Bleeding events in people with congenital haemophilia A without factor VIII inhibitors receiving prophylactic factor VIII treatment: A systematic literature review

Authors: Mannucci, PM; Kessler, CM; Germini, F; Nissen, F; Ofori-Asenso, R; Brocchieri, C; Bendinelli, S; Iorio, A

Affiliations: Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi, Hemophilia and Thrombosis Center, Milan, Italy. Georgetown University Medical Center, Lombardi Comprehensive Cancer Center, Washington District of Columbia, USA. McMaster University, Hamilton, ON, Canada. F. Hoffmann-La Roche Ltd, Basel, Switzerland. Real World Data Enabling Platform, Roche Products Ltd, Welwyn Garden City, UK. Medical Affairs, F. Hoffmann-La Roche Ltd, Monza, Italy.

Publication: Haemophilia;2023

Abstract: BACKGROUND: Evidence on bleeding rates in people with congenital haemophilia A (PwcHA) without inhibitors on factor VIII (FVIII) replacement products is inconsistent. AIM: This systematic literature review assessed bleeding outcomes in PwcHA using FVIII-containing products as prophylactic treatment. METHODS: A search was conducted using the bibliographic databases Medline, Embase and Cochrane Central Register of Controlled Trials on the Ovid platform. The search involved a bibliographic review of clinical trial studies, routine clinical care studies and registries and a search of ClinicalTrials.gov, EU Clinical Trials Register and conference abstracts. RESULTS: The search yielded 5548 citations. A total of 58 publications were included for analysis. In 48 interventional studies, the pooled estimated mean (95% confidence interval [CI]) annualized bleeding rate (ABR), annualized joint bleeding rate (AJBR) and proportion of participants with zero bleeding events were 3.4 (3.0-3.7), 2.0 (1.6-2.5), and 38.5% (33.1-43.9), respectively. In 10 observational studies, the pooled estimated mean (95% CI) ABR, AJBR and proportion of participants with zero bleeding events were 4.8 (4.0-5.5), 2.6 (2.1-3.2), and 21.8% (19.9-47.5), respectively. A large variation in mean effect size for ABR, AJBR and zero bleeding event data across cohorts and cohort types was observed. Funnel plots indicated potential reporting bias for publications incorporating ABR and AJBR data across both interventional and observational studies. CONCLUSION: This meta-analysis shows that PwcHA without inhibitors still have bleeds despite FVIII prophylaxis. Improved standardization on capturing and reporting bleeding outcomes is needed so that effective comparisons between treatments can be made.