Long‐term quality of life and cost‐effectiveness of treatment of partial thickness burns: A randomized controlled trial comparing enzyme alginogel vs silver sulfadiazine (FLAM study)

Abstract The clinical effectiveness and scar quality of the randomized controlled trial comparing enzyme alginogel with silver sulfadiazine (SSD) for treatment of partial thickness burns were previously reported. Enzyme alginogel did not lead to faster wound healing (primary outcome) or less scar formation. In the current study, the health‐related quality of life (HRQoL), costs, and cost‐effectiveness of enzyme alginogel compared with SSD in the treatment of partial thickness burns were studied. HRQoL was evaluated using the Burn Specific Health Scale‐Brief (BSHS‐B) and the EQ‐5D‐5L questionnaire 1 week before discharge and at 3, 6, and 12 months postburn. Costs were studied from a societal perspective (health care and nonhealth‐care costs) for a follow‐up period of 1 year. A cost‐effectiveness analysis was performed using cost‐effectiveness acceptability curves and comparing differences in societal costs and Quality Adjusted Life Years (QALYs) at 1 year postburn. Forty‐one patients were analyzed in the enzyme alginogel group and 48 patients in the SSD group. None of the domains of BSHS‐B showed a statistically significant difference between the treatment groups. Also, no statistically significant difference in QALYs was found between enzyme alginogel and SSD (difference −0.03; 95% confidence interval [CI], −0.09 to 0.03; P = .30). From both the health care and the societal perspective, the difference in costs between enzyme alginogel and SSD was not statistically significant: the difference in health‐care costs was €3210 (95% CI, €‐1247 to €7667; P = .47) and in societal costs was €3377 (95% CI €‐6229 to €12 982; P = .49). The nonsignificant differences in costs and quality‐adjusted life‐years in favor of SSD resulted in a low probability (<25%) that enzyme alginogel is cost‐effective compared to SSD. In conclusion, there were no significant differences in quality of life between both treatment groups. Enzyme alginogel is unlikely to be cost‐effective compared with SSD in the treatment of partial thickness burns.

in costs between enzyme alginogel and SSD was not statistically significant: the difference in health-care costs was €3210 (95% CI, €-1247 to €7667; P = .47) and in societal costs was €3377 (95% CI €-6229 to €12 982; P = .49). The nonsignificant differences in costs and quality-adjusted life-years in favor of SSD resulted in a low probability (<25%) that enzyme alginogel is cost-effective compared to SSD. In conclusion, there were no significant differences in quality of life between both treatment groups. Enzyme alginogel is unlikely to be cost-effective compared with SSD in the treatment of partial thickness burns.

| INTRODUCTION
The optimal treatment of partial thickness burns remains an unsolved challenge in the absence of a gold standard treatment. [1][2][3] The available literature is mainly based on clinical studies of poor quality that report mostly on clinical outcomes (eg, wound healing) and incidentally on scar quality. 1,4,5 Therefore, there is a need for well-designed trials that not only evaluate clinical outcomes and scar formation but also health-related quality of life (HRQoL), costs, and cost-effectiveness to help establish optimal treatment of partial thickness burns.
Two retrospective studies showed faster wound healing when enzyme alginogel, which is a hydrated alginates polymers in a polyethyleneglycol (PEG) matrix embedded with a biologic enzyme system of glucose oxidase, lactoperoxidase and guaiacol was compared with SSD in the treatment of partial thickness burns, while no data were available with regard to scar formation, HRQoL, costs, or cost-effectiveness. 6,7 Therefore, our research group performed a randomized controlled trial (RCT) comparing enzyme alginogel with SSD in the treatment of partial thickness burns (FLAM study). 8 Enzyme alginogel was not found to be superior with regard to clinical outcomes such as wound healing time (primary outcome), pain, incidence of infection, and scar quality, although patients in the enzyme alginogel group required significantly less dressing changes compared with the SSD group. 9 Less dressing changes in the enzyme alginogel group were expected to lead to less treatment costs compared with the SSD group. In this light, HRQoL, costs, and cost-effectiveness of the treatment modalities might be decisive factors for choosing between the two treatments in clinical practice. Therefore, this study evaluated the HRQoL, costs, and cost-effectiveness of enzyme alginogel compared with SSD in the treatment of partial thickness burns.

