Primary and secondary prophylaxis in children with haemophilia A reduces bleeding frequency and arthropathy development compared to on-demand treatment : a 10-year, randomized, clinical trial

Introduction. Regular continuous replacement therapy can lower bleeding frequency and prevent progressive joint damage. As the very first bleeding in a joint can irreversibly damage its sophisticated structure, preventative treatment should start as early as possible. ESPRIT (Evaluation Study on Prophylaxis: a Randomized Italian Trial) was designed to evaluate efficacy, feasibility and safety of prophylaxis started in children up to 7 year of age, compared to ondemand treatment (ODT) over a 10-year follow-up period. Methods: Forty children with severe hemophilia A (FVIII < 1%) (CWH), aged ≤ 7 years (median 2 years), with negative clinical-radiological joint score at entry and at least 1 bleed during the previous 6 months were randomized to receive prophylactically Recombinate (and subsequently Advate) 25 IU/kg 3 times a week or on-demand treatment with at least 25 U/kg until complete healing. Safety, feasibility, efficacy in preventing bleeding episodes and arthropathy, direct costs and quality of life were evaluated on an intent-to-treat basis. Results: Ten of 21 prophylaxis children required indwelling catheters, while none of 19 ODT children. Three patients on prophylaxis and 2 ODT patients developed inhibitors. Prophylaxis with ≤ 25 IU/kg maintained FVIII > 1% in 7 of 18 prophylaxis patients (39%) without inhibitors. Prophylaxis children showed a significant lower number of breakthrough bleeds compared to ODT children (0.52 vs. 1.08 bleeds/patient/month respectively, P < 0.05), with 0.20 joint bleeds/month vs. 0.52 in ODT children (P < 0.02). Radiological evaluation showed signs of haemophilic arthropathy in 6 prophylaxis patients (29%) (median Petterson score 5; range: 3–14) and in 14 ODT patients (74%) (median score 8; range: 2–12) (P < 0.05). Prophylaxis was more effective when started in the first 36 months of age. Conclusions: This study confirms safety, feasibility and efficacy of prophylaxis in preventing bleeds and arthropathy in all children, even though better results can be observed when started in the very first years of age