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Evaluation of the Patient Who Presents With Critical Limb Ischemia: Diagnosis, Prognosis, and Medical Management
Evaluation of the Patient Who Presents With Critical Limb Ischemia: Diagnosis, Prognosis, and Medical Management Ian Del Conde, MD,* and Phillip A. Erwin, MD, PhD† Patients with critical limb ischemia usually have severe atherosclerotic disease and are at a high risk of limb loss as well as major adverse cardiovascular events. The current article provides a description of the clinical presentation of patients with critical limb ischemia and also discusses the initial evaluation of these patients, including physical examination, use of noninvasive vascular tests, and other imaging modalities. An overview of the general management of these patients is also provided, including the identification of patients who benefit from revascularization or primary amputation, principles of wound care, and therapies for cardiovascular risk reduction. Tech Vasc Interventional Rad 17:140-146 C 2014 Elsevier Inc. All rights reserved. KEYWORDS critical limb ischemia, peripheral arterial disease, arterial ulcer
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ritical limb ischemia (CLI) is the most serious manifestation of peripheral arterial disease (PAD) and is characterized by ischemic pain of the limb at rest or by tissue loss (usually nonhealing ulcers or gangrene). By definition, these patients correspond to a stage between 4 and 6 of the Rutherford classification (Table 1).1 Patients with CLI should have objective evidence of severe ischemia, for example, with markedly decreased ankle or toe systolic pressures or with a reduced transcutaneous tissue oxygen concentration or with a combination of both. Ischemic rest pain most commonly occurs when the ankle systolic pressure is less than 50 mm Hg or when the toe pressure is less than 30 mm Hg. When clinicians encounter a patient with severe lower extremity PAD and an ulcer, the following 2 fundamental questions must be addressed: (1) Is ischemia the cause of the ulcer? (2) Will ischemia prevent the wound from healing? The goal of this article is to describe the clinical features and evaluation of patients with CLI.
Clinical Features Risk Factors The risk factors for CLI are the same as those associated with systemic atherosclerosis affecting other vascular beds, such as the coronary or carotid arteries. These risk factors include age, cigarette smoking, diabetes mellitus, hyperlipidemia, hypertension, and male sex. Epidemiologic studies of PAD confirm that the strongest risk factors for developing CLI (odds ratio 43) include advanced age, diabetes mellitus, and cigarette smoking.2 In a recent study from the Veterans Administration of 50 consecutive patients referred for CLI, the mean age was 69.5 years; of these, 86% had hypertension, 72% had hyperlipidemia, 78% had diabetes mellitus, and 86% had a history of tobacco use.3 In addition, a strong link has been found between PAD, including CLI, and chronic kidney disease.4
Prognosis *Miami Cardiac and Vascular Institute, Miami, FL. †Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, OH. Address reprint requests to Ian del Conde, MD, Baptist Cardiac and Vascular Institute, 8900 North Kendall Drive, Miami, FL 33176. E-mail: [email protected]
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Patients with CLI have a very poor prognosis overall, for both cardiovascular morbidity and mortality as well as limb loss and persistent disability. There is a strong correlation between the ankle-brachial index (ABI) as a measure of the severity of PAD and mortality. For example, in a study of approximately 2000 claudicants, patients with an ABI o 0.50 had twice the mortality of claudicants with an ABI of 4 0.50.5 At 1 year
1089-2516/13/$ - see front matter & 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1053/j.tvir.2014.08.002
Evaluation of the patient with critical limb ischemia Table 1 Rutherford Ischemia.1
Classification
of
Chronic
141 Limb
Category Clinical Description 0 1 2 3 4 5 6
Asymptomatic—no hemodynamically significant occlusive disease Mild claudication Moderate claudication Severe claudication Ischemic rest pain Minor tissue loss (nonhealing ulcer and focal gangrene with diffuse pedal ischemia) Major tissue loss (functional foot no longer salvageable)
following presentation, 25% of patients with CLI died, mostly from cardiovascular events, and 30% of them were alive but had undergone an amputation.6 Although more than two-thirds of patients who present with CLI have a history of PAD, the assumption that CLI represents gradual worsening of PAD is incorrect. In a study, more than half of patients who underwent a below-the-knee amputation for CLI had no symptoms of PAD 6 months before presentation.
Physical Examination A complete vascular examination is critical in all patients presenting with CLI, as these patients usually have advanced atherosclerotic disease that may involve other vascular territories, including the carotid and coronary arteries. Although a detailed review on the vascular examination is beyond the scope of this review, readers are referred to an excellent monograph on this topic.7 At a minimum, blood pressure should be checked in both arms to ensure the absence of subclavian artery stenosis and falsely decreased blood pressures. The carotids should be auscultated at the level of the angle of the mandible for the presence of bruits. The abdomen should be auscultated for the presence of epigastric bruits, which may indicate renal, celiac, or mesenteric artery stenosis. The abdomen should also be palpated to search for an abdominal aortic aneurysm. The lower extremities should be inspected for any changes in color. A side-byside comparison with the contralateral limb may reveal pallor or discoloration. Signs of chronic ischemia include loss of subcutaneous fat, shininess, and dystrophic nail changes. A detailed assessment of any ulceration is crucial. The wound dimensions should be measured and documented with each visit to track healing over time. Arterial ulcers are usually round with sharply demarcated borders and appear “dry” (as opposed to “wet” ulcers seen in venous disease or with diabetic ulcerations). Ischemic ulcers tend to localize distally in the leg or foot, over bony prominences, or in the toes (Fig. 1 and Table 2). Significant pain is common in arterial ulcers and may be exacerbated by leg elevation. By contrast, diabetic foot ulcers have a thickened callus around the ulcer and tend not to be painful. Capillary refill time should be assessed. Normally, capillaries in the pulps of the digits or the toes refill in fewer than 5 seconds following pressure and
Figure 1 An arterial ulcer located in the lateral malleolar area of the right leg. The ulcer is round, appears “dry,” and has sharply demarcated borders. (Color version of figure is available online.)
release. In cases of significant ischemia, capillary refill time may be greater than 20 seconds. Another simple test that may reveal ischemia consists of noting color changes with elevation and dependency of the affected limb: a normal limb would remain pink in both the elevated and dependent positions. By contrast, an ischemic limb becomes pale in the elevated position (4451), gradually becomes pink in the dependent position, and may even develop a bright red color, termed dependent rubor, which is reflective of reactive hyperemia. Peripheral pulse assessment is perhaps the most important part of the vascular examination. Arterial pulsations typically diminish or disappear distal to the level of occlusion or severe stenosis. If extensive collateral circulation has been developed around an area of occlusion, distal pulsations are usually present but diminished.
