Review: Comparing the Effectiveness of Cellular and/or Tissue-Based Products for Treating Diabetic Foot Ulcers

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Wound Care Journal Club Review

Temple University School of Podiatric Medicine Journal Review Club
Editor's note: This post is part of the Temple University School of Podiatric Medicine (TUSPM) journal review club blog series. In each blog post, a TUSPM student will review a journal article relevant to wound management and related topics and provide their evaluation of the clinical research therein.

Article title: The Comparative Effectiveness of a Human Fibroblast Dermal Substitute versus a Dehydrated Human Amnion/Chorion Membrane Allograft for the Treatment of Diabetic Foot Ulcers in a Real-world Setting
Author(s): Kraus, Ira; Sabolinski, Michael; Skornicki, Michelle; Parsons, Nathan B.
Journal name and issue: Wounds, May 2017
Reviewed by: Rafay Qureshi, Class of 2019, Temple University School of Podiatric Medicine

Introduction

One fourth of the approximately 22.3 million patients with diabetes in the United States are expected to develop a diabetic foot ulcer (DFU) at some point during their lives, and it is estimated to affect 1-8% of individuals with diabetes annually. DFUs have shown to be challenging to treat, and often result in extended hospital stays, increased risk of infection, and subsequent amputation in certain patients. A major concern regarding amputees is a 5-year mortality rate that rivals that of patients with colon cancer. In addition, DFUs contribute heavily to the financial load of payers, with an estimated annual medical cost of up to $13 billion.

Prior studies have indicated that wounds that penetrate bone, are prolonged and recurrent, and those associated with peripheral vascular disease pose a great risk for eventual amputation. Studies have shown that, even with proper care of DFUs by podiatric physicians and other clinical personnel, these wounds are slow to heal. Advanced therapies are often explored to improve outcomes.

This study compares the effectiveness of two such advanced therapies: dehydrated human amnion/chorion membrane (dHACM) and human fibroblast-derived dermal substitute (HFDS). Randomized controlled trials (RCTs) have been conducted in the past, exploring the effectiveness of HFDS, but the efficacy of HFDS versus dHACM has not been investigated extensively in their treatment of DFUs in real-world settings, which is the aim of this study.

Materials and Methods

A retrospective study comparing the effectiveness of the two therapies was conducted using a wound care-specific EHR utilized in the majority of wound care clinics across the country. Records included patient baseline demographics, wound location, wound size and duration, and specific information such as area measurements and treatments of the wound during each visit. DFUs that were treated with either their first HFDS or dHACM treatment were studied from 2014 in 72 wound care facilities. The principal observation was the frequency of wound closure by 12- and 24-weeks, as well as the median time required to close the wound. Area was calculated in cm2, and wound closure was defined as an ulcer displaying an area of under 0.25 cm2.

Participants must have received at least 1 treatment of HFDS or dHACM on a DFU. Inclusion criteria of wound size, duration, and healing course were based on a prior study conducted by Zelen et al, in which findings of dHACM were observed for DFUs. Ulcers must have been between 1 cm2 and 25 cm in size, less than 1 year in duration, and observed to have an area reduction of under 20% in the past 14 days, prior to their first treatment of HFDS or dHACM. Exclusion criteria was composed of non-compliance with follow-up visits, lack of baseline wound measurements, as well as wounds that were previously treated with alternate cellular-based or tissue-based products up to 28 days prior to, or simultaneous treatment with, HFDS or dHACM treatment.

The onset of the treatment period was noted with the first application of HFDS or dHACM. Baseline characteristics were compared using two sample t-tests for continuous variables, and Fisher’s exact tests for difference in treatment proportions. P < 0.05 was established as the statistical significance. The Cox model was used to estimate frequency of wound closure at weeks 12 and 24, median of wound closure, P value, and hazard ratio of 95% confidence interval, based on the terms for treatment, baseline wound area, baseline wound duration, baseline wound depth, and wound location.

Results

59 wounds were treated with HFDS and 63 wounds were treated with dHACM, with an average age of patient participants of ~61 years old. No statistically significant differences were noted in the baseline patient characteristics or baseline wound characteristics between the 2 groups. Women notably outnumbered men in both groups, with 46 women receiving HFDS and 48 women receiving dHACM. Only 1 wound per patient was treated. The average wound size was determined to be 4.8 cm2 for patients treated with HFDS, and 5.2 cm2 for patients treated with dHACM. Prior to treatment, the average wound duration was 4.2 months for HFDS treated patients, and 4.6 months for dHACM treated patients. HFDS was applied an average of 4.6 times, while dHACM was applied an average of 3.5 times. Patients who received multiple treatments had an average of 11.2 days between applications for the HFDS group, while the average interval of application for the dHACM group was 17 days.

