An Overview of Clinical and Health Economic Evidence Regarding Porcine Small Intestine Submucosa Extracellular Matrix in the Management of Chronic Wounds and Burns
Small intestine submucosa (SIS) has been extensively evaluated in preclinical models and developed into commercially produced medical technologies intended for use in several different indications. The SIS extracellular matrix cellular and/or tissue-based product is a commercially available, porcine-derived SIS dressing. The purpose of this review was to consider the role of the SIS dressing in the management of chronic wounds and burns.
Using a variety of search terms from the literature to describe the SIS dressing, the following databases were searched: PubMed, York Centre for Reviews and Dissemination database, National Health Service Economic Evaluation database, Health Technology Assessment database, and the Cochrane Library. The search identified 78 studies of which 21 met the inclusion/exclusion criteria. Of those, 14 involved chronic wounds, 3 described the management of burn wounds, and 4 were economic evaluations. The wide variety of comparative treatments and outcomes studied precluded the use of meta-analysis techniques. Study results show SIS dressings may improve outcomes in chronic wounds and cost less than several alternative biological wound treatments. Studies to examine their efficacy in burn wound management are warranted.
A wound survey conducted by Vowden et al1 in 2 local health authorities in the United Kingdom found wounds of various causes in all types of health care settings from acute care facilities to long-term institutions contribute substantially to the costs of hospitalization and nursing time. Similarly, Posnett et al2 considered the cost and impact of chronic wounds on patients and health care systems in the UK and also reviewed evidence on prevalence and costs of chronic wounds in the European Union3; the authors concluded chronic wounds are a hidden but significant health care burden. In the European Union alone, 1.5 to 2.0 million individuals receive regular wound care from a health care professional at any one time.3 In addition to their economic burden, wounds also cause substantial pain and distress to patients. A systematic review4 that included 37 studies examining the impact of leg ulcers on quality of life noted patients were concerned about pain. A prospective study5 that included 10 patients living with wounds and a cross-sectional study6 among 73 patients found wounds had a negative impact on quality of life and that appropriate services should be designed to take into account patients’ needs. Furthermore, with an aging population and increasing rates of chronic conditions such as diabetes and obesity, the incidence of wounds is expected to increase. In light of these factors, there is a continual need to improve the efficiency of wound care services and to consider the role of technologies that accelerate wound resolution and, consequently, optimize patient outcomes.2 However, the desire to use promising, novel technologies needs to be counterbalanced against the need to make the best use of scarce budgets.
The majority of chronic wounds are comprised of venous leg ulcers (VLUs), pressure ulcers (PUs), and diabetic foot ulcers (DFUs). VLUs account for 40% to 70% of chronic lower extremity wounds.6 A review of the evidence and costs of diabetes ulceration7 noted DFUs are a common complication in diabetes and the largest contributor of morbidity in diabetic neuropathy. PUs are a frequent and predominantly age-related occurrence for bedridden patients in hospitals and institutions; severe ulcers (those that extend beyond the skin into muscle, tendon, and bone) pose a particularly high risk of infection and mortality.2 EUCOMED8 recently underscored the burden of wounds by reiterating that between 25% and 50% of acute hospital beds are occupied by patients with either acute or chronic wounds.3 A prospective observational study in Spain9 found wounds are a large contributor to the incidence of nosocomial infections and other complications related to hospitalization among hospitalized elderly patients.
