Evaluation of Wound Closure Rates Using a Human Fibroblast-derived Dermal Substitute Versus a Fetal Bovine Collagen Dressing: A Retrospective Study

Diabetic foot ulcers (DFUs) are associated with an increased risk for serious and costly outcomes such as osteomyelitis, amputation, and hospitalization. Purpose: A retrospective study was conducted to evaluate the proportion of patients healed and time to healing of DFUs treated with a human fibroblast-derived dermal substitute (HFDS) or a fetal bovine collagen dressing (FBCD). Methods: Data from patients with a DFU who received the first treatment in 2014 were extracted from the electronic record database of 93 wound care centers. Baseline demographics (eg, age, gender, body mass index, and number of wounds); wound location, size, and duration; and wound-specific information such as wound size and number of and interval between applications were obtained. Study criteria stipulated patients who received at least one treatment in 2014 with HFDS or FBCD on a DFU with location coded as foot, toe, heel, metatarsal head, toe web space, toe amputation site, or transmetatarsal amputation site; ulcer size ≥1 cm² to <20 cm²; and ulcer area reduction ≤50% in the 28 days before the first treatment with HFDS or FBCD were eligible for inclusion. Wounds that received an alternate skin substitute treatment up to 28 days before or concurrent with the first HFDS or FBCD treatment or if patient data that lacked baseline or follow-up wound area measurement were excluded. Deidentified data were extracted directly into data files and transferred to a third-party data management and statistical group for analysis. The frequency of DFUs achieving wound closure (defined as area ≤0.25 cm²) by weeks 12 and 24 and median time to wound closure of wounds that healed were analyzed. Baseline characteristics were compared using 2-sample t tests for continuous variables and 2-tailed Fisher’s exact tests for difference in proportions between treatments. Frequency of and median time to wound closure were determined by Cox proportional hazards analysis. The frequency of wounds closed at 12 and 24 weeks, median time to wound closure, hazard ratio with 95% confidence interval, and P value were estimated from the Cox model. Statistical significance was defined as P <.05. Results: Records showed 206 patients with 208 DFUs received treatment (108 HFDS, mean age 60.2 years, mean wound duration 8.8 months; 100 FBCD, mean age 65.2 years, mean wound duration 12.8 months) and were included. Mean number of treatment applications was 4.5 and 2.4 for HFDS and FBCD, respectively. After 12 and 24 weeks 44 (41%) and 69 (64%) of HFDS-treated wounds, respectively, and 21 (21%) and 43 (43%) of FBCD-treated wounds, respectively, were healed (at 12 weeks, P = .03; at 24 weeks, P = .03, log rank 2-tailed test, unadjusted). Median time to wound closure for HFDS and FBCD was 14.6 and 25 weeks, respectively (P = .03; log rank, 2-tailed test; Kaplan-Meier analysis). HFDS treatment significantly increased the probability of wound healing compared to FBCD treatment in the Cox proportional hazards analysis after adjusting for treatment terms, baseline wound area, baseline wound duration, baseline wound depth, wound location, and patient age at first treatment (HR = 1.77; 95% CI: 1.06-2.97; P = .03). Conclusion: DFU wounds are more likely to heal when treated with HFDS than with FBCD as used by facilities in this database. Studies examining the efficacy, cost-effectiveness, and patient-centered outcomes of these treatments is warranted. 

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 review^5,7 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.

Study design and data collection. Deidentified data consistent with the terms and conditions of the Health Insurance Portability and Accountability Act (HIPAA) of 1996 from the WoundExpert EMR database (Net Health, Pittsburgh, PA) were extracted to perform a retrospective analysis comparing the effectiveness of HFDS versus FBCD for the treatment of DFUs. This wound care-specific EMR database is utilized by wound care facilities across the US and is a leading EMR in the field of wound care.¹⁶ All treatment records for DFUs that received their first HFDS or FBCD treatment in 2014 at a treatment center participating in the transfer of deidentified data to Net Health for research purposes were analyzed. Treatment records included patient baseline demographics (eg, age, gender, body mass index [BMI], and number of wounds); wound location, size, and duration; and wound-specific information (area, number of and interval between treatments, and adjunct therapy) recorded at each visit. 

