Original Title: Seguridad, efectividad clínica y coste-efectividad del plasma rico en plaquetas para el tratamiento de heridas crónicas

Authors' objectives: The main objective of the present health technology assessment (HTA) report was to evaluate the safety, clinical effectiveness and cost-effectiveness of PRP for the treatment of complex chronic wounds.

Authors' results and conclusions: RESULTS: SYSTEMATIC REVIEW OF EFFECTIVENESS AND SAFETY: Sixteen RCTs and four controlled observational studies were finally included according to the pre-established selection criteria. Among the 20 trials, a total of 1,245 participants were recruited, 877 were assigned to either group (70.44%), 448 to intervention and 399 to control. The mean wound size at baseline was 19.13 cm2 for patients in the PRP intervention group and 16.37 cm2 for patients in the control group and the mean duration of pre-treatment wounds was 51.68 weeks for the PRP intervention group and 54.25 weeks for the control group. The etiology of the wound in participants was: diabetic foot ulcer; chronic venous ulcers in the lower limb; pressure ulcers; and mixed ulcers, which included ulcers of more than one etiology. Outcomes considered critical for decision-making by the working group of this report were the proportion of complete-healed wounds, the total epithelialized area, the total epithelialized volume, the percentage of wound area healed, time to complete the wound healing, wound complications, adverse events, wound pain and health-related quality of life. The global quality of evidence was considered low. The results showed that PRP treatment increased the likelihood of chronic wound healing compared to standard treatment (RR=1.68; 95% CI: 1.22, 2.31; P<0.01; I2=73%). By type of wound, it was observed that PRP may increase the likelihood of complete healing in people with diabetic foot ulcers (RR=1.50; 95% CI: 1.11, 2.01; P<0.01; I2=57%), however, it is not clear whether PRP affects complete healing of venous leg ulcers (RR=1.02; 95% CI: 0.81, 1.27; P=0.89; I2= 0%). When considering platelet growth factor release methods, it is observed that chemically released PRP had a RR= 1.97 of complete cure (95% CI: 1.28,3.02; P<0.01; I2=79%), while those who used physically released PRP did not have a greater chance of cure (RR= 1.03; 95% CI: 0.83, 1.28; P= 0.76; I2= 0%). Regarding the total epithelialized area at the end of the intervention, it was observed that adding PRP to standard treatment did not increase the epithelized area compared to standard treatment (MD= -1.26; 95% CI: -6.51, 3.99; P<0.64; I2= 53%). By type of wound, no differences were observed between intervention and control groups in patients with venous ulcers (MD= -0.83; 95% CI: -19.87, 18.21; P=0.93; I2=NA), however, in patients with diabetic foot ulcers, PRP can increase total epithelized area at the end of the intervention (MD= 1.85; 95% CI: 0.67, 3.03; P> 0.01 I2= NA). No effect or difference was observed between different methods of releasing platelet growth factors. The percentage of epithelized wound area showed a statistically significant difference in favor of PRP treatment (MD=54.82; 95% CI: 42.28, 67.37; P<0.01; I2= 0%) without differences due to wound etiology. A favorable treatment effect was also detected when PRP was chemically released (MD=55.79; 95% CI: 41.26, 70.33; P<0.01; I2= 0%). Time taken for wound healing was reduced in patients treated with PRP (MD= -14.76; 95% CI: -19.77, 9.75; P<0.01; I2=81%), effect observed in patients with diabetic foot ulcers (MD= -12.96; 95% CI: -18.12, -7.81; P>0.01; I2=53%). Regarding adverse events, although no statistically significant difference between PRP and standard treatment was in general observed, in the analysis by type of wound, difference was observed between groups for diabetic foot ulcers (RR=0.28; 95% CI: 0.13, 0.63; P>0.01; I2=NA) and, in the analysis by method of platelet growth factor release, difference were observed for the chemically released PRP was also observed (RR = 0.30; 95% CI: 0.14, 0.63; P> 0.01; I2 = NA). On the other hand, for epithelialized volume and wound complications, no differences were found between the intervention and the control groups. The measures pain and health-related quality of life could not be synthesized. SYSTEMATIC REVIEW OF COST-EFFECTIVENESS: Three comprehensive economic evaluations have been identified that estimated the cost-effectiveness of PRP in different types of chronic wounds. All three studies concluded that PRP treatment is cost-effective compared to usual care. However, all studies have methodological quality limitations, therefore, their results cannot be transferred to the context of Spanish healthcare system. ECONOMIC EVALUATION: [COST-EFFECTIVENESS ANALYSIS] The effectiveness of treatments was estimated through a meta-analysis (71.5% with PRP vs. 54.2% with standard treatment) and the resources were valued with Spanish unit costs expressed in euros of 2017. For the base case, in which the price of the PRP was set at 174€ per