Cost-effectiveness Analysis of Silver Delivery Approaches in the Management of Partial-thickness Burns

Introduction. Burn injury is a common type of traumatic injury that causes considerable morbidity and mortality, resulting in about 30 000 admissions annually in specialist burn centers and costing around $1 billion per year in the United States. One percent silver sulfadiazine has been utilized widely in the management of burns and newer silver dressings are on the market, including nanocrystalline silver dressings, silver-impregnated hydrofiber dressings, and silver-impregnated foam dressings. Objective. This study sought to determine the cost effectiveness of the newer silver dressings using clinical data from an indirect treatment comparison using silver sulfadiazine as the baseline. Materials and Methods. A decision analytic model was developed from a US payer’s perspective for burn patients with a total body surface area of < 20%. Outcomes were length of stay, infections and incidence of surgical procedures, quality adjusted life years (QALYs), and cost. Results. The meta-analysis reported a statistically significant reduction in length of hospital stay and clinically important reductions in infections and incidence of surgical procedures in favor of the silver barrier dressing compared with other silver dressings. The estimated QALYs were 0.970 versus 0.969 versus 0.969 and mean cost per patient was $15 892, $23 799, and $24 269 for the nanocrystalline silver dressing, silver-impregnated hydrofiber dressing, and silver-impregnated foam dressing, respectively. The analysis showed the nanocrystalline silver dressing to be a dominant strategy (less costly with better outcomes). These findings were robust to a range of sensitivity analyses. Conclusions. According to data from an indirect treatment comparison, this analysis suggests that nanocrystalline silver dressing is the most cost-effective silver delivery system. Prospective head-to-head research on the costs and outcomes of these silver delivery systems in this patient population is necessary to validate the results of this economic evaluation.

Burn injury is a common type of traumatic injury that causes considerable morbidity and mortality. Infection continues to be the primary source of morbidity and mortality in patients with burns. The risk of wound infection is related to the extent of the injury, including the total body surface area (TBSA) affected and the depth of the burn wound.^1,2 Topical antimicrobial therapy remains the primary focus of wound care. This practice attempts to ensure controlling microbial colonization and avoiding/reducing burn wound infections while maintaining an environment in which tissues can regenerate at their optimum rate.³ Silver-containing products remain one of the most frequently applied topical antimicrobials used as a first-line therapy in burn wound treatment. 

For almost 50 years, positively charged silver ions delivered from silver sulfadiazine (SSD) has been the standard treatment for partial-thickness burns.^1,2 However, SSD has well-documented challenges that are largely practical, including short-acting effects and frequent reapplication needs.⁴ Newer, improved silver delivery approaches, designed to overcome some of these problems, have become available over the past few decades, including nanocrystalline silver, silver-impregnated hydrofiber, and silver-impregnated foam dressings. These dressings have been designed to provide a more sustained availability of silver over extended time periods, resulting in less frequent dressing changes.⁴ These silver delivery methods are achieved through the use of different substrates and types of silver incorporated into the overall architectural structure of the dressing. There is a lack of direct comparative studies of newer silver dressings to illustrate the superiority of any particular dressing. According to the European Burns Association’s clinical practice guidelines⁵ for burn care, the choice of wound care dressing should be based on the cause, size, depth, and location of the burn; amount of exudate; and contamination level. However, they advise clinicians to “be creative because there is no clinical directive evidence to support the choice of one dressing over another.”⁵ Nonetheless, a degree of objectivity can be aligned with product choice. For example, in large burns with a high risk of infection, a more interventional approach may be taken with consideration given to utilizing higher levels of silver associated with a rapid speed of kill. In such cases, the priority of getting control of the invading bacteria dictates choice. In burns associated with less risk of infection, the priority may change to a more preventative treatment strategy utilizing lower levels of silver incorporated into dressings that manage exudate, reduce pain, and provide comfort to the patient.⁶ In the real world, the treatment pathway associated with topical silver use may incorporate the use of several approaches over the healing phase.

Burn care is undeniably expensive and arguably has one of the highest financial costs in health care, yet limited health economic research has been conducted in the burns arena.⁷ In the United States, it is estimated that there are about 30 000 admissions annually in specialist burn centers, costing around $1 billion per year.^8,9 In the United Kingdom, burn patients cost twice as much compared with other hospitalized patients, and a study in South West England estimated costs of pediatric burns 30% to 40% TBSA to be £63 157 (range, £55 354–£74 494),¹⁰ which converts to $85 262 (range, $74 728–$100 567) in the United States based on 2016 dollars using the purchasing power parity conversion factor of 1.35 (available at https://wdi.worldbank.org/table/4.16).

