Thrombotic events remain low with use of coagulation factor VIIa recombinant
The rate of thrombotic events among patients treated with coagulation factor VIIa recombinant within its licensed indications continues to be low and has remained stable in postapproval surveillance, according to findings presented at the ASH Annual Meeting and Exposition.
Coagulation factor VIIa recombinant (NovoSeven RT, Novo Nordisk) is licensed for the treatment of congenital hemophilia with inhibitors, acquired hemophilia, congenital factor VII deficiency and Glanzmann thrombasthenia that is refractory to platelets.
“Serious thrombotic events have been reported in clinical trials and postmarketing surveillance,” the researchers wrote. “However, the incidence of this risk is considered to be low within labeled indications. While many general risk factors are noted in the prescribing information, the association of reported thrombotic events with certain risk factors noted in the prescribing information has not been established.”
Madhvi Rajpurkar, MD, division chief of hematology and director of the pediatric thrombosis program at Children’s Hospital of Michigan and professor at Wayne State University, and colleagues conducted a retrospective safety analysis of clinical trials and registries that validated the licensed indications for coagulation factor VIIa recombinant and evaluated postmarketing use of the agent. This analysis was used to calculate the rate of thrombotic events across licensed indications for coagulation factor VIIa recombinant. The researchers also examined all postmarketing case reports of thrombotic events in the Novo Nordisk safety database – from registries, spontaneous reports and the literature – for risk factors included in the prescribing information that increased the likelihood of events and “the temporal relationship to coagulation factor VIIa recombinant use,” defined as 48 hours or less because of the agent’s half-life of 2-3 hours.
An overall thrombosis rate of 0.17% in 12,288 bleeding and surgical episodes was observed in clinical trials and registries as well as postmarketing analysis for coagulation factor VIIa recombinant. The total number of thrombotic events was 21, including 12 among patients with congenital hemophilia with inhibitors, 5 in patients with acquired hemophilia, 3 in patients with factor VII deficiency and 1 in a patient with Glanzmann’s thrombasthenia. The level of specific risk according to indication was 0.11% for congenital hemophilia with inhibitors (11,121 episodes), 0.19% for Glanzmann’s thrombasthenia (518 episodes), 0.82% for factor VII deficiency (367 episodes) and 1.77% for acquired hemophilia (282 episodes).
The examination of all postmarketing databases identified 213 thrombotic events, including 88 in congenital hemophilia with inhibitors, 61 in acquired hemophilia, 53 in factor VII deficiency and 11 in Glanzmann’s thrombasthenia. Most events (n = 141) were conveyed spontaneously; fewer events were described in the literature (n = 47) or in registries or investigator-supported studies (n = 25).
The temporal relationship was determined to be “plausible” in 188 (88%) of 213 thrombotic events when treatment with coagulation factor VIIa recombinant was noted within 48 hours before the event or the timing was not known. The timing of treatment with coagulation factor VIIa recombinant occurred more than 48 hours before the event in 25 (12%) of cases.
The most frequent risk factor associated with an increased likelihood of thrombotic events was “elderly” age, defined in the prescribing information as 65 years and older (29%). This risk factor was most often observed in patients with acquired hemophilia and thrombotic events (67%). Simultaneous use of activated prothrombin complex concentrates also increased the likelihood of thrombotic events; this approach was observed in 18% of all thrombotic events and 34% of thrombotic events in patients with congenital hemophilia with inhibitors. “Broadly defined” cardiovascular disease, including arrhythmias, was seen in 18% of all thrombotic events, including 36% of events in patients with acquired hemophilia, 15% of events in patients with factor VII deficiency and 9% of events in patients with congenital hemophilia with inhibitors, and was much more likely than the “specific note of atherosclerotic disease (2%),” according to the study results.
Additional risk factors listed in the prescribing information occurred infrequently, or not at all, in the reports of thrombotic events. These risk factors included postoperative immobilization, sepsis, liver disease, disseminated intravascular coagulation, postpartum hemorrhage, crush injury, being a neonate and being pregnant.
The rate of thrombotic events within the licensed indications for coagulation factor VIIa recombinant is low, “as was originally described in the U.S. prescribing information from 1999-2009,” the researchers wrote, and “... has remained stable over time during postapproval surveillance in multiple U.S. and global registries.” - by Julia Ernst, MS
Rajpurkar M, et al. Abstract 1203. Presented at: ASH Annual Meeting and Exposition; Dec. 1-4, 2018; San Diego.
Disclosures: Rajpurkar reports receiving honoraria from HEMA Biologics, Novo Nordisk, Pfizer and Shire and receiving research funding from Bristol-Myers Squibb and Pfizer. Please see the abstract for all other authors’ relevant financial disclosures.