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A systematic review of cost-effectiveness analyses of complex wound interventions reveals optimal treatments for specific wound types

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Abstract

Background

Complex wounds present a substantial economic burden on healthcare systems, costing billions of dollars annually in North America alone. The prevalence of complex wounds is a significant patient and societal healthcare concern and cost-effective wound care management remains unclear. This article summarizes the cost-effectiveness of interventions for complex wound care through a systematic review of the evidence base.

Methods

We searched multiple databases (MEDLINE, EMBASE, Cochrane Library) for cost-effectiveness studies that examined adults treated for complex wounds. Two reviewers independently screened the literature, abstracted data from full-text articles, and assessed methodological quality using the Drummond 10-item methodological quality tool. Incremental cost-effectiveness ratios were reported, or, if not reported, calculated and converted to United States Dollars for the year 2013.

Results

Overall, 59 cost-effectiveness analyses were included; 71% (42 out of 59) of the included studies scored 8 or more points on the Drummond 10-item checklist tool. Based on these, 22 interventions were found to be more effective and less costly (i.e., dominant) compared to the study comparators: 9 for diabetic ulcers, 8 for venous ulcers, 3 for pressure ulcers, 1 for mixed venous and venous/arterial ulcers, and 1 for mixed complex wound types.

Conclusions

Our results can be used by decision-makers in maximizing the deployment of clinically effective and resource efficient wound care interventions. Our analysis also highlights specific treatments that are not cost-effective, thereby indicating areas of resource savings.

Please see related article: http://dx.doi.org/10.1186/s12916-015-0288-5

Background

Complex wounds are those that do not heal after a period of 3 months or more [1]. These types of wounds are a significant burden on the healthcare system and result in patient and caregiver stress, economic loss, and decreased quality of life. At least 1% of individuals living in high economy countries will experience a complex wound in their lifetime [2], and over 6.5 million individuals have a complex wound in the United States alone [3]. Moreover, these types of wounds have a significant economic impact. For example, $10 billion United States dollars (USD) per year in North America is spent managing complex wounds [4], and 4% of the annual National Health Service expenditure in the United Kingdom is spent on care for patients with pressure ulcers [5].

There are three main categories of complex wounds: i) wounds resulting from chronic disease (e.g., venous insufficiency, diabetes), ii) pressure ulcers, and iii) non-healing surgical wounds [6-8]. Treatment is targeted to the type of wound. Managing complex wounds resulting from disease usually involves improving the underlying disease; for example, optimizing diabetes control for patients with diabetes [9]. A clinical assessment and history of mobility and neurological disability is often necessary to treat patients with pressure ulcers [9]. Considerations for managing surgical wound infections include previous antibiotic treatment and immune response [3].

It is estimated that the global wound care market will reach over $22 billion USD annually by 2020 [10]. Due to the burgeoning costs from the management of patients requiring complex wound care, policymakers are interested in finding cost-effective treatments. However, the cost-effectiveness of all interventions available to treat complex wounds is currently unclear. As such, we sought to elucidate cost-effective treatment strategies for complex wounds through a systematic review of cost-effectiveness analyses.

Methods

Protocol

The systematic review question was posed by members of the Toronto Central Local Health Integrated Network. In collaboration with the Toronto Central Local Health Integrated Network, our research team prepared a draft protocol that was revised to incorporate feedback from systematic review methodologists, policymakers, and clinicians with expertise in wound care (Additional file 1). Our protocol also included conducting a related project comprising an overview of systematic reviews for treating complex wounds, and these results are available in a separate publication [11].

Information sources and search strategy

On October 26, 2012, an experienced librarian conducted comprehensive literature searches in the following electronic databases from inception onwards: MEDLINE, EMBASE, and the Cochrane Library. The literature search was limited to adult patients and economic studies. The Peer Review of Electronic Search Strategies (PRESS) checklist [12] was used by another expert librarian to peer review the literature search. The search was revised, as necessary, and the final MEDLINE search is presented in Additional file 2. Full literature searches for the other databases are available upon request. The reference lists of the included studies were searched to identify additional relevant studies.

Eligibility criteria

Inclusion criteria were defined using the ‘Patients, interventions, comparators, outcomes, study designs, timeframe’ (PICOST) framework [13], as follows:

Patients

Adults aged 18 years and older experiencing complex wounds. Complex wounds included those due to chronic disease (such as diabetic foot ulcers or venous leg ulcers), pressure ulcers (such as decubitus ulcers or bed sores), and non-healing surgical wounds.

