Successful Pharmacologic Treatment of Lower Extremity Ulcerations in 5 Patients With Chronic Critical Limb Ischemia

Steven M. Dean, DO, Patrick S. Vaccaro, MD


J Am Board Fam Med. 2002;15(1) 

In This Article


Chronic critical limb ischemia defines a subset of patients with peripheral arterial occlusive disease that manifests with ischemic rest pain, ulcerations, or gangrene. Despite collateral vessel development and compensatory vasodilatation, in a patient with chronic critical limb ischemia, arterial perfusion is severely compromised and is not sufficient to meet the metabolic needs of the extremity. From a macrovascular standpoint, patients with chronic critical limb ischemia usually have multisegmental peripheral arterial occlusive disease. The microvascular circulation is impaired as well from a variety of mechanisms, including capillary collapse, arteriolar vasospasm, leukocyte activation and adhesion, platelet aggregation, and microthrombosis.[1] As a result, not only are patients with chronic critical limb ischemia functionally disabled, but they are also at high risk for limb loss and cardiovascular and cerebrovascular complications.

Corroborative noninvasive objective criteria for chronic critical limb ischemia include an ankle systolic pressure of 50 mm Hg or less and toe systolic pressure of 30 mm Hg or less.[1] If the patient has diabetes mellitus and arterial medial calcinosis, absolute pressure measurements might not be reliable or even obtainable. In such a case, a pulsed volume recording waveform of less than 5 mm2 or a photoplethysmographic waveform of 4 mm or less is suggestive of chronic critical limb ischemia.[3] Alternatively, a transcutaneous oxygen tension reading of 10 mm Hg or less in the supine position or 40 mm Hg or less while sitting suggests severe ischemia.[4]

Minimal data on the prevalence of chronic critical limb ischemia exists, although an incidence of 300 per million per year has been calculated[5] by using intermittent claudication statistics (and assuming that 5% of patients with intermittent claudication progress to chronic critical limb ischemia within 5 years). Weitz et al[6] estimated that 1%, or 20 million, of Americans older than 50 years might ultimately acquire chronic critical limb ischemia. Of 100 patients with intermittent claudication, at least 1 each year will progress to chronic critical limb ischemia.[5]

Risk factors for chronic critical limb ischemia parallel those of generalized atherosclerosis, although diabetes mellitus, smoking, and age assume the most importance.[5] Diabetes is noteworthy because it underlies 50% to 70% of the amputations performed in the United States.[7,8] Additionally, a diabetic patient with peripheral arterial occlusive disease is anywhere from 7 to 11 times more likely to require leg amputation.[9,10] In Kannel's study,[11] 40% of diabetic patients with chronic critical limb ischemia progressed to gangrene, whereas only 9% of patients who were not diabetic had a similar outcome.

The prognosis for limb salvage as well as survival is frequently dismal in a patient with chronic critical limb ischemia. Within a 6-month period, 20% of patients die, 35% live but require amputation, and the remaining 45% live with no immediate need for amputation.[5] In the United States, 150,000 leg amputations each year are performed for unremitting chronic critical limb ischemia.[12]

Effective treatment alternatives are traditionally restricted to endovascular or surgical revascularization. Neither surgical bypass nor percutaneous transluminal angioplasty might be technically possible, however, when the tibioperoneal or below-knee arteries are severely diseased. Not uncommonly, the patient with chronic critical limb ischemia is typically affected by advanced tibioperoneal arterial occlusive disease, especially if the patient has diabetes mellitus. In addition, comorbid coronary, cerebral, and renal atherosclerosis can increase the risk of developing revascularization-associated complications. Although risk factor modification, proper foot care, antibiotics, and topical therapy for ulcerations are frequently warranted, these measures play more of an adjunctive role and are unlikely to be successful as primary therapy for chronic critical limb ischemia.

