Are Tissue Replacements Cost Effective?
Yes, these authors say tissue replacements can facilitate shorter healing times and reduce the risk of complications from chronic wounds. By Jason R. Hanft, DPM, Andre Williams, DPM, Constantine Kyramarios, DPM, and Kerry Temar, DPM, MS The goals in treating diabetic foot ulcers are to obtain wound closure as quickly as possible, lower the probability of amputation and decrease recurrent ulcerations. Timely healing is important because the longer a diabetic foot ulcer remains unhealed, the greater the risk for infection, hospitalization and progression of the ulcer to require limb amputation. Diabetic wounds can become chronic and non-healing for multiple reasons. Infection, biomechanical abnormalities, systemic illnesses, poor nutrition and vascular insufficiency have all been documented as causes for non-healing ulcers.1 The wound bed of chronic wounds also has characteristics which impede wound healing, contributing to the vicious cycle of the continued non-healing state. Elevated proteases, senescent fibroblasts, accumulation of exudate, necrotic tissue, chronic inflammation, bacterial contamination and the absence of growth factors have all been demonstrated to occur in the wound bed of chronic ulcers.2 Tissue replacements offer a viable alternative to other wound care products as they actually change the physiology and chemistry of the wound bed. They are also advantageous over split thickness skin grafts as they do not create an additional wound or increase morbidity. Once you have determined and addressed the etiology of the wound, tissue replacements are an excellent treatment option that you use either alone or adjunctively with other treatment modalities. There are currently two tissue replacements approved for use on lower extremity wounds. Their composition varies from bovine collagen to human-derived fibroblasts. The efficacy and success rate of each product is slightly different. However, the function is essentially the same. The goal of each product is to initiate the wound healing process by providing certain components of a wound which are required to heal, such as fibroblasts, protease inhibitors and growth factors. Tissue replacements also provide a lattice for migration of epithelial tissue across the wound surface. Each product mentioned below has different indications. New products are constantly being engineered for the treatment of burns, diabetic wounds, trophic ulcers and venous stasis wounds. It is up to each individual practitioner to stay informed on the latest products available. A Closer Look At Apligraf Apligraf® (graftskin, Novartis, Organogensis) is a bilayered living skin substitute. It has both an epidermis and dermis, with living keratinocytes and fibroblasts derived from neonatal foreskin.3 The epidermal layer is formed by human keratinocytes and has a well-differentiated stratum corneum. The dermal layer is composed of human fibroblasts in a bovine type collagen lattice. It does not contain Langerhans’ cell, melanocytes, macrophages, lymphocytes, blood vessels or hair follicles. Therefore, it will not illicit an immune response.4 The Food and Drug Administration approved Apligraf for the treatment of diabetic foot wounds and venous leg ulcers. The exact mechanism of action is unknown, but researchers believe it works to promote healing by providing immediate coverage and by stimulating healing via cytokines, matrix proteins and cell-to-cell interactions.5 Epithelialization occurs from the edge of the wound and from islands within the wound bed. Apligraf is supplied as a circular disk approximately 7.5 cm in diameter and is intended for single-use. The cost of Apligraf is $1,000 to $1,200 per use. In a 2000 study by Attilasoy, a higher percentage of wounds were healed with Apligraf (55 percent) compared to the control (40 percent). Chronic venous leg ulcers were healed to complete closure with an average of 1.41 applications of Apligraf.5 Diabetic ulcers treated with Apligraf once a week for a maximum of four weeks reduced the median time to complete wound closure from 91 days in the control group to 38.5 days in the Apligraf group.6 What You Should Know About Dermagraft Dermagraft® uses a bioabsorbable polyglactin mesh as a platform upon which fibroblasts from neonatal foreskin are grown. The cells multiply and generate a mixture of collagen, growth factors, glycosaminoglycans and cytokines, all of which are components of a healthy human dermis.7 When one implants Dermagraft into an adequately prepared diabetic foot ulcer, it assists in restoring the dermal bed, allowing a patient’s wound to re-epithelialize. Dermagraft is indicated for use in treating full-thickness diabetic foot ulcers that are greater than six weeks in duration and extend through the dermis, but without tendon, muscle, joint capsule or bone exposure. The patient also must have adequate blood supply to the foot in order to support tissue growth. Dermagraft is supplied in a frozen section measuring approximately 2 inches by 3 inches. It is intended for a single use. One should apply additional