Risk of Bleeds in Hemophilia A Influenced by Treatment History, Other Factors, Study Suggests

The risk of spontaneous bleeding episodes in patients with severe hemophilia A receiving preventive treatment changes over time and can be influenced by treatment history and other patient-related factors, a study has found.

As such, the choice of an individual preventive — or prophylactic — regimen should take into account each patient’s age, joint disease activity, and other parameters that have a direct impact on the risk of bleeds, according to the investigators who conducted the research.

Published in the journal Haematologica, the study is titled “Factor VIII activity and bleeding risk during prophylaxis for severe hemophilia A: a population pharmacokinetic model.”

Hemophilia impairs the body’s ability to prevent excessive bleeding. In hemophilia A, this is caused by a lack of a clotting protein called factor VIII (FVIII).

One of the standard treatments for hemophilia A is based on providing the missing FVIII to patients prophylactically, or as a preventive measure, to avoid spontaneous bleeding episodes — a form of treatment known as replacement therapy.

Prior research has shown that in patients with severe hemophilia A — those who have less than 1% of normal FVIII activity — on prophylactic treatment, longer periods with FVIII activity levels below 1% mean a greater risk of spontaneous bleeds.

However, data from an epidemiological study in patients with mild or moderate forms of the disease suggested that maintaining FVIII activity levels above 1% is insufficient to protect all patients from spontaneous bleeds.

To investigate the relationship between FVIII activity levels and the risk of spontaneous bleeds in people with severe hemophilia A on prophylaxis, the researchers analyzed data from three clinical trials that assessed Novoeight (turoctocog alfa).

Novoeight, marketed by Novo Nordisk, is approved by the U.S. Food and Drug Administration to control and prevent bleeding in hemophilia A patients. The three Novo Nordisk-sponsored studies — two Phase 3 trials called guardian 1 (NCT00840086) and guardian 3 (NCT01138501), and an extension study called guardian 2 (NCT00984126) — assessed the safety and efficacy of Novoeight in adults, adolescents, and children with severe hemophilia A.

Using data from the three trials and with funding from Novo Nordisk, the investigators created a population-based pharmacokinetic model of Novoeight. Pharmacokinetics is the study of how a compound is absorbed, distributed, metabolized, and eliminated from the body.

They then combined these data with patient diaries containing information about treatment dosing and spontaneous bleeds.

The patients’ time on prophylaxis was divided into five groups, based on estimations of FVIII activity levels in relation to their normal range: up to 1% (group 1); 1–5% (group 2); 5–15% (group 3); 15–50% (group 4); and more than 50% (group 5).

Exposure time, mean FVIII activity, and number of bleeds (from patient diaries) were calculated for each group. Statistical analyses were used to estimate annualized bleeding rates (ABRs), that is, the number of bleeds occurring within one year.

Relationships between ABRs and FVIII activity levels were assessed by trial phase (pivotal versus extension study) and patients’ age — adults and adolescents ages 12 and older; and children under 12.

Analyses included data from 231 patients — 168 adults and 63 children — with hemophilia A who participated in at least one of the three trials. All patients received Novoeight prophylactically, at a dose of 20–50 international units (IU)/kg every second day, or 20–60 IU/kg three times weekly, depending on their age.

A total of 1,237 spontaneous bleeds occurred over the course of the three studies. Of these, 1,063 were in adults and adolescents, and 174 in children. Most of these episodes (85.3%) were joint bleeds.

Estimates indicated that FVIII activity levels remained at 1% or higher 85.6% of the time patients were on prophylaxis.

ABRs also tended to decrease when FVIII activity levels increased, according to the analyses. This was true in both types of trials across all patient ages.

However, for each FVIII activity level group, ABRs were lower in children than in adults and adolescents during the pivotal trials, and in all patients during the extension study compared with the pivotal stages.

“This suggests that bleeding risk can change over time and is influenced by factors independent of factor VIII pharmacokinetics and trough [minimum] levels,” the researchers wrote.

“Choice of prophylactic regimens to target certain trough levels should take into account patient age, joint disease activity, and other determinants of bleeding risk,” they added.