Burn injuries also pose a significant challenge to wound care providers. Extensive and/or deep burns have been shown in a meta-analysis10 of observational and randomized controlled trials to be more difficult to manage, often requiring lengthy hospitalization and complex treatments; these complex burns also are associated with a significant risk of complication that can result in a protracted healing process. According to the Expert Working Group International Best Practice Guidelines on management of noncomplex burns,11 a decline in the severity and incidence of burn injuries in Europe during the last 2 decades is attributed to enhanced public awareness and prevention strategies that facilitated management of many burns outside of specialist burn units. However, a cross-sectional cohort study12 of burn patients presenting for formal treatment at 2 UK city hospitals over a 10-year period identified a relatively high proportion of burn victims (up to 11%) are admitted to specialist burn units. In addition, the study revealed that over this same time frame, there was a total incidence of 4577 cases of second-degree and third-degree burn presentations and improvements in predicted mortality. A retrospective review13 of patients with thermal injuries admitted to a single center in a German hospital considered treatment of burns in 2 different decades (1991–2000 [911 patients] and 2001-2010 [695 patients]); it concluded the severity of burns has declined, probably due to the effectiveness of prevention campaigns.
According to in vivo, in vitro, and clinical studies,14,15 porcine small intestine submucosa (SIS) extracellular matrix contains critical components considered key in supporting granulation and epithelialization in dermal wounds and providing a scaffold for tissue repair such as collagen, proteoglycans, and growth factors. SIS is commercially available in biological dressings designed to mimic the human cutaneous natural extracellular matrix and initially received regulatory clearance in August 1997; it is currently available for sale in the United States, Canada, Mexico, Europe, and Australia.16,17 SIS is indicated for the management of acute and chronic and partial-thickness and full-thickness wounds; multiple variants are available, comprising 1, 2, and 3 layers for various indications. The product is supplied in a freeze-dried, sterile form, has a shelf life of 24 months, and is currently available in 4 sizes ranging from 10.5 cm2 to 140 cm2.
Since the first SIS dressings became commercially available, a growing body of evidence has been established on their clinical value in the treatment of chronic wounds; this includes a systematic review18 that examined dressings, including growth factors, used in VLUs; a nonsystematic review19 that assessed a variety of SIS extracellular matrix technology in hard-to-heal wounds; and a Health Technology Assessment (HTA) report20 that assessed all skin substitutes used in chronic wounds. These studies concluded that in patients with chronic wounds for whom standard treatment has been unsuccessful, the use of adjunctive therapies, such as SIS and other growth factors, may improve outcomes in the long term.
More recently, clinical evidence from observational studies and case series21-23 has begun to emerge on the applicability of SIS dressings to burns. Similar in all other ways, SIS specifically for burns is produced as 2 layers to maximize infection control and minimize fluid loss, potential complications specific to burns.
No reviews have been published of either the clinical and economic evidence showing SIS can maximize infection control and minimize fluid loss or on potential complications specific to burns that have been treated with SIS dressings. Given the scarcity of health care resources, it is important that clinical outcomes are considered along with evidence on the economic value of new technologies. Thus, the purpose of this nonsystematic review was to consider the role of an advanced cellular and/or tissue-based product (CTP) — specifically, porcine SIS (OASIS™ Extracellular Matrix; HealthPoint, Ltd, Fort Worth, TX) — in the management of chronic wounds and burns.
Although individual studies have been reported, no concerted attempt has been made to collate all the published clinical and cost-effectiveness evidence on porcine SIS in the management of wounds.
This review is based on a nonsystematic, top-level keyword search in PubMed, University of York Centre for Reviews and Dissemination (CRD) databases (ie, National Health Service Economic Evaluation Database and HTA) and the Cochrane Library up to July 2016; an update search was run in April 2017. The search was not limited by date. Search terms were determined by index: the search terms used in PubMed were OASIS® WOUND matrix or OASIS® WOUND healing, porcine small intestine submucosa (SIS), and extracellular matrix; OASIS was used for the CRD database; and OASIS® wound matrix was used for the Cochrane Library. In addition, the reference lists of identified systematic reviews or published HTA reports were hand-searched for references. All studies reporting clinical and cost-effectiveness evidence in chronic wounds and burns were included in the review. The intervention had to be SIS compared to standard care, which could be any of the advanced wound care dressings. Laboratory and animal studies were excluded. One author assessed the abstracts and full texts of studies identified from the search following a discussion of the inclusion criteria. Data on the population (ie, all patients with chronic wounds or burns treated with SIS) and its comparators, authors, and year of publication, outcomes such as healing, length of hospital stay, epithelialization, and costs were abstracted and are presented in Table 1.