applications of Dermagraft weekly until wound closure occurs. Since Dermagraft heals ulcers more rapidly, the average cost per ulcer healed is lower than conventional treatments.8 In a randomized, controlled, multi-center clinical trial with 245 patients, Dermagraft healed more chronic diabetic foot ulcers and healed them faster than conventional therapy alone.9,10 Conventional therapy included sharp debridement, saline-moistened gauze and pressure-reducing footwear. After 12 weeks of treatment, 30 percent of ulcers treated with Dermagraft plus conventional therapy achieved 100 percent wound closure versus 18 percent with conventional therapy alone. Patients treated with Dermagraft were 1.7 times more likely to heal than the control group at any given time during the study regardless of ulcer location. The patients also remained ambulatory for an average of eight hours per day during the study and total non-weightbearing with crutches or a wheelchair was not required. Results of the clinical trial at the Foot and Ankle Institute of South Florida showed that 71.4 percent of chronic diabetic foot ulcers healed in the Dermagraft group versus 14.3 percent in the control group after 12 weeks.9 After a single treatment with Dermagraft, researchers found that they could detect cells for up to six months in wounds using a male specific SRY marker. Current clinical trials are ongoing in exploring the use of Dermagraft in other types of wounds. When Should You Consider OrCel For Your Patients? OrCel® is a bilayered cell matrix product that is derived from human cells and contains cultured neonatal human keratinocytes and fibroblasts in separate compartments in a collagen sponge. The fibroblast and keratinocyte cells secrete cytokines and growth factors. OrCel serves as an absorbable biocompatible matrix that provides a favorable environment for host cell migration. OrCel is indicated for treating mitten deformities with recessive dystrophic epidermolysis bullosa (RDEB) as well as donor sites in burn patients. It is currently being investigated for treating venous leg ulcers and diabetic foot ulcers. The cost of the product is $995 per unit. Final Notes Tissue replacements have been combined with adjunctive therapies with marked success, although these combinations are not approved by the FDA or the manufacturers. Armstrong combined Dermagraft with a vacuum-assisted closure system.11 Doing so gives one the advantage of closing cavernous wounds with granular wound beds and at quicker rates. One may also combine tissue replacements with hyperbaric oxygen treatment in wounds with local ischemia. This increases the likelihood of graft take.12 Patients with mild to moderate edema may wear multi-layered compression bandages for excellent edema control. You may consider a total contact cast for patients who are non-compliant with non-weightbearing orders. Tissue replacements are cost effective because they reduce the healing time of chronic wounds. Reducing healing time decreases wound infection rates and lowers the risk of amputation. Also consider the fact that when patients have faster healing wounds, the necessity for adjunctive diagnostic studies diminishes. Patients may return more quickly to normal function, thus preventing escalating psychosocial issues associated with persistent wounds. Although there is a higher cost per product, there is a reduced cost overall when there is a decreased time for wound closure. If a wound remains open longer, then there is a higher cost incurred due to the increased number of supplies used over time as well as more physician office visits. Tissue replacements serve to stimulate a stagnant wound but one must use them in conjuction with other treatments including proper debridement and offloading with an emphasis on controlling the bacterial burden. Dr. Hanft (shown at the right) is the Director of Podiatric Medical Education within the South Miami Hospital/Baptist Health Systems. He is a Fellow of the American College of Foot and Ankle Surgeons. Drs. Williams and Kyramarios are first-year residents of the South Miami Hospital Foot and Ankle Program. Dr. Temar is a second-year resident of the South Miami Hospital Foot and Ankle Program. References 1. Harding KG, Morris HL, Patel GK. Healing Chronic wounds. British Medical Journal. 2002; 324: 160-163. 2. Falanga V. Wound bed preparation and the role of enzymes: A case for multiple actions of therapeutic agents. Wounds. 2002; 14(2): 47-57. 3. Dolynchuk K, Hull P, Guenther L, et al. The role of Apligraf in the treatment of venous leg ulcers. Ostomy Wound Management. 1999; 45: 34-43. 4. Milstone LM, Asgari MM, Schwartz PM, et al. Growth factor expression, healing and structural characterisitcs of Graftskin (Apligraf®). Wounds. 2000; 12 (5 Supplement A): 12A-19A. 5. Atillasoy E. The safety and efficacy of Graftskin (Apligraf‚) in the treatment of venous leg ulcers: A multicenter, randomized, controlled clinical trial. Wounds 2000; 12 (5 Supplement A): 20A-26A. 6. Sabolinski ML, Veves A. Graftskin (Apligraf) in neuropathic diabetic foot ulcers. Wounds 2000; 12 (5 Supplement A): 33A-36A. 7. Krejei-Papa NC, Hoang A, Hansbrough, JF. Fibroblast sheets enable epithelialization of wounds that do not support keratinocyte migration. Tissue Eng. 1999; 5:555-561. 