Table 2 Physical Examination Nonhealing wound or ulcers with features that suggest an ischemic etiology: dry-appearing, sharply demarcated borders and located distally, especially over bony prominences or toes Decreased or absent pulses Dry skin, hair loss, dystrophic nails, and loss of subcutaneous fat Cool extremities Pallor on elevation and dependent rubor Delayed capillary refill time
I.D. Conde and P.A. Erwin
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Differential Diagnosis Nonhealing leg ulcers often occur in patients with diabetes mellitus, neuropathy, and frequent mechanical insults. Although PAD may coexist in these patient populations, their tissue loss may not be a consequence of arterial ischemia, and they should therefore not be deemed as having CLI until decreased blood flow can be objectively demonstrated by noninvasive testing. Other conditions that may mimic CLI include nonatherosclerotic arterial occlusive diseases that involve the small, distal arteries of the limbs, resulting in foot (or hand) ischemia with severe pain at rest and possibly also with ulcerations and tissue loss. Examples include Buerger disease, vasculitis (large-, medium-, and small-artery vasculitides), drug-induced arterial occlusive disease (especially cocaine), antiphospholipid antibody syndrome, and connective tissue disorders such as scleroderma/CREST. Raynaud's phenomenon, esophageal dysfunction, sclerodactyly, telangiectasias.
Noninvasive Methods of Assessing the Circulation As mentioned earlier, it is important that ischemia be objectively demonstrated in patients who are presumed to have CLI. The diagnosis of CLI is a functional one. Although imaging studies, such as computed tomography or ultrasound, help in planning interventions, the initial diagnosis of limb ischemia is typically made with physiological tests that inform about tissue perfusion and help predict wound healing. These tests can be subdivided broadly into tests that assess the arterial macrocirculation and those that assess the microcirculation (Table 3).
Macrocirculation The ankle systolic pressure and the ABI are measured using Doppler ultrasound and an appropriately sized cuff (which should have a width of at least 40% of the limb circumference). The ABI of each leg should be calculated by dividing the higher of the posterior tibialis (PT) or dorsalis pedis (DP) pressures by a higher of the 2 brachial systolic blood pressures.8 A normal ABI exists when the ratio between the ankle and brachial systolic pressures is 1.0. Patients with CLI often, but not always, have markedly diminished ABIs. Generally, an ABI of less than Table 3 Macrocirculation ABI o 0.4 Absolute ankle systolic pressure o50 mm Hg Microcirculation Absolute toe systolic pressure o30 mm Hg Toe PPG pulse wave amplitude o4 mm Transcutaneous oxygen pressure o20 mm Hg Other: skin perfusion pressure (o40 mm Hg), transcutaneous carbon dioxide (4100 mm Hg), and capillary density (o20 mm2)
0.4 or any ankle systolic pressure o 50 mm Hg is indicative of severe PAD (usually multilevel disease) and suggests that a wound may not have sufficient perfusion to heal. Ankle pressures in patients with ischemic ulcers are typically in the range of 50-70 mm Hg, whereas patients with ischemic rest pain typically have even lower ankle pressures, in the 30-50 mm Hg range.6 However, it should be noted that heavily calcified, noncompressible arteries may result in falsely elevated ABIs. If this is suspected, a toe-brachial index (TBI) results should be obtained by comparing the great toe systolic pressure obtained by photoplethysmography (PPG) with the highest brachial systolic blood pressure obtained by Doppler ultrasound. A normal TBI is considered as 0.75 or higher. An important pitfall of the ABI method in establishing CLI is that, by definition, the ABI ratio is calculated using the higher systolic pressure of the DP or PT pulses. Therefore, the more diseased artery supplying the region or angiosome where an ischemic ulcer may be located9 could be missed in the ABI interpretation (see the article by Mariano Palena et al10for a discussion on the angiosome concept). For example, a patient with a nonhealing heel ulcer, with a brachial systolic blood pressure of 120 mm Hg, a DP systolic blood pressure of 100 mm Hg, and a PT systolic blood pressure of 40 mm Hg, may be reported as having a mildly decreased ABI of 0.83, when in reality, the ABI of the artery that supplies the heel (where the ulcer is) is only 0.33. As such, reviewing the actual results, rather than merely the interpretation, for each artery when an ABI has been performed is critical.
Microcirculation Noninvasive assessment of the microcirculation is emerging as an important strategy for predicting the wound-healing potential. Nevertheless, these methods are generally less standardized, less reproducible, and less available when compared with those that assess the macrocirculation. Because digital arteries rarely calcify, toe pressures and TBIs are useful for assessing perfusion and healing potential. In patients with extensive tissue loss or amputation of the great toe, the toe pressure can be obtained in the second toe. Toe pressures have been proposed as being superior to either the absolute ankle pressure or the transcutaneous oxygen pressure (TcPO2) for identifying CLI and predicting the course of the disease.11 Another manner of assessing the microcirculation is to evaluate the morphology and amplitude of the toe PPG waveforms. A PPG wave amplitude less than 4 mm has been associated with the presence of CLI as well as increased risk of amputation and all-cause mortality.12,13 Although measurement of toe PPG pulse wave amplitudes is challenging and difficult to reproduce, some clinicians use it to complement other tests of the macrocirculation and microcirculation. TcPO2 is another noninvasive method for measuring tissue perfusion. Usually, a few (2-4) electrodes are placed on the site of interest, for example, near an ulcer (Fig. 2). Oxygen pressures are monitored continuously. Different
Evaluation of the patient with critical limb ischemia
143
Figure 2 TcPO2 values obtained with 4 electrodes for the evaluation of foot ulceration. Baseline TcPO2 values are indeterminate in all 4 electrodes. The healing potential is suggested based on (1) minimal reductions (o10 mm Hg) in TcPO2 on leg elevation and (2) almost doubling of the TcPO2 compared with baseline with 100% FiO2. (Image courtesy: Dr Heather Gornik, Cleveland Clinic). (Color version of figure is available online.)
