Adjunctive Therapy for Ischemic Wounds Using Cilostazol

PUBLICATION DATE: Mar 10 2003

Stanley N. Carson, MD, FACS;1 Karen Overall, PT, CWS2 Portions of this work were selected for presentation at the 17th Annual Clinical Symposium on Advances in Skin and Wound Care, September 23, 2002, Dallas, Texas.

Introduction
Cilostazol (Pletal, Otsuka Pharmaceutical Co., Rockville, Maryland) has been available in the United States as an oral medication for the treatment of intermittent vascular claudication since 1999. Claudication is the current Food and Drug Administration indication for use of the drug, and improvement in claudication on cilostazol directly correlates with an increase in blood flow in the affected limb.[1] Cilostazol belongs to a group of drugs that are cyclic adenosine monophosphate phosphodiesterase inhibitors. As such, the drug shows activities leading to inhibition of platelet aggregation, vasodilatation, improvement of dyslipidemia, inhibition of smooth muscle proliferation, and increase in blood flow in limbs with stenotic or occluded arteries.[13] At this time, the authors are reporting an apparent beneficial effect on wound healing in ischemic limbs using cilostazol. Symptoms of chronic arterial occlusion, leg claudication, and pain frequently precede ischemic ulceration in the lower extremities.[4] In 42 percent of lower-extremity ulcers in nondiabetic patients and 67 percent of lower-extremity ulcers in diabetic patients, compromise of arterial blood flow makes a significant contribution to the healing problems of these wounds.[5,6] In the diabetic patient, concomitant neuropathy may prevent the patient from adequately appreciating their ischemic pain. Although injuries to the legs and feet of patients with arterial disease may not occur because of ischemia, they often fail to heal because of arterial disease. Thus, a diabetic patient who usually acquires a foot ulcer from repeat trauma, unrecognized in the presence of neuropathy, may not heal primarily because of underlying arterial disease. This has also been seen in the authors experience in neuropathic patients with other injuries, including venous ulcer patients and patients with blunt trauma.[79] Therapeutic interventions for ischemic lower-extremity ulcers usually consist of topical wound care and interventions that improve arterial supply. If arterial circulation is severely compromised, revascularization of the ischemic area by angioplasty, bypass surgery, or both is usually done. Control and correction of nutrition and metabolic problems are also addressed. Topical wound care in the authors area consists of debridement and maintenance debridement, moist wound care with nontoxic agents, occasional use of modalities of electrical stimulation, and ultrasound with control of bacterial involvement in the

wound. Reconstructive techniques, such as skin graft and myocutaneous flaps, may be necessary to expedite closure of the ulcers after bacterial colonization has been controlled and healing has begun. Multiple clinical trials have been performed using cilostazol for intermittent claudication with a great deal of success.[10] In a placebo-controlled, randomized trial, Dawson, et al., demonstrated on treadmill testing a 35-percent increase in initial claudication distance and a 41-percent increase in maximal walking distance in patients treated with cilostazol.[1,11] Other indices of improvement with cilostazol in claudicants include improved ankle-brachial index.[3] Investigators have also demonstrated an increase in blood flow and cross-sectional area in the dorsalis pedis artery with cilostazol in an open trial.[12] There have been reported experiences with cilostazol in the treatment of skin wounds. Kondo treated 24 patients with ulcers from collagen diseases in an openlabel study and found a significant decrease in the size of the ulcer.[13] Arakawa and Arada evaluated the efficacy of cilostazol 100mg twice daily in patients with poorly healing skin ulcers and other dermatologic problems associated with vascular disorders.[14] Twenty-one subjects were treated for a minimum of six weeks. Improvement was demonstrated by a decrease in pain, numbness, rest pain, and erythema. Subjects with diabetes showed the greatest improvement. Overall, 48 percent showed marked improvement of symptoms and 24 percent showed some improvement. Arakawa and Arada concluded that cilostazol could be useful in the treatment of skin ulcers associated with vascular disorders. Early on in the course of the authors use of cilostazol in ischemic disease of the lower extremities, the authors noted an obvious trend towards healing of wounds in the legs and feet of most of these patients. All of these patients were given cilostazol based on the indication of claudication-type ischemia of the legs confirmed by physical exam and duplex Doppler exam.