When revascularization is not possible, medical therapy is sometimes attempted. Anticoagulants, antiplatelet therapy, defibrinogenating agents,[13] rheologic drugs,[14] and prostanoids[15,16] have been used for treatment of chronic critical limb ischemia. Unfortunately, none of these agents have produced major, long-term improvement in the critically ischemic limb. In their recent consensus document, the TASC Working Group noted, "because the results are unconvincing or negative, current drugs cannot be recommended in patients with chronic critical limb ischemia."[17] As a group, prostanoids have received the most attention; however, the medication must be administered by prolonged intravenous infusion, and any improvement is only short term.

In 1988, cilostazol, a phosphodiesterase III inhibitor, was approved in Japan for the treatment of ulcerations, pain, and coldness associated with peripheral artery disease. In one study, the efficacy of cilostazol, 100 mg twice a day, was evaluated in a mixed cohort of patients with intractable skin ulcerations from a variety of causes that included severe peripheral artery disease. After 6 weeks, 48% of patients showed marked improvement, and only 19% worsened. The authors concluded that cilostazol might be useful in the treatment of skin ulcerations caused by vascular disease.[18] In a group of 26 patients with arterial occlusive disease from varying causes (arteriosclerosis obliterans, Takayasu arteritis, and thromboangiitis obliterans), cilostazol, 200 mg each day, for 3 months improved ulcer healing and rest pain in 50% of the patients.[19]

Several studies have objectively documented increases in arterial perfusion after treatment with cilostazol. Money et al[20] documented a statistically significant increase in the posttreatment ankle-brachial index when cilostazol was compared with placebo (0.64-0.70 in the cilostazol group vs 0.68-0.69 in the placebo group, P .0125). In a study of 9 patients with peripheral artery disease, cilostazol administered for 2 weeks increased the mean ankle blood flow by 16.2% (P .05 vs baseline).[21] Ohashi et al compared 100 mg with 200 mg of cilostazol each day for 6 weeks in 10 patients with peripheral artery disease. significant increases in skin temperature and blood flow were documented in 7 of the 10 patients only when the higher dose was used.[22]

The Food and Drug Administration approved cilostazol in 1999 as a new treatment option for intermittent claudication. In addition to its antiplatelet and antithrombotic properties, the agent induces vasodilatation, increases plasma high-density lipoprotein cholesterol, and decreases plasma triglycerides.[23] The precise mechanisms of action of the medication remain incompletely de ned, however. It is known that cilostazol inhibits cyclic adenosine monophosphate (cAMP) phosphodiesterase III, resulting in decreased phosphodiesterase activity and suppression of cAMP degradation.[24] In turn, the level of cAMP in platelets and blood vessels is increased, leading to inhibition of platelet aggregation and to vasodilatation, respectively.

The patients described here were either not ideal candidates for invasive therapy or refused such an approach. Thus, the addition of a relatively new pharmacologic agent was a feasible option when the course of traditional supportive measures failed. Despite underlying chronic critical limb ischemia, between 7 and 24 weeks after starting cilostazol, the ischemic ulcerations completely healed in all 5 patients. Moreover, 3 patients experienced resolution of attendant ischemic rest pain. One patient erroneously discontinued cilostazol after his ulcer healed and subsequently developed a second ulcer after minor trauma to the right distal hallux. Resumption of cilostazol resulted in healing of the second ulcer within 2 months. Finally, a posttreatment noninvasive arterial study performed on 1 patient objectively illustrated improvement in both large and small arterial perfusion. All 5 patients have continued taking cilostazol and remain free of recurrent ulcerations during a follow-up period ranging from 2 to 12 months.

Primary care physicians often encounter similar patients. For instance, family physicians are sometimes asked to evaluate and treat ischemic foot and toe ulcerations in bedridden, demented patients residing in extended-care facilities (eg, case 4). These patients rarely warrant referral for aggressive interventional vascular therapy and are preferably managed with a conservative treatment approach that could include the use of cilostazol.

Considering the long-standing discouraging results of pharmacotherapy for chronic critical limb ischemia, the preliminary data showing the successful use of cilostazol in such patients are promising, and subsequent randomized, placebo controlled trials are warranted. To the best of our knowledge, our case series is the first report in the English literature investigating the use of cilostazol for treating lower extremity ischemic ulcerations.


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