authors have proposed different cutoff values for suggesting severe ischemia and low likelihood of healing. A baseline TcPO2 o10 mm Hg is very specific for severe ischemia, o20 mm Hg predicts very poor healing, and 440 mm Hg is seen in either normal or mildly reduced perfusion with good likelihood of healing. The range between 20 and 40 mm Hg represents moderately reduced perfusion and is a “gray zone” in which the potential for healing cannot be ascertained. In these cases, specific maneuvers are employed to further assess the degree of ischemia. For example, the patient may be placed on 100% FiO2 for 10 minutes and the TCPO2 is remeasured while breathing 100% oxygen. Different facilities have different thresholds, but we generally consider doubling or tripling of the baseline TCPO2 to be predictive of a response to hyperbaric oxygen therapy.14,15 That said, hyperbaric oxygen therapy for CLI is controversial and not widely available. Another maneuver used in cases of indeterminate TcPO2 at baseline is to elevate the limb; if the TcPO2 decreases by less than 10 mm Hg, then healing potential is suggested. In practice, several technical factors related to
the reproducibility of the TcPO2 test have limited its widespread availability. For example, changes in room temperature or even the emotional state of the patient may result in significant differences in TcPO2 measurements, potentially resulting in erroneous conclusions. Although the TASC-II guidelines support the use of TcPO2 to assess the microcirculation in patients with CLI,6 at present, only a small percentage of noninvasive vascular laboratories offer TcPO2 testing.
Initial Management of Patients with CLI The primary goals of the treatment of CLI are to prevent amputation, relieve ischemic pain, allow wound healing, and improve the patient's ability to ambulate. Once the patient has been diagnosed with CLI, a decision has to be made on whether the patient is a suitable candidate for revascularization. Revascularization is the main treatment of CLI as it directly addresses the driving force of ischemic ulceration (Fig. 3). However, revascularization is
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Figure 3 Algorithm for the management of patients with CLI.6
technically not possible in all patients, and not all patients benefit meaningfully from revascularization. For example, older patients, who are bedridden and with comorbidities such as advanced dementia and present with extensive tissue loss, may not benefit from revascularization. Indeed, their quality of life may improve more with either primary amputation or conservative medical therapy focused on pain relief and wound care.16 Younger patients with limited tissue loss and good potential for rehabilitation are candidates for revascularization. The technical considerations of revascularization have been reviewed by a number of articles in this issue. An additional therapy that is available for ischemic wounds consists of intermittent pneumatic compression devices, also known as arterial flow pumps. These systems generate alternating intermittent compression of the limbs. They are typically worn for 6-8 hours per day. Although there are scant data, intermittent pneumatic compressions are hypothesized to increase circulation to the lower extremity both by (1) decreasing venous pressure in the limb, thereby increasing the arteriovenous pressure gradient, and (2) by stimulating paracrine and subcellular pathways that modulate endothelial function and angiogenesis.17,18 Clinical benefit is uncertain, and their use is limited by patient compliance and affordability.19 The management of patients with CLI should be undertaken through a multidisciplinary approach involving peripheral interventionalists and vascular surgeons, medical vascular specialists, podiatrists, and wound care specialists.
Medical Therapy The medical therapy for CLI in patients includes aggressive cardiovascular risk factor modification, pain relief, treatment of infections, wound care, and pressure off-loading (Table 4). Wound Care Regardless of revascularization, ischemic ulcers should be managed with off-loading, which can be achieved through
several methods such as orthotics and shoe modifications. Although a detailed review on wound care of ischemic ulcers is beyond the scope of this review, we believe that the acronym DIME (standing for Debridement, Infection, Moisture control, and Edge) is a useful pneumonic that should guide chronic wound management.20 Debridement —In general, ischemic wounds should be debrided after revascularization to stimulate wound healing. There are different methods for debridement, which include surgical, enzymatic, autolytic, and mechanical methods. Infection—Infection prevents wound healing, and the risk of infection increases following revascularization with reestablishment of tissue perfusion. The possibility of infection, including osteomyelitis, should always be considered in ischemic wounds, and should be aggressively treated with local antimicrobials or systemic antibiotics or both when indicated. Moisture control is a critical aspect of wound healing. Numerous products are available to help maintain an ideal level of moisture that permits proliferation of granulation tissue.21 Finally, Edge of the wound refers to advanced wound products that may serve as skin substitutes to help the wound edges close.
Table 4 Medical Therapy in Patients With CLI Cardiovascular risk factor optimization Antiplatelet therapy with either 81-325 mg of aspirin daily or 75 mg of clopidogrel daily High-intensity statin therapy (40-80 mg of atorvastatin daily or 20-40 mg of rosuvastatin daily) Consideration of use of ACEi Diabetes management Smoking cessation Pain relief Treatment of infections Wound care Pressure off-loading ACEi, angiotensin-converting enzyme inhibitors.
