The evidence for the use of growth factors and active skin substitutes for the treatment of non-infected diabetic foot ulcers (DFU): a health technology assessment (HTA).

AIMS: Assessment of the safety, efficacy and effectiveness of growth factors alone or in combination with other technologies in the treatment of DFU including medical, economical, social, ethical and juridical aspects. METHODS: We systematically searched relevant data bases limited to English and German language and publications since 1990. Review and assessment of the quality of publications followed methods conforming to widely accepted standards for evidence-based medicine and health economics. RESULTS: We identified 25 studies comparing becaplermin, rhEGF, bFGF and the metabolically active skin grafts Dermagraft and Apligraf with standard wound care (SWC) alone or extracellular wound matrix. Study duration ranged from 12 to 20 weeks and the study population comprised between 17 and 382 patients. Treatment with becaplermin, rhEGF, Dermagraft and Apligraf resulted in a higher incidence of complete wound closure and shorter time to complete wound healing with statistically significant differences. Regarding the proportion of adverse events there was no difference between treatment groups. The methodological quality of the studies was affected by significant deficiencies. Economic evaluations showed becaplermin being cost-effective. CONCLUSIONS: Add-on therapy with growth factors and active skin substitutes for treating uncomplicated DFU could be an alternative to SWC alone. For explicit recommendations further studies with stronger evidence are necessary.

Benefit-risk assessment of becaplermin in the treatment of diabetic foot ulcers.

Becaplermin is a recombinant platelet-derived growth factor composed of two B chains that is approved for the treatment of neuropathic diabetic foot ulcers extending into or beyond the subcutaneous tissue in patients with adequate arterial perfusion. The aim of this review is to assess the benefits and risks associated with the use of this agent. Randomized controlled trials have provided evidence for the efficacy of becaplermin in increasing healing rates, and cost analyses have repeatedly shown a favourable cost-effectiveness ratio. However, clinical experience has not met these high expectations and becaplermin is not widely used. Moreover, this agent has not been compared with other additional treatment modalities, notably bioengineered skin substitutes and extracellular matrix proteins, and such comparisons are eagerly awaited. Of particular note, increased cancer risk has been reported in patients treated with more than three tubes of becaplermin; thus, this agent should be used only when the anticipated benefits outweigh the potential harm, and with extreme caution in patients with diagnosed malignancy. Finally, longer follow-up data are necessary to shed more light on the potential risk of malignancy in connection with becaplermin use.

Systematic review of economic evaluations of human cell-derived wound care products for the treatment of venous leg and diabetic foot ulcers.

BACKGROUND: Tissue engineering is an emerging field. Novel bioengineered skin substitutes and genetically derived growth factors offer innovative approaches to reduce the burden of diabetic foot and venous leg ulcers for both patients and health care systems. However, they frequently are very costly. Based on a systematic review of the literature, this study assesses the cost-effectiveness of these growth factors and tissue-engineered artificial skin for treating chronic wounds. METHODS: On the basis of an extensive explorative search, an appropriate algorithm for a systematic database search was developed. The following databases were searched: BIOSIS Previews, CRD databases, Cochrane Library, EconLit, Embase, Medline, and Web of Science. Only completed and published trial- or model-based studies which contained a full economic evaluation of growth factors and bioengineered skin substitutes for the treatment of chronic wounds were included. Two reviewers independently undertook the assessment of study quality. The relevant studies were assessed by a modified version of the Consensus on Health Economic Criteria (CHEC) list and a published checklist for evaluating model-based economic evaluations. RESULTS: Eleven health economic evaluations were included. Three biotechnology products were identified for which topical growth factors or bioengineered skin substitutes for the treatment of chronic leg ulceration were economically assessed: (1) Apligraf, a bilayered living human skin equivalent indicated for the treatment of diabetic foot and venous leg ulcers (five studies); (2) Dermagraft, a human fibroblast-derived dermal substitute, which is indicated only for use in the treatment of full-thickness diabetic foot ulcers (one study); (3) REGRANEX Gel, a human platelet-derived growth factor for the treatment of deep neuropathic diabetic foot ulcers (five studies). The studies considered in this review were of varying and partly low methodological quality. They calculated that due to shorter treatment periods, fewer complications and fewer inpatient episodes the initial cost of the novel biotechnology products may be offset, making the treatment cost-effective or even cost-saving. The results of most studies were sensitive to initial costs of the products and the evidence of effectiveness. CONCLUSION: The study results suggest that some growth factors and tissue-engineered artificial skin products feature favourable cost-effectiveness ratios in selected patient groups with chronic wounds. Despite the limitations of the studies considered, it is evident that health care providers and coverage decision makers should take not only the high cost of the biotechnology product but the total cost of care into account when deciding about the appropriate allocation of their financial resources. However, not only the cost-effectiveness but first of all the effectiveness of these novel biotechnology products deserve further research.