The primary analyses were the frequency of DFUs achieving wound closure by weeks 12 and 24 and median time to wound closure. Wound measurements (length and width) were used to calculate wound area in cm²; these measurements were taken and area calculated at the wound care facilities and recorded in the EMR. The EMRs from these facilities comprised the raw electronic record data for each DFU. 

Because patients with healed wounds do not always follow-up, wound closure was defined as an ulcer achieving area ≤0.25 cm².

Patients. Patients who had diabetes mellitus and who received at least one treatment with HFDS or FBCD for a DFU with location coded as foot, toe, heel, metatarsal head, toe web space, toe amputation site, or transmetatarsal amputation site; had an ulcer size ≥1 cm²  to <20 cm²; and with ulcer area reduction ≤50% in the 28 days before the first treatment with HFDS or FBCD were included for analysis. Patients with wounds that received alternate skin substitute treatment such as Apligraf (Organogenesis Inc, Canton, MA), Oasis (Cook Biotech Inc, West Lafayette, IN), Epifix (MiMedx Group, Marietta, GA), Grafix (Smith and Nephew, Columbia, MD), Theraskin (Soluble Systems, Newport News, VA), Graftjacket (Acelity, San Antonio, TX) up to 28 days before or concurrent with the first HFDS or FBCD treatment or if their data lacked baseline or follow-up wound area measurement were excluded.

Data collection. Wound-specific data were collected at the 93 facilities, entered directly into the EMR database, then collected by Net Health, which acted in compliance with all terms and conditions of their client contracts and HIPAA requirements. Net Health was not involved in data analysis, interpretation, or reporting of the data; deidentified data were extracted directly into the SAS 9.4 (SAS Institute, Cary, NC) and transferred directly to a third-party data management and statistical group (Biostatical Consulting Inc, Lexington, MA). Net Health ensured patient anonymity by only transferring data from the electronic records that were purged of patient names, dates of clinic visits, and all other unique identifiers of the patients’ personal information. Nonspecific patient information such as patient demographics, wound characteristics, and treatment characteristics (eg, number of visits, number of treatment applications, and the interval of time between treatment applications) were part of the data transfer.

Statistical analysis. Baseline patient (age, gender, BMI, number of wounds), wound (area, duration, depth, location), and treatment (number of treatments, interval between treatments, adjunctive treatments) characteristics were compared between treatment groups. Normal theory variables were analyzed using the 2-sample t test, other continuous variables were analyzed using the Mann-Whitney U and Wilcoxon tests, and categorical variables were subject to the chi-square test. Descriptive data were expressed as mean (standard deviation) and median for continuous variables and n (%) for categorical variables. Baseline characteristics were compared using 2-sample t tests for continuous variables and 2-tailed Fisher’s exact tests for difference in proportions between treatments. The primary analyses comparing frequency of and median time to wound closure were determined by Cox proportional hazards analysis using all available data through the end of 2014. Data were censored at the following points: the last visit with an area measurement for nonhealed wounds, when an alternate product was applied, or when 183 days had passed since prior application of the same product. The Cox model included terms for treatment, baseline wound area, baseline wound duration, baseline wound depth, wound location, and patient age at first treatment. [Of note: the number of applications and application interval were not included in the Cox model because these 2 variables are not baseline covariates. Only baseline patient and wound characteristics (patient and wound characteristics) were entered into the forward selection Cox proportional hazards regression model. Number of applications and application intervals were study-emergent data.] The frequency of wounds closed at 12 and 24 weeks, hazard ratio (HR) with 95% confidence interval (CI), and P value were determined by the Wald test for Cox. Median time to healing was estimated using KM analysis and the log rank 2-tailed test. Statistical significance was defined as P <.05.

Patient population. A total of 208 records (106 patients with 108 HFDS-treated and 100 patients with 100 FBCD-treated DFUs) were reviewed for patient, wound, and treatment characteristics and were included for analysis. Patient records were collected at all 93 centers; no one center contributed significantly more data used for this study. Further, the proportion of HFDS and FBCD records were comparable between wound care facilities. 

