Continuous into-the-vein (intravenous) infusions of Advate immediately before and after major orthopedic surgery is as safe and effective as standard, short, bolus infusions at preventing bleeds in men with moderate-to-severe hemophilia A.
That finding from a Phase 3/4 clinical trial — the first controlled trial to compare the two types of treatment administration — suggests continuous infusion may be a viable alternative to bolus infusion in hemophilia A patients undergoing major surgery requiring drain placement.
Trial data was reported in the study, “Results of a randomized phase III/IV trial comparing intermittent bolus versus continuous infusion of antihaemophilic factor (recombinant) in adults with severe or moderately severe haemophilia A undergoing major orthopaedic surgery,” published in the journal Haemophilia.
Hemophilia A is caused by a missing or defective blood-clotting protein, called factor VIII (FVIII), that impairs the body’s ability to prevent excessive bleeding.
Originally developed by Shire, now part of Takeda, Advate is a replacement therapy that works by delivering a lab-made version of FVIII to hemophilia A patients as a prophylactic, or preventive measure, to avoid spontaneous bleeds, as well as excessive bleeding after surgery.
When used in the perioperative period — starting immediately before surgery up until recovery, once the procedure is completed — this type of treatment is typically administered via low-dose, short bolus infusions at regular time points determined by its pharmacological profile.
Continuous, gradual infusion was developed to reduce the wide variations in blood FVIII levels that usually are observed with bolus infusions and may increase the risk of bleeds, as well as to lower the amount of FVIII used.
While previous studies have shown that continuous infusion of FVIII is well-tolerated and effective for managing perioperative bleeds, no appropriately-controlled study has compared continuous versus bolus infusions in the same setting.
This international Phase 3/4 trial (NCT00357656) evaluated whether Advate’s continuous infusion was at least as safe and effective at preventing bleeds as standard, bolus infusions in 72 men with moderate-to-severe hemophilia A undergoing major orthopedic surgery that required drain placement.
The study comprised a pre-surgery period, in which participants received a single dose of Advate to assess its pharmacokinetics (movement into, through, and out of the body) and determine the optimal doses for the perioperative period — covering the immediate moment before surgery until a week after the procedure. This was followed by a safety follow-up period, from post-surgery day 8 to the end‐of‐study visit (six weeks following surgery).
Of the 72 men receiving the therapy in the pre-surgery period, 63 were assigned randomly to receive Advate, either through continuous infusion (32 patients, 23 with severe hemophilia A) or bolus infusion (31 patients, 26 with severe disease), during the perioperative period.
Three patients in the continuous infusion group did not undergo surgery, and for that reason were not included in the effectiveness analysis. In the remaining 60 patients from both groups, 48 (80%) underwent knee replacement surgery, eight (13%) had surgery involving the shoulder, elbow, ankle, or knee, and four (7%) had hip surgery.
Results showed that the cumulative volume of red blood cells in the drainage fluid 24 hours post-surgery was similar between the two groups, meeting the trial’s main goal of demonstrating both modes of administration were equally effective at controlling bleeds.
Total blood loss until drain removal, number of bleeding episodes up until post-surgery day 7, and number of units of red blood cells transfused also were not significantly different between the two groups.
Notably, of the four bleeding episodes reported up until day 7 after surgery, three (75%) occurred in the bolus infusion group.
Both groups also received similar Advate doses per kilogram of body weight to maintain target FVIII levels during or after surgery, again highlighting the comparable effectiveness of both treatment regimens.
Safety analysis, comprising data from the 72 participants, showed that 51 (70.8%) patients experienced an adverse side effect, which were deemed to be related to treatment in 10 of them (five from each group) and were mostly considered non-serious.
A total of 10 serious adverse events were reported, including the development of antibodies against the delivered FVIII in four men, two from each group, and all with severe hemophilia A. The other six serious adverse events were deemed to be unrelated to treatment.
Continuous infusion of replacement therapy “is a viable alternative to BI [bolus infusion] in patients with hemophilia A undergoing major orthopedic surgery, providing comparable efficacy and safety,” the researchers wrote.
“These findings may help inform perioperative [bleeding] management of these patients, with the goal of maintaining stable FVIII levels during and after surgery, whether by the use of CI [continuous infusion] or BI regimens,” the team added.
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