Using the Cox proportional hazards analysis, it was demonstrated that patients in the HFDS group exhibited a significantly improved median time - by 38% - to DFU wound closure when compared to patients in the dHACM group. Wound closure in the HFDS group was noted to have occurred about 7.4 weeks sooner than wound closure in the dHACM group. Using the Cox regression model, by week 12, HFDS treated patients saw a wound closure of 55% versus dHACM treated patients, which saw a wound closure of 32%. By week 24, HFDS treated patients saw a wound closure of 76% versus dHACM treated patients, which saw a wound closure of 50%. Treatment with HFDS markedly increased wound closure probability by 107%, when compared to treatment with dHACM.

Discussion

While prior studies have been conducted concerning the effectiveness of HFDS in the treatment of DFUs, they were all carried out in RCTs. The use of EHRs provides a real-world setting to observe the effectiveness of DFU therapies by providing a detailed record of treatment regimens, failures, and successes, without the limitations that are inherent in RCTs. Much of the criteria used in RCTs prevents data from being replicated, or does not give a comprehensive picture of how treatments would respond in DFU patients going about their day-to-day lives. RCTs may also be prone to geographical bias, as well as the inability to provide sufficient evidence for treatment of the condition clinically.

In a prior RCT study conducted by Marston et al, the efficacy of HFDS has been observed with positive results, showing the HFDS group healing a higher percentage of ulcers compared to the control, and doing so in a shorter amount of time. Additionally, of the 8.9% of patients in the study that required amputation, only 5.5% of patients in the HFDS group required amputation - as compared to 12.6% of patients in the control group. Therefore, HFDS has been shown to deliver a positive effect in wound closure, and has warranted ongoing study.

In this study, HFDS treatment was compared against dHACM treatment from a clinical perspective. Results indicated that HFDS treatment significantly reduced the time and increased the overall probability of wound closure. When comparing the HFDS results to that of Zelen et al’s RCT study of HFDS, promising outcomes of HFDS treatment in a clinical setting were observed, as a higher percentage of ulcers healed in this study.

Based on these observations, the implementation of HFDS treatments in DFU patients have shown to be effective and encouraging in efficient wound closure in RCT, and more importantly, in clinical settings. Further studies in a larger patient population need to be conducted to support these findings, and to eventually determine if this treatment can become part of a more standard method of treating DFUs. The effectiveness of dHACM in DFU treatment also needs to be further analyzed in determining its place in wound care, as HDFS has shown to be more beneficial according to this study.

Limitations of this study include common limitations seen in retrospective studies. Retrospective EHR analysis has not been used extensively for research purposes, as standardization of this data can be difficult. Data collected and analyzed retrospectively was not continually monitored, and certain aspects of documentation may have been incomplete. Cost analysis on the use of HFDS was not studied, due to the retrospective nature of this study, as well as EHR limiting the knowledge of costs required for these treatments. However, the significant decrease in time required for wound closure suggests a reduced cost of comprehensive DFU care with the utilization of HFDS. Separate cost analysis studies should be conducted to further expand on these findings, and to yield actual data regarding any cost savings.

Disclosure: This study was funded by Organogenesis, Inc. See the original article for full disclosure statement.

About the Authors:Rafay Qureshi
Rafay Qureshi is a second year podiatric medical student at Temple University School of Podiatric Medicine (TUSPM) in Philadelphia, Pennsylvania. He graduated from the University of Houston with a Bachelor of Science degree in Biology with a minor in Human Nutrition. He is currently the Vice President of the TUSPM Journal Society and Treasurer of the Dermatology Club. In addition to general podiatric medicine, Rafay holds particular interest in the diabetic foot, reconstructive surgery, and sports medicine. He would like to use his education and training to emphasize the importance of foot and ankle care to the general public as well as volunteer his time treating patients in underserved communities.

Dr. James McGuire is the director of the Leonard S. Abrams Center for Advanced Wound Healing and an associate professor of the Department of Podiatric Medicine and Orthopedics at the Temple University School of Podiatric Medicine in Philadelphia.

The views and opinions expressed in this blog are solely those of the author, and do not represent the views of WoundSource, Kestrel Health Information, Inc., its affiliates, or subsidiary companies.

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