Search results. The search identified 78 studies, 21 of which addressed SIS in wound management and were included in the nonsystematic review (see Table 1). The 21 comprised 6 randomized controlled trials (RCTs)16,17,24-27 and 8 observational studies in chronic wounds.28-35 Three (3) studies involved burns21-23 and 4 were economic evaluations36-39 that compared SIS to conventional dressings as well as newer medical devices. The observational study by Martinson and Martinson29 also reported on economic endpoints.
Clinical evidence on SIS dressings in chronic wounds: clinical and patient outcomes. Wound closure is typically the preferred endpoint in trials of treatments for chronic wounds20; it is measured as the rate of or time to complete wound closure, defined as full epithelialization with no drainage.16,17,25 In the studies reviewed, SIS as an adjunct to compression therapy dressings achieved statistically significant (P ≤.05) enhanced rates of healing compared with compression therapy alone (55% versus 34%, respectively),16 moist gauze (80% and 65%, respectively),17 and hyaluronic dressings (82.6% versus 46.3%, respectively)25 in VLUs and compared with becaplermin wound gel (Regranex◊; Smith & Nephew, Fort Worth, TX), 49% versus 28%, respectively,26 in DFUs. However, no difference was observed by Landsman24 for SIS dressings compared with living skin equivalent (LSE; Dermagraft®; Organogenesis, Canton, MA) in DFUs. A recent RCT27 in patients with DFUs found a statistically significant difference in wound closure between SIS and standard care as selected by the study investigator, including silver dressings, hydrogel, wet-to-dry wound dressings, or triple antibiotic dressings (54% versus 32%, P = .021). A retrospective study29 using claims data from the Centers for Medicare and Medicaid Services (CMS) Standard Analytical Files (SAF) between January 2011 and December 2014 from DFU patients (13 193 skin substitute treatment episodes) also found SIS was less expensive than its comparators and more wounds were healed at 90 days.
Other reported outcomes observed for SIS in chronic wounds relative to other active treatment modalities observed in RCTs and observational studies included fewer dressing changes in VLUs and DFUs,16,17,25 fewer re-hospitalizations in VLUs,16 and improved pain and comfort per Visual Analog Scale scores for VLUs.25 SIS has been observed to be well tolerated and easy to apply,31 facilitate grafting,28,30 and improve quality of life.31
Cost effectiveness evidence in chronic wounds. Five (5) published studies compared the cost effectiveness of SIS dressings with active treatments or best supportive care in chronic wounds: 2 involved patients with VLUs36,37 and 3 considered patients with DFUs.29,38,39 Martinson and Martinson29 conducted a retrospective database analysis using data from the CMS SAF collected between 2011 and 2014 in patients with DFUs that analyzed 13 193 skin substitute treatment episodes comparing human skin equivalent (HSE) (Apligraf®; Organogenesis) (4926, 37.3%), LSE (5530, 41.9%), SIS (2458, 18.6%), and MatriStem® Urinary Bladder Matrix (UBM; ACell Inc, Columbia, MD) (279, 2.1%). The authors found that on average the mean application was 5.5 times per episode of DFU and the percentage of wounds that healed at 90 days was 63% for SIS, 62% for UBM, and 58% each for HSE and LSE. Mean cost (standard deviation) per episode was estimated to be $1901 ± $5394 for SIS, $1435 ± $3160 for UBM, $5364 ± $6966 for HSE, and $14 424 ± $15 074 for LSE. Using SIS resulted in higher healing rates and was a less-expensive option compared to HSE and LSE and is therefore considered a dominant strategy.
