Cost and effectiveness of Platelet Rich Plasma in the healing of varicose ulcer : Meta-analysis

Rev Bras Enferm. 2020;73(4): e20180981 http://dx.doi.org/10.1590/0034-7167-2018-0981 8 of ABSTRACT Objectives: to analyze the evidence on the cost and effectiveness of Plaque Rich Plasma in the treatment of venous ulcers compared to other topical therapies. Methods: systematic review, with search in the databases: COCHRANE, EMBASE, MEDLINE via PubMed, LILACS, CINAHL, SCOPUS, without temporal cut and in the English, Portuguese and Spanish languages. Results: fifteen articles were included, a cost-minimization analysis showed that the cost of Plaque Rich Plasma is € 163.00 ± 65.90, slightly higher than the cost of standard dressing. Regarding effectiveness, the results of the studies associated with the meta-analysis suggest a tendency that Plaque Rich Plasma is effective in the healing of venous ulcers. Conclusions: it is concluded that there are few studies about the cost of Platelet Rich Plasma and this product tends to be effective in the healing of venous ulcers. However, more controlled and randomized clinical studies are necessary in order to establish a stronger recommendation. Descriptors: Platelet-Rich Plasma; Varicose Ulcer; Costs and Cost Analysis; Wound Healing; Meta-Analysis.


INTRODUCTION
Venous ulcers represent 70-80% of chronic leg ulcers, and their etiology is chronic venous insufficiency and venous hypertension (1) . Venous ulcers are considered a challenge for patients, professionals and healthcare systems, since they are recurrent, chronic and require high cost treatment. In addition, venous ulcers can have a considerable negative impact on the patient's quality of life (2) .
Compression therapy has been considered the gold standard for the treatment of venous ulcers, as it promotes the healing process and prevents recurrence (3) . However, it is necessary to use dressings that can contribute to the healing process of venous ulcers by keeping a moist environment, reducing pain, exudate and offering more comfort to the patient (4) .
A technology that has been considered promising in the healing process is Platelet-Rich Plasma (PRP). PRP results from the centrifugation of whole blood and it is rich in growth factors and structural proteins, which stimulate collagen and extracellular matrix production requiring minimal amounts of plasma, stimulating tissue repair, neovascularization and tissue regeneration (5) .
PRP acts in the different phases of healing, shortening the inflammatory phase through hemostasis, provisional fibrin matrix and reduction of biofilm, which favors the formation of granulation tissue (chemotaxis, angiogenesis and cell proliferation) and stimulates epithelial growth, proliferation, migration of keratinocytes and extracellular matrix remodeling (6) . PRP has been used in wounds of different etiologies and in graft integration, and its preparation technique is considered efficient, safe and low cost (7) .
PRP has been associated with improved quality of life of patients with diabetic ulcers and lower cost of care over a 5-year period (8) . Also, it has been considered a cost-effective technology that allows faster healing and that should be taken into account, especially in long-term ulcers (9) .
Given the need for cost-effective technologies for venous ulcer treatment, the following research questions arose: Is Platelet-Rich Plasma effective in healing venous ulcers compared to other topical therapies? Is Platelet Rich-Plasma cost-effective in treating venous ulcers compared to other topical therapies?

OBJECTIVES
To analyze the evidence on the cost-effectiveness of PRP in the treatment of venous ulcers compared to other topical therapies.

Ethical aspects
As this is a systematic review, there is no need to obtain approval from Research Ethics Committee.

Design, period and setting
This is a systematic review, with searches conducted from July 4 to July 6, 2018. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist was used to elaborate the flowchart and for the Systematic Review and Meta-Analysis (10) .

Population or sample; inclusion and exclusion criteria
The following inclusion criteria were considered: randomized and nonrandomized controlled trials; prospective studies such as cohorts and case series; quasi-experimental studies; economic studies -cost-effectiveness, cost-utility, cost-minimization, direct and/or indirect cost; studies analyzing the cost and/or effectiveness of topical application of autologous PRP in venous ulcers, regardless of age, in outpatient units or hospitals. Exclusion criteria were: studies with intradermal, subcutaneous, perilesional or wound bed PRP application; research protocols without results; PRP associated with grafts; homologous PRP; studies that included ulcers of different etiologies without subgroup analysis.
Studies using subcutaneous or intradermal PRP were excluded after reading the title, abstract or full text. The exposure of interest of this review was topical PRP. Therefore, studies with other routes of administration were excluded, as the presentation and formulation of topical PRP is different from intradermal or subcutaneous PRP, as different substances may be added to change the consistency of the PRP into a gel. In addition, the response mechanism associated with topical administration may differ from the other routes.