Evaluation of the patient with critical limb ischemia Cardiovascular Risk Factor Modification As mentioned previously, patients presenting with CLI have a 25% mortality rate at 1 year, mostly from cardiovascular disease, including stroke. Therefore, regardless of the revascularization strategy, it is imperative that the specialists managing patients with CLI ensure that patients are on an appropriate medical therapy for cardiovascular risk reduction. Antiplatelet therapy—The current American College of Cardiology-American Heart Association (ACC-AHA) guidelines give a class Ia recommendation to the use of antiplatelet therapy in patients with PAD. Patients should be administered either 81325 mg of aspirin once daily or 75 mg of clopidogrel daily.22 The results of the Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Event (CAPRIE) trial suggest that patients with PAD may benefit more from clopidogrel than they do from aspirin.23 In this trial, more than 19,000 patients with prior myocardial infarction, stroke, or PAD were randomized to treatment with aspirin or with clopidogrel. Although clopidogrel was associated with a modest reduction (relative risk (RR) reduction of 8.7%) in a composite cardiovascular standpoint when compared with aspirin, the subset of patients with PAD (n ¼ 6452) had an impressive 23.8% RR reduction in the primary end point consisting of the composite of ischemic stroke, myocardial infarction, or vascular death. Regarding dual antiplatelet therapy, at this time, there is no data to support its long-term use in patients with PAD. In the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance trial, the combination of aspirin and clopidogrel did not lead to decreased rates of cardiovascular events when compared with aspirin alone, but it did lead to increased bleeding complications.22,24 Currently, the role of another platelet adenosine diphosphate (ADP) receptor antagonist, ticagrelor, is being tested in the EUCLID trial, a large multicenter prospective, randomized, controlled trial. This study is due to be completed in 2016. Regarding anticoagulation, although some degree of benefit of anticoagulation has been demonstrated in small trials of patients with CLI undergoing surgical bypass grafting, generally, CLI is not an indication by itself for instituting systemic anticoagulation. However, this decision should be individualized and considered in specific high-risk situations, such as following bypass grafting in low flow states. Statins—Although there are data that suggest that statins may reduce the risk of amputation in patients with PAD, the primary indication for statin use in this population is cardiovascular risk reduction. The current ACC-AHA guidelines give a class Ia recommendation to the use of high-intensity statin therapy with either 40 mg or more of atorvastatin daily or 20 mg or more of Crestor in all patients with established atherosclerotic arterial disease, including PAD.25 Angiotensinconverting enzyme inhibitors (ACEi)—There are 2 important reasons why most patients with PAD should be administered an angiotensin-converting enzyme inhibitors, unless a clear contraindication to this therapy exists: cardiovascular risk reduction and improvement in walking ability. In the HOPE study, more than 9200 patients with
145 evidence of vascular disease or high cardiovascular risk were randomly assigned to treatment with 10 mg of ramipril once daily or to placebo. Approximately 40% of patients had PAD. At 5 years, treatment with ramipril reduced the risk of the primary end point (the composite of myocardial infarction, stroke, or cardiovascular death) by 22% (14% vs 17.8%, RR ¼ 0.78, P o 0.001).26 In a more recent study (randomized, double blind, and placebo controlled), patients with PAD who were assigned to treatment with ramipril increased their pain-free walking time and mean walking time at 6 months by 77% and 123%, respectively, when compared with those assigned to placebo.27 The mechanisms explaining such an effect are unclear. Smoking cessation—Although there are no prospective randomized data on the effect of smoking cessation on cardiovascular and limb outcomes in patients with PAD, a very strong body of evidence consistently points toward a robust negative effect of cigarette smoking on PAD outcomes. Not only is the risk of myocardial infarction, and amputation is substantially greater with continued smoking, but patency rates following lower extremity angioplasty and surgical revascularization are greatly reduced in patients who continue to smoke compared with that of those who stop doing so.28–30 The current ACC-AHA guidelines give a class Ia recommendation to ask patients with PAD about their status of tobacco use at every visit and also to assist patients with counseling and developing a plan for quitting smoking, which may include pharmacotherapy or referral to a smoking cessation program or both.22
Conclusion Patients with CLI usually have advanced diffuse atherosclerotic disease and should be managed not only for limb salvage but also for cardiovascular risk reduction. Patients with CLI are best managed through a multidisciplinary approach involving peripheral interventionalists, vascular surgeons, cardiovascular specialists, podiatrists, and wound care specialists. Whenever possible, ambulatory patients with CLI should undergo revascularization. Primary amputation should be considered in nonambulatory patients who have no real prospect of becoming ambulatory again, in whom revascularization cannot be performed, or with extensive tissue loss. Patients who are not candidates for revascularization and who do not wish (or cannot undergo) amputation should be managed medically with wound care and pain control. Regardless of the strategy pursued, all patients with CLI should be aggressively treated for secondary prevention of cardiovascular disease.
References 1. Rutherford RB, Baker JD, Ernst C, et al: Recommended standards for reports dealing with lower extremity ischemia: Revised version. J Vasc Surg 26:517-538, 1997 2. Fowkes FG, Housley E, Cawood EH, et al: Edinburgh Artery Study: Prevalence of asymptomatic and symptomatic peripheral arterial disease in the general population. Int J Epidemiol 20:384-392, 1991
146 3. Shah AP, Klein AJ, Sterrett A, et al: Clinical outcomes using aggressive approach to anatomic screening and endovascular revascularization in a veterans affairs population with critical limb ischemia. Catheter Cardiovas Interv 74:11-19, 2009 4. Ix JH, Katz R, De Boer IH, et al: Association of chronic kidney disease with the spectrum of ankle brachial index the CHS (Cardiovascular Health Study). J Am Coll Cardiol 54:1176-1184, 2009 5. Dormandy JA, Murray GD: The fate of the claudicant—A prospective study of 1969 claudicants. Eur J Vasc Surg 5:131-133, 1991 6. Norgren L, Hiatt WR, Dormandy JA, et al: Inter-society consensus for the management of peripheral arterial disease (TASC II). J Vasc Surg 45:S5-67, 2007 (suppl S) 7. Young JR: Peripheral Vascular Diseases. St. Louis: Mosby Year Book, 1991 8. Aboyans V, Criqui MH, Abraham P, et al: Measurement and interpretation of the ankle-brachial index: A scientific statement from the American Heart Association. Circulation 126:2890-2909, 2012 9. Taylor GI, Pan WR: Angiosomes of the leg: Anatomic study and clinical implications. Plast Reconstr Surg 102:599-616, 1998 [discussion 7-8] 10. Mariano Palena Luis, Fernando Garcia Luis, Brigato Cesare, et al: Angiosomes: How do they effect my treatment? Tech Vasc Interv Radiol 2014 11. Zwicky S, Mahler F, Baumgartner I: Evaluation of clinical tests to assess perfusion in chronic critical limb ischemia. Vasa 31:173-178, 2002 12. Carter SA, Tate RB: Value of toe pulse waves in addition to systolic pressures in the assessment of the severity of peripheral arterial disease and critical limb ischemia. J Vasc Surg 24:258-265, 1996 13. Carter SA, Tate RB: The value of toe pulse waves in determination of risks for limb amputation and death in patients with peripheral arterial disease and skin ulcers or gangrene. J Vasc Surg 33:708-714, 2001 14. Kalani M, Jorneskog G, Naderi N, et al: Hyperbaric oxygen (HBO) therapy in treatment of diabetic foot ulcers. Long-term follow-up. J Diabetes Complications 16:153-158, 2002 15. Kranke P, Bennett MH, Martyn-St James M, et al: Hyperbaric oxygen therapy for chronic wounds. Cochrane Database Syst Rev 4: CD004123, 2012 16. Sottiurai V, White JV: Extensive revascularization or primary amputation: Which patients with critical limb ischemia should not be revascularized? Semin Vasc Surg 20:68-72, 2007 17. Dai G, Tsukurov O, Orkin RW, et al: An in vitro cell culture system to study the influence of external pneumatic compression on endothelial function. J Vasc Surg 32:977-987, 2000