Methods
Twenty-five patients over a 32-month period were given cilostazol for claudicationtype ischemia of the legs. All of the patients had nonhealing wounds of the lower extremities. All of the patients had experienced modern wound care consisting of debridement and moist healing techniques for at least six weeks (652 weeks, average 12.5 weeks) without evidence of closure before starting on cilostazol. The wound care was continued without significant change or alteration after cilostazol was begun. In these patients, maintenance debridement consisted of sharp debridement and occasional use of chlorophyllin-papain-urea ointments. Cilostazol was given at a dose of 100mg twice a day and continued through to total wound healing or definitive wound healing failure.

Fourteen of the patients had prior correction of their ischemia by bypass (5), angioplasty (5), or bypass and angioplasty (4). Interventional corrections had been done from six weeks to one year before starting cilostazol. Eleven of these patients had no surgical correction of their lower-extremity disease because of refusal of surgery (5) or because only nonbypassable lower-extremity arterial disease was present (6). Thirteen of the patients were diabetic, of which seven were insulin dependent. There were sixteen men and nine women and ages ranged from 49 to 89, with an average age of 63 years and a median age of 59 years old. Ten patients were cigarette smokers, of which five also had diabetes. Ankle-arm indices were less than or equal to 0.7 (0.30.7) in 18 patients and falsely elevated in seven patients (over 1.2). All patients had duplex arterial exam of the lower extremities showing evidence of ischemia below the knee and a clinical exam showing evidence of ischemia at the knee or below (i.e., decreased palpable pulses, slow capillary refill, monophasic hand-held Doppler signals of the pedal arteries, or rubor and pallor [Table 1]). Additional studies that might evidence ischemia, such as transcutaneous oxygen measurements or laser Doppler, were not done as they have not consistently been shown to be useful in the authors wound care program. Ankle-arm indices were remeasured in all patients at monthly intervals. Eight of the wounds were on the foot, 11 were on the ankle and heel, and six were on the lower leg. All of the wounds were full thickness and five were Stage 4 heel decubiti (Table 2). All of these patients had undergone standard moist wound healing modalities (e.g., hydrogel, saline gauze, and maintenance debridement) for at least six weeks (652 weeks, average 12.5 weeks), had their diabetes reasonably controlled, and had received adequate nutrition and hygiene prior to institution of cilostazol. Results Fifteen of the patients progressed to satisfactory healing, being over 70-percent epithelialized and having healthy granulation tissue with no necrosis and little exudate within 60 days (3060 days, average five weeks). Five patients did not progress this well at 60 days, but this same subgroup did show some wound improvement at 30 days (e.g., granulation tissue and decreased slough). These patients subsequently healed with use of skin grafts (3) and skin substitutes (2). Five patients, 20 percent, showed no improvement; in fact, they deteriorated. All of these required amputation and two were done expeditiously, secondary to infection and sepsis (Table 3). Ankle-arm indices tended to increase in all patients who were not falsely elevated (measurements in those patients with falsely elevated ankle-arm indices were inconsistent and highly variable) by an average of 0.15 0.05, but over half of these