Study protocol
The following descriptors (Mesh terms) were used: Varicose ulcer (Úlcera varicose); Leg ulcer (Úlcera da perna); Platelet-Rich Plasma (Plasma Rico em Plaquetas); and related keywords Venous ulcer, Venous leg ulcer, in English, Spanish and Portuguese. Terms related to the outcomes were not used, aiming to broaden the search results, thus opting for a sensitive search. Search strategies were adapted for each database. There were no limitations to date of publication.
Database searches and selected studies were assessed for relevance to the research theme, study design, results, indications and main conclusions.
The systematic review design allows gathering evidence that can contribute for decision-making regarding the evaluation of health technologies. The steps followed were: definition of the clinical problem and searching criteria, selection of databases and descriptors, development of relevance tests, application of the Relevance Test I to the abstracts of the articles identified, application of the Relevance Test II to the full articles and elaboration of the table summarizing the articles (11) . Article selection and data extraction were performed by two independent researchers, (A.P.L.R.) and (M.R.C.). After reading the title and abstract, the disagreements regarding the inclusion of articles were discussed with a third reviewer (B.G.R.B.G.). All potential studies were read in full, and then exclusion criteria were applied. Specific forms and databases were used for each step of the Systematic Review and included names of the authors, title, country of Cost and effectiveness of Platelet Rich Plasma in the healing of varicose ulcer: Meta-analysis Oliveira BGRB, Carvalho MR, Ribeiro APL.
of origin, year and journal of publication, study design, population, intervention, evaluated outcomes and results. The effectiveness of PRP in healing was evaluated considering the following outcome variables: reduction of wound area in cm2, percentage of healing, number of ulcers healed (complete healing), and time to healing. The cost of PRP was evaluated considering the costs extracted from cost analyzes and economic evaluations.

Analysis of results and statistics
The level of evidence and grade for recommendation of the studies were analyzed according to the Oxford Centre for Evidence-Based Medicine, which considers the study design as the criterion for the level of evidence, which ranges from 1 to 5, and for the grades for recommendation, which range from A to D. This evaluation is made by two evaluators, with no disagreement (12)(13) . The level of agreement between the evaluators was assessed by the Kappa coefficient, 0.873 (p-value < 0.001), with a 95% confidence interval of Kappa (1.0-0.718) Burgos-Alonso et al. (14) 2018 A meta-analysis of controlled clinical trials was conducted. Heterogeneity was statistically evaluated using the Chi-square test, with fixed effect analysis when heterogeneity is less than 50%.
A total of 201 records were found. The flowchart of the studies is presented in Figure 1.