session, the treatment with PRP was more expensive (difference of 597€ per patient) and more effective (difference of 0.0143 quality-adjusted life-years-QALYs per patient). The incremental cost-effectiveness ratio (ICER) was estimated at 41,800 €/QALY, which is above the acceptability threshold used in Spain. Deterministic sensitivity analysis revealed that the results are sensitive to treatment effectiveness values and PRP unit cost. With a decrease in the price of the PRP to 124€ per session, the ICER would fall to 3,550€/QALY, being PRP in that case highly cost-effective. [BUDGETARY IMPACT] This hypothetical scenario, in which the PRP substitute the standard treatment of diabetic foot ulcers, would have an annual impact of more than 75 million euros, although it would avoid multiple cases of infections and amputations and consequently save costs of these complications. The gradual introduction of PRP up to 50% of acceptance at 5 years would cause the net impact of 112.6 million euros, avoiding almost 9,500 infections and 1,190 amputations. This analysis should be repeated with PRP prices agreed between the NHS and the manufacturers. ORGANIZATIONAL, ETHICAL, SOCIAL AND/OR LEGAL ASPECTS: Regarding these aspects, 41 references were included. Its analysis showed that, among other considerations, the implementation of this technology must take into account ethical aspects derived from religious motives as well as normative aspects derived from the regulations of the Spanish Agency of Medicines and Health Devices (AEMPS). CONCLUSIONS: The current available evidence allows us to establish the following conclusions about the use of PRP for the treatment of chronic wounds: • Evidence for the effectiveness and clinical safety of PRP comes from 16 RCTs and 4 prospective observational longitudinal-observational studies with control group, with very heterogeneous samples of participants. • The combination of results from existing studies shows that the use of PRP for the treatment of chronic and complex wounds increases the proportion of completely epithelialized wounds as well as the percentage of epithelialized wound area at the end of the intervention while decreasing the time to complete wound healing. On the other hand, no evidence of a significant effect of the use of PRP as compared to standard treatment on the epithelialized area or volume at the end of the intervention was found. • Safety profile of the PRP does not differ from the standard treatment in the probability of occurrence of wound complications or adverse events. • Analysis of subgroup allows identifying that: - In diabetic foot ulcers, PRP increases the proportion of completely epithelialized wounds and decreases the time to complete wound healing, the likelihood of occurrence of wound complications or adverse events. No evidence of a significant effect of PRP on the epithelialized volume or the probability of the appearance of wound complications was found. - In venous ulcers, PRP does not have a significant effect compared to standard treatment except for the percentage of healed area at the end of treatment and for the reduction of complications. - In pressure ulcers, the use of PRP has no effect as compared to the standard treatment. - Chemically-released PRP increases the proportion of completely epithelialized wounds as well as the percentage of epithelial wound area at the end of the intervention, while decreasing the time to complete the wound healing and the likelihood of occurrence of adverse events. However, there is no evidence of a significant effect of chemically released PRP versus standard treatment in the final wound area or the likelihood of wound infections. - Physically-released PRP does not show superiority to the standard treatment in any of the outcome measures evaluated. • There is a scarcity of economic studies evaluating the use of PRP in chronic wounds. Three identified economic evaluations showed PRP treatment as a cost-effective option compared to standard treatment. • Cost-effectiveness analysis de novo in patients with diabetic foot ulcers showed that PRP treatment is more effective and more expensive than standard treatment, with an ICER above the acceptability threshold in Spain. This result depends to a large extent on the effectiveness values and the price of PRP. • The incorporation of this technology in the NHS would have an important budgetary impact but it would avoid multiple cases of infections and amputations. • No issues that affect the acceptability of PRP as a treatment for chronic wounds have been identified except in the case of Jehovah’s Witnesses who could reject this treatment for religious reasons and to whom it would be convenient to offer alternatives. • The implementation of this treatment must comply with the regulation of the AEMPS regarding the quality of production, guarantees of efficacy, futility, pharmacological and information to patients. These guarantees will imply organizational changes that will have to be planned to refer patients with chronic wounds.