Table 1 shows patient demographic data. Men represented the majority of patients treated (78/106 [74.3%] and 66/100 [66.0%], HFDS and FBCD, respectively; P = .223), and the average BMI was 33 kg/m² for both treatment groups. Most patients had a single wound (104/106 [98.1%] and 100/100 [100%], HFDS and FBCD, respectively; P = .498). Patients treated with HFDS were significantly younger (mean age 60.2 vs. 65.2 years, HFDS and FBCD, respectively; P = .005) with smaller wound sizes (mean area 4 ± 3.6 cm² vs. 5.8 ± 4.6 cm², HFDS and FBCD, respectively; P = .014) (see Table 2). 

Wound location was also significantly different between treatment groups. Comparing HFDS to FBCD, the anatomical locations treated were foot (69 [63.9%] vs. 59 [59%], respectively); heel (20 [18.5%] vs. 29 [29.0%]) and toes (14 [13%] vs. 3 [3%]), respectively); metatarsal heads (4 [3.7%] vs. 8 [8/0%], respectively); and transmetatarsal amputation (1 [0.9%]) vs. 1 [1%]), respectively). The distribution of these 5 anatomical locations between the HFDS and FBCD treatment groups was statistically significant (P = .018) (see Table 2). These data may be interpreted to mean HDFS and FBCD were used to treat DFUs at anatomical locations that were significantly different in this real-world study; thus, meaningful clinical conclusions regarding the anatomical locations treated cannot be drawn. 

Differences in mean wound duration between HFDS to FBCD (8.8 ± 11.7 months versus 12.8 ± 48.3 months, respectively [P = .448]) and mean wound depth in wounds treated using HFDS and FBCD (3.7 mm ± 3.5 mm versus 3.8 mm ± 4.0 mm, respectively [P = .892]) were not statistically significant.

The average number of treatment applications received by patients in the HFDS group (4.5 ± 2.6) was significantly higher than FBCD-treated patients (2.4 ± 1.3; P <.0001)  (see Table 3). For patients receiving multiple applications, the median interval between applications was significantly longer in the FBCD group (9 versus 17 days, respectively; P <.0001). The difference between HFDS versus FBCD patients receiving hyperbaric oxygen (34/108 [31.5%] vs. 41 of 100 [41%]; P = .193) or negative pressure wound therapy (22/108 [20.4%] vs. 24/100 [24%]; P = 0.617) before initial HFDS or FBCD treatment was not significant.

Wound closure. A KM analysis (an unadjusted time-to-event analysis) showed the estimated proportion of wound closure for HFDS compared with FBCD was significantly improved by weeks 12 (41% vs. 21%; P = .03; log rank, 2-tailed test) and 24 (64% vs. 43%; P = .03; log rank, 2-tailed test). KM analysis of median times to healing were 14.6 weeks versus 25 weeks for HFDS and FBCD, respectively (P = .03, log rank, 2-tailed test). A Cox analysis that adjusted for ulcer area, duration, depth, location, and patient age at first treatment showed the estimated proportion of wound closure for HFDS compared with FBCD was significantly improved by weeks 12 (43% vs. 27%; P = .03, Wald Test) and 24 (66% vs. 46%; P = .03, Wald Test). The Figure shows the proportion (%) of ulcers healed in the HFDS and FBCD groups as a function of time (weeks). The 2 curves (HFDS and FBCD) demonstrate that significantly greater proportions of wounds closed (P = .03; Wald Test) in the HFDS group compared to the FBCD group from study week 1 to study week 24. Table 4 shows that the proportions (%) of DFUs healed at weeks 12 and 24 were significantly in favor of HFDS when tested for superiority versus FBCD (Wald Test statistic). HFDS treatment also significantly increased the probability of wound healing compared to FBCD treatment in the Cox proportional hazards analysis after adjusting for treatment, baseline wound area, baseline wound duration, baseline wound depth, wound location, and patient age at first treatment (HR = 1.77; 95% CI: 1.06-2.97; P = .03).