Health care budgets are falling, which creates a conflict as informed patients demand quality services.¹¹ In the United Kingdom, as in many developed countries, a Quality, Innovation, Productivity, and Prevention (QIPP) program was initiated with the aim of improving efficiencies within the National Health Service and cutting waste in the face of increased demand for better health care services with stagnant or falling budgets.¹² One of the ways of achieving this QIPP objective is the use of health economic evidence. Health economic analysis allows for the comparison of competing health care alternatives using an explicit methodology that takes into account the clinical and cost data simultaneously and choosing the intervention that maximizes outcomes at the least cost overall.

This study aims to determine the cost effectiveness of 4 commonly used silver delivery approaches using clinical data from an indirect treatment comparison of a nanocrystalline silver dressing (ACTICOAT; Smith & Nephew, Inc, Andover, MA), silver-impregnated hydrofiber dressing (AQUACEL AG; ConvaTec, Skillman, NJ), silver-impregnated foam dressing (MEPILEX AG; Mölnlycke Health Care, Göteborg, Sweden), and SSD for partial-thickness burn patients with TBSA < 20%.

Data for the analysis were derived from an indirect treatment comparison (ITC) and meta-analysis of randomized controlled trials (RCTs) and observational studies with a total of 1873 patients. There were 6 studies of nanocrystalline silver dressings (3 RCTs and 3 observational studies), 4 studies of silver-impregnated hydrofiber silver dressings (3 RCTs and 1 observational study), and 2 RCTs for silver-impregnated foam dressings, all compared with SSD. Results of the ITC have been published elsewhere.¹³ A decision analytic model was then used to estimate the expected cost and benefits of the different silver delivery approaches in accordance with recommended guidance for conducting economic evaluations (ie, Consolidated Health Economic Evaluation Reporting Standards).¹⁴ The analysis was conducted from the US health care payer’s perspective. The outcomes assessed were complications defined as infections, incidence of surgical procedures (defined as surgical debridement or skin grafting), quality-adjusted life years (QALYs), and length of stay (LOS). Baseline complication rates with standard care were taken from the meta-analysis (ie, from the SSD arm of the meta-analysis), and the treatment effect of the different silver delivery approaches reported in the ITC analysis¹³ were applied to the reported outcomes in patients treated with SSD. 

The economic model adopted a 6-week time horizon to capture complications following surgery to cater to patients who had surgical interventions. This modelled time horizon was dictated by reported clinical study follow-up; however, the follow-up did not allow the capture of scarring outcomes. No discounting was applied to either costs or health benefits because the time horizon of the model was less than 1 year. There was an absence of data on mortality from the included studies of silver delivery approaches, which typically considered less severe burn patients with a mean TBSA ≤ 20%; therefore, the investigators did not model the impact of interventions on mortality. The schematic representation of part of the model is shown in Figure 1 for nanocrystalline silver compared with SSD. There are similar branches for silver-impregnated hydrofiber dressings and silver-impregnated foam dressings. 

Following treatment with an antimicrobial, the investigators modelled 2 possible outcomes: healed or complication of the burn wound. A healed wound was defined as complete epithelialization within 3 weeks for uncomplicated burns. Two previous cost-effectiveness studies, one on silver-impregnated foam dressings¹⁵ and another silver-impregnated hydrofiber dressings,¹⁶ identified a healing rate of 60% to 65% for SSD and between 72% to 75% for the newer silver delivery approaches, with one study¹⁶ on nanocrystalline silver even reporting 100% healing rate at 3 weeks. However, the present model used data from the meta-analysis where a healing rate of 72% and 89% for SSD and newer silver delivery approaches, respectively, was observed. The complication node has 2 further outcomes: infection or noninfected. Infection is the most commonly reported complication in 75% of all burns that do not heal within 3 weeks.¹⁶ 

Resource use and costs

Costs were derived from standard reference costs with resource utilization valued in US currency (2017). Treatment costs of the infected state reflected a 3-week course of an orally administered, first-generation cephalosporin. Infection would result in 4.5 additional days compared with the usual LOS associated with an uninfected burn. Following the resolution of infection, the burns followed the pathway of uninfected burns (ie, they were either treated with surgery or no surgery). For complicated burns that did not require surgery, the investigators assumed an additional 14-day course of outpatient treatment with the initial silver product of choice as was reported in an earlier cost-effectiveness study by Sheckter et al.¹⁶