| Study design
Patients with partial thickness burns participated in an open label, multicenter RCT comparing the clinical effectiveness, quality of life, and costs of enzyme alginogel with SSD. The detailed study protocol was published previously. 8  or if the treating physician expected the patients not to be compliant with the study protocol. The patients were randomly allocated to treatment with either Flaminal Forte (Flen Pharma, Belgium), which is an enzyme alginogel consists of 5.5% hydrated alginates and a biologic antimicrobial system (glucose oxidase, lactoperoxidase, and guaiacol) or Flamazine (Sinclair Pharmaceuticals, Surrey, United Kingdom) which consists of silver sulfadiazine (SSD) 10 mg/g in hydrophilic crème base.

| Time to wound healing and operation
In addition to previously published results on clinical effectiveness of the treatment modalities in the FLAM study, 9 of the results for time to wound healing and need for operation were analyzed in subgroups of patients with different wound depths, based on results of the Laser Doppler imager in combination with the clinical diagnosis. 10,11 From a clinical point of view, stratification of different wound depths of partial thickness wounds is important because superficial and intermediate partial thickness burns are likely to heal spontaneously in less than 3 weeks, while deep partial thickness burns often require operation. 11

| Health-related quality of life
HRQoL was evaluated using the Dutch version of the Burn Specific Health Scale-Brief (BSHS-B) and the EQ-5D-5L questionnaire 1 week before discharge and at 3, 6, and 12 months postburn. The BSHS-B is a valid and reliable self-administered questionnaire with 40 items that cover nine domains: simple abilities, heat sensitivity, hand function, treatment regimens, work, body image, affect, interpersonal relationships and sexuality. All items are scored on a scale from 0 (extreme difficulty) to 4 (no difficulty at all). 12,13 The EQ-5D-5L is a generic quality of life questionnaire, which is widely used in economic evaluations, because it enables the comparison of quality of life outcomes for all kinds of interventions and different diseases. The questionnaire comprises two components. 14 The first is a descriptive system that defines health states based on five dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension is scored with one item on five levels ranging from no problems to extreme problems. The combination of the scores for the five dimensions can be translated to utility values, ranging from 0 (health as bad as death) to 1 (perfect health), based on a so-called tariff, which is obtained by the valuation of the Dutch population for the different health states. 15 The second component is a Visual Analogue Scale (VAS), on which the burn patients rate their health state, ranging from 0 (worst imaginable health state) to 100 (perfect health). The VAS score can also be transformed to a utility value using the power transformation 1-(1-VAS/100) 1.61 . 16 Quality adjusted life years (QALYs) were used to evaluate the cost-effectiveness over a period of 12 months. QALYs combine EQ-5D-5L and EQ-VAS utilities values with duration of the follow-up period. 17 QALYs were calculated from the area-under-the-curve method of the utilities obtained from the EQ-5D during the 12 months of follow-up. 14

| Costs
Costs were studied from the societal perspective, which included both health-care costs in and outside the hospital and nonhealth-care costs (productivity loss and travel costs). Data on health-care use were recorded prospectively by the FLAM study research team as part of the case record form during admission and by means of patient questionnaires at 3, 6, and 12 months postburn. Costs were calculated by multiplying the volumes of health-care use by the corresponding unit prices. Because of the 1-year time horizon, costs were not discounted.
Costs were expressed in Euros and converted to the 2018 price level using the general Dutch consumer price index. 18