I.D. Conde and P.A. Erwin 18. Delis KT: The case for intermittent pneumatic compression of the lower extremity as a novel treatment in arterial claudication. Perspect Vasc Surg Endovasc Ther 17:29-42, 2005 19. Louridas G, Saadia R, Spelay J, et al: The ArtAssist Device in chronic lower limb ischemia. A pilot study. Int Angiol 21:28-35, 2002 20. Morse JN: The essentials of ischemic wound care. Endovasc Today S1-S6, 2009. 21. Fonder MA, Lazarus GS, Cowan DA, et al: Treating the chronic wound: A practical approach to the care of nonhealing wounds and wound care dressings. J Am Acad Dermatol 58:185-206, 2008 22. Rooke TW, Hirsch AT, Misra S, et al: ACCF/AHA focused update of the guideline for the management of patients with peripheral artery disease (updating the 2005 guideline): A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 58:2020-2045, 2011 23. CAPRIE Steering Committee: A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE Steering Committee. Lancet 348:1329-1339, 1996 24. Bhatt DL, Fox KA, Hacke W, et al: Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med 354:1706-1717, 2006 25. Stone NJ, Robinson J, Lichtenstein AH, et al: ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines, Circulation. Published online Nov 12, 2013. 26. Yusuf S, Sleight P, Pogue J, et al: Effects of an angiotensinconverting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 342:145-153, 2000 27. Ahimastos AA, Walker PJ, Askew C, et al: Effect of ramipril on walking times and quality of life among patients with peripheral artery disease and intermittent claudication: A randomized controlled trial. J Am Med Assoc 309:453-460, 2013 28. Faulkner KW, House AK, Castleden WM: The effect of cessation of smoking on the accumulative survival rates of patients with symptomatic peripheral vascular disease. Med J Aust 1:217-219, 1983 29. Jonason T, Bergstrom R: Cessation of smoking in patients with intermittent claudication. Effects on the risk of peripheral vascular complications, myocardial infarction and mortality. Acta Med Scand 221:253-260, 1987 30. Lassila R, Lepantalo M: Cigarette smoking and the outcome after lower limb arterial surgery. Acta Chir Scand 154:635-640, 1988
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ritical limb ischemia (CLI) is the most serious manifestation of peripheral arterial disease (PAD) and is characterized by ischemic pain of the limb at rest or by tissue loss (usually nonhealing ulcers or gangrene). By definition, these patients correspond to a stage between 4 and 6 of the Rutherford classification (Table 1).1 Patients with CLI should have objective evidence of severe ischemia, for example, with markedly decreased ankle or toe systolic pressures or with a reduced transcutaneous tissue oxygen concentration or with a combination of both. Ischemic rest pain most commonly occurs when the ankle systolic pressure is less than 50 mm Hg or when the toe pressure is less than 30 mm Hg. When clinicians encounter a patient with severe lower extremity PAD and an ulcer, the following 2 fundamental questions must be addressed: (1) Is ischemia the cause of the ulcer? (2) Will ischemia prevent the wound from healing? The goal of this article is to describe the clinical features and evaluation of patients with CLI.
Clinical Features Risk Factors The risk factors for CLI are the same as those associated with systemic atherosclerosis affecting other vascular beds, such as the coronary or carotid arteries. These risk factors include age, cigarette smoking, diabetes mellitus, hyperlipidemia, hypertension, and male sex. Epidemiologic studies of PAD confirm that the strongest risk factors for developing CLI (odds ratio 43) include advanced age, diabetes mellitus, and cigarette smoking.2 In a recent study from the Veterans Administration of 50 consecutive patients referred for CLI, the mean age was 69.5 years; of these, 86% had hypertension, 72% had hyperlipidemia, 78% had diabetes mellitus, and 86% had a history of tobacco use.3 In addition, a strong link has been found between PAD, including CLI, and chronic kidney disease.4
Prognosis *Miami Cardiac and Vascular Institute, Miami, FL. †Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, OH. Address reprint requests to Ian del Conde, MD, Baptist Cardiac and Vascular Institute, 8900 North Kendall Drive, Miami, FL 33176. E-mail: [email protected]
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Patients with CLI have a very poor prognosis overall, for both cardiovascular morbidity and mortality as well as limb loss and persistent disability. There is a strong correlation between the ankle-brachial index (ABI) as a measure of the severity of PAD and mortality. For example, in a study of approximately 2000 claudicants, patients with an ABI o 0.50 had twice the mortality of claudicants with an ABI of 4 0.50.5 At 1 year
1089-2516/13/$ - see front matter & 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1053/j.tvir.2014.08.002
Evaluation of the patient with critical limb ischemia Table 1 Rutherford Ischemia.1
Classification
of
Chronic
141 Limb
Category Clinical Description 0 1 2 3 4 5 6
Asymptomatic—no hemodynamically significant occlusive disease Mild claudication Moderate claudication Severe claudication Ischemic rest pain Minor tissue loss (nonhealing ulcer and focal gangrene with diffuse pedal ischemia) Major tissue loss (functional foot no longer salvageable)
following presentation, 25% of patients with CLI died, mostly from cardiovascular events, and 30% of them were alive but had undergone an amputation.6 Although more than two-thirds of patients who present with CLI have a history of PAD, the assumption that CLI represents gradual worsening of PAD is incorrect. In a study, more than half of patients who underwent a below-the-knee amputation for CLI had no symptoms of PAD 6 months before presentation.
Physical Examination A complete vascular examination is critical in all patients presenting with CLI, as these patients usually have advanced atherosclerotic disease that may involve other vascular territories, including the carotid and coronary arteries. Although a detailed review on the vascular examination is beyond the scope of this review, readers are referred to an excellent monograph on this topic.7 At a minimum, blood pressure should be checked in both arms to ensure the absence of subclavian artery stenosis and falsely decreased blood pressures. The carotids should be auscultated at the level of the angle of the mandible for the presence of bruits. The abdomen should be auscultated for the presence of epigastric bruits, which may indicate renal, celiac, or mesenteric artery stenosis. The abdomen should also be palpated to search for an abdominal aortic aneurysm. The lower extremities should be inspected for any changes in color. A side-byside comparison with the contralateral limb may reveal pallor or discoloration. Signs of chronic ischemia include loss of subcutaneous fat, shininess, and dystrophic nail changes. A detailed assessment of any ulceration is crucial. The wound dimensions should be measured and documented with each visit to track healing over time. Arterial ulcers are usually round with sharply demarcated borders and appear “dry” (as opposed to “wet” ulcers seen in venous disease or with diabetic ulcerations). Ischemic ulcers tend to localize distally in the leg or foot, over bony prominences, or in the toes (Fig. 1 and Table 2). Significant pain is common in arterial ulcers and may be exacerbated by leg elevation. By contrast, diabetic foot ulcers have a thickened callus around the ulcer and tend not to be painful. Capillary refill time should be assessed. Normally, capillaries in the pulps of the digits or the toes refill in fewer than 5 seconds following pressure and
Figure 1 An arterial ulcer located in the lateral malleolar area of the right leg. The ulcer is round, appears “dry,” and has sharply demarcated borders. (Color version of figure is available online.)