The costs of the interventions (nanocrystalline silver dressing, silver-impregnated hydrofiber dressing, silver-impregnated foam dressing) were obtained from the Centers for Medicare & Medicaid Services (CMS) adjusted average wholesale price. The wear time for dressings was assumed to be 3 days to allow for regular monitoring of the burn status. Each dressing change was assumed to require 30 minutes of nursing time; however, there were no discrete additional charges for dressing changes while the patient was hospitalized as these are assumed to be covered by the case payment (diagnosis-related groups [DRGs]) while the patient is in the hospital setting. Once patients were discharged, the investigators calculated the nurses’ time needed in hours and the number of dressing changes based on a 3-day wear time. In sensitivity analysis (SA), the investigators assumed the wear time was for 2 or 7 days to assess changes in expected total costs. Costs of SSD were obtained from the same source (ie, a 500-g jar of SSD covers a surface area of 500 cm² and each jar costs $37.09). In the base case model, the investigators assumed dressing changes once daily. In the SA, the investigators assumed that dressings were changed twice daily. 

The number of dressings needed was assumed to vary by TBSA. The formula used was body surface area (BSA) (m²) = ([√(height x weight]/3600) x TBSA x 10 000. 

The model used the biggest dressing first and then smaller ones last to ensure the burn was completely covered. The model used average height (cm) and weight (kg) for an adult or teenage and pediatric child using data from McDowell et al.¹⁷ The base case assumes an adult with a weight of 83 kg and height of 170 cm, teenage child of 65 kg and 167 cm, and a pediatric child of 15 kg and 90 cm. 

For inpatient care, the investigators used the Healthcare Cost and Utilization Project website (https://hcupnet.ahrq.gov/) data for 2017 (ie, LOS, additional LOS attributable to infection and surgical procedures) and the respective medical DRGs. Length of stay attributable to burns had an estimate of 8.9 days (standard error [SE], 0.402 days). The mean cost and SE for the LOS also was taken from this source as $29 174 (SE, $1808). For burns with infection, the additional bed days were 4.5 (SE, 0.098 days). The DRGs code 858 had a mean cost of $10 618 (SE, $232). For surgical procedures, the additional bed days were 5.8 (SE, 0.253 days) and the DRGs code 575 with a mean cost of $12 263 (SE, $556). Physician current procedural terminology (CPT) procedure costs were taken from the CMS website. The Qualified Healthcare Professional Facility Allowable CPT Code 15100 (90 days) was used for physician procedure costs/surgical, which is $870.85. All other drugs and medications, including analgesia, were assumed to be the same between the interventions.

Quality-adjusted life year calculation

There are no specific measures that assess outcomes following burns, hence generic quality of life measures are used in studies such as the Short Form 36. Furthermore, there is no evidence that using one silver dressing over another results in long-term functional difference. Therefore, the investigators assumed equal utility weights for all silver dressings for the different health states. The QALY for each health state was calculated by multiplying the health state utility (ie, infection, surgery, and healed) by the model lifespan using the roll-back method. The utility in the healed state was assumed to be 1.0 for all treatments (equivalent to perfect health) and that of infections and surgery were taken from the literature.¹⁸ See Table 1 and continued for the data used in the model. 

Cost-effectiveness analysis

The incremental cost-effectiveness ratio (ICER) is the incremental costs of implementing one program over the other divided by the incremental health gain of adopting the next intervention:

(Cost of silver dressing A – Cost of silver dressing B)/(QALY of silver dressing A – QALY of silver dressing B)

Cost effectiveness is then determined by comparing the estimated ICER with the maximum willingness to pay (WTP) of the health care payer. In this case, the US maximum willingness to pay is usually assumed to be $50 000 per QALY threshold as commonly cited in the literature.¹⁹ If the calculated ICER is less than the WTP, then the intervention is said to be cost effective; if the ICER is greater than the WTP, then the intervention is deemed not cost effective.

Sensitivity analysis

The SA makes it possible for analysts to assess the impact of uncertainty on the results of an analysis.²⁰ The investigators used 2 commonly used types of SA: 1-way SA and probabilistic SA. A 1-way SA involves varying one input parameter at a time by assigning a high and low value when all other inputs remain constant at their baseline value and recording the results. A probabilistic SA assigns a distribution to each model parameter and then randomly draws values from the distribution.^20,21 This allows the uncertainty around multiple input parameters to be tested simultaneously and is deemed to produce more reliable results than 1-way SA.²⁰ Parameters varied in this model were costs of hospital stay, cost of dressings, and clinical outcomes using ranges obtained from the published literature.^13,15,16 

