PB1032 - Four-factor prothrombin complex concentrates for vitamin K antagonist reversal before urgent surgery: dosing and hemostatic efficacy in a double-blind randomized study

Background: Four-factor prothrombin complex concentrates (4F-PCCs) are effective for rapidly reversing vitamin K antagonists (VKA) and correcting the International Normalized Ratio (INR). Two 4F-PCCs are available in Canada, from Octapharma and CSL Behring; the labelled infusion rate is lower and the dosing scheme higher for Octapharma 4F-PCC.

Aims: LEX-209 (Octapharma; NCT02740335) was a double-blind randomized controlled trial comparing hemostatic efficacy of investigational 4F-PCC (Octapharma) vs. control 4F-PCC (CSL Behring) infused at the same rate and concentration for VKA reversal before urgent surgery.

Methods: Patients were ≥18 years, on VKA, had INR ≥2.0, and needed urgent surgery with significant bleeding risk (≥50 mL). A 4F-PCC dose of 25, 35, or 50 international units (IU)/kg was given for baseline INR 2– < 4, 4–6, or >6. For both 4F-PCCs, intravenous infusion was at 0.12 mL/kg/minute (~3 IU/kg/minute), up to maximum 8.4 mL/minute (~210 IU/minute), based on the labelled infusion rate of control 4F-PCC. The primary endpoint was hemostatic efficacy at surgery-end, objectively assessed by a blinded independent adjudication board. Non-inferiority was assessed by Farrington–Manning test.

Results: Patients received investigational (N=105) or control (N=103) 4F-PCC. Median dose was 25 IU/kg (both groups). Median (range) infusion time was 12 (8–50) minutes for investigational 4F-PCC, 13 (7–30) minutes for control (Table 1). No patients prematurely discontinued infusion. Median (range) time from infusion-start to surgery-start was 1.42 (0.25–15.25) hours with investigational 4F-PCC, 1.50 (0.42–18.50) hours with control. Investigational 4F-PCC was non-inferior to control for effective hemostasis: 94.3% vs. 94.2%; proportion difference 0.001; 95% confidence interval −0.080, 0.082; p< 0.001. Safety was comparable (Table 2).

Conclusion(s): Investigational 4F-PCC, infused at the same rate and dosed according to the same scheme as the control 4F-PCC, was hemostatically non-inferior for rapid VKA reversal before urgent surgeries carrying significant bleeding risk, with a similar safety profile.