OBJECTIVES: Hemophilia A (HA) is a rare bleeding disorder due to reduced/absent activity of the clotting factor VIII (FVIII). Replacement of FVIII to treat (episodic) or prevent (prophylaxis) bleeding is the main therapeutic recommendation for people with HA (PwHA) and a hemorrhagic phenotype. However, up to 30% of these PwHA may develop anti-FVIII neutralizing alloantibodies (inhibitors), then requiring bypassing agents (BPA). Emicizumab is a monoclonal antibody recently approved for prophylaxis of both PwHA without and with inhibitors. We aimed to perform a systematic review to evaluate efficacy/effectiveness and safety of emicizumab prophylaxis for PwHA, compared to previous prophylaxis with FVIII or BPA.

METHODS: The study was conducted following PRISMA 2020 statement. Electronic bibliographic databases were used as search strategy. No language nor publication period were used as restrictions on the search. The types of studies included were randomized controlled trials, non-randomized controlled trials, and observational studies that evaluated the use of FVIII or BPA versus emicizumab as prophylaxis for PwHA without or with inhibitors, respectively. Two independent reviewers selected the articles and extracted the data. Total annualized bleeding rates (ABR) for treated bleeding were evaluated by meta-analysis. [PROSPERO CRD42021282088]

RESULTS: Of 109 retrieved publications, 12 publications were included in this systematic review. A total of 366 PwHA were evaluated (289 inhibitor-negative and 77 inhibitor-positive). The standard mean differences for total ABR for treated bleeding were -0,52 (95%CI -0,81 to -0,24; p = 0,0003; I² = 45%; p = 0,08), in PwHA without inhibitors, and in PwHA with inhibitors were -1,66 (95%CI -2,47 to -0,86; p = 0,03; I² = 66%; p = 0,03).

CONCLUSIONS: The superiority of emicizumab prophylaxis in reducing the total ABR for treated bleeding when compared with prophylaxis with FVIII, in PwHA without inhibitors, or BPA, in PwHA with inhibitors, was demonstrated by this meta-analysis.