Interventions

All complex wound care interventions were included, as identified from our overview of systematic reviews [11] and outlined in Additional file 3.

Comparators

All comparators were eligible for inclusion, including any of the eligible interventions in comparison with each other or versus no treatment or placebo or usual care.

Outcomes

Cost-effectiveness (i.e., both incremental cost and incremental effectiveness) was included, where effectiveness was measured by at least one of the following outcomes: quality-adjusted life-years (QALYs), wounds healed, ulcer-free/healing time, wound size reduction/improvement, or hospitalizations (number/length of stay).

Study designs

Economic evaluations were included in which the incremental cost-effectiveness ratios (ICERs) were reported or could be derived.

Timeframe

We did not limit inclusion to year of publication.

Other limitations

We limited cost-effectiveness analyses to those based on a study with a control group, and where the data were from direct comparisons (versus a review using indirect data). Both published and unpublished studies were eligible for inclusion. Although we focused inclusion on those studies written in English, we contacted the authors of potentially relevant non-English studies to obtain the English translation.

Screening process for study selection

The team pilot-tested the pre-defined eligibility criteria using a random sample of 50 included titles and abstracts. After 90% agreement was reached, each title and abstract was screened by two team members, independently, using our Synthesi.SR tool [14]. Discrepancies were resolved by discussion or the involvement of a third reviewer. The same process was followed for screening full-text articles that were identified as being potentially relevant after screening their titles and abstracts.

Data abstraction and data collection process

The team pilot-tested data abstraction forms using a random sample of five included cost-effectiveness analyses. Subsequently, two investigators independently read each article and abstracted relevant data. Differences in abstraction were resolved by discussion or the involvement of a third reviewer. Data items included study characteristics (e.g., type of economic evaluation, time horizon, treatment interventions examined, study comparators), patient characteristics (e.g., clinical population, wound type), and cost-effectiveness results (e.g., ICERs, cost per QALY, cost per wound healed). The perspective of the economic evaluation was categorized as: patient, public payer, provider, healthcare system, or society [15].

Cost-effectiveness studies can have four possible overall results, which are often represented graphically in quadrants on a cost-effectiveness plane [16]. The possibilities for the intervention versus a comparator are: 1) more effective and less costly, which we noted as ‘dominant’; 2) more effective and more costly; 3) less effective and less costly; and 4) less effective and more costly, which we noted as ‘dominated’. The first possibility is considered to be cost-effective; whereas possibility 4 is not cost-effective. Situations 2 and 3 requires judgment by the decision-maker to interpret [17], and in such cases, the decision is often dependent on the decision-maker’s willingness to pay. For interventions that were found to be more effective yet more costly (i.e., situation 2) or less effective and less costly (situation 3), ICERs were reported or derived from both the differences in cost (i.e., incremental cost) and effectiveness (i.e., incremental effectiveness) between the study’s intervention and comparator groups using the formula:

(Cost of the intervention – Cost of the comparator) ÷ (Effectiveness of the intervention – Effectiveness of the comparator)

To assess key variables influencing the cost-effectiveness results, sensitivity analyses, level of uncertainty in the cost and benefit estimates, and incremental variabilities (i.e., the variability of the incremental cost and the variability of the incremental effectiveness), were reported.

Authors of the included cost-effectiveness analyses were contacted for data verification, as necessary. Further, multiple studies reporting the same economic data were sorted into the major publication (e.g., most recent paper or largest sample size) and companion report. Our results focus on the major publications and the companion reports were used to provide supplementary material.

Methodological quality appraisal

The methodological quality of the cost-effectiveness analyses was appraised using a 10-item tool developed by Drummond et al. (Additional file 4) [18]. The items on this tool include the appraisal of question definition, description of competing alternatives, effectiveness of the intervention, consideration of all relevant costs, measurement of costs, valuation of costs and consequences, cost adjustment/discounting, incremental analysis, uncertainty/sensitivity analysis, and discussion of study results. The Drummond score can range from 0 to 10. Each included cost-effectiveness analysis was appraised by two team members and conflicts were resolved by discussion or the involvement of a third reviewer.

