Smaller Volume and Faster Infusion Rate of aPCC: What Do Current Data Say About This Modification?

Introduction

Activated prothrombin complex concentrate (aPCC) is a bypassing agent (BPA) used in the treatment of acute bleeding or perioperative management of patients with hemophilia A with inhibitors. It can also be used for prophylaxis of bleeding episodes in these patients. Dosage is, of course, individualized, with a general recommendation of 50−100 U/kg body weight, and an infusion rate of 2 U/kg/min.

Study Methodology

This prospective, multicenter, open-label, randomized, crossover study included patients aged 18−65 years with hemophilia A or B of any severity, and with an inhibitor level > 0.6 BU. Participants were required to have a negative test for hepatitis C and HIV, or stable conditions if positive. Excluded were patients taking emicizumab, immunomodulators, or other study medications.

The study took place across 18 centers in 8 countries and consisted of two parts:

1. In the first part, patients were randomized into two groups. The first group received three standard-volume aPCC infusions (85 ± 15 U/kg) followed by three reduced-volume aPCC infusions, all administered at 2 U/kg/min. The second group received the infusions in the reverse order—reduced volume first, then standard volume.
2. In the second part, patients who received at least two out of three infusions in the first part and reported no issues continued. They were given three aPCC infusions at reduced volume—first at 4 U/kg/min, then at 10 U/kg/min.

The study evaluated adverse events (AEs), allergic hypersensitivity reactions, infusion reactions, thromboembolic events, factor II (FII) activity, and patient satisfaction with treatment.

Results

The study ultimately enrolled 33 male patients with hemophilia A, with a mean age of 35.4 years and a median inhibitor level of 14.4 BU. Of these, 90.9% (30 patients) completed the first part of the study. Two patients discontinued the study due to drug-related hypersensitivity. In the second part, 93.3% (28 patients) completed the study, with two patients discontinuing early due to severe D-dimer elevation and physician decision.

A total of 33 AEs were reported in 15 patients, with 12 AEs in 9 patients related to aPCC administration. No cases of thromboembolism were reported. The most common AEs were joint pain and headache. Four serious AEs were reported, including epilepsy, muscle bleeding, and hypersensitivity reactions. More AEs were reported in the first part of the study (7 patients vs. 3 in the second part). Hypersensitivity reactions were noted in 5 cases among 4 patients, with one serious case. Three infusion reactions occurred in two patients, all in the first part. FII levels showed no clinically significant differences between the different types of administration.

Patient satisfaction was highest after the 4 U/kg/min infusion in the second part of the study.

Conclusion

The administration of aPCC at infusion rates of 4 and 10 U/kg/min with a 50% reduction in volume was well-tolerated by patients, with no worsening of the safety profile compared to the standard infusion method.

(Author initials: jala)

Source:

Zülfikar B., Mahlangu J., Nekkal S. M. et al. Reduced volume and faster infusion rate of activated prothrombin complex concentrate: a phase 3b/4 trial in adults with hemophilia A with inhibitors. TH Open 2024 Jul 8; 8 (3): e273–e282, doi: 10.1055/s-0044-1787781.