8. Allenet B. Paree F. Lebrun T. Carr L. Posnett J. Martini J. Yvon C. Cost-effectiveness modeling of Dermagraft for the treatment of diabetic foot ulcers in the french context. Diabetes & Metabolism. 2000 Apr ;26(2):125-32. 9. Hanft JR, Surprenant MS. Healing of chronic foot ulcers in diabetic patients treated with a human fibroblast-derived dermis. Journal of Foot and Ankle Surgery. 2002; 5:1-9. 10. Gentzkow GD, Jensen JL, Pollak RA, et. al. Improved healing of diabetic foot ulcers after grafting with a living human dermal replacement. Wounds 1999;3:77-84. 11. Espensen EH, Nixon BP, Lavery LA. Use of subatmospheric (VAC) therapy to improve bioengineered tissue grafting in diabetic foot wounds. Journal of the American Podiatric Medical Association. 2002; 92(7): 395-401. 12. Hopf HW, Humphrey LM, Puzziferri N, et al. Adjuncts to preparing wounds for closure hyperbaric oxygen, growth factors, skin substitutes, negative pressure wound therapy (vacuum-assited closure). Foot and Ankle Clinics. 2001; 6: 661-682. 13. Phillips T, Stanton B, Provan BA, Lew R. A study of the impact of leg ulcers on quality of life: Financial, social, and psychologic implications. Journal of the American Academy of Dermatologists. 1994; 31: 49-53. 14. Olin JW, Beusterien KM, Childs MB, et al. Medical costs of treating venous stasis ulcers: Evidence from a retrospective cohort study. Vascular Medicine. 1999; 4: 1-7. 15. Phillips TJ, Dover JS. Leg ulcers. Journal of the American Academy of Dermatologists. 1991; 25: 965-987. No, tissue replacements often are not cost effective. Although these modalities can be an effective adjunct in wound healing, there is a strong potential for misuse. The authors emphasize the need for education and experience in adhering to proper indications. By Guy R. Pupp, DPM, and Mark B. Hellmann, DPM Tissue replacements are not cost effective if they are used unjudiciously. Clinicians must have a thorough understanding of the pathophysiology of the condition they are treating, the treatment alternatives and the associated technology. This sounds reasonable, but there is the potential for misuse of tissue replacements when one considers the following clinical scenarios. How many times have expensive tissue replacements been used on wounds that are infected? How many times have they been used on plantar foot wounds without proper offloading? How many times have tissue replacements been used on a venous ulcer without compression to control venous hypertension? How many times have they been used over tendon or bone in wounds with little or no granulation tissue? How many times have tissue replacements been used over fibrotic tissue or limbs that have arterial compromise? When tissue replacements are used in these clinical scenarios, they will fail. This is not cost-effective medicine. There are many medical and pharmaceutical claims associated with lower extremity healing rates. Healing depends on so many variables and one must assess all factors that are required for successful healing in each individual patient. In our clinics, we employ both dermal and dermal-epidermal origin tissue replacements very successfully. However, we have strict criteria for when we utilize these modalities. When tissue replacements are used properly, they can reduce the cost of wound healing. This has been demonstrated in many studies.1 An Overview Of Wound Healing Costs Chronic wounds are notoriously difficult to heal. These include decubitus ulcers, venous ulcers, diabetic ulcers, burn injuries and defects secondary to soft tissue excision. The cost of treating these wounds is astronomical. Wounds associated with burns are estimated to cost $70 million a year. Leg ulcers related to chronic venous insufficiency are estimated to affect over 2 million people in the United States alone. Valve incompetence with resultant failure of the venous muscle pump leads to edema and eventual ulceration. The cost of treating chronic leg ulcers is substantial. A retrospective study of venous leg ulcers, alone, determined the mean total cost to be $9,685 per patient or over $19 billion overall. Although compression therapy and debridement are the standard of care for the management of leg ulcers, approximately 40 to 50 percent of ulcers do not achieve complete closure within six months of therapy.2,3 In our clinics, we consider tissue replacements if the wound does not respond to conservative treatment in six to eight weeks or if there are poor prognostic factors such as large wound size and a long duration of ulcers at presentation. There are 17 million people with diabetes in the U.S. and approximately 15 percent will develop foot ulcers.4-6 These people are at a high risk for amputation and prolonged hospitalization. It has been estimated that diabetic ulcer costs add up to $5 billion per year. Treatment failure and subsequent lower extremity amputation costs an additional $1 billion per year in the