Analysis of patient cost for recombinant human platelet-derived growth factor therapy as the first-line treatment of the insured patient with a diabetic foot ulcer.

INTRODUCTION: The 2-year cost of a new diabetic foot ulcer (DFU) is estimated to be $27,987. These costs are thought to be secondary to hospitalization, amputation, and the duration of care. Treatments that accelerate rapid and complete healing of DFUs reduce the need for hospitalization, thus reducing the costs of care. One of the therapies previously shown to lead to more rapid and complete wound healing of DFUs is recombinant human platelet-derived growth factor (rhPDGF). Many centers, however, do not initiate rhPDGF therapy, based on patient cost issues. Therefore, many centers reserve a potentially cost-saving therapy as a second- or third-line therapy. The goal of the authors' analysis was to examine the actual cost to patients of a policy of initiating rhPDGF as the initial therapy for appropriately debrided DFUs. METHODS: A 12-month retrospective analysis of all patients presenting to a tertiary care referral wound practice with the diagnosis of DFUs was performed. The algorithm the authors followed specified that all wounds of patients with an ankle brachial index of greater than 0.7 and a diagnosis of DFUs (that were not enrolled in a research protocol) were debrided widely (ie, all wounds were debrided sharply with a 45-degree bevel on the border and the bases of the wounds were sharply debrided to a clean granular base), provided off-loading, and initiated on rhPDGF at the patients' first center visit. The patient payer mix and average cost-per-patient per year were analyzed, and the average number of tubes of rhPDGF was recorded. RESULTS: There were 121 patients with the diagnosis of DFUs, representing 766 visits. A total of 187 tubes of rhPDGF were prescribed for these 121 patients over the course of 12 months. There was an average use of 1.54 tubes per patient. The primary payer mix was Medicare, 44%; Medicaid, 27%; and private-payer mix, 29%, representing 10 companies. The average patient cost per tube was $28, the average cost for Medicare was $25 (many with secondary payers, as data predate 2006 Medicare D), Medicaid was $2, and private insurance was $71. Therefore, the average patient cost per course of therapy was $42. DISCUSSION: The average cost to patients with prescription benefits for a course of rhPDGF therapy, over a diverse and representative patient mix, is less than $50 in an inner-city tertiary care facility. Thus, patient cost alone should not provide a barrier to initiating active therapy in the form of rhPDGF to the patient presenting with a DFU. This early initiation could potentially lead to lower overall health costs by improving wound-healing outcomes.

Immunomodulatory role of Tinospora cordifolia as an adjuvant in surgical treatment of diabetic foot ulcers: a prospective randomized controlled study.