Hankin et al36 considered the number needed to treat (NNT) to achieve 1 additional treatment success (defined as wound closure) in patients with VLUs treated with SIS, HSE, or an advanced sterile wound matrix (Talymed® Marine Polymer Technologies, Inc, Danvers, MA) compared to standard care (compression therapy). Costs of treatment then were considered to determine the cost of an additional successfully treated patient. NNT point estimates of clinical efficacy were 2 for the advanced sterile wound matrix (95% CI; 2-8), 5 for SIS (CI; 3-39), and 6 for HSE (95% CI; 3-24). Incremental costs per additional successfully treated patient were $1600 for the advanced sterile wound matrix, $3150 for SIS, and $29 952 for HSE. On this basis, SIS dressings appear to offer a more cost-effective solution than other advanced biologic dressings.
Carter et al37 developed a Markov model to estimate the cost effectiveness of 3 topically applied CTPs used as adjunct therapies to best supportive care in the management of VLUs. CTPs evaluated in the study included SIS dressings, HSE, and LSE over the course of 1 year. The outcomes of interest were the number of ulcer-free weeks and expected costs of therapies from a payer’s perspective. Results demonstrated SIS dressings were the most cost-effective CTP when used in the management of VLUs as an adjunct to standard care. When compared to best supportive care, the estimated incremental cost effectiveness ratio of SIS was $86/ulcer-free day.
Guest et al38 estimated the cost effectiveness from a Medicare perspective of using trilayer porcine SIS as an adjunct to standard care compared with standard care alone in managing DFUs in the US using a 6-state Markov model utilizing 2016 prices. The model costs were calculated over a 12-month period; clinical data were obtained from a published RCT by Cazzell et al.27 The model results showed patients treated with SIS in addition to standard care had better clinical outcomes — specifically, it was estimated that patients treated with SIS had a 42% increase in the number of ulcer-free months, a 32% increase in the probability of healing, a 3% decrease in the probability of developing complicated ulcers, and a 1% decrease in the probability of undergoing an amputation compared to those treated with standard care alone. The total health care cost per patient of using SIS over 12 months was estimated to be $13 858 compared to $13 962 standard care alone, saving the health system $105 per patient. These findings were consistent in a sensitivity analysis where cost and clinical inputs were varied.
Gilligan et al39 developed a 2-state Markov model based on a published RCT to estimate the cost effectiveness for SIS dressings relative to human fibroblast-derived dermal substitute (HFDS) on wound closure for the treatment of DFUs. A 12-week time horizon of weekly cycle length was employed. Clinical outcomes did not differ between the interventions. HFDS incurred substantially higher cumulative costs per DFU ($3889, £2524) compared to SIS dressings ($2522, £1634) (see Table 1). The authors concluded health care providers should consider SIS dressings as a cost-saving alternative to HFDS.
SIS dressings in burns: clinical and patient outcomes. A single-center observational study by Cuenca-Pardo,21 a prospective study,22 and a case series23 reported the clinical outcomes of treatment with SIS dressings, with facilitating reepithelialization as the key outcome measure. In the study by Cuenca-Pardo and Peralta-Conde,21 wounds of 14 patients undergoing tangential excisions for facial burns were covered with SIS. Mean days to complete epithelialization in both second-degree and superficial burns was 8.8 ± 2.4 (range 7–14) days. The rate of epithelialization was 20% to 40% by the third week, and small lesions healed without grafts (see Table 1).
A prospective study by Salgado et al22 of 5 patients with mid-thickness to partial-thickness burns reported that, compared to patients treated with a silver cellulose hydrofiber dressing (AgH; Aquacel® Ag; ConvaTec, Reading, Berkshire, UK) covered with sterile gauze, patients treated with SIS dressings had a higher epithelial maturation index (ie, progress of the epithelialization process and ranges between -2 and 8) (6.2 ± 0.84 versus 3.2 ± 3.28; P = .029). The study also reported that patients treated with SIS dressings had better orientation and differentiation of epithelial cells, as well as an appropriate basal lamina structure, collagen deposition, and higher transforming growth factor–β3 expression (7.4 ± 8.1 versus 2.1 ± 2.6; P = .055) than tissues treated with AgH dressings. Furthermore, SIS dressings were not integrated in healed tissues, and after 3 months of treatment significantly (P = .025) less scarring was noted than with AgH dressing.