U.S.7 These costs continue to escalate due to the increasing diabetic population as well as continuing inflation in the costs of patient care. Understanding the epidemiology of the diabetic foot, we are aggressive in our approach to wound healing and utilize gold standards such as debridement, total contact casting and surgical intervention when they are indicated. We have found tissue replacements to be a useful adjunct in achieving diabetic wound healing. However, if the patient is not managed properly, tissue replacements will often fail. Examples of mismanagement are failure to offload a plantar ulcer with a graft cover or utilizing the graft over a bony prominence that cannot be accommodated with a brace and/or shoe gear. Why Education On Proper Indications Is Essential Obviously, physician education plays a large role in the proper use of tissue replacement grafts. This can be achieved, in part, through company representatives, who are well educated on their product and can effectively teach proper use and application of the bioengineered graft product. However, this does not prevent those physicians who have minimal wound care experience from improperly using these bioengineered products. Indeed, having a good clinical background is key to recognizing appropriate clinical situations in which to use these materials. Another arguable con to the cost effectiveness of tissue graft usage is simple greed. Reimbursement for bioengineered replacement grafts can be quite lucrative although application requires little clinical time. This is especially true for those bioengineered tissue grafts that often require multiple applications. Unfortunately, this may lead to situations in which tissue replacement grafts are overused in ulcerations that would otherwise heal with judicious wound care. With a simple literature search, one can appreciate the obviousness that a majority of literature gives favorable reports to bioengineered tissue graft products.3,8,9 Extensive promotional detailing occurs with all new medical products and, oftentimes, they are overused. With this process, these bioengineered tissue grafts, as with many products, can be mistakenly perceived as a “cure-all” for the common ulcer. Why Patient Education Is A Must As Well Whatever the treatment course in wound care, patient education is essential. In our practice, we ensure that patients understand the pathology of the ulceration and continually reinforce the importance of adhering to the treatment regimen. As with any treatment scenario, patient compliance can dictate success or failure. When treating patients with ulcers, we stress key preventive factors including non- or partial weightbearing, extremity elevation and the need for a follow-up evaluation. Patient education is paramount when one uses these expensive modalities. Final Notes In the vast majority of wounds, whether they are chronic or acute, the real cure-all is diligent wound care utilizing proper debridement, offloading of the ulceration, an optimal moisture environment, glycemic control, proper antibiosis and compression when indicated. However, when tissue replacements are indicated, they can be a great cost-effective adjunct to wound healing. Dr. Pupp (right) is the Clinical Director of the Kern Hospital Foot and Ankle Clinic in Warren, Mich. He is a Fellow of the American College of Foot and Ankle Surgeons and is also the Clinic Director at the Sinai Grace Diabetic Foot Center in Detroit. Dr. Hellmann is a Fellow in Rearfoot/Charcot Reconstructive Surgery at Kern Hospital in Warren, Mich. References 1. Sabolinski, ML, Veves A. Graftskin (Apligraf)in neuropathic diabetic foot ulcers. Wounds 2000; 12 (5 supplement A):33A-36A. 2. Falanga, V. Care of venous leg ulcers. Ost Wound Mgmt 1999;45:33S-43S. 3. Kirsner, R. et.al. Clinical experience with a human skin equivalent for treatment of venous leg ulcers: process and outcomes. Wounds. 1999; 6:137. 4. Palumbo, PJ, Melton, LJ. Peripheral Vascular Disease and diabetes. In: Diabetes in America. Data Compiled 1984 (NIH publ. no.85-1468), p.1. U.S. Government Printing Office, Washington, DC, 1985. 5. Reiber, GE, et.al. Lower extremity foot ulcers and amputations in diabetes. In: Diabetes in America, 2nd ed. (NIH publ. no. 95-1468), U.S. government printing office, Washington, DC, 1995. 6. Frykberg, RG, et. al. Epidemiology of the diabetic foot: ulcerations and amputations. In: Contemporary Endocrinology: Clinical Management Of Diabetic Neuropathy, p.273, edited by A Veves, Humana Press, Totowa, NJ, 1998. 7. Amato, D., et.al. The cost of illness in patients with diabetic foot ulcers [abstract]. 59th annual meeting of the American Diabetes Association, San Diego, CA, June 1999. 8. Snyder, R. Graftskin (Apligraf) and Regranex gel: an Overview. Podiatry Management, Vol.11, No.6, 1999:39-41. 9. Sumit, K., et.al. Wound treatment with hman skin equivalent. J Am Podiatric Med Assoc 2002 92: 19-23. Editor’s note: For further reading about tissue replacement products and other wound modalities, see “A Comprehensive Review Of Topical Agents” in the July 2002 issue of Podiatry Today.