A multicenter, observational study to evaluate hemostasis following recombinant activated FVII treatment in patients in Japan with congenital factor VII deficiency

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TL;DR

This multicenter observational study in Japan evaluated recombinant activated factor VII (rFVIIa) for bleeding episodes and surgical prophylaxis in 20 patients with congenital factor VII deficiency. rFVIIa was highly effective, with 79.3% of bleeding episodes rated as excellent or effective and 93.75% of surgeries rated as effective or partially effective, using a median dose of 41.7 μg/kg for bleeds and 36.9 μg/kg for surgeries. No thromboembolic events or inhibitors were detected, supporting the safety and efficacy of rFVIIa in this rare disorder.

Full summary

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**Background:** Congenital factor VII (FVII) deficiency is a rare coagulation disorder with a global prevalence of 1 per 500,000 persons. Bleeding phenotypes are heterogeneous, ranging from asymptomatic to life-threatening hemorrhages, particularly in patients with FVII activity ≤2 IU/dl. Recombinant activated FVII (rFVIIa) is the most common treatment, but data from Asian populations are limited. This study aimed to evaluate the safety and hemostatic effectiveness of rFVIIa in Japanese patients with congenital FVII deficiency.

**Methods:** This multicenter, observational study was conducted at 30 sites in Japan from March 2011 to September 2014 (NCT01312636). Patients were enrolled based on the 2011 Japanese national survey (64 patients with FVII deficiency). Inclusion criteria: all registered patients receiving rFVIIa during the collection period, regardless of baseline FVII activity. Exclusion criteria: septicemia and history of hypersensitivity to product components. Of 36 eligible patients, 35 were enrolled, 23 provided informed consent, and 20 were included in the final analysis (one site declined). Data were collected retrospectively from the approval date (12 March 2010) and annually after enrolment. Primary endpoints: presence of inhibitory alloantibodies to FVII and thromboembolic events. Secondary endpoints: hemostatic effectiveness of rFVIIa for bleeding episodes and surgery (rated as excellent, effective, partially effective, or ineffective per protocol definitions), changes in laboratory parameters (PT-INR, aPTT, FVII activity, platelet count, fibrinogen), and adverse events. rFVIIa was administered per Japanese package insert (15–30 μg/kg every 4–6 hours). Descriptive analyses were performed.

**Key Results:** Among 20 patients (7 male, 12 female, 1 not recorded), mean follow-up was 11 months (range 1–49 months). Baseline FVII activity: <10 IU/dl in 9 patients, 10–20 IU/dl in 4, >20 IU/dl in 5, not recorded in 2. A total of 401 bleeding episodes were recorded in 8 patients; 348 episodes in 7 patients were analyzed (one excluded due to unverifiable dosing). Of these, 48.9% (170/348) were intra-articular, 17.8% (62/348) menorrhagia, 4.6% (16/348) intramuscular, 3.4% (12/348) epistaxis, and 25.3% (88/348) other. Most bleeding episodes (95.4%) occurred in patients with FVII activity ≤20 IU/dl. For bleeding episodes, median (IQR) total dose was 41.7 (21.3–73.5) μg/kg, median number of doses 2.0 (1.0–3.0), and median treatment duration 2.0 (1.0–4.0) days. Menorrhagia required the highest total dose (median 127.7 μg/kg) and longest duration (median 4.0 days). Hemostatic effectiveness was rated excellent in 45.7% (159/348), effective in 33.6% (117/348), partially effective in 18.4% (64/348), and ineffective in 0.6% (2/348) of episodes. The two ineffective episodes occurred in the same patient with extended dosing intervals (>12 hours). A total of 16 surgical procedures (10 major, 6 minor) were performed in 13 patients. For surgeries, median (IQR) total dose was 36.9 (21.5–57.0) μg/kg, median number of doses 2.0 (1.0–2.0), and median treatment duration 1.0 (1.0–2.0) days. Hemostatic effectiveness was rated effective in 93.75% (15/16) and partially effective in 6.25% (1/16). No thromboembolic events or FVII inhibitory antibodies were detected (only 4 samples tested). No adverse events, serious adverse events, or deaths were reported. Median PT-INR decreased from 3.13 to 1.29 in bleeding patients and from 4.8 to 1.20 in surgical patients. Median FVII activity increased from 3.0 to 335.1 IU/dl in bleeding patients and from 12.0 to 137.0 IU/dl in surgical patients.

**Clinical Implications:** This study provides real-world evidence that rFVIIa at the recommended dose of 15–30 μg/kg is highly effective for achieving hemostasis in Japanese patients with congenital FVII deficiency, both for bleeding episodes and surgical prophylaxis. The majority of bleeding events occurred in patients with FVII activity ≤20 IU/dl, and menorrhagia required higher doses and longer treatment. The absence of thromboembolic events and inhibitors supports the safety profile. Limitations include small sample size, incomplete data, and lack of standardized monitoring. Despite these, the findings align with global data (e.g., STER registry) and emphasize the need for individualized treatment. Further studies with larger populations are warranted.