Finally, Cinat23 reported on 2 cases of partial-thickness burns that had not healed after 14 and 33 days of standard care (Adaptic Touch™; Acelity, San Antonio, TX), Allevyn◊ (Smith & Nephew), Hypafix™ (BSN Medical, Hamburg, Germany), Coban™ (3M, St Paul, MN), and a hydrogel that then were treated with SIS dressings. The SIS-treated burns showed complete closure within 10 days for 1 case and 35 days with the other. Furthermore, closure was sustained at follow-up (4.5 and 7 months, respectively, for the 2 cases), with continued positive functional and cosmetic outcome, leading to avoidance of surgery.
Cost effectiveness in burns. No studies reported the cost effectiveness of SIS dressings in the management of burns, which reflects the low volume and quality of evidence on the use of these dressings in this indication.
Wounds and burns, especially those that are persistent and complex, present a significant burden in all health care settings. Given the scale of this burden, the efficacy and cost-effectiveness of treatment approaches must be considered.
This review assembled the published clinical experience with porcine-derived SIS dressings in chronic wounds and burns evaluated using RCT and observational studies. Compared with other standard care modalities, the available evidence indicates SIS dressings offer enhanced clinical outcomes across multiple clinical goals, including complete wound closure, when compared with a number of alternative treatment options. Three (3) RCTs16,17,25 reported statistically significant accelerated healing and wound closure in VLU wounds in favor of SIS compared to standard care and other active skin substitutes, 2 studies26,27 found significant results in favor of SIS in DFU wounds, and 1 did not show any difference on healing outcome.21
The studies also report positive outcomes for SIS dressings on other patient outcomes. For example, data on patient-centered endpoints reported in key clinical SIS dressing studies compared with other skin substitutes demonstrate SIS dressings are less painful to remove, more comfortable to wear, easier to use, and easier to store.21,26,36-38 Furthermore, cost modeling studies suggest the use of SIS as an adjunct to standard care was either cost saving (ie, resulted in fewer costs overall and better clinical outcomes) or cost effective when compared to standard of care alone in chronic wounds.29,36-38 However, a need remains for further evidence on the value of SIS relative to standard dressings and other advanced treatment modalities that are used more widely in chronic wound care practice, such as negative pressure.
Although limited, evidence on SIS dressings used in the management of partial-thickness to full-thickness burns suggests these dressings may offer a safe, effective, and comfortable option for burn patients who may be candidates for grafting but seek an alternative to surgery.23 Initial observational studies21,22 and case series23 suggest SIS dressings have the potential to improve burn wound outcomes, but these study results should be considered exploratory and studies examining the dressing’s efficacy and cost effectiveness are needed.
This review was limited and not systematic, which may have biased the results. In addition, studies identified did not permit a meta-analysis to be conducted because they included different comparators including gauze, compression therapy, becaplermin wound gel, HSE, LSE, and hyaluronic acid biomaterial.
The results of this literature review show SIS dressings may improve outcomes in chronic wounds. Although evidence is limited, the dressings also show promise in burn management. In addition, the studies reviewed showed SIS dressing costs are lower than those of several alternative biological wound treatments. The current evidence suggests SIS dressings are safe and effective. Additional efficacy studies, especially in burn wound management, are warranted.
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Potential Conflicts of Interest: Mr. Nherera and Mr. Trueman are employees of Smith & Nephew, Hull, UK, which distributes the small intestine submucosa dressing.