RESULTS
A total of 15 articles that evaluated the effectiveness of autologous Platelet-Rich Plasma were found. One of these articles presented results of a cost-minimization analysis (14) .
The cost-minimization analysis conducted by Burgos-Alonso et al. (14) showed that the cost of PRP is €163.0 ± 65.9 [81.2 -244.8] Euros when it is applied once a week in outpatient care, while the standard treatment performed 2 to 3 times a week, with a mean of 2.5 times/week, cost €147.3 ± 29.7 [110.4-184.2] (p-value=0.640), in a nine-week follow-up. The mean time of treatment of the Intervention Group was 46.6 minutes, while the Control Group presented mean time of treatment of 21.7 minutes (p < 0.001). Table 1 presents the studies on the effectiveness of PRP in the treatment of venous ulcers.
According to Table 1, five studies (33%) are randomized controlled trials, eight (53%) are prospective studies without control group, one (7%) is a case-control and one (7%) is an observational study. Regarding location, the studies were conducted in several countries, mainly in Europe (33%) and Asia (26%), followed by the United States (20%), Egypt (7%), Australia (7%) and Chile (7%). It is observed that the term for Platelet-Rich Plasma also varied in the studies; however, the description of the method of obtaining the product showed that all had similar preparation, differing only in final form (liquid or gel). The follow-up time varied from 2.1 weeks (24) to 12 months (20) .
In the studies evaluated, the mean initial wound size ranged from 5.06 ± 8.7 (20) to 26.3 cm 2 (25) . The frequency of PRP application varied from one to five times a week, with predominance of once a week, in 47% of the studies (7,(14)(15)(16)(17)20) . Only one study did not inform the frequency of application (27) .
Regarding the level of evidence and grade of recommendation, 54% of the studies had level of evidence 4 and grade for recommendation C. Five studies (33%) were randomized controlled trials with evidence level 1b and grade for recommendation A. Another study had level and grade 2b/B, as it was a Cohort, and another one was a case control with level and grade 3b/B.  Pinto et al. (20) 2018   Table 2 presents the outcomes regarding the effectiveness of the PRP in the studies included.
As there was only one study that presented the cost of PRP (14) , it was not possible to perform the meta-analysis of the outcome cost and/or cost-effectiveness. Figure 2 presents the meta-analysis of the outcome complete healing of venous ulcers. Figure 2 shows that there was no significant difference regarding the effectiveness of PRP considering the outcome complete healing. Figure 3 presents the meta-analysis of the outcome reduction in wound area. Figure 3 shows that Platelet-Rich Plasma was effective in reducing area, according to the meta-analysis of the two studies that evaluated this outcome.

DISCUSSION
The studies were analyzed according to the following categories:

Category 1: PRP Cost
In this review, it was found that in the cost-minimization analysis performed by Burgos-Alonso et al. (14) the cost of PRP was higher than the cost of standard treatment (p-value 0.640). Even though PRP was applied once a week and standard treatment 2 to 3 times a week, the time spent with PRP was longer than with standard treatment (p < 0,001) (14) .
In the analysis (14) , to calculate the cost, the items evaluated were: time spent with treatment, cost of performing the procedure and labor cost referring to the nurse and assistant professionals, frequency of changes, dressings and costs of PRP preparation material. PRP treatment occurred in five steps: Collection of autologous blood; Centrifugation; Separation of red blood cells and leukocytes PRP; Coagulation of PRP to form a biological cover applied to the wound bed; and secondary dressing made of foam, polyurethane or hydrofiber.
A cost-effectiveness analysis of Rich Platelet Plasma in skin ulcers, with meta-analysis of five articles addressing ulcers of various etiologies and using the Markov Model, demonstrated that the probability of healing was 56% using PRP and 31% with standard treatment, while associated direct costs were €5224 and €5133 respectively. The incremental cost to achieve additional healing is € 364 Euro, within a 48-week time of treatment (28) .
In another comparative study, the cost of PRP was evaluated with 81 participants with ulcers of various etiologies, of which eight were venous ulcers in the hospital and outpatient setting. It was found that the use of PRP reduced the average length of stay (11 ± 2.5 days), and cost € 785.25, while in the control group, which used the standard treatment (povidone-iodine gel, Olasol™ spray, Actovegin™ gel and interactive dressing) the cost was € 1649.02, and the mean length of stay in the hospital was 23.1 ± 1.5 days. The direct costs assessed were related to PRP treatment for 90 days and considered days of hospitalization, blood collection and PRP preparation, dressings and outpatient care (29) .
The only study (14) found in the literature that used autologous topical PRP specifically for venous ulcers performed a cost-minimization analysis, which evaluated only the cost without considering the effectiveness of the technologies involved. The authors' suggested conducting studies with larger samples for cost-effectiveness evaluation. In another study (28) , conducted a cost-effectiveness analysis; it evaluated skin ulcers of various etiologies and concluded that the use of PRP is cost-effective, since the extra cost with the use of PRP is much lower than the long-term use of standard treatment. The direct costs of PRP treatment presented in another study (29) show that it had a lower cost and was considered cost-effective; however, no actual cost-effectiveness assessment was performed and the sample was composed of ulcers of various etiologies, without specific cost analysis of the venous ulcer subgroup.
Thus, further studies applying more robust methodology and assessing the cost-effectiveness of PRP specifically in venous ulcers are required to accurately determine whether topical autologous PRP is cost-effective for treating these ulcers and then make a stronger recommendation.