Synthesis

Since the purpose of this systematic review was to summarize the cost-effectiveness of interventions for complex wound care, the results are reported descriptively. The costing data from all studies were converted to 2013 USD to increase the comparability of the economic results across cost-effectiveness studies. This process entailed first converting the currencies into USD using purchasing power parities for the particular year of the data [19,20], and then adjusting these for inflation to the year 2013 (rounded to the nearest dollar) using the consumer price index for medical care in the United States [21].

Results

Literature search and screening

The literature search identified 422 potentially relevant full-text articles after screening 6,200 titles and abstracts (Figure 1). There were 59 included cost-effectiveness analyses that fulfilled our eligibility criteria and were included [22-80], plus an additional three companion reports [81-83].

Figure 1
figure1

Study flow diagram.

Study and patient characteristics

The cost-effectiveness analyses evaluated interventions to treat venous ulcers (41%), diabetic ulcers (27%), and pressure ulcers (24%) (Table 1). The studies were published between 1988 and 2012. Most of the papers were conducted in the United Kingdom (29%) and United States (27%). Almost half (49%) reported private or mixed (private and public) funding sources of the studies, while one-third (34%) did not report a source of funding.

Table 1 Summary characteristics of all cost-effectiveness analyses (CEAs)

While the majority of studies based effectiveness on a (single) randomized clinical trial (75%), only a few based effectiveness on a systematic review (9%) and 15% were based on observational studies (Tables 2, 3, 4, 5 and 6). Almost half (46%) of the economic studies included a sample size of 10 to 100 patients and the rest had a sample of >100 patients. In addition, 48% were conducted in a timeframe of 12 weeks or less, while the other studies had a duration of >12 weeks follow-up. Across the 59 economic studies, 9 different units of effectiveness were used, with the most common ones being healed wound (44%) and QALY (17%). Regarding the perspective of the cost-effectiveness analysis, almost half (46%) did not report this explicitly and 29% reported using the public payer perspective.

Table 2 Characteristics of each cost-effectiveness analysis (CEA) for venous ulcers (n = 24)
Table 3 Characteristics of each cost-effectiveness analysis (CEA) for venous and venous/arterial ulcers (n = 2)
Table 4 Characteristics of each cost-effectiveness analysis (CEA) for diabetic ulcers (n = 16)
Table 5 Characteristics of each cost-effectiveness analysis (CEA) for pressure ulcers (n = 14)
Table 6 Characteristics of each cost-effectiveness analysis (CEA) for mixed wound types (n = 3)

Methodological quality appraisal

Approximately 71% (42 out of 59) of the cost-effectiveness analyses had a score of 8 or higher out of a total possible score of 10 (Additional file 5, Figure 2). Using the Drummond 10-item tool [18], the key methodological shortcoming across the cost-effectiveness analyses was that only 51% (30 out of 59) had established the ‘effectiveness’ of the intervention using data from efficacy studies (i.e., systematic reviews, randomized clinical trials or observational studies) that had sufficiently large sample sizes according to the International Conference on Harmonisation guidelines for establishing efficacy [84]. Consistent methodological strengths across the cost-effectiveness analyses included a clear research question, costs and consequences measured in appropriate physical units, credibly valued costs and consequences, and discounted costs (when applicable).

Figure 2
figure2

Drummond methodological quality summary results (n = 59). Items: 1. Well-defined question. 2. Competing alternatives well described. 3. Effectiveness established. 4. All important and relevant costs and consequences identified. 5. Measurement accurately performed. 6. Valuation credibility. 7. Discounting. 8. Incremental analysis performed. 9. Allowance made for uncertainty. 10. Discussion.

Cost-effectiveness results

Due to the large number of cost-effectiveness studies included and the numerous results, we have focused on dominant results in the text. However, all of the cost-effectiveness results are presented in Tables 7, 8, 9, 10 and 11 and the sensitivity analyses, level of uncertainty, and incremental variabilities are outlined in Additional file 6.