release. In cases of significant ischemia, capillary refill time may be greater than 20 seconds. Another simple test that may reveal ischemia consists of noting color changes with elevation and dependency of the affected limb: a normal limb would remain pink in both the elevated and dependent positions. By contrast, an ischemic limb becomes pale in the elevated position (4451), gradually becomes pink in the dependent position, and may even develop a bright red color, termed dependent rubor, which is reflective of reactive hyperemia. Peripheral pulse assessment is perhaps the most important part of the vascular examination. Arterial pulsations typically diminish or disappear distal to the level of occlusion or severe stenosis. If extensive collateral circulation has been developed around an area of occlusion, distal pulsations are usually present but diminished.
Table 2 Physical Examination Nonhealing wound or ulcers with features that suggest an ischemic etiology: dry-appearing, sharply demarcated borders and located distally, especially over bony prominences or toes Decreased or absent pulses Dry skin, hair loss, dystrophic nails, and loss of subcutaneous fat Cool extremities Pallor on elevation and dependent rubor Delayed capillary refill time
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Differential Diagnosis Nonhealing leg ulcers often occur in patients with diabetes mellitus, neuropathy, and frequent mechanical insults. Although PAD may coexist in these patient populations, their tissue loss may not be a consequence of arterial ischemia, and they should therefore not be deemed as having CLI until decreased blood flow can be objectively demonstrated by noninvasive testing. Other conditions that may mimic CLI include nonatherosclerotic arterial occlusive diseases that involve the small, distal arteries of the limbs, resulting in foot (or hand) ischemia with severe pain at rest and possibly also with ulcerations and tissue loss. Examples include Buerger disease, vasculitis (large-, medium-, and small-artery vasculitides), drug-induced arterial occlusive disease (especially cocaine), antiphospholipid antibody syndrome, and connective tissue disorders such as scleroderma/CREST. Raynaud's phenomenon, esophageal dysfunction, sclerodactyly, telangiectasias.
Noninvasive Methods of Assessing the Circulation As mentioned earlier, it is important that ischemia be objectively demonstrated in patients who are presumed to have CLI. The diagnosis of CLI is a functional one. Although imaging studies, such as computed tomography or ultrasound, help in planning interventions, the initial diagnosis of limb ischemia is typically made with physiological tests that inform about tissue perfusion and help predict wound healing. These tests can be subdivided broadly into tests that assess the arterial macrocirculation and those that assess the microcirculation (Table 3).
Macrocirculation The ankle systolic pressure and the ABI are measured using Doppler ultrasound and an appropriately sized cuff (which should have a width of at least 40% of the limb circumference). The ABI of each leg should be calculated by dividing the higher of the posterior tibialis (PT) or dorsalis pedis (DP) pressures by a higher of the 2 brachial systolic blood pressures.8 A normal ABI exists when the ratio between the ankle and brachial systolic pressures is 1.0. Patients with CLI often, but not always, have markedly diminished ABIs. Generally, an ABI of less than Table 3 Macrocirculation ABI o 0.4 Absolute ankle systolic pressure o50 mm Hg Microcirculation Absolute toe systolic pressure o30 mm Hg Toe PPG pulse wave amplitude o4 mm Transcutaneous oxygen pressure o20 mm Hg Other: skin perfusion pressure (o40 mm Hg), transcutaneous carbon dioxide (4100 mm Hg), and capillary density (o20 mm2)
0.4 or any ankle systolic pressure o 50 mm Hg is indicative of severe PAD (usually multilevel disease) and suggests that a wound may not have sufficient perfusion to heal. Ankle pressures in patients with ischemic ulcers are typically in the range of 50-70 mm Hg, whereas patients with ischemic rest pain typically have even lower ankle pressures, in the 30-50 mm Hg range.6 However, it should be noted that heavily calcified, noncompressible arteries may result in falsely elevated ABIs. If this is suspected, a toe-brachial index (TBI) results should be obtained by comparing the great toe systolic pressure obtained by photoplethysmography (PPG) with the highest brachial systolic blood pressure obtained by Doppler ultrasound. A normal TBI is considered as 0.75 or higher. An important pitfall of the ABI method in establishing CLI is that, by definition, the ABI ratio is calculated using the higher systolic pressure of the DP or PT pulses. Therefore, the more diseased artery supplying the region or angiosome where an ischemic ulcer may be located9 could be missed in the ABI interpretation (see the article by Mariano Palena et al10for a discussion on the angiosome concept). For example, a patient with a nonhealing heel ulcer, with a brachial systolic blood pressure of 120 mm Hg, a DP systolic blood pressure of 100 mm Hg, and a PT systolic blood pressure of 40 mm Hg, may be reported as having a mildly decreased ABI of 0.83, when in reality, the ABI of the artery that supplies the heel (where the ulcer is) is only 0.33. As such, reviewing the actual results, rather than merely the interpretation, for each artery when an ABI has been performed is critical.