Category 2: Effectiveness of the PRP
PRP has been considered a promising technology for ulcer healing because it stimulates fibroblasts, macrophages, mesenchymal    cells and growth factors that promote re-epithelization and neovascularization in chronic ulcers (30) .
Considering the prospective (case series) and observational studies and the randomized controlled trials included in this metaanalysis, there is a tendency for PRP to be effective in complete healing and reduction of venous ulcers.
It was found that the relative risk (RR) of a venous ulcer to completely heal after PRP was 2.54, with a Confidence Interval (CI) of 0.42-15.30. However, the result was not statistically significant, as the CI includes the value 1. There was a discrepancy between recent (15,17) and older studies (18)(19) , with most promising results in studies conducted in 2017 and 2018 (15,17) . However, it should be noted that the number of study participants was limited because, despite of the fact that venous ulcers presented a 7.7 times greater chance of completely healing in the study by Somani & Rai (17) (RR: 7.70, 95%CI: 0.50-117.97) and 15 times greater chance in the study by Moneib et al. (15) (RR: 15.0, 95%CI: 0.91-246.20), the confidence intervals in these studies are very broad and include 1, which indicates that caution is required when interpreting these findings. The evaluation of the outcome reduction in wound area showed that venous ulcers treated with PRP had a 55.7% greater reduction in area than control group ulcers (Mean: 55.70, 95%CI: 44.76-66.64), p < 0.005. Therefore, further studies with methodological rigor and higher number of participants should be conducted to validate this favorable tendency of PRP use.
A review that evaluated the effectiveness of various types of venous ulcer treatment demonstrated that the few randomized clinical trials that evaluated the effectiveness of PRP do not confirm the effectiveness of venous ulcer healing and, therefore, more studies should be performed (31) .
A recent review evaluating the effectiveness of Platelet-Rich Plasma in chronic ulcers showed that, of the 10 randomized controlled trials evaluated, four were with patients with chronic ulcers, three were with patients with venous ulcers and three with patients with diabetic ulcers. It concluded that it was unclear whether autologous PRP improved the healing of chronic ulcers overall compared to standard treatment but considered that PRP enhances the healing of diabetic ulcers. In the case of venous ulcers, the effectiveness of PRP was unclear, and more controlled clinical studies should be performed for a recommendation (32)(33) .
The reviews cited evaluated the randomized controlled trials (31,33) published prior to this review, and did not consider cost assessment. Thus, this review provides evidence of the costeffectiveness of PRP in recent studies, and also presents the results of prospective studies that, even with level of evidence C, showed good results with the use of PRP.

Study Limitations
As limitations of this review, we highlight the small number of studies that assessed the cost of PRP specifically in venous ulcers, making it difficult to compare cost-effectiveness. Regarding the effectiveness of PRP, it is observed that the number of studies is also reduced, limiting the results for the elaboration of meta-analysis.

Contributions to the area of Nursing, Health or Public Health
The evidence found in this study contributes to the knowledge of health professionals, such as orthopedists, dentists and also nurses, regarding technology for the treatment of venous ulcers. It is considered that nurses have an important role in decision making regarding the technologies used for venous ulcer healing.
In addition, this study generated evidence that can assist the decision making of managers of public and private health. Thus, it enables a debate in Brazilian public health about an issue that is already an agenda of the National Health Surveillance Agency (34) and the Professional Councils (35)(36) .
Further research on cost-effectiveness is encouraged, especially in the Brazilian healthcare context, as the Unified Health System is quite different compared to countries where evidence of the cost-effectiveness of PRP was found.
As for effectiveness, the meta-analysis of two studies suggests that Platelet-Rich Plasma was effective in reducing venous ulcer area. Regarding complete healing, the results of prospective studies included in the meta-analysis suggest a trend towards the effectiveness of Platelet-Rich Plasma.
Further studies to evaluate the cost-effectiveness of PRP should be conducted, especially in the Brazilian context, allowing a stronger recommendation regarding its use and supporting decision making of managers and other professionals, such as nurses, in clinical practice.