Table 7 Cost-effectiveness analysis (CEA) outcomes for venous ulcers (n = 24)
Table 8 Cost-effectiveness analysis (CEA) outcomes for venous and venous/arterial ulcers (n = 2)
Table 9 Cost-effectiveness analysis (CEA) outcomes for diabetic ulcers (n = 16)
Table 10 Cost-effectiveness analysis (CEA) outcomes for pressure ulcers (n = 14)
Table 11 Cost-effectiveness analysis (CEA) outcomes for mixed wound types (n = 3)

Venous ulcers

Twenty-four cost-effectiveness analyses examined interventions for venous ulcers (Table 7) [22-45,83]. Sixteen studies found the interventions were dominant (i.e., more effective and less costly) [22-24,26-29,31,32,35,38,42-45], and 12 of these were studies with a Drummond score ≥8 [24,26-29,32,35,38,39,42,44,45]. These included Apligraf (Graftskin) vs. Unna’s Boot [42], Unna’s boot vs. hydrocolloid (DuoDERM) [32], micronized purified flavonoid fraction plus usual care vs. usual care alone [24], durable barrier cream vs. no skin protectant [26], pentoxifylline plus compression vs. placebo plus compression [27], Manuka honey dressing vs. usual care [29], amelogenin plus compression therapy vs. compression therapy only [45], and four-layer compression bandaging vs. usual care [35,38,44]. Although four-layer compression bandaging vs. short-stretch compression bandaging was found to be dominant in two studies [28,39]], this intervention was more effective and more costly in another economic evaluation [41].

Dominant interventions from four studies scoring <8 on the Drummond tool [22,23,31,43] included hydrocolloid dressing vs. Vaseline gauze dressing [22], hydrocolloid dressing plus compression hosiery vs. Unna’s boot [31], Thera-boot vs. Unna’s boot [23], and community leg ulcer clinic vs. usual care clinic [43].

Mixed venous and venous/arterial ulcers

Two cost-effectiveness analyses evaluated interventions for mixed venous and venous/arterial ulcers (Table 8) [46,47]. Only one study found an intervention to be dominant (and had a Drummond score ≥8); hydrocolloid (DuoDERM) dressing was dominant compared to saline gauze [47].

Diabetic ulcers

Sixteen cost-effectiveness analyses examined interventions for diabetic ulcers (Table 9) [48-63]. Twelve studies found the interventions were dominant [48-50,52-54,56,57,59,61-63], and 10 of these were studies with a Drummond score ≥8 [49,50,52-54,56,57,59,61,62]. These included becaplermin gel (containing recombinant human platelet-derived growth factor) plus good wound care (GWC) vs. GWC alone (note: the various GWC definitions used are outlined in Table 9) [57,62], cadexomer iodine ointment vs. usual care [49], filgrastim vs. placebo [50], intensified treatment vs. usual care [52], staged management diabetes foot program vs. usual care [53], ertapenem vs. piperacillin/tazobactam [54], ampicillin/sulbactam vs. imipenem/cilastatin [56], Apligraf (skin substitute) plus GWC vs. GWC alone [59], and promogran dressing plus GWC vs. GWC alone [61]. Hyperbaric oxygen therapy plus usual care vs. usual care alone was found to be dominant in one study [63], yet was more effective and more costly in another economic evaluation [51].

Dominant interventions from studies scoring <8 on the Drummond tool included hyperbaric oxygen therapy vs. control [48], and hyperbaric oxygen therapy plus standard care vs. standard care alone [63].

Pressure ulcers

Fourteen cost-effectiveness analyses evaluated pressure ulcer interventions (Table 10) [64-77]. Ten studies found the interventions were dominant [64,67,69,71-77], and four of these were studies with a Drummond score ≥8 [69,71,76,77]. These included moisture vapor permeable dressing vs. gauze [for grade II pressure ulcers] [77], advanced dressings vs. simple dressings [69], and hydrocolloid (DuoDERM) vs. gauze [76]. Collagenase-containing ointment (Novuxol) vs. hydrocolloid (DuoDERM) dressing was found to be dominant in one study [71], while collagen (Medifil) vs. hydrocolloid (DuoDERM) was more effective and more costly in another cost-effectiveness analysis [70].