| Treatment
Costs of treatment were determined by microcosting, taking into account used materials and personnel time. To assess costs of wound care, material and personnel time (ICU and non-ICU nurse) needed for each dressing change were recorded daily for each patient. The unit price for materials was obtained from the financial department of the Red Cross Hospital, Beverwijk. Subsequently, total material costs were calculated for each patient. Personnel time needed for each dressing change was recorded in hours. Costs of personnel time per hour were based on the gross salary of the nurses, increased with a surcharge for holiday allowance and social charges. 19 Personnel, material, and equipment costs of surgery were obtained from a previous Dutch study by Hop et al. 20 Personnel costs were multiplied by time (surgical and anesthesia team) needed for each operation recorded in the current study. For each patient, information on reconstructive surgery, use of blood products, pressure clothes and silicone therapy were recorded prospectively during hospital admission and the follow-up period up to 12 months postburn. The unit price for the reconstructive surgery was derived from a previous Dutch study on this subject. 21 Unit prices of blood products, pressure clothes, and silicone therapy were derived from the financial department and supplier.

| Diagnostics and clinical consultations during hospitalization
Diagnostic procedures included bronchoscopy, swabs, laboratory tests, and radiology, which were recorded daily during admission. Unit prices of these diagnostic procedures were obtained from the Dutch manual for costing in economic evaluation and the Dutch Healthcare Authority. 19,22

| Burn center stay and outpatient burn care
Length of burn center stay in days and number of outpatient burn care visits during the follow-up period of 12 months postburn were recorded on the case record forms. Burn center stay in days included days spent in the Intensive care Unit (ICU) of the burn center, non-ICU burn center days and readmittance days. Unit costs were obtained from a previous Dutch study by Hop et al. 23 Other healthcare use (rehabilitation, nursing home, visits to general practitioners, and allied health-care professionals outside the hospital) was assessed by questionnaires during follow-up period of 12 months. Unit costs were obtained from the Dutch manual for costing in economic evaluation. 19

| Nonhealth-care costs
Nonhealth-care costs included costs of loss of economic productivity due to absence from work (by both patients and partner) and travel costs. Data on work absence were collected by questionnaires from the patients at 3, 6, and 12 months postburn. Productivity losses were valued using the friction cost method. 24

| STATISTICAL ANALYSIS
All analyses followed the intention-to-treat principle. All statistical analyses were conducted with IBM SPSS Statistics for Windows, version 22 (IBM Corp., Armonk, N.Y., USA). BSHS results were presented as median, while utility values and costs were presented as mean. Furthermore, a two-sided t-test or Mann-Whitney test was used for comparing continuous data, and a two-sided Chi-square test or Fisher's exact test for categorical data.
For the cost-effectiveness analysis, multiple imputation by chained equations was used to reduce possible bias caused by missing data. Missing utility values or cost items were imputed using a switching regression model that included age, gender, TBSA, location of the study area and randomization group. Cost and QALYs were compared using the net benefit approach. 25 Depending on the willingness to pay for a QALY, a strategy is cost-effective compared with an alternative strategy if it has a higher net benefit (willingness to pay × QALYs -costs). Cost-effectiveness acceptability curves depict the probability that a strategy is cost-effective as a function of willingness to pay, given the statistical uncertainty in costs and QALYs. The threshold of willingness to pay that is commonly accepted in the Netherlands is between €20 000 and € 80 000 per QALY, depending on disease burden. 26 The base-case cost-utility analysis compared QALYs at 1 year on the basis of the EQ-5D-5L (Dutch tariff). Sensitivity analyses were carried out using the EQ-VAS as a utility measure.

| Study population
Of the 90 included patients, 89 patients were analyzed. One patient in the enzyme alginogel group discontinued participation in the trial during the admission period. The treatment groups were comparable with regard to age, gender, percentage of TBSA of the study area, trauma mechanism and anatomical location of the study area (Table 1). Lost to follow-up were 4/41 (10%) patients in the enzyme alginogel group and 3/48 (6%) patients in the SSD group.

