular bed will affect the healing potential of the tissue.

Certainly, a paradigm exists since we have a significant amount of data demonstrating efficacy of the platforms utilized in trials, and changing any part of the drug-coated balloon platform may have unpredictable affects. The use of drug-coated bioabsorbable stents may allow for the best of both worlds: dependable luminal gain, along with predictable drug delivery. Though many of these assumptions are still theoretical, bioabsorbable technology may increase the safety and long-term results in the superficial femoral and tibial vascular beds. Specific advantages that seem to be present include improved biocompatibility with less deep-wall injury, inflammation and hypersensitivity responses, improved conformability (reduced compliance mismatch), facilitation of arterial remodeling, restoration of vasoreactivity, no stent fractures and improved ability to repeat treatment either percutaneously or by open surgery.

Other potential benefits of a bioabsorbable platform are also apparent. Preservation of side-branch patency allows for follow-up with non-invasive imaging (computed tomography [CT] and magnetic resonance imaging [MRI]), reduced stent thrombosis (especially late/very late) and potentially the reduced need for prolonged antiplatelet therapy. Finally, most interested parties appear to inherently favor the idea of a disappearing stent. But can drug-eluting bioabsorbable stents really lead to improved outcomes? Early registry data that have been presented on the Zilver PTX (non-polymer based, paclitaxol covered; Cook Medical, Inc., Bloomington, Indiana) appears to demonstrate efficacy. More insight may soon be available when the Zilver PTX randomized trial data become available. To date, the superficial femoral artery (SFA) has shown suboptimal results with both bare-metal and drug-eluting (polymer-based) stents. Interestingly, the early drug-eluting trials seem to demonstrate benefit at 6-months, but the benefit appeared to be lost by 12 months. This may be due to the chronic external forces on the vessel/stent interface, resulting in a chronic stimulus for restenosis or the effects of the polymer, etc. The use of drug-eluting bioabsorbable stents may lead to the ability to successfully treat more complex and longer lesions than balloons alone, but absorption of the stent may allow for removal of the restenosis stimulus before losing the benefit of drug action on the restenosis variables. Early suggestion of support for this approach appears evident in the ABSORB trial. In the coronary vascular bed, scaffolding appears to be needed for approximately 3 months, and no new major adverse cardiac events (MACE) occurred at 24-month follow-up.¹³ The tibial arterial bed may be particularly attractive for bioabsorbable technology. These patients with CLI are often very sick with multiple comorbidities. Utilizing these stents may allow for an increased patency interval long enough for resolution of tissue damage. Bioabsorbable stents may also allow for shorter procedure times and decreased contrast usage compared to balloon angioplasty. So why do we predict that these bioabsorbable platforms will not be readily available clinically for 7–10 years? Due to the shear volume of procedures, the coronary vascular bed will be focused upon. With the longest coronary stents currently utilized being

Summary

Patients with CLI are at risk for both limb loss and premature death, but as refinements of endovascular devices and techniques mature, the need for open surgical procedures will likely diminish. Coupled with an epidemic of metabolic syndrome and diabetes, CLI will lead to the continued growth in endovascular revascularization. Successful outcomes rely on adequate initial diagnostic testing, including comprehensive cardiac evaluation, followed by expert application of endovascular techniques. Drug-eluting balloons and bioabsorbable stents appear to be the most promising technology in the short and mid-term.

References

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2. Adam DJ, Beard JD, Cleveland T, et al; BASIL trial participants. Bypass versus angioplasty in severe ischaemia of the leg (BASIL): Multicentre, randomised controlled trial. Lancet 2005;366:1925–1934.

3. 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;29:620–627.

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8. 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;13:1–11.

9. 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.

10. Botti CF Jr, Ansel GM, Silver MJ, et al. Percutaneous retrograde tibial access in limb salvage. J Endovasc Ther 2003;10:614–618.

11. Werk M, Langner S, Reinkensmeier B, et al. Inhibition of restenosis in femoropopliteal arteries: Paclitaxel-coated versus uncoated balloon: Femoral paclitaxel randomized pilot trial. Circulation 2008;118:1358–1365.

12. Tepe G, Schmitmeier S, Speck U, et al. Advances on drug-coated balloons. J Cardiovasc Surg (Torino) 2010;51:125–143.

13. Serruys PW, Ormiston JA, Onuma Y, et al. A bioabsorbable everolimus-eluting coronary stent system (ABSORB): 2-year outcomes and results from multiple imaging methods. Lancet 2009;373:897–910.

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From MidOhio Cardiology and Vascular Consultants, Columbus, Ohio. Disclosures: Dr. Ansel discloses the following: Research/speakers bureau – Abbott/Guidant Vascular; Advisory board – Bard, Inc.; Advisory board and research – Boston Scientific Corp.; Research and product royalties – Cook, Inc.; Speaker and advisory board – Cordis/Johnson & Johnson; Advisory board – Medrad/Possis. Dr. Botti discloses the following: Honoraria and speakers bureau – Bard and Cook Medical; Travel expenses – Cook Medical. Dr. Silver discloses the following: Honoraria – Bristol-Meyers Squibb and Eli Lilly; Speakers bureau – Bard Peripheral Vascular, Cook Medical, Medtronic; Travel expenses – Eli Lilly and Bristol-Meyers Squibb. Address for correspondence: Gary M. Ansel, MD, FACC, MidOhio Cardiology and Vascular Consultants, Columbus, Ohio. E-mail: gansel@mocvc.com