Table 2 shows mean cost and QALY gains per 1000 persons for the different interventions (nanocrystalline silver dressing, silver-impregnated hydrofiber dressing, silver-impregnated foam dressing, and SSD) while Figure 2 shows the graphical illustration of the results. Compared with all other silver delivery systems, nanocrystalline silver provided more QALYs at a lower cost. Furthermore, all newer silver delivery systems provided more QALYs at lower costs compared with SSD. The estimated QALYs were 0.970 versus 0.969 versus 0.969 and mean cost per patient was $15 892, $23 799, and $24 269 for the nanocrystalline silver dressing, silver-impregnated hydrofiber dressing, and silver-impregnated foam dressing, respectively. Cost per patient for SSD was $31 538 and estimated QALYs were 0.919. The analysis showed nanocrystalline silver to be a dominant strategy (less costly with better outcomes) compared with silver-impregnated hydrofiber dressings and silver-impregnated foam dressings, saving $7907 and $8377 per patient, respectively. 

In order to assess the robustness of the model, both 1-way and probabilistic SAs were calculated as described. The 1-way SA results remained robust, retaining the initial conclusions that nanocrystalline silver is the dominant strategy. This analysis showed hospitalization costs were a major cost driver, although the model remained cost saving when the costs were changed (Table 3). One-way results were validated by the probabilistic results, which simultaneously varied the inputs of the model at the same time. The probabilistic results showed the nanocrystalline silver dressing had 86% probability of being cost effective when compared with the second best strategy of silver-impregnated hydrofiber dressing.

The authors conducted an economic analysis using robust clinical data from an indirect treatment comparison of different silver delivery systems used in the management of patients with superficial and partial-thickness burns. The comparators chosen represented what were considered commonly used approaches for infection prevention management and offered a wide range of silver levels available for release and replenishment of this antiseptic within the barrier dressing. Faced with rising costs and falling budgets, health care providers are forced to implement efficient saving mechanisms in order to provide better quality services and improved health outcomes.¹² This has placed emphasis on decision- making tools, and chief among them is the use of cost-effectiveness evidence. Cost-effectiveness analysis allows for the efficient allocation of resources by allowing the decision makers to choose the best and most appropriate intervention among competing alternatives. 

The meta-analysis results showed a statistically significant difference for all outcomes (P < .0001) for the nanocrystalline silver dressing while showing no difference for the silver-impregnated hydrofiber dressing in infections and significant differences in surgical procedures and LOS compared with SSD, respectively. For silver-impregnated foam dressings, only LOS was significantly shorter compared with SSD. Nanocrystalline silver was associated with a statistically significant reduction in LOS, but data on infection rates and surgical procedures were less clear; in most cases, the differences between dressing types were not statistically significant. However, Monte-Carlo techniques reported¹³ that nanocrystalline silver remained the most clinically effective dressing after repeated sampling. Because burn wound infections are associated with an increased hospital LOS, the statistically significant reduction in LOS may be a consequence of the improved rate associated with reduced infections. 

The modelling results showed the health benefits measured in QALYs were estimated to be 0.970 versus 0.969 versus 0.969 versus 0.919 and mean cost per patient was estimated to be $15 892, $23 799, $24 269, and $31 538 for nanocrystalline silver dressings, silver-impregnated hydrofiber dressings, silver-impregnated foam dressings, and SSD, respectively. The analysis showed nanocrystalline silver to be a dominant or superior strategy as it resulted in better clinical outcomes at lower overall treatment costs compared with silver-impregnated hydrofiber dressings, silver-impregnated foam dressings, and SSD. The estimated savings were $7907, $8377, and $15 646 per patient compared with silver-impregnated hydrofiber dressings, silver-impregnated foam dressings, and SSD, respectively. Silver-impregnated hydrofiber dressings were the second most cost effective, and SSD was dominated by all other silver dressings. The authors conducted a number of 1-way SAs with varied clinical input parameters and costs using the upper and lower values from the 95% confidence intervals and those reported in the published literature as shown in Table 1 and continued. Probabilistic SA also was completed, and the conclusions of the model remained the same. Because the results of the model remained stable in both 1-way and probabilistic SAs, the authors are confident these results do not represent a chance finding. 

One of the major strengths of this model is the depth of the body of literature providing primary data on outcomes after burns. The authors used data from a well-conducted ITC,¹³ which used all available information from the network of evidence (both RCT and observational evidence). Observational studies were included, and while they may be associated with a greater potential for bias compared with RCTs, they provide insights into real-world situations and include diverse populations and, therefore, external validity. Anglemyer et al²² has shown that meta-analysis of well-conducted observational studies usually produce similar effects to those from meta-analyses of RCTs; thus, this should be a valid approach. Sensitivity and subgroup analyses confirmed the superiority of nanocrystalline silver when compared with other silver delivery systems in patients with superficial and partial-thickness burns. The present study is unique in that it is the first of its kind to compare different silver delivery systems in this patient population using data from a meta-analysis and indirect treatment comparison. 