Authors' recommendations: With the available evidence at the time of preparation of this report and using the more usual willingness to pay used to assess the results of such studies in Spain, it is suggested to consider PRP for the treatment of diabetic foot ulcers, as long as the price of the PRP per session does not exceed 120€ (Strength of recommendation: CONDITIONAL) With the available evidence at the time of preparation of this report, it is not possible to make a recommendation for or against the implementation of PRP for the treatment of chronic and complex wounds of different etiologies.

Authors' methods: SYSTEMATIC REVIEW OF EFFECTIVENESS AND SAFETY: Systematic review of published literature with no time limits until February 2017. MEDLINE/ PREMEDLINE, EMBASE, CINAHL, CENTRAL and CRD NHS EED were searched. A comprehensive search strategy that included controlled vocabulary and free text terms was used. In addition, a manual search was performed with the references of included articles. Original published studies that assessed PRP compared to standard treatment or any other therapy for the treatment of chronic wounds were selected. No language restriction was imposed. Randomized and non-randomized controlled trials and prospective observational controlled studies on PRP in adults with chronic wounds of any etiology were included. Considered outcome measures were: proportion of complete-healed chronic wounds, total epithelialized area, total epithelialized volume, percentage of wound area healed, time to complete wound healing, wound complications (infection, necrosis), pain in the wound, other adverse events, health-related quality of life and recurrences. Methodological limitations were assessed using the criteria of The Cochrane Collaboration’s tools for assessing risk of bias for randomized controlled trials and non-randomized studies of interventions. Quantitative synthesis of the results was performed through meta-analysis using the statistical program Review Manager (RevMan) computer program. The methodology of the international working group Grading of Recommendations Assessment, Development and Evaluation (GRADE) was followed to assess the quality of evidence and to grade the strength of the recommendations. SYSTEMATIC REVIEW OF COST-EFFECTIVENESS: Only complete economic evaluations of PRP treatment compared to standard treatment or other alternative therapy were considered. Inclusion criteria regarding participants, intervention and comparator were the same as those of the effectiveness and safety review. A specific search was not carried out since the strategy developed to identify studies on the effectiveness and safety of the PRP was designed without restrictions, in such a way that it allowed finding economic evaluations. To complete the search for economic studies, NHS EED database of the CRD (Center for reviews and dissemination) was consulted. ECONOMIC EVALUATION: [COST-EFFECTIVENESS ANALYSIS] An economic evaluation was performed using the Markov model of PRP treatment versus standard treatment in patients with diabetic foot ulcer without severe ischemia with a 5-year time horizon from NHS perspective. Costs and outcomes were included in the treatment of both arms as well as complications (infections and amputations), recurrences and follow-up of cured and amputee patients. [BUDGETARY IMPACT] A budget impact analysis simulated a substitution of standard treatment for PRP treatment in all patients with diabetic foot ulcers. For a more realistic scenario, a gradual introduction of PRP (from 10% to 50% acceptance) was simulated as an option for the treatment of diabetic foot ulcers in the Spanish NHS. ORGANIZATIONAL, ETHICAL, SOCIAL, LEGAL AND PATIENT-RELATED ASPECTS: The scope of this evaluation included the same population, intervention and comparison described above for the evaluation of safety, effectiveness and cost effectiveness and explored the categories and domains established by EUnetHTA on organizational, ethical, social, legal and patient-related aspects. Articles were searched in the following electronic databases: MEDLINE, EMBASE and CINAHL with no time limits until June 2017. Inclusion and exclusion criteria were established. The extraction of data from the included documents was carried out using electronic sheets in Word designed ad hoc. A narrative synthesis of the results taking into account criteria of relevance, coherence and triangulation of data and/or sources was undertaken.

Project Status: Completed

Year Published: 2017

URL for published report: https://sescs.es/seguridad-efectividad-clinica-y-coste-efectividad-del-plasma-rico-en-plaquetas-para-el-tratamiento-de-heridas-cronicas/

English language abstract: An English language summary is available

Publication Type: Full HTA

Country: Spain

Organisation Name: Canary Health Service

Contact Address: Dirección del Servicio. Servicio Canario de la Salud, Camino Candelaria 44, 1ª planta, 38109 El Rosario, Santa Cruz de Tenerife

Contact Name: sescs@sescs.es

Contact Email: sescs@sescs.es