| Time to wound healing and operation
As represented in Table 2, the median time to wound healing and need for operation did not differ between the enzyme alginogel group and the SSD group, neither within the subgroup of patients with superficial and/or intermediate partial thickness buns nor in the subgroup of patients with deep partial thickness burns.

| Health-care costs
The mean costs of treatment per patient, including wound care, operation and scar therapy, were €4352 for the enzyme alginogel group and €3712 for the SSD group (

| Nonhealth-care costs and societal costs
The nonhealth-care costs consisted mainly of loss of economic productivity due to the absence of the patient from work, next to the absence of the partner of the patient from work and travel costs to the burn center (

| Cost-utility analysis
The combination of nonstatistically higher societal costs and less favorable QALY outcomes after treatment with enzyme alginogel compared with SSD, resulted in a low probability that enzyme alginogel is cost effective compared to SSD. The probability that enzyme alginogel is cost-effective compared with SSD was less than 25% for all values of the willingness to pay (Figure 1). The same results were obtained when EQ-VAS utilities were used.

| DISCUSSION
The FLAM study did not show any significant differences in QALYs and health care and societal costs between enzyme alginogel and SSD in the treatment of partial thickness burns over a period of 1 year.
Based on the nonsignificant differences in QALYs and costs in favor of SSD, it was concluded that enzyme alginogel is not likely to be cost-effective compared to SSD (<25% In the present study, no statistically significant or clinically rele-   9 This difference in dressing changes did not lead to significantly lower costs in the enzyme alginogel group for several reasons. First, wound colonization in the enzyme alginogel group was much more common compared with the SSD group (78% vs 33%, respectively; P < .0001), which required daily dressing changes according to our study protocol. For this reason, we think that the a priori assumed advantage of less dressing changes in the enzyme alginogel group was less prominent than expected, as reflected by similar utility scores in both treatment groups. Second, the unit price of enzyme alginogel was higher compared with SSD, which also resulted in comparable total costs of wound care in both treatment groups. Finally, wound care costs in the FLAM study contributed only to a small part of the societal costs (enzyme alginogel 6%, SSD 5.7%; P = .42).
In the current study, burn center stay was a major component of  38 This study included direct medical costs related to wound treatments and medical visits by physicians and nurses and length of hospital stay. These costs were compared to reduction in hospital days and time of recovery. MEBO was found to result in nonsignificantly lower total costs than standard care and better effectiveness. Overall, it can be concluded that there is a wide variety between studies in regard to which costs and healthcare effects are used in the economic evaluation.
To the best of our knowledge, the FLAM study is the only study that comprehensively studied the clinical effectiveness, quality of life, and cost-effectiveness of two standard treatments in the treatment of partial thickness burns for a follow-up period of 1 year. Our study had some limitations. First, the current study was not powered to detect relevant differences in quality of life or costs. Second, data on the daily dressing changes were missing in less than 10% and data on QALYs (EQ-5D-5L and EQ-VAS) were missing in 14%, 17%, and 23% at, respectively, 3, 6, and 12 months postburn. As advocated, however, multiple imputation was used to handle these missing data. 39 Third, the follow-up period of this trial was 1 year, which does not cover the long-term effects of both treatments on quality of life and costs. However, no significant differences were found in quality of life and costs between the treatment groups at 12 months postburn.
Since burn scar maturation and recovery is (nearly) completed at that point in patients with partial thickness burns, it is not expected that there are significant differences in quality of life and costs beyond 1 year postburn.
In conclusion, no significant differences were found between enzyme alginogel and SSD in regard to burn-specific and general quality of life. From a societal perspective, treatment of partial thickness burns with enzyme alginogel is unlikely to be cost-effective compared with SSD. Finally, from an economic perspective, treatment and management of partial thickness burns should focus on reducing length of hospital stay and early return to work, to achieve optimal outcome.