BACKGROUND: Chronic diabetic patients with wounds have deficient growth factors and impaired local and systemic cellular immunity. Treatment with growth factors is expensive with risk of infection transmission and these factors may not achieve optimum wound concentration. We evaluated the role of generalized immunomodulation in diabetic ulcers by using Tinospora cordifolia as an adjuvant therapy and studied its influence on parameters/determinants of healing, on bacterial eradication and on polymorphonuclear phagocytosis. MATERIALS AND METHODS: A prospective double-blind randomized controlled study lasting for over 18 months in 50 patients. The ulcer was classified by wound morphology and severity with Wound Severity Score (Pecoraro-Reiber system). Mean ulcer area, depth and perimeter were measured and swabs taken for culture. Blood was collected to assess polymorphonuclear % phagocytosis (PMN function by Lehrer-Cline C. albicans method). Medical therapy, glycemic control, debridement, wound care were optimized. At 4 weeks, parameters were reassessed. PMN function was reviewed at 3 months. RESULTS AND ANALYSIS: Forty-five patients completed the trial: study group - 23 (M:F = 17:1; mean age = 56.3 years; mean ulcer duration = 21.1 days); control group 22 (M:F = 19:3; mean age = 56.3 years; mean ulcer duration = 30.4 days). Net improvement was seen in 17 patients (73.9%) in the study group; while in the control group, in 13 patients (59.1%); P = 0.292. Specific parameters included rate of change of ulcer area - cm(2) /day (study - 0.15; control - 0.07; P = 0.145); rate of change of ulcer perimeter - mm/day (study - 0.09; control = - 0.07; P = 0.089); change of depth - mm (study - 2.2; control - 1.4; P = 0.096); change of wound score (study - 14.4; control - 10.6; P = 0.149); total number of debridements (study - 1.9; control - 2.5; P = 0.03) and change in % phagocytosis (study - 3.9; control - 2.3; P = 0.048). CONCLUSION: Diabetic patients with foot ulcers on T. cordifolia as an adjuvant therapy showed significantly better final outcome with improvement in wound healing. Reduced debridements and improved phagocytosis were statistically significant, indicating beneficial effects of immunomodulation for ulcer healing.

Cost-effectiveness of becaplermin for nonhealing neuropathic diabetic foot ulcers.

Foot ulcers secondary to peripheral neuropathy and vascular disease are a commonly occurring complication for people with diabetes. Becaplermin, a genetically-engineered growth factor in a hydrogel vehicle, has been shown to be more effective than vehicle-only control in healing chronic foot ulcers of patients with adequate vasculature receiving best clinical care. To evaluate the cost-effectiveness of adding up to 20 weeks of becaplermin to a regimen of best clinical care, a 1-year decision-analytic model was developed and tested using data from a previously published controlled clinical study involving 251 people with diabetes (124 becaplermin/127 control) and adequate vasculature presenting with an infection-free ulcer that had failed to heal despite appropriate therapy. A 20-week healing rate was estimated based on the clinical trial data assuming becaplermin treatment was terminated at 10 weeks in non-responding ulcers, and follow-up data were extended to 1 year. Resource utilization was estimated by an expert panel using a modified Delphi approach. Using the model, it was found that incorporating becaplermin with best clinical care resulted in 26 fewer ulcer-days per patient per year compared to best clinical care alone with an incremental cost-effectiveness ratio of $6 per ulcer-day averted. Results were sensitive to becaplermin cost, efficacy, and effect on infection and recurrence rates. The clinical benefits of becaplermin deserve further investigation to enhance cost-effectiveness information for informed treatment decisions.

Cost-effective management of recalcitrant diabetic foot ulcers.

The worldwide increase in prevalence of type 2 diabetes has resulted in a parallel increase in diabetic foot ulcers--a pervasive and significant problem associated with this disease [2]. Currently, an estimated 10.3 million people have been diagnosed with diabetes, while an additional estimated 5.4 million people with diabetes remain undiagnosed, representing a sixfold increase in the incidence of diabetes over the past four decades [9]. Approximately 15% (more than 2 million individuals, based on these estimates) of all people with diabetes will develop a lower-extremity ulcer during the course of the disease [10-12]. While most of these ulcers can be treated successfully on an outpatient basis, some will persist and become infected. Ultimately, between 14% and 20% of patients with lower-extremity diabetic ulcers will require amputation of the affected limb [13-15]. Diabetic foot ulcers can result in staggering financial burdens for both the healthcare system and the patient. For example, analysis of the 1995 Medicare claims revealed that lower-extremity ulcer care accounted for $1.45 billion in Medicare costs and contributed substantially to the high cost of care for diabetics, compared with Medicare costs for the general population [5]. Therapies that promote rapid and complete healing and reduce the need for expensive surgical procedures would impact these costs substantially. Results of this analysis suggest that becaplermin may ultimately be more cost-effective for the treatment of chronic diabetic foot ulcers than other treatment modalities, despite its higher initial dollar cost. This finding may be attributed to a combination of factors. First, expenses incurred in more prolonged treatment, such as office visits and the need for additional dressings, can be avoided when healing completes in a shorter period. Second, rapid and complete ulcer healing may reduce the incidence of significant morbidities (such as amputation or infection) and premature mortality; consequently, the financial burden associated with these complications would be reduced. Finally, the value of improved quality of life in patients with healed ulcers and the reduction in financial burden for patients who return to work cannot be ignored. These promising results warrant further investigation in larger controlled clinical studies to define more clearly the cost-effectiveness of becaplermin in this patient population.

