Is there a difference in inhibitor incidence with recombinant products? A meta-analysis of 2000 previously untreated patients

Aim: Recent cohort studies showed differences in inhibitor incidence in previously untreated patients (PUPs) with haemophilia A treated with recombinant factor VIII concentrates (rFVIII).This study aimed to evaluate the risk of inhibitor development and to clarify the relationship between rFVIII product used and inhibitor development in PUPs and minimally treated patients (MTPs). Methods: Prospective and retrospective clinical studies, published from 1 January 1988 to 31 August 2015, with PUPs and MTPs with severe and moderate hemophilia A were identified in a systematic literature search in electronic databases. The primary outcome measure was development of clinically relevant inhibitors. We computed pooled meta-analytic estimates according to the rFVIII product used by applying the inverse-variance method, assuming a fixed, or a random-effects model if significant between-studies heterogeneity was present. Results: Out of 781 papers, 17 studies were included in the final meta-analysis. The pooled estimate of all inhibitors (548/ 1852 PUPs/MTPs) in the overall population considered was 0.27 (95% CI 0.24–0.31). Also in only PUPs with severe hemophilia (331/1153 PUPs), the pooled estimate of all inhibitors was 0.27 (0.22–0.32) (Figure1). Significant heterogeneity due to different incidences among studies was found for Recombinate® and Kogenate®. Pooled inhibitor incidence estimates among products ranged from 0.20 to 0.42 without heterogeneity between products. Meta-analysis of studies reporting inhibitor hazard ratios with different rFVIII products, adjusted to different risk factors, showed PUPs/MTPs treated with ADVATE® had a pooled inhibitor hazard ratio estimate of 0.63 (95% CI 0.48–0.83) as compared to Kogenate FS®. The pooled estimates of other rFVIII were not significantly different. Conclusion: The overall incidence of inhibitors in PUPs/MTPs included in this meta-analysis was 27%. Differences between products used were found only when considering multivariable adjusted hazard ratios.