Use of Recombinant Factor VIIa (rFVIIa) for Acute Bleeding Episodes in Acquired Hemophilia: Final Analysis From the Hemostasis and Thrombosis Research Society (HTRS) Registry AH Study

Abstract

4624 Introduction: Acquired hemophilia (AH) is a rare disorder marked by the development of autoantibodies to factor VIII. Patients typically present with bleeding and a prolonged aPTT that does not correct with mixing with normal plasma. Recombinant factor VIIa (rFVIIa) is the only FDA approved bypassing agent for treatment of bleeding in AH. The Hemostasis and Thrombosis Research Society Registry was established as an IRB-monitored web-based platform with informed consent in 1999 to support the society's research needs and monitor rFVIIa use after its FDA approval. AH surveillance was initiated in October 2006. Methods: Data on bleeding episodes entered between January 2004-November 2011 were analyzed. For each rFVIIa-treated bleed, the initial dose, total dose, mean dose per infusion, number of doses, and treatment duration were calculated. Results: Of 166 registered AH patients, 110 had bleeding episodes reported. Of 237 bleeds, 17 (7%) occurred in patients aged ≤40, 54 (23%) in ages 41–60, and 166 (70%) with age >60. The most common sites were subcutaneous (40%), mucosal (32%), muscle (20%) and joint (11%). Subcutaneous bleeds were more commonly reported in females (55% vs. 40% males) and white patients (44% vs. 27% black). Mucosal bleeds were more common in black patients (49% vs. 25%) and muscle bleeds more common in white patients (14% vs. 23%). There were 139 (59%) rFVIIa-treated bleeds (89 rFVIIa alone, 50 rFVIIa plus other agents/blood components); 127 were treated with rFVIIa first-line. There were 75 episodes (43 patients) treated with other hemostatic agents or blood components only, 21 episodes (18 patients) recorded with no treatment for the episode, and 2 episodes (2 patients) with no treatment data recorded. For rFVIIa-treated episodes, 71 were in males and 68 females; 101 were Caucasian and 30 were black. Mean (median) age at bleeding was 67 (69) years. rFVIIa-treated bleeds were spontaneous (95), traumatic (30), surgical/procedure-related (7), dental (2) or other (4). Median (IQR) initial rFVIIa dose was 90 (88–100) mcg/kg, and average dose per injection was 90 (88–99). The total dose per episode was 334 (166–1383) mcg/kg administered as 3 (2–14) injections over 1 (0–2.75) day. Median (IQR) data for rFVIIa dosing by treatment sequence, bleed location and type is described below: Efficacy of rFVIIa, physician-rated for each regimen, was reported as “bleeding stopped” in 117 (85%) episodes; “bleeding slowed” in 15 (11%) episodes (stopped with other agents in 3 episodes); “no improvement” in 5 (4%) episodes (no bleed stop date identified in 4, stopped with other agent in 1), and was not documented in 1. Considering only the 4 rFVIIa treatment failures where bleeding stopped after switching to another agent, overall rFVIIa efficacy was 97%. The only thromboembolic event was transient neurologic symptoms in a 31-year-old post-partum patient after 110 doses of 90 mcg/kg every 2 hours. The neurologist reported it most likely related to eclampsia and vasculitis. Conclusions: The HTRS registry final analysis represents the 2nd largest data set in AH. While subcutaneous bleeding as a first bleed location was uncommon outside of Caucasians, it represents the most common bleed location of recorded bleeds in all race/ethnicity groups. As this registry was originally intended in part to track the safety of rFVIIa, the proportion of bleeds treated with rFVIIa (59%) and associated data derived from those bleeds may be somewhat biased and selective. Nevertheless, they are certainly indicative that rapid and safe hemostasis can be achieved with rFVIIa in an aging population with AH where thrombogenicity is of concern. Disclosures: Ma: Novo Nordisk Inc.: Consultancy, Speakers Bureau. Kessler:Novo Nordisk: Consultancy, Research Funding. Fisher:Novo Nordisk Inc.: Employment. Gut:Novo Nordisk Inc.: Employment. Cooper:Novo Nordisk Inc.: Employment.

Lessons from a systematic literature review of the effectiveness of recombinant factor VIIa in acquired haemophilia

“…1 ) met the inclusion criteria of the review. Additionally, data for three studies were available from reports provided by Novo Nordisk and an external expert (one a clinical study report for the study conducted by Ma et al [ 18 ], the data for which have subsequently been published [ 19 , 20 ], the second a report for the study conducted by Seita et al [ 21 ], which has also subsequently been published [ 22 ], and the last data on file provided by an author [A Tiede]).

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“…The majority of included studies were published as journal articles (58.3%); two studies (16.7%) were published as conference abstracts, two were clinical study reports for data subsequently published [ 18 , 22 ], and one was data on file for GTH (8.3%) provided by the external expert [ 24 ]. Two of the studies included > 150 patients [ 7 , 18 ], while three studies recruited 10 to 30 patients [ 23 , 25 , 26 ]. The number of bleeds was not reported in five of the 12 included studies [ 2 , 23 , 25 , 27 , 28 ].…”

“…Ethnicity data were reported in just one study by Ma and colleagues [ 18 ] and have subsequently been fully published since the time the systematic review was undertaken [ 20 ]. Of individuals treated with rFVIIa, Whites/Caucasians made up the largest percentage of the population (73.5%), which included White non-Hispanic (67.6%) and White Hispanic (5.9%) patients.…”

“…RBC transfusion and anti-fibrinolytic agents were the major ancillary therapies given to patients across the seven studies that reported this information [ 2 , 7 , 18 , 25 , 26 , 29 , 30 ]. In the early study by Hay et al, 66% of rFVIIa-treated bleeds were also treated with anti-fibrinolytic agents [ 30 ].…”

Acquired haemophilia: an overview for clinical practice

“…This is a longitudinal US database established in 1999 to study treatment strategies for patients with bleeding disorders and monitor the postapproval use of rFVIIa, which since 2006 (date of approval of rFVIIa for AHA in the US) has provided postmarketing surveillance on rFVIIa‐treated patients with AHA. We await the full publication of the HTRS data set with interest.…”