To the authors’ knowledge, this is the first comparative effectiveness study to evaluate HFDS and FBCD for the treatment of DFUs. The use of HFDS was found to heal significantly more DFUs and in less time compared with FBCD. Further, HFDS increased the probability of healing by 77% compared with FBCD throughout all timepoints in the study. The 77% greater chance of healing with HFDS was true from study day 0 (the first day of treatment) to the end of the study according to Cox proportional hazards regression methodology. Cox analysis compared the entire HFDS and FBCD healing datasets (deriving group-to- group regression lines) and used all data collected at every timepoint in the study to calculate the HR or chance of healing in the HFDS group divided by the chance of healing in the FBCD group. The HR >1.0 showed HFDS had a greater probability of healing compared to FBCD (HR = 1.77; 95% CI: 1.06-2.97; P = .03; Wald Test).

Comparative effectiveness research (CER) studies, especially prospective studies, are important to inform decisions about clinical care in real-world settings and differ from traditional efficacy trials. Efficacy trials are typically RCTs conducted to prove that a product works. They are designed to operate under a highly controlled environment to optimize circumstances and the chances of showing a difference between the study drug and (usually) a control or placebo.¹⁷ As such, inclusion and exclusion criteria are developed to select for a highly defined, homogenous population in order to maximize the potential response to treatment. Products that demonstrate efficacy in RCTs may perform differently in routine clinical practice where variations in treatment applications, patient adherence, and other important factors can substantially impact the net benefits of a chosen therapy.^18,19 In contrast, CER studies are designed to evaluate the real-world applicability of a product and a comparator that reflect a much more generalizable and diverse range of patients. When results are consistent between RCTs and CER studies, especially prospective CER studies, the evidence generally is considered strong.^16,19 

The current retrospective study results were consistent with the results from a previously published RCT using HFDS in DFUs.¹⁴ In the RCT, Marston et al¹⁴ reported 30% of ulcers treated with HFDS plus SC healed at the end of 12 weeks. In the current analysis, 43% of ulcers in the HFDS group healed at 12 weeks. In contrast, the effectiveness results for FBCD were somewhat different from the prospective (nonrandomized) clinical study in which Kavros et al¹² found 76% of DFUs healed by 12 weeks in patients treated with FBCD plus SC therapy. This is much higher than results reported in the current analysis, which found a healing rate of 27% at 12 weeks with FBCD.

In the current study, HFDS was found to be more effective and wounds healed faster than when using FBCD. In this study, Cox forward selection modeling showed that in the final model, age and duration, when handled as continuous variables, did not achieve the level of alpha (P <.05) to be considered as statistically significant risk factors for nonhealing. Although area (also handled as a continuous variable) was determined to be a significant predictor of nonhealing, no treatment by area (ie, treatment by factor) interaction was noted, meaning FBCD healed patients regardless of ulcer size. This was also true for the HFDS-treated ulcers. The resulting adjusted analysis (Cox) showed improved FBCD healing results (frequency of and time to healing) when compared to unadjusted results because the areas of the FBCD-treated ulcers were larger than the areas of the HFDS-treated ulcers (ulcer size being a significant negative risk factor for healing). The mean values and standard deviations that were large must be taken into consideration when interpreting adjusted data. The final result of the adjusted analysis shows the FBCD healing results in their most favorable light. It should be noted that the adjusted analysis was considered as the primary analysis in this study because the results for healing were believed to be the most clinically meaningful. 

HFDS is a bioengineered dermal substitute containing living human fibroblasts, whereas FBCD contains no living cells. Fibroblasts play a critically important role in the wound healing process; they are present from the late inflammatory phase through full epithelialization and remodeling.^20-23 However,  wound healing is impaired in DFUs. An in vitro study of biopsies from DFUs >8 weeks evaluated function of T cells, B cells, plasma cells, granulocytes, and macrophages, as well as fibroblast-derived extracellular matrix molecules, fibronectin, chondroitin sulfate, and tenascin. In chronic DFUs, the CD4/CD8 ratio was significantly lower, a significantly higher number of macrophages were present, and the fibroblasts of patients with diabetes may be phenotypically altered and impaired.²¹ An in vitro study of wound biopsies taken from chronic DFU patients showed fibroblasts demonstrated a decreased proliferative response to growth factors.²⁴ 

