Cost-effectiveness analysis of the treatment with compressive therapy in the healing of venous ulcers

Objective: to analyze the cost-effectiveness and calculate the incremental cost-effectiveness ratio of multilayer compressive treatment in relation to inelastic (Unna boot and short stretch) therapy according to the current literature. Method: quantitative study about cost-effectiveness through modeling with the aid of TreeAge® software for construction of the decision tree. The anticipated assumptions were obtained by using secondary literature data to estimate the cost and effectiveness of the assumed parameters. A systematic literature review with meta-analysis was performed for this end. Results: the decision tree after Roll Back showed that the multilayer therapy dominated the alternatives in the base case, representing an intermediate cost per application, although with the highest effectiveness. The cost-effectiveness analysis graph also showed extended dominance of the Unna boot in relation to the short stretch bandage. The sensitivity analysis showed that multilayer bandage remains a more cost-effective alternative, within the threshold of willingness to pay. Conclusion: the most cost-effective alternative was multilayer bandage, considered the gold standard in the literature. The second most cost-effective alternative was the Unna boot, the most used therapy in Brazil.


Introduction
Venous Ulcer (VU) is the result of an advanced stage of chronic venous disease and is caused by venous hypertension complications. This type of injury is characterized by chronicity and can generate physical dysfunction, pain and problems for performing daily activities. The recurrence rate is uncertain and can vary from 26% to 70%, which shows the need for interdisciplinary monitoring and care until the end of life, therefore with the possibility of resulting in increased health costs (1)(2) .
Data show that approximately 75% of the leg ulcers are of venous etiology, affect nearly 1% of the world population, and are more prevalent in older adults (1,3) .
There is already international consensus that compressive therapy is the gold standard for the treatment of venous ulcers, being contraindicated in patients with severe peripheral arterial disease. Compression makes it possible to reverse venous hypertension at the level of the superficial veins in the lower limbs and, according to experts, ideal therapeutic levels should fluctuate between 35 and 45 mmHg in the ankle region and the patient should be encouraged to walk (1,(5)(6)(7) .
Among the compression methods available and recommended for use in venous ulcers are inelastic and elastic compression therapies. As an example of inelastic therapy we can mention short stretch bandages and the Unna paste bandage (Unna boot), the method most used in Brazil and in some other countries such as the United States of America (USA). Among the elastic compression methods, it is worth mentioning the multilayer bandage system, which can be found with two, three or four layers, producing a cumulative effect and providing constant compression (8) .
A Cochrane review carried out in 2012 concluded that the most effective compressive therapy method in the treatment of venous ulcers is the multilayer system when compared to other therapies such as Unna boot and short stretch bandage; however, this system has a higher unit cost than other technologies, requiring studies to evaluate the cost-effectiveness ratio (7,9) .
A number of studies show that the USA spends approximately US$ 25 billion per year on the treatment of chronic injuries of vascular etiology (10) . In Brazil, these lesions are responsible for high morbidity and mortality rates, exerting a significant impact on the costs, which are still little explored in scientific studies (1,8) .
Precisely because of their chronicity, high prevalence and need for long-term care, they are considered a worldwide public health problem. These injuries impair quality of life and productivity in the people affected by them and generate a socioeconomic impact, which needs to be considered in countries with universal health systems such as Brazil, despite the fact that they are not associated with high mortality rates (6,(11)(12) .
In the search for efficiency in the allocation of financial resources, for at least 20 years, countries with universal health systems such as the United Kingdom have sought to inform their decisions and choices based on the best scientific evidence available. Although still incipient in Brazil, Health Technology Assessments (HTAs) have been increasingly used, not only among managers, but also among health professionals, as a way to reduce uncertainties around the best available alternatives, especially in cases involving countless options and highcost technologies.
In this sense, HTA studies have become increasingly common and indispensable among decision-makers, such as cost-effectiveness studies that represent a widely used method, as they allow for comparisons between different alternatives considering their costs and effectiveness (consequences), as not always a more effective option justifies the cost of its use for the payer (13) .
In Brazil, it is necessary to discuss why the Unna boot is the type of compressive therapy most used to treat patients with ulcers, to the detriment of others such as multilayer and short stretching bandages, much more used in other countries. Are such choices being based only on the cost of the alternatives and personal preferences or is effectiveness also considered at the same time?
Thus, the structured research question is as follows: Is multilayer compression therapy more costeffective in the healing of venous ulcers than the Unna boot and short-stretch bandage inelastic compression therapies?
This study aims at analyzing the cost-effectiveness and calculate the incremental cost-effectiveness ratio (ICER) of the multilayer compressive treatment in relation to the inelastic (Unna boot and short stretch) therapy according to the current literature.