The following interventions were dominant in six studies with a Drummond score <8: constant force technology mattress vs. low-air-loss mattress [64], silver mesh dressing vs. silver sulfadiazine cream [67], balsam Peru plus hydrogenated castor oil plus trypsin ointment vs. balsam Peru plus hydrogenated castor oil plus trypsin ointment plus other treatment (unspecified) for stage 1 and 2 wounds [72], balsam Peru plus hydrogenated castor oil plus trypsin ointment plus other treatment (unspecified) vs. other treatment (unspecified) for stage 1 wounds [72], balsam Peru plus hydrogenated castor oil plus trypsin ointment vs. other treatment (unspecified) for stage 2 wounds [72], polyurethane foam dressing vs. saline gauze [73], sequential granulocyte-macrophage/colony-stimulating factor and basic fibroblast growth factor vs. basic fibroblast growth factor alone [74], sequential granulocyte-macrophage/colony-stimulating factor and basic fibroblast growth factor vs. granulocyte-macrophage/colony-stimulating factor alone [74], and new hospital incentive system vs. non-introduced control [75].

Mixed wound types

Three cost-effectiveness analyses evaluated mixed complex wound types (Table 11) [78-80]. One study with a Drummond score ≥8 found that a multidisciplinary wound care team was dominant compared to usual care [80].

Discussion

We conducted a comprehensive systematic review to summarize the cost-effectiveness of interventions for complex wound care including data from 59 cost-effectiveness analyses. These economic studies examined numerous interventions and comparators and used different outcomes to assess effectiveness. In a few situations, the intervention considered in one cost-effectiveness analysis comprised the comparator in another cost-effectiveness analysis. Therefore, cost-effectiveness results are presented as comparisons of one treatment option relative to another.

Based on evidence from 42 cost-effectiveness studies with a Drummond score ≥8, 22 intervention comparisons were dominant (Additional file 7). For venous ulcers, these were four-layer compression bandaging vs. usual care, skin replacement vs. Unna’s Boot, Unna’s boot vs. hydrocolloid, micronized purified flavonoid fraction plus usual care vs. usual care, durable barrier cream vs. no skin protectant, pentoxifylline plus compression vs. placebo plus compression, Manuka honey dressing vs. usual care, and amelogenin plus compression therapy vs. compression therapy only. For mixed venous and venous/arterial ulcers, only hydrocolloid dressing vs. saline gauze was dominant according to high quality cost-effectiveness analyses. For diabetic ulcers, cadexomer iodine ointment vs. usual care, filgrastim vs. placebo, intensified treatment vs. usual care, staged management diabetes foot program vs. usual care, ertapenem vs. piperacillin/tazobactam, ampicillin/sulbactam vs. imipenem/cilastatin, skin replacement plus GWC vs. GWC alone, promogran dressing plus GWC vs. GWC alone, and becaplermin gel (containing recombinant human platelet-derived growth factor) plus GWC vs. GWC alone were dominant. For pressure ulcers, moisture vapor permeable dressing vs. gauze, advanced dressings vs. simple dressings, and hydrocolloid vs. gauze were dominant. Finally, for mixed wound types, multidisciplinary wound care team was dominant vs. usual care.

Our results highlight a need for a future network meta-analysis given the numerous interventions and comparators available. Network meta-analysis is a statistical technique that can be used to combine direct evidence of effectiveness from head-to-head studies and indirect evidence of the relative benefits of interventions versus a common comparator (usually placebo). This powerful statistical approach can also be used to select the best treatment option available from a ranking of all treatments. An attractive property of network meta-analysis is that it allows researchers and health economists the opportunity to use the ranking analysis to generate a de novo cost-effectiveness analysis more efficiently. Another potential future study is to conduct a systematic review of clinical practice guidelines on complex wounds, and compare the interventions recommended in these with those found to be cost-effective in our review.

The major methodological quality limitation found in the included cost-effectiveness analyses was that the majority did not adequately establish the effectiveness of the wound care intervention using data from systematic reviews, randomized clinical trials, or observational studies that had sufficiently large sample sizes. Moreover, many of the included economic studies did not report on uncertainty of the cost-effectiveness estimates, incremental variabilities, or sensitivity analyses, thereby further limiting the utility of those results. Further, many of the cost-effectiveness analyses did not assess long-term cost-effectiveness, and the choice of timeframe for an economic evaluation might significantly affect the cost-effectiveness results. Given the chronic nature of many types of wounds, economic modeling of a longer time horizon would provide a clearer picture in many circumstances. As an example, an intervention might be more effective yet more costly in the first 2 months of usage but it might be cost saving over a 1 year or longer timeframe due to overall fewer additional interventions required. Furthermore, most of the cost-effectiveness studies did not include information on patient-reported quality of life, which is a major limitation of this literature.