patients were healed or well on their way to healing when this became a consistent finding. Most patients (90%) experienced an increased sensation of warmth in their extremities and noted improved color in their limbs by 30 days after beginning cilostazol. However, these side effects of increased circulation appeared in patients who healed as well as those who did not heal. Discussion In the wound care practice and program from which these patients come, a large number of patients are seen each year. These patients are referred for nonhealing wounds or wounds that are difficult to manage. Many of these patients have already had interventional correction of their vascular disease as well as control of diabetes and other medical problems when present. Infections and nutrition have usually been treated or are concurrently undergoing treatment. Following bypass or other intervention to correct ischemia of the lower extremities, there can still be residual, uncorrected disease that may interfere with healing. For example, many of these patients have already lost by occlusion one, two, or all three of their tibial arteries. The literature in vascular surgery currently discloses that bypass surgery of the lower extremities is a viable limb salvage technique in patients with wounds.[15] Of those bypassed or with other successful vascular intervention, failures of healing seem higher in those with renal failure or larger pressure ulcerations of the extremities. In addition, those patients with large amounts of tissue necrosis seem more likely to fail to heal satisfactorily. In many series, the presence of a dorsal pedal pulse does not guarantee healing of the plantar foot or heel wounds. Also, it is noted that a successful bypass or vascular intervention that increases limb flow does not always guarantee healing.[16] In many series, healing occurs in approximately 60 to 70 percent of patent successful bypasses done for limb salvage in patients with leg wounds in the lower extremities. In patients with severe ischemia, lower-extremity arterial anatomy that is not adequate for successful bypass grafting along with major proximal foot or leg wounds often leads to leg amputation.[16] What is reported here is not a controlled study, nor was it meant to be. This is a select group of ischemic patients who did not heal with ordinary wound care measures. In this report, healing was apparently potentiated by cilostazol, as this was the only significant change in treatment of the patients. It is noteworthy that 10 of the healing patients already had successful bypasses/interventions restoring, in part, circulation to the lower extremities. They still did not heal prior to cilostazol. In the authors patients, deterioration occurred in all three renal patients. The additional two failures occurred in heavy smokers with large heel wounds, one of whom had a strong dorsal pedal pulse and had been revascularized. All of these factors have been reported as significant concomitants to prevention of healing.[17]

Of the patients who needed additional modalities to heal, two had successful vascular interventions and three were not able to have vascular interventions. The authors observed changes in the characteristics of a nonhealing wound when it is responding to cilostazol. The usually pale granulation tissue when present becomes redder and appears more vascular in nature (Figures 1AC). The slough and deterioration with additional necrosis seen in the wound ceases to be a daily occurrence and the wound begins to fill in. This can be observed as early as two weeks in about 33 percent of the cases reported here (Figures 2AC). Patients generally describe a decrease in pain (routinely measured at each wound care visit), when present, in their affected extremities at about the same time that healthy appearing granulation tissue began to appear. In those that did not heal, there was no noted decrease in pain observed. The lack of correlation between increased ankle-brachial index (occurring later in the course of therapy) and a positive change in wound appearance (occurring earlier in the course of therapy) at the same time may be due to the fact the even a small increase in blood flow to a wound exerts an effect on healing that cannot be measured by ankle-brachial index. The finding that improved circulation in the limb did not always correlate with a particular wound healing should come as no surprise. Many of the patients reported here had unhealed wounds even after interventional correction of their ischemia. Circulation in the wound may not always improve with overall circulation in the limb and a chronic wound may not always respond to correction of ischemia.[16] The authors wound program, along with others, has not seen a consistent correlation between ankle-brachial index and healing, except at the very high and very low levels (below 0.3 and above 0.9); the authors tend to rely on clinical expertise and formal full duplex scans of the associated limbs, which also has had the added advantage of predicting possible vascular intervention.[17,18] Consistent correlation between transcutaneous oxygen measurements in chronic wounds and healing has not always occurred, and the authors do not currently use this modality.[19,20] It is assumed that the cilostazol used here potentiated wound healing by increasing the blood flow to the affected extremities. Although the manufacturer states that the drug should be used for at least 90 days to see if it is useful in relieving a patients intermittent claudication, most patients who are going to experience relief do so earlier than 90 days.[1,2] Clearly, in this report, a positive effect on healing was observed at least by five weeks and even earlier in some patients. In view of this and provided patient safety is not compromised, it may seem reasonable to wait at least 90 days before discontinuing cilostazol therapy in wound patients without a noted early response. Cilostazol is not available in a generic form. In the authors location, a months supply costs almost 100 dollars and is usually covered by insurance. Although somewhat expensive, it has been proven to be a formidable drug in