Type of study
This is a quantitative study about cost-effectiveness a cost-effectiveness study based on modeling, using the TreeAge ® software, 2021. The decision model used in this study was the decision tree with use of data from a systematic review with meta-analysis.

Scenario
The hypothetical scenario was the Wounds medical office, a place for the application of compressive therapy in health services.

Study period
The secondary data collection procedure took place between 2019 and 2021. The statistical and costeffectiveness analyses were performed in 2021.

Data collection and instruments used
The technologies evaluated were multilayer bandage, Unna boot and short-stretch bandage, all characterized as compressive therapy methods, used in the treatment of venous ulcers.
The secondary data used to estimate effectiveness in elaboration of the model were obtained from a systematic review of the "rapid review" type, part of the main author's PhD thesis (14) . It is worth mentioning that the search was In relation to the design, all 12 studies included in the meta-analysis comprised randomized clinical trials. In all these studies, it was not possible to shield the participants and professionals, considering the visual characteristics of each compressive therapy (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26) .
The primary outcome analyzed was ulcer healing and the secondary outcomes were healing time and reduction percentage. Some of the studies evaluated presented the data in different periods, and the mean was calculated. Most of the studies evaluated (n=10) compared multilayer bandage with short-stretch. Only 3 studies compared multilayer with Unna boot. Of these, 1 compared 5 compressive therapy methods. Therefore, the data were used both for the intervention (multilayer) and for the two comparators (short-stretch and Unna boot) (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26) .  previous guidance and has a 28-item checklist (28) . It is important to highlight that the study was carried out in the pre-pandemic period, in which the costs for acquiring technologies, inputs and human resources were not as pressured as in the pandemic period, which directly affected the supply chain and the economic and industrial health complex, which caused these costs to increase considerably in relation to the pre-pandemic period.

Data treatment and analysis
In the model proposed in Figure 2

Ethical aspects
The study in question does not directly involve human beings because it is carried out through secondary sources, being submitted to and approved by Plataforma Brasil with waiver of an Ethics and Research Committee through Certificate of Presentation of Ethical Appreciation (CAAE) 16947419.0.00 00.5285.

Study protocol
The following assumptions were presumed in the model: 1-The analysis perspective was the Health Operators'.

Results
The results of the model after Roll Back show that the compressive therapy using multilayer bandages  (13) .
In the proposed economic model designed to evaluate effectiveness of the treatment of venous ulcers, many parameters, which represent, for example, the injury healing probability, can assume different values, reflecting a mean among the various spectra of severity of chronic venous failure (CVF), that is, the parameter has variation in the target population and that more than two alternatives were compared in the base case.    In quadrant II, the iterations represent an increase in cost that is not accompanied by the same proportion of increased effectiveness. In quadrant III, cost and effectiveness are lower, and the cost-effective technology may also depend on willingness to pay. Finally, in quadrant IV, the iterations represent the lowest costs and highest effectiveness. The ellipse represents 95% confidence.
It is therefore easy to understand that the iterations in quadrants I and III are those that will represent the "Trade Off", in which the technology can be cost-effective depending on how much a person is willing to pay, so that such a provision is higher than the ICER. Thus, the multilayer bandage was considered as the most effective alternative. In the comparison with Unna boot there was no significant difference between these therapies (9) .
Another meta-analysis that compared multilayer with short-stretch bandages was carried out by Brazilian researchers in 2018, with inclusion of 7 articles and 1,446 participants, resulting in a RR of 1.11 [0.99-1.24], which shows the need for more clinical trials that provide consistent effectiveness data, as well as for analyses that compare the costs to the effectiveness of such technologies (29) . Important factors to be considered in the comparison between compression systems are size of the ulcer and its duration, which can slow down the healing process. In Brazil, a clinical trial that compared Unna boot to simple elastic bandages showed that the former provided better results in lesions larger than 10 cm 2 while the elastic bandages showed better results in smaller ulcers. This evidences the need for clinical trials in patients with large VUs, something very common in our country, when compared to the injuries of individuals living in First-World countries (8)(9) .
All models are subjected to uncertainties related to the anticipated assumptions. In order to minimize the possible errors arising from such uncertainties, imputed in the decision tree model, sensitivity analyses were performed in accordance with the recommendations of the Brazilian Economic Assessment Guidelines.
The probabilistic sensitivity analysis showed that, considering the willingness to pay adopted in this study, It is important to ratify that, regardless of the technology to be used, compressive therapy remains the most effective method for VU treatment, provided that it is properly indicated and implemented, with nurses as the professionals who deserve to be highlighted in the multidisciplinary team for the treatment of these patients.