Microcirculation Noninvasive assessment of the microcirculation is emerging as an important strategy for predicting the wound-healing potential. Nevertheless, these methods are generally less standardized, less reproducible, and less available when compared with those that assess the macrocirculation. Because digital arteries rarely calcify, toe pressures and TBIs are useful for assessing perfusion and healing potential. In patients with extensive tissue loss or amputation of the great toe, the toe pressure can be obtained in the second toe. Toe pressures have been proposed as being superior to either the absolute ankle pressure or the transcutaneous oxygen pressure (TcPO2) for identifying CLI and predicting the course of the disease.11 Another manner of assessing the microcirculation is to evaluate the morphology and amplitude of the toe PPG waveforms. A PPG wave amplitude less than 4 mm has been associated with the presence of CLI as well as increased risk of amputation and all-cause mortality.12,13 Although measurement of toe PPG pulse wave amplitudes is challenging and difficult to reproduce, some clinicians use it to complement other tests of the macrocirculation and microcirculation. TcPO2 is another noninvasive method for measuring tissue perfusion. Usually, a few (2-4) electrodes are placed on the site of interest, for example, near an ulcer (Fig. 2). Oxygen pressures are monitored continuously. Different
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Figure 2 TcPO2 values obtained with 4 electrodes for the evaluation of foot ulceration. Baseline TcPO2 values are indeterminate in all 4 electrodes. The healing potential is suggested based on (1) minimal reductions (o10 mm Hg) in TcPO2 on leg elevation and (2) almost doubling of the TcPO2 compared with baseline with 100% FiO2. (Image courtesy: Dr Heather Gornik, Cleveland Clinic). (Color version of figure is available online.)
authors have proposed different cutoff values for suggesting severe ischemia and low likelihood of healing. A baseline TcPO2 o10 mm Hg is very specific for severe ischemia, o20 mm Hg predicts very poor healing, and 440 mm Hg is seen in either normal or mildly reduced perfusion with good likelihood of healing. The range between 20 and 40 mm Hg represents moderately reduced perfusion and is a “gray zone” in which the potential for healing cannot be ascertained. In these cases, specific maneuvers are employed to further assess the degree of ischemia. For example, the patient may be placed on 100% FiO2 for 10 minutes and the TCPO2 is remeasured while breathing 100% oxygen. Different facilities have different thresholds, but we generally consider doubling or tripling of the baseline TCPO2 to be predictive of a response to hyperbaric oxygen therapy.14,15 That said, hyperbaric oxygen therapy for CLI is controversial and not widely available. Another maneuver used in cases of indeterminate TcPO2 at baseline is to elevate the limb; if the TcPO2 decreases by less than 10 mm Hg, then healing potential is suggested. In practice, several technical factors related to
the reproducibility of the TcPO2 test have limited its widespread availability. For example, changes in room temperature or even the emotional state of the patient may result in significant differences in TcPO2 measurements, potentially resulting in erroneous conclusions. Although the TASC-II guidelines support the use of TcPO2 to assess the microcirculation in patients with CLI,6 at present, only a small percentage of noninvasive vascular laboratories offer TcPO2 testing.
Initial Management of Patients with CLI The primary goals of the treatment of CLI are to prevent amputation, relieve ischemic pain, allow wound healing, and improve the patient's ability to ambulate. Once the patient has been diagnosed with CLI, a decision has to be made on whether the patient is a suitable candidate for revascularization. Revascularization is the main treatment of CLI as it directly addresses the driving force of ischemic ulceration (Fig. 3). However, revascularization is
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Figure 3 Algorithm for the management of patients with CLI.6
technically not possible in all patients, and not all patients benefit meaningfully from revascularization. For example, older patients, who are bedridden and with comorbidities such as advanced dementia and present with extensive tissue loss, may not benefit from revascularization. Indeed, their quality of life may improve more with either primary amputation or conservative medical therapy focused on pain relief and wound care.16 Younger patients with limited tissue loss and good potential for rehabilitation are candidates for revascularization. The technical considerations of revascularization have been reviewed by a number of articles in this issue. An additional therapy that is available for ischemic wounds consists of intermittent pneumatic compression devices, also known as arterial flow pumps. These systems generate alternating intermittent compression of the limbs. They are typically worn for 6-8 hours per day. Although there are scant data, intermittent pneumatic compressions are hypothesized to increase circulation to the lower extremity both by (1) decreasing venous pressure in the limb, thereby increasing the arteriovenous pressure gradient, and (2) by stimulating paracrine and subcellular pathways that modulate endothelial function and angiogenesis.17,18 Clinical benefit is uncertain, and their use is limited by patient compliance and affordability.19 The management of patients with CLI should be undertaken through a multidisciplinary approach involving peripheral interventionalists and vascular surgeons, medical vascular specialists, podiatrists, and wound care specialists.
Medical Therapy The medical therapy for CLI in patients includes aggressive cardiovascular risk factor modification, pain relief, treatment of infections, wound care, and pressure off-loading (Table 4). Wound Care Regardless of revascularization, ischemic ulcers should be managed with off-loading, which can be achieved through
several methods such as orthotics and shoe modifications. Although a detailed review on wound care of ischemic ulcers is beyond the scope of this review, we believe that the acronym DIME (standing for Debridement, Infection, Moisture control, and Edge) is a useful pneumonic that should guide chronic wound management.20 Debridement —In general, ischemic wounds should be debrided after revascularization to stimulate wound healing. There are different methods for debridement, which include surgical, enzymatic, autolytic, and mechanical methods. Infection—Infection prevents wound healing, and the risk of infection increases following revascularization with reestablishment of tissue perfusion. The possibility of infection, including osteomyelitis, should always be considered in ischemic wounds, and should be aggressively treated with local antimicrobials or systemic antibiotics or both when indicated. Moisture control is a critical aspect of wound healing. Numerous products are available to help maintain an ideal level of moisture that permits proliferation of granulation tissue.21 Finally, Edge of the wound refers to advanced wound products that may serve as skin substitutes to help the wound edges close.
Table 4 Medical Therapy in Patients With CLI Cardiovascular risk factor optimization Antiplatelet therapy with either 81-325 mg of aspirin daily or 75 mg of clopidogrel daily High-intensity statin therapy (40-80 mg of atorvastatin daily or 20-40 mg of rosuvastatin daily) Consideration of use of ACEi Diabetes management Smoking cessation Pain relief Treatment of infections Wound care Pressure off-loading ACEi, angiotensin-converting enzyme inhibitors.
