The global prevalence of diabetes mellitus is growing at epidemic proportions, having nearly doubled over the last 3 decades. In 2014, an estimated 8.5% of the adult population (422 million adults) worldwide were living with diabetes.1 In their review of data spanning 183 publications, Yazdanpanah et al2 found diabetic foot ulcers (DFUs) are a common and costly complication of diabetes that increase the risk of infection, amputation, and death. In a review of the economic effects of diabetic foot disease, Boulton et al3 showed the recurrence of foot ulcers is >50% after 3 years from the time of healing the DFU. A systematic review by Singh et al4 reported the prevalence of foot ulcers worldwide is 4% to 10% in persons diagnosed with diabetes mellitus, the annual worldwide population-based incidence is 1.0% to 4.1%, and the lifetime incidence may be as high as 25%; the review also states DFUs frequently become infected, cause great morbidity, engender considerable financial costs, and are the usual first step to lower extremity amputation.4 A review5 of 111 primary source references from United States’ societies and associations reported that patients with diabetes have a 15% to 25% lifetime risk of developing a DFU. For persons that develop a DFU, recurrence rates are as high as 50% to 70% over a 5-year period.3-5
DFUs are associated with an increased risk for serious and costly outcomes such as osteomyelitis and amputation and are a leading cause of diabetes-related hospitalizations. A review6 evaluating administrative claims data of Medicare and private insurers found that patients with DFUs had incremental annual health care costs of $11 710 to $16 883 (US dollars), over and above the health care expenditures of matched controls without DFUs, which translates to an estimated $9 to $13 billion annually in the US. A review5,7 of articles regarding morbidity and mortality associated with DFU found in the US and United Kingdom, approximately 15% of DFUs result in lower extremity amputation, and patients with a history of DFU have a nearly 50% increased risk of mortality compared with patients with diabetes who did not have a history of DFU.
Standard wound management for DFUs consists of debridement, infection elimination, use of dressings, and offloading. Treatment guidelines that address debridement/devitalized tissue, infection or inflammation, moisture balance, and wound edge preparation/wound depth (the DIME paradigm)8 include consideration of patient-centered concerns, wound etiology, and wound bed preparation. DIME principles encompass assessment and treatment of a DFU8; however, a high percentage of DFUs do not respond to guideline standard care (SC). In a retrospective analysis9 of one large database (N = 6440 DFUs), treatment of DFUs included debridement, infection elimination, use of dressings, and offloading. The likelihood of healing, determined using a wound healing index based on identified risk factors for healing such as wound age (duration), wound size (open area), number of concurrent wounds, evidence of infection, Wagner grade, and peripheral vascular disease, was 50% and 70% for moderate and severe ulcers, respectively. However, limitations to this analysis exist. Although treatment impact was assessed, data regarding variations in care were not consistently available. Helping ensure the quality of care, electronic medical records (EMRs) were used for data collection and to internally audit the patient chart and the facility to determine physician level of service. Adjunctive therapies and the Wound Healing Society10 guidelines level-1 recommendation urged the use of SC therapy for an initial period of 4 weeks, at which time, if a wound size reduction of at least 50% is not observed, intervention with advanced therapies (including skin substitutes) is recommended to accelerate healing and reduce the risk of costly complications.
The Center for Medicare and Medicaid Services11 established Q codes for more than 100 skin substitutes (Q4100 – Q4204) available for treating chronic wounds. These products can be more broadly categorized based on whether they are acellular or cellular, derived from human or animal tissue, and how they are processed. In the US, the majority of skin substitutes have received clearance either under a 510(k) submission and are considered “wound dressings,” or they are registered as Section 361 Human Cells, Tissues and Cellular and Tissue-based Products and are for homologous use as wound coverings. One wound dressing cleared for marketing in the US as a Class II device under a 510(k) classification is fetal bovine collagen dressing (FBCD; Primatrix; Integra, Plainsboro, NJ), an animal-derived acellular collagen dressing that has been processed and treated to remove cellular elements, lipids, carbohydrates, and noncollagenous proteins, resulting in a scaffold with physiological amounts of collagen but without viable cells. FBCD was evaluated for use in DFUs in a 12-week, single-arm, multicenter prospective study12; among the 46 participants that completed the study (mean baseline ulcer wound age 286 days, mean baseline ulcer area 4.34 cm²), 59% of FBCD-treated DFUs healed with a single application of the animal-derived acellular collagen dressing and 22.9% healed with 2 applications in addition to debridement and offloading. For persons not healed by 12 weeks, the average wound area reduction was 71.4%. The authors concluded the FBCD “integrated with standard care therapy” and was shown to be a “successful treatment regimen to heal DFUs”.12 As a Class II device, the FBCD was not required to be submitted to the US Food and Drug Administration (FDA) for premarket review of clinical study protocols or reports of clinical outcomes.
Only 2 cellular skin substitute products have been approved by the FDA for DFUs: a bioengineered living cellular construct (BLCC; Apligraf, Organogenesis Inc, Canton, MA) with a 2001 premarketing marketing approval (PMA) and an indication for use in DFUs; and a human fibroblast-derived dermal substitute (HFDS; Dermagraft; Organogenesis Inc, Canton, MA) with a 2001 PMA approval and an indication for use in DFUs. These products were approved via the PMA process, the most stringent type of device marketing application required by the FDA and which requires at least 1 pivotal clinical trial demonstrating efficacy and safety to support the indication. HFDS is a bioengineered living cellular technology containing metabolically active fibroblasts obtained from human newborn foreskin tissue. The fibroblasts are seeded onto a bioabsorbable polyglactin mesh scaffold and are known to produce human collagen, extracellular matrix proteins, cytokines, and growth factors.13 The efficacy of HFDS is supported by a pivotal, randomized controlled trial14 (RCT) that showed treatment with HFDS resulted in a significantly greater percentage of healed ulcers compared with SC therapy; by week 12, 39/130 (30.0%) of HFDS-treated DFUs healed compared with 21/115 (18.3%) of control-treated DFUs (P = .023).
Considering the number of skin substitute products commercially available on the market for chronic wound care, few systematic evaluations of clinical outcomes have been conducted. A draft Agency for Healthcare Research and Quality technical brief on skin substitutes15 (Project ID: 039-015-334; January 28, 2019) summarized key findings from a panel review of all available completed skin substitute studies that were categorized as meta-analyses/systematic reviews, RCTs, and prospective nonrandomized comparative studies in chronic wounds. Only 3 systematic reviews and 17 RCTs examined use of 13 distinct skin substitutes. The lack of studies examining the efficacy of most skin substitute products and the need for better-designed and reported studies providing more clinically relevant data in this field is the key implication of the Agency’s technical brief on skin substitutes. Even the studies that have been completed and reviewed “rarely reported clinical outcomes such as amputation, wound recurrence at least 2 weeks after treatment ended, and patient-related outcomes such as return to function, pain, exudate, and odor.” Further, these 20 completed studies “rarely reported outcomes important to patients, such as return of function and pain relief.” Future studies may be improved by using a 4-week, run-in period before study enrollment and at least a 12-week study period; they should also report whether wounds recur during 6-month follow-up. Additionally, information regarding clinical effectiveness, which looks at patient outcomes in real-world settings, is lacking. Such data are becoming increasingly important in the US health care environment, which today is driven by outcomes and cost efficiencies.
The purpose of this study was to evaluate the proportions of DFUs healed and their median time to healing of using a HFDS compared with a FBCD in a real-world clinical setting.