The majority of the included economic studies were from European countries and 16 were from the United States. When trying to apply the cost-effectiveness results to a country-specific context, several factors need to be assessed such as the perspective of the economic evaluation (e.g., public payer, healthcare provider), the type of healthcare system (e.g., publicly-funded healthcare), the local practice of medicine, and local costs.

There are a few limitations related to our systematic review process worth noting. Due to resource constraints, we only included studies written in English. However, we contacted authors of non-English studies to obtain the English translations. In addition, although we contacted authors to share their unpublished data, only published literature was identified for inclusion. Finally, due to the numerous number of cost-effectiveness analyses included, we focused reporting on those with dominant results and a score ≥8 on the Drummond tool in the main text. We note that this is an arbitrary cut-off, and there is not an agreed upon method to provide a summary score on this tool. However, all of our results for all studies are presented in the tables and appendices despite dominance and score on the Drummond tool.

Conclusions

We conducted a comprehensive systematic review of cost-effectiveness studies for interventions to treat adult patients with complex wounds. Our results can be used by decision-makers to assist in maximizing the deployment of clinically effective and resource efficient wound care interventions. Our analysis also highlights specific treatments that are not cost-effective, thus indicating areas for potential improvements in efficiency. A network meta-analysis and de novo cost-effectiveness analysis will likely bring additional clarity to the field, as some of the findings were conflicting.

Abbreviations

GWC:

Good wound care

ICER:

Incremental cost-effectiveness ratio

QALY:

Quality-adjusted life-year

USD:

United States dollar

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Acknowledgements

We thank the Toronto Central Local Health Integrated Network (TC LHIN) for their generous funding. ACT is funded by Canadian Institutes for Health Research/Drug Safety and Effectiveness Network (CIHR/DSEN) New Investigator Award in Knowledge Synthesis. SES is funded by a CIHR Tier 1 Research Chair in Knowledge Translation. We thank Dr. James Mahoney and Chris Shumway from the TC LHIN who provided invaluable feedback on our original report. We thank Laure Perrier for conducting the literature searches, and Afshin Vafaei, Alana Harrington, Charlotte Wilson, and John Ivory for screening articles. We also thank Inthuja Selvaratnam and Wasifa Zarin for formatting the report and references, and Judy Tran for obtaining the full-text articles.

Author information

Correspondence to Sharon E Straus.

Additional information

Competing interests

The authors declare that they have no competing interests.

Authors’ contributions

ACT conceived the study, helped obtain funding for the study, screened articles, analyzed the data, interpreted the results, and wrote the manuscript. EC coordinated the study, peer reviewed the MEDLINE search, screened articles, abstracted data, appraised quality, cleaned the data, converted the costs, analyzed the data, generated tables, interpreted the results, and helped write the manuscript. WI abstracted data, appraised quality, and edited the manuscript. PAK screened articles, abstracted data, scanned reference lists, and edited the manuscript. GS screened articles, abstracted data, appraised quality, and edited the manuscript. JA helped coordinate the review, screened articles, and edited the manuscript. JSH provided economic guidance and edited the manuscript. SES conceived and designed the study, obtained the funding, interpreted the results, and edited the manuscript. All authors read and approved the final manuscript.

Additional files

Additional file 1:

Wound care protocol. Outlines the protocol used in the systematic review.

Additional file 2:

MEDLINE search strategy. Lists MEDLINE search terms.

Additional file 3:

Classification of wound care interventions. Lists the wound care interventions in each classification.

Additional file 4:

Drummond’s 10-item checklist tool used for cost-effectiveness analyses quality appraisal. Provides the descriptions of the 10 items in Drummond’s 10-item checklist tool.

Additional file 5:

Cost-effectiveness analysis methodological quality appraisal results. Lists the quality appraisal results for the 59 included cost-effectiveness analyses.

Additional file 6:

Cost-effectiveness analyses sensitivity analysis, uncertainty of results and incremental variabilities. Outlines the sensitivity analyses, level of uncertainty, and incremental variabilities for the cost-effectiveness analyses results.

Additional file 7:

Summary of the less costly and more effective interventions for studies with a Drummond score ≥8. Lists 42 cost-effectiveness studies with a Drummond score ≥8.

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Keywords

  • Complex wound
  • Cost-benefit analysis
  • Cost-effectiveness analysis
  • Research design
  • Skin ulcer
  • Systematic review