The authors believe this model was conservative and the results may favor less-effective dressings, suggesting the estimated savings from this analysis could be more than the ones reported. For instance, disutility associated with adverse events was not included. In reality, if a person has a surgical procedure or an infection, this has a negative impact on their quality of life, which was not captured in the study herein. By not capturing the disutility associated with the adverse events, the authors may have underestimated the health benefits of the interventions that have a better impact on infection and surgical procedures. The cost of pain medication also was excluded in the base case analysis. Although burn pain is often described as one of the major clinical problems,²³ the authors believe the cost of pain medication is negligible, and, if anything, excluding this cost favors the less effective silver systems that had many wound-related complications. These findings are in line with other published studies^15,16 that have compared SSD with newer antimicrobials. Silverstein et al¹⁵ found that silver-impregnated foam dressings were cost saving when compared with SSD in patients with partial-thickness burns, and Sheckter et al¹⁶ also found silver-impregnated hydrofiber dressings to be cost effective when compared with SSD in the same patient population.

There are some limitations associated with this analysis. While the authors are confident these findings are largely applicable to developed economies and health care systems, they appreciate the results cannot be easily generalized in developing countries or even some developed countries. This is commonly explained by the differences in clinical practices in different health care systems as well as the availability and costs of dressings. Published studies^24,25 have indeed identified local health care costs as one of the major issues with the generalizability of economic evaluations between countries. Although the clinical evidence used strongly suggested nanocrystalline silver dressings offer better clinical outcomes (and this analysis showed it is a dominant strategy compared with competitor dressings), the authors would nonetheless like to encourage decision makers in other health care settings to investigate the cost effectiveness of silver delivery systems in their own settings to validate the present findings.

Furthermore, the quality of the evidence provided by some of these studies was low and relatively limited, which may potentially bias the results. This analysis focused on 4 commonly used silver delivery approaches and was not exhaustive, and other silver products also are available. As with any ITC, additional studies verifying the results drawn solely from direct comparisons are warranted; in this case, direct studies comparing nanocrystalline silver to the other silver delivery approaches in deep and/or widespread burns, which are more prone to infection, are needed. 

As is the case with most modelling excises, the authors did not model all possible clinical scenarios or outcomes. For instance, the investigators did not model long-term outcomes of scarring since the present study only considered costs involved in treating complications 6 weeks following the burn wound, as in line with the short-term follow-up in the studies that were included in the meta-analysis.¹³ Studies^26,27 have shown burn wounds that take a long time to heal usually result in abnormal scarring and the scarring may cause functional and cosmetic problems, leading to impaired psychosocial wellbeing of the patient. However, the present study showed nanocrystalline silver resulted in better clinical outcomes, and the majority of costs are realized during the inpatient phase. The authors are confident that the majority of the resources involved in managing burn patients were captured, therefore the exclusion of scarring outcomes in the model is not expected to change the model conclusions but rather favor the less effective interventions.

This analysis found nanocrystalline silver dressings to be a cost-effective silver delivery system followed by silver-impregnated hydrofiber dressings, while SSD is the least cost effective in patients with superficial and deep partial-thickness burns. The analysis demonstrated savings of $7907, $8377, and $15 646 per patient for the nanocrystalline silver dressing compared with silver-impregnated hydrofiber dressings, silver-impregnated foam dressings, and SSD, respectively. These results were robust in SA. This conclusion supports the clinical evidence that showed greater reductions in infection rates, LOS, and surgical procedures in favor of nanocrystalline silver dressings when compared with other silvery delivery systems included in the analysis. Prospective head-to-head research on the costs and outcomes of these silver delivery systems in this patient population is necessary to validate the results of this economic evaluation.

Affiliations: Smith & Nephew Advanced Wound Management, Hull, UK; Clinical Resolutions, Hessle, East Yorkshire, UK; and Department of Plastic Surgery, Kuopio University Hospital, Kuopio, Finland

Correspondence: Leo Nherera, Health Economics Director, Smith & Nephew Global Market Access, 101 Hessle Road, Hull, HU3 2BN, United Kingdom;
leo.nherera@smith-nephew.com

Disclosure: Mr. Nherera and Mr. Trueman are employees of Smith & Nephew. Dr. Roberts provides consultancy support to Smith and Nephew. Dr. Berg has no conflict of interest.