Four Decade Cumulative Review of Thrombo-Embolic Events Reported with the Use of Activated Prothrombin Complex Concentrate in Congenital Haemophilia

Introduction and Objectives: The use of bypassing agents have contributed to a better management of bleeding (prevention and treatment) of persons with haemophilia (PWH) and inhibitors. One of these, an activated prothrombin complex concentrate (APCC - FEIBA - FVIII inhibitor bypassing activity, Shire) became commercially available 40 years ago in 1975. While bypassing therapy has been proven effective, it introduced a potentially increased risk of treatment-associated thrombo-embolic events (TEEs). The small size of clinical trials and post-authorization surveillance studies in PWH with inhibitors limits the capability to ascertain risk factors for APCC-associated TEEs. The present review provides an overview of clinical details of all spontaneous and literature cases TEEs reported with the use of APCC in congenital haemophilia, documented in the Company's global safety database.

Materials and Methods: The global safety database was reviewed for all spontaneous and literature adverse events reports of APCC received from 1975 through July 2016, addressing patient demographics, dosing regimens, confounding and risk factors deemed relevant for the development of TEEs in temporal association with APCC treatment.

Results: More than 7 billion units of APCC (more than 2million infusions) were distributed during the review period. Overall 108 TEE have been reported in patients with different indications (congenital haemophilia, acquired haemophilia, anticoagulation reversal, etc.). Of these, 85 reports including one or more thromboembolic events were received for PWH (thereof 60 spontaneous reports), aged 0-73 years (mean 32, median 22). Of the 85 TEEs, 13 were reported as deep vein thrombosis and/or pulmonary embolism (median age: 11 years, min-max 3-22), 32 as myocardial infarction or stroke (median age: 41 years; min-max 8-73), 18 as disseminated intravascular coagulation (median age: 49; min-max: 0-71) and 22 as other events (median age: 30 years; min-max: 3-57). Of the 85 TEEs, 31 TEEs were reported with rFVIIa as a concomitant medication (7 DVT/PE, 9 MI/stroke, 9 DIC, 6 others).

Conclusion: The reporting rate of TEEs associated with APCC remains comparable with data published earlier and confirms its long-time overall safety profile. Moreover, the majority of the TEEs occurred in the presence of additional/confounding risk factors such as underlying disease and concomitant medications. The review of clinical details of all TEEs reported in temporal association with the use of APCC is a valuable resource for the understanding and perhaps the prevention.