Search results. The search identified 78 studies, 21 of which addressed SIS in wound management and were included in the nonsystematic review (see Table 1A, 1B, 1C, 1D, 1E, and 1F). 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 1A, 1B, 1C, 1D, 1E, and 1F). 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 1A, 1B, 1C, 1D, 1E, and 1F).
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.