Benefit of Early Treatment with Room Temperature Stable Recombinant Activated Factor VII (rFVIIa) in Patients with Hemophilia a or B with Inhibitors: Subgroup Analysis from the Prospective, Post-Authorization, Non-Interventional SMART-7^™ Study

Introduction: SMART-7^™ (NCT01220141) was a prospective, post-authorization, single-arm, multinational, multi-center, non-interventional study investigating the safety and effectiveness of room temperature stable rFVIIa (NovoSeven^®) in patients with hemophilia A or B with inhibitors in a real-world setting. Here, we present a subgroup analysis of the hemostatic response of bleeding episodes to treatment with rFVIIa.

Methods: Study medication was not provided; use was at the discretion of the treating physician in accordance with the local label. Bleeding history was collected at the initiation visit. Information on bleeding episodes, including home treatment, was recorded in patient diaries during the study. Patients evaluated the status of bleeding episodes after treatment as 'bleed stopped', 'bleed slowed', or 'no change/worsened'. Overall bleed outcome was defined as the last given patient evaluation of the bleed. Patients were observed until they had achieved ≥25 exposure days, defined as any exposure to rFVIIa during one 24 h period.

Results: From November 2010 to March 2015, 51 patients were enrolled at 24 sites in 14 countries; 31 (60.8%) patients completed the study and 20 discontinued (11 of these due to global study discontinuation, a decision endorsed by the European Medicines Agency). Patients were aged 1.6-69.5 years (median 22.0 years) with an historical median bleeding rate of 1.0 episode per month. During the study, 48 patients experienced a total of 618 bleeding episodes: median number of bleeding episodes per patient was 10.5; median study duration per patient was 13.9 months. 63.4% of bleeding episodes occurred spontaneously and 31.2% were categorized as traumatic. Effectiveness evaluation at end of treatment was available for 609 bleeding episodes: 569 (93.4%) resolved, 35 (5.7%) slowed and 5 (0.8%) were unchanged/worsened. Nine bleeds had no reported outcome. A total of 538 bleeds were treated with rFVIIa monotherapy: 507 (94.2%) resolved, 27 (5.0%) slowed and 4 (0.7%) were unchanged/worsened. In a post-hoc analysis in which the data were divided by time to first treatment into 3 groups, the best hemostatic response (96.5%) was observed when rFVIIa treatment was initiated ≤1 h after onset of bleed; effectiveness was also high (93.1%) for bleeds treated >1-≤4 h of onset, decreasing for those treated >4 h after onset (87.3%; representing 13.1% of bleeds). Early treatment (≤1 h) with rFVIIa monotherapy was effective for both joint and muscle bleeds (96.2% and 97.3%, respectively). The initial rFVIIa dose administered was comparable for bleeds treated ≤1 h and those treated >1-≤4 h or >4 h after onset (Table). The median number of rFVIIa doses was higher for bleeds treated >4 h after onset than for those treated within 4 h, however these data should be interpreted with caution due to the low number of bleeds represented (13.1% of total) (Table).

Conclusion: A subanalysis of the SMART-7^™ study demonstrates higher effectiveness of early treatment with rFVIIa, with 96.5% of bleeds resolved when treatment was initiated ≤1 h after bleed onset, and remaining high (93.1%) for bleeding treatment >1-≤4 h. Total effectiveness was >87% in bleeds treated >4 hours after bleed onset.

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