The cost-effectiveness of treating diabetic lower extremity ulcers with becaplermin (Regranex): a core model with an application using Swedish cost data.

OBJECTIVES: The objective of this study was to develop a model capable of assessing the cost-effectiveness in Sweden of treating diabetic neuropathic lower extremity ulcers with becaplermin gel (Regranex) plus good wound care (GWC) relative to treating them with GWC alone. METHODS: A Markov simulation model was developed that includes six health states: Uninfected Ulcer, Infected Ulcer, Gangrene, Healed Ulcer, Healed Ulcer-History of Amputation, and Deceased. To predict clinical outcomes, information was taken from a specially designed prospective 9-month follow-up study of 183 neuropathic patients in the US treated with GWC. Cost of treatment data were taken primarily from a study of a cohort of 314 patients in Sweden. The efficacy of becaplermin was assumed equal to that achieved in a pooled analysis of four randomized clinical trials. A model application provides expected clinical outcomes for a cohort of patients. Annual treatment costs per patient were estimated using treatment practice and unit prices from Sweden. RESULTS: Due to a higher rate of healing and a shorter average healing time, treatment with becaplermin gel was predicted to increase the average number of months spent in the healed state over the first year following development of an ulcer by 24% relative to GWC alone. In addition, the corresponding number of amputations was 9% lower for the becaplermin-treated cohort. The average expected cost of $12,078 US for an individual treated with GWC alone declines to $11,708 US for one treated with becaplermin, in spite of $1262 becaplermin costs. Expenses related to topical treatment and inpatient care account for 83% of the resources conserved. CONCLUSIONS: Our results suggest that in Sweden treatment with becaplermin in conjunction with GWC consumes fewer resources and generates better outcomes than treatment with GWC alone for diabetic neuropathic ulcers. In light of the high and increasing incidence of such ulcers, the potential savings in costs and suffering may be important. Results are difficult to extrapolate internationally because they are strongly related to country-specific treatment practices and price levels.

Original articles: ease of wound closure as an endpoint of treatment efficacy.

New treatments for chronic wounds require carefully performed clinical trials with significant endpoints. Total wound closure is the only endpoint currently accepted by the Food and Drug Administration. This study describes a scale that measures ease of wound closure and applies it to a four-arm prospectively randomized, blinded pressure ulcer trial of recombinant human platelet-derived growth factor-BB. Following validation of interrater reliability, 83 evaluable subjects' photographs were given a weekly ease of closure score by four raters blinded to treatment. The change of ease of closure score was correlated with the change of wound area and volume. Each ease of closure score was given a procedural cost. Results showed ease of closure did not directly correlate with either wound area or volume, suggesting that it was measuring additional information. The mean change in ease of closure score was 6 for subjects treated with 100 microg recombinant human platelet-derived growth factor-BB daily; 5 for those treated with 300 microg growth factor daily or 100 microg recombinant human platelet-derived growth factor-BB bid; and 4 for those treated with placebo. The cost savings ranged from $7200 for the group receiving 100 microg recombinant human platelet-derived growth factor-BB daily to $6300 for the controls. Outcomes in all 4 groups were significantly improved from their starting evaluation (p < 0.001). Based on this study, ease of closure is a verifiable endpoint that can be related to cost efficiency and may be a measure of efficacy.