Eficácia, efetividade e segurança dos fatores VIII de meia-vida estendida no tratamento profilático de pessoas com hemofilia A: revisão sistemática e metanálise.

Abstract

Introduction: The treatment of people with hemophilia A (PwHA) consists of the infusion of coagulation factor VIII (FVIII), either as prophylaxis (to prevent bleeding) or on demand (after a bleeding episode). Due to pharmacokinetics, infusion of standard half-life FVIII (plasma-derived or recombinant [SHL]) in prophylaxis occurs at a certain frequency, to ensure residual FVIII activity between 1% and 3%. This results in the reduction of spontaneous bleeding, mainly hemarthroses. Finally, it prevents the development or worsening of hemophilic arthropathy and improves health-related quality of life (HRQoL). To reduce the stress caused by frequent infusions or allow for higher FVIII residual activity (up to 5% to 10%), extended half-life rFVIII (EHL) have been developed. Objective: To carry out a systematic review of the efficacy, effectiveness and safety of EHL compared to SHL for the prophylactic treatment of PwHA. Methodology: A systematic review with meta-analysis was conducted in accordance with the recommendations of the Cochrane Collaboration. Search strategies (June 11, 2023) were structured in accordance with electronic databases (Cochrane Library, EMBASE, LILACS, PUBMED, and CRD). Clinical trials and observational studies that assessed prophylaxis with EHL in comparison to SHL were included. Two independent reviewers selected publications and extracted data using a standardized form. Meta-analyses were performed for outcomes such as bleeding rate, PwHA with zero bleeding, weekly consumed dose of FVIII, and treatment adherence. The Risk of Bias in Non-randomized Studies - of Interventions (ROBINS-I) tool was employed to assess the methodological quality of non-randomized studies. The certainty of evidence was evaluated through the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE). [PROSPERO CRD42023394281] Results: Twenty-six publications evaluated rurioctocog alfa pegol, damoctocog alfa pegol and efmoroctocog alfa. However, conducting the meta-analysis was possible for the publications that evaluated the rurioctocog alfa pegol and efmoroctocog alfa. Overall bleeding outcomes were lower for PwHA on EHL prophylaxis compared to SHL: total bleeding rate rate (12 publications, 639 EHL vs. 1240 SHL; standardized mean difference [SMD] -0.68 confidence interval {CI 95% -1.30 to -0.05}, p = 0.03; I2 = 94%, p < 0,01) and joint bleeding rate (7 publications, 239 EHL vs. 239 SHL; SMD -0.41 CI 95% -0.59 to -0.23, p < 0.01; I2 = 0%, p = 0.48), except for spontaneous bleeding rate (3 publications, 199 EHL vs. 497 SHL; SMD -0.15 95% CI -0.32 to 0.01, p = 0.07; I2 = 0%; p = 0.78). The frequency of PwHA with zero bleeding total (10 publications, 612 EHL vs. 1185 SHL; relative risk [RR] 1.47 95% CI 1.13 to 1.90, p < 0.01; I2 = 63%, p < 0.01) and with zero joint bleeding (5 publications, 195 EHL vs. 273 SHL; RR 1.48 95% CI 1.05 to 2.10, p = 0.03; I2 = 57%, p = 0.06) was lower in the PwHA group on prophylaxis with EHL. PwHA on prophylaxis with EHL compared to SHL were more adherent (4 publications, 243 EHL vs. 297 SHL; RR 1.14 95% CI 1.03 to 1.26, p = 0.01; I2 = 0%, p = 0.87). However, consumed dose of FVIII weekly were similar for EHL and SHL prophylaxis (12 publications, 673 EHL vs. 1274 SHL; SMD -0.05 95% CI -0.76 to 0.67, p = 0.90; I2 = 95%, p < 0.01). HRQoL was assessed using different tools (specific or not for hemophilia). Therefore, some tools reported improvement in HRQoL with the use of the intervention, while other tools did not. Among the publications that reported adverse events (44%), the most common adverse events were respiratory tract infection and headache. Almost all publications did not report the development of inhibitors after prophylaxis with EHL, but all evaluated previously treated PwHA. Of the total 760 PwHA, 63 (8%) discontinued EHL treatment. The methodological quality in most of the included publications was moderate for total bleeding rate and consumed dose of FVIII weekly. However, for frequency of PwHA with zero bleeding, adherence to treatment and HRQoL, the methodological quality was severe for most of the included publications. The certainty of evidence was high for the rate of joint bleeding, low for total bleeding rate, frequency of PwHA with zero bleeding and adherence to treatment and very low for consumed dose of FVIII weekly and HRQoL. Conclusion: The evidence presented in this review suggests that prophylaxis with EHL, when compared to SHL, results in a slight reduction in the rate of total bleeding. However, for spontaneous bleeding rate no difference was identified between prophylaxis with EHL and SHL. On the other hand, prophylaxis with EHLwhen compared to SHL, may result in an increase in adherence and in the proportion of PcHA with zero bleeding, both joint and total. Our analysis reinforces that the effect of EHL on SHL results in a reduction in the rate of joint bleeding. Otherwise, the evidence is very uncertain for EHL, which showed little or no effect in reducing the dose of FVIII consumed weekly compared to SHL. Overall, EHL were well tolerated.