alleviating claudication and improving circulation in the lower extremities and has been extensively studied. Its cost is comparable and even less than many wound care products when used on a daily basis. It would appear that in many ischemic patients with persistent wounds, cilostazol may be a useful adjunctive help in healing wounds.
References: 1. Dawson DL, Cutler BS, Meissner MH, Strandness DE, Jr. Cilostazol has beneficial effects in treatment of intermittent claudication: Results from a multicenter, randomized, prospective, double-blind trial. Circulation 1998;98(7):67886. 2. Tsuchikane E, Fukuhara A, Kobayashi T, et al. Impact of cilostazol on restenosis after percutaneous coronary balloon angioplasty. Circulation 1999;100:216. 3. Money SR, Herd JA, Isaacsohn JL, et al. Effect of cilostazol on walking distances in patients with intermittent claudication caused by peripheral vascular disease. J Vasc Surg 1998;27(2):2675. 4. Levine JM. Leg ulcers: Differential diagnosis in the elderly. Geriatrics 1990;45(6):3242. 5. Nelzen O, Bergqvist D, Lindhagen A. High prevalence of diabetes in chronic leg ulcer patients: A cross-sectional population study. Diabet Med 1993;10(4):34550. 6. Pecoraro RE, Reiber GE, Burgess EM. Pathways to diabetic limb amputation: Basis for prevention. Diabetes Care 1990;13(5):51321. 7. Ebakov B, Josephsen P. Incidence of reamputation and death after gangrene of the lower extremity. Prosthet Orthotics Int 1980;4:7781. 8. Ruckley CV. Socioeconomic impact of chronic venous insufficiency and leg ulcers. Angiology 1997;48(1):679. 9. Nehler MR, Whitehill TA, Steven P, et al. Intermediate-term outcome of primary digit amputations in patients with diabetes mellitus who have forefoot sepsis requiring hospitalization and presumed adequate circulatory status. J Vasc Surg 1999;30(3):50918. 10. Reilly MP, Mohler ER III. Cilostazol: Treatment of intermittent claudication. Ann Pharmacother 2001;35(1):4856. 11. Dawson DL, Cutler BS, Hiatt WR, et al. A comparison of cilostazol and pentoxifylline for treating intermittent claudication. Amer J Med 2000;109(7):52330. 12. Okuda Y, Mizutani M, Ikegami T, Ueno E, Yamashita K. Hemodynamic effects of cilostazol on peripheral artery in patients with diabetic neuropathy. Arzneimittel-Forschung (German) 1992;42(4):5402. 13. Kondo H, Mori S, Hori Y, et al. Clinical usefulness of cilostazol in the treatment of skin ulcer of patients with collagen diseases. Drug Eval 1994;14(6):537. 14. Arakawa K, Arada J. Clinical analysis of Pletal for intractable skin ulcer based on vascular damage and cutis symptom. Shin'yaku to Rinsho (J New Remedies Clin) (Japanese) 1993;42(1):608. 15. Pomposelli FB Jr, Marcaccio EJ, Gibbons GW, et al. Dorsalis pedis arterial bypass: Durable limb salvage for foot ischemia in patients with diabetes mellitus. J Vasc Surg 1995; 21(3):37584. 16. McCarthy WJ, Matsumura JS, Fine NA, Dumanian GA, Pearce WH. Combined arterial reconstruction and free tissue transfer for limb salvage. J Vasc Surg 1999;29(5):81420. 17. Treiman GS, Oderich GS, Ashrafi A, Schneider PA. Management of ischemic heel ulceration and gangrene: An evaluation of factors associated with successful healing. J Vasc Surg 2000; 31(6):11108. 18. Hafner J, Schaad I, Schneider E, et al. Leg ulcers in peripheral arterial disease (arterial leg ulcers): Impaired wound healing above the threshold of chronic critical limb ischemia. J Am Acad Dermatol 2000;43(6):10018. 19. Rich K. Transcutaneous oxygen measurements: Implications for nursing. J Vasc Nurs 2001;19(2):559. 20. Black J. Tissue oxygen perfusion and pressure ulcer healing. Plast Surg Nurs Spring 2000;20(1):10 24.