Evaluation of the patient with critical limb ischemia Cardiovascular Risk Factor Modification As mentioned previously, patients presenting with CLI have a 25% mortality rate at 1 year, mostly from cardiovascular disease, including stroke. Therefore, regardless of the revascularization strategy, it is imperative that the specialists managing patients with CLI ensure that patients are on an appropriate medical therapy for cardiovascular risk reduction. Antiplatelet therapy—The current American College of Cardiology-American Heart Association (ACC-AHA) guidelines give a class Ia recommendation to the use of antiplatelet therapy in patients with PAD. Patients should be administered either 81325 mg of aspirin once daily or 75 mg of clopidogrel daily.22 The results of the Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Event (CAPRIE) trial suggest that patients with PAD may benefit more from clopidogrel than they do from aspirin.23 In this trial, more than 19,000 patients with prior myocardial infarction, stroke, or PAD were randomized to treatment with aspirin or with clopidogrel. Although clopidogrel was associated with a modest reduction (relative risk (RR) reduction of 8.7%) in a composite cardiovascular standpoint when compared with aspirin, the subset of patients with PAD (n ¼ 6452) had an impressive 23.8% RR reduction in the primary end point consisting of the composite of ischemic stroke, myocardial infarction, or vascular death. Regarding dual antiplatelet therapy, at this time, there is no data to support its long-term use in patients with PAD. In the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance trial, the combination of aspirin and clopidogrel did not lead to decreased rates of cardiovascular events when compared with aspirin alone, but it did lead to increased bleeding complications.22,24 Currently, the role of another platelet adenosine diphosphate (ADP) receptor antagonist, ticagrelor, is being tested in the EUCLID trial, a large multicenter prospective, randomized, controlled trial. This study is due to be completed in 2016. Regarding anticoagulation, although some degree of benefit of anticoagulation has been demonstrated in small trials of patients with CLI undergoing surgical bypass grafting, generally, CLI is not an indication by itself for instituting systemic anticoagulation. However, this decision should be individualized and considered in specific high-risk situations, such as following bypass grafting in low flow states. Statins—Although there are data that suggest that statins may reduce the risk of amputation in patients with PAD, the primary indication for statin use in this population is cardiovascular risk reduction. The current ACC-AHA guidelines give a class Ia recommendation to the use of high-intensity statin therapy with either 40 mg or more of atorvastatin daily or 20 mg or more of Crestor in all patients with established atherosclerotic arterial disease, including PAD.25 Angiotensinconverting enzyme inhibitors (ACEi)—There are 2 important reasons why most patients with PAD should be administered an angiotensin-converting enzyme inhibitors, unless a clear contraindication to this therapy exists: cardiovascular risk reduction and improvement in walking ability. In the HOPE study, more than 9200 patients with
145 evidence of vascular disease or high cardiovascular risk were randomly assigned to treatment with 10 mg of ramipril once daily or to placebo. Approximately 40% of patients had PAD. At 5 years, treatment with ramipril reduced the risk of the primary end point (the composite of myocardial infarction, stroke, or cardiovascular death) by 22% (14% vs 17.8%, RR ¼ 0.78, P o 0.001).26 In a more recent study (randomized, double blind, and placebo controlled), patients with PAD who were assigned to treatment with ramipril increased their pain-free walking time and mean walking time at 6 months by 77% and 123%, respectively, when compared with those assigned to placebo.27 The mechanisms explaining such an effect are unclear. Smoking cessation—Although there are no prospective randomized data on the effect of smoking cessation on cardiovascular and limb outcomes in patients with PAD, a very strong body of evidence consistently points toward a robust negative effect of cigarette smoking on PAD outcomes. Not only is the risk of myocardial infarction, and amputation is substantially greater with continued smoking, but patency rates following lower extremity angioplasty and surgical revascularization are greatly reduced in patients who continue to smoke compared with that of those who stop doing so.28–30 The current ACC-AHA guidelines give a class Ia recommendation to ask patients with PAD about their status of tobacco use at every visit and also to assist patients with counseling and developing a plan for quitting smoking, which may include pharmacotherapy or referral to a smoking cessation program or both.22
Conclusion Patients with CLI usually have advanced diffuse atherosclerotic disease and should be managed not only for limb salvage but also for cardiovascular risk reduction. Patients with CLI are best managed through a multidisciplinary approach involving peripheral interventionalists, vascular surgeons, cardiovascular specialists, podiatrists, and wound care specialists. Whenever possible, ambulatory patients with CLI should undergo revascularization. Primary amputation should be considered in nonambulatory patients who have no real prospect of becoming ambulatory again, in whom revascularization cannot be performed, or with extensive tissue loss. Patients who are not candidates for revascularization and who do not wish (or cannot undergo) amputation should be managed medically with wound care and pain control. Regardless of the strategy pursued, all patients with CLI should be aggressively treated for secondary prevention of cardiovascular disease.
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I.D. Conde and P.A. Erwin 18. Delis KT: The case for intermittent pneumatic compression of the lower extremity as a novel treatment in arterial claudication. Perspect Vasc Surg Endovasc Ther 17:29-42, 2005 19. Louridas G, Saadia R, Spelay J, et al: The ArtAssist Device in chronic lower limb ischemia. A pilot study. Int Angiol 21:28-35, 2002 20. Morse JN: The essentials of ischemic wound care. Endovasc Today S1-S6, 2009. 21. Fonder MA, Lazarus GS, Cowan DA, et al: Treating the chronic wound: A practical approach to the care of nonhealing wounds and wound care dressings. J Am Acad Dermatol 58:185-206, 2008 22. Rooke TW, Hirsch AT, Misra S, et al: ACCF/AHA focused update of the guideline for the management of patients with peripheral artery disease (updating the 2005 guideline): A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 58:2020-2045, 2011 23. CAPRIE Steering Committee: A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE Steering Committee. Lancet 348:1329-1339, 1996 24. Bhatt DL, Fox KA, Hacke W, et al: Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med 354:1706-1717, 2006 25. Stone NJ, Robinson J, Lichtenstein AH, et al: ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines, Circulation. Published online Nov 12, 2013. 26. Yusuf S, Sleight P, Pogue J, et al: Effects of an angiotensinconverting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 342:145-153, 2000 27. Ahimastos AA, Walker PJ, Askew C, et al: Effect of ramipril on walking times and quality of life among patients with peripheral artery disease and intermittent claudication: A randomized controlled trial. J Am Med Assoc 309:453-460, 2013 28. Faulkner KW, House AK, Castleden WM: The effect of cessation of smoking on the accumulative survival rates of patients with symptomatic peripheral vascular disease. Med J Aust 1:217-219, 1983 29. Jonason T, Bergstrom R: Cessation of smoking in patients with intermittent claudication. Effects on the risk of peripheral vascular complications, myocardial infarction and mortality. Acta Med Scand 221:253-260, 1987 30. Lassila R, Lepantalo M: Cigarette smoking and the outcome after lower limb arterial surgery. Acta Chir Scand 154:635-640, 1988