The current study is among a series of retrospective analyses^25,26 utilizing a particular EMR database to examine the comparative effectiveness of skin substitutes. A CER study²⁵ compared the effectiveness of BLCC with a dehydrated human amniotic allograft (dHACM; Epifix; MiMedx Group Inc, Marietta, GA). Similar to HFDS, BLCC is approved as a wound treatment. It is comprised of living human neonatal keratinocytes and fibroblasts in an ECM. dHACM is a collagenous covering with no living cells and is derived from donated human placenta following a planned Caesarian section. The analysis found the skin substitute containing living human cells was more effective in healing DFUs than the nonviable comparator. At 12 weeks, the frequency of wound closure with BLCC was 48% versus 28% with dHACM. At 24 weeks, closure was 72% versus 47%, respectively. In addition, BLCC treatment significantly improved the median time to DFU wound closure by 49% (13.3 weeks vs. 26 weeks). Interestingly, these results are similar to those reported in the current analysis with the living cellular product HFDS. Health economic outcomes research involving similar product comparisons was specific to the treatment of venous leg ulcers.²⁶

Although the EMR database in this study did not capture costs related to wound care and outcomes, the significant differences in incidence and time to healing in this study suggest potential cost savings with HFDS. DFUs lead to substantial costs and resource use related to care, including home health, prescription drugs, physician office visits, emergency department visits, and hospitalizations. Compared with non-DFU controls, the average annual incremental cost of treating a patient with DFU is approximately $14 000 USD.⁶ The potential cost savings may be even greater if compared against SC therapy alone. In a recent economic outcomes analysis²⁷ that evaluated Medicare administrative claims data, patients with DFUs who received HFDS had a 22% reduction in lower-limb amputations, 25% fewer emergency department visits, and 42% fewer days hospitalized when compared with matched conventional care counterparts. Consequently, this translated to a nearly $7000 USD lower per-patient average health care costs during the 18-month follow-up. Although patients treated with HFDS incurred greater costs of direct treatment and greater intensity of physician office services, these costs were offset by reductions in lower-limb amputations and other resource use, especially inpatient services. In a post-hoc analysis²⁸ of the pivotal trial adverse event data, the incidence of ulcer-related amputation or bone resection was significantly lower in patients who received HFDS versus conventional care (5.5% vs. 12.6%, respectively; P = .031).

The limitations of this study include those inherent to retrospective data collection and analysis. The Net Health database was not designed specifically for research purposes, and as such, data may be missing or inaccurate. The database provides consistent and reliably completed information as it pertains to wound characteristics and measurements, making this database ideal for assessing healing outcomes. However, adequate completion of patient-level demographic and baseline information such as medical history, prior surgeries, or concurrent medications varied across centers, making analyses of certain subgroups difficult. Moreover, products were used differently (number and frequency of applications) and specifics regarding the type of offloading, debridement, or use of other SC therapies were not reliably captured. Safety-related outcomes or adverse events were captured by spontaneous adverse event reporting and not by active data collection. Lastly, given the lack of randomization, a possibility of bias exists with regard to patient selection for HFDS or FBCD. 

This retrospective comparative effectiveness study showed that the proportion of patients whose DFU wounds were treated with HFDS was significantly higher and that their time until healing was lower than patients whose wounds were treated with the nonviable collagen matrix FBCD. The HFDS treatment outcomes were similar to those reported in a previously published RCT of HFDS in the treatment of DFUs. Additional efficacy and cost-effectiveness studies, including research to examine pertinent patient outcomes such as mobility, pain, quality of life, and recurrence, are warranted.

Dr. Sabolinski serves as Chief Medical Officer and managing member of Sabolinski LLC (Franklin, MA), and as a medical consultant to Organogenesis Inc (Canton, MA). Mr. Parsons and Ms. Skornicki are former employees of Organogenesis Inc. This study was funded by Organogenesis Inc.  

Dr. Fitzgerald is a Clinical Assistant Professor of Surgery, University of South Carolina School of Medicine, Greenville, SC. Dr. Sabolinski is Chief Medical Officer and managing member, Sabolinski LLC, Franklin, MA. Ms. Skornicki is a senior research scientist, Precision Health Economics, New York, NY. Mr. Parsons is a medical consultant, Parsons Medical Communications, Boston, MA, formerly of Organogenesis Inc, Canton, MA.

Please address correspondence to: Michael L. Sabolinski, MD, Sabolinski, LLC, 55 Jefferson Road, Franklin, MA 02038; email: sabolinski@gmail.com.