Octaplex, an investigational 4-factor prothrombin complex concentrate (4F-PCC), was noninferior to a control 4F-PCC for reversal of vitamin K antagonist (VKA) anticoagulant therapy in patients undergoing urgent surgery with significant bleeding risk, according to study results presented at the 2022 ASH Annual Meeting.
The phase 3 LEX-209 study compared the hemostatic efficacy of Octaplex (Octapharma) with a control 4F-PCC (Beriplex P/N, also known as Kcentra; CSL Behring).
Participants were aged 18 years and older, were receiving VKA therapy, were hospitalized for urgent surgery with significant bleeding risk (50 mL or more) for which VKA withdrawal and intravenous (IV) vitamin K were considered insufficient, and had an International Normalized Ratio (INR) ≥2.0. All patients received 1 dose of IV 4F-PCC 25, 35, or 50 IU/kg body weight per baseline INR (2 to <4, 4 to 6, and >6, respectively). The infusion rate was 0.12 mL/kg/min (approximately 3 IU/kg/min) up to 8.4 mL/min (approximately 210 IU/min).
Hemostatic efficacy rating after surgery, evaluated by a blinded independent endpoint adjudication board, was the primary endpoint. Secondary efficacy endpoints were the proportion of patients with INR reduction to ≤1.5 and changes in coagulation factor levels (Factor II, Factor VII, Factor IX, Factor X) at 30±15 minutes after infusion. Safety endpoints included treatment-emergent adverse events (TEAEs); thromboembolic events (TEEs); and mortality at 3, 21, and 45 days postsurgery.
The primary hypothesis that the investigational 4F-PCC was noninferior to the control 4F-PCC (80% power, 15% noninferiority margin) was assessed using the Farrington–Manning test. An interim analysis was conducted in the first 50% of patients (at least 185 patients) randomly assigned to either study arm.
A total of 208 patients at 24 sites in the United States and Europe from June 2017 to November 2021 were randomly assigned to receive the investigational 4F-PCC (n=105; median age, 67.0 years; 55.2% male) or the control 4F-PCC (n=103; median age, 68.0 years; 58.3% male). Median baseline INR was 3.0 in both groups.
The presurgical estimated maximum blood loss of 200 mL or more was comparable in the investigational and control groups (67.6% vs 67.0%, respectively). Both groups received a median dose of 25 IU/kg (range, 16-50 IU/kg and 15-50 IU/kg, respectively). The median infusion duration was 12 minutes (range, 8 to 50) and 13 minutes (range, 7 to 30), respectively. The most common location of planned surgeries was gastrointestinal.
The primary objective was achieved during the interim analysis, and the study was stopped for noninferiority. The final analysis demonstrated that the investigational 4F-PCC was noninferior to the control 4F-PCC (proportional difference, 0.001; 95% CI, −0.080 to 0.082; P <.001). Effective hemostasis at the end of surgery occurred in 94.3% of patients in the investigational group and 94.2% in the control group.
The proportion of patients with an INR correction to ≤1.5 was 78.1% in the investigational group compared with 71.8% in the control group (proportion difference, 0.063; 95% CI, −0.056 to 0.181). No patient had a surgery cancelled owing to inadequate INR correction, and the mean activities of coagulation factors were comparable in the 2 treatment groups.
TEAEs occurred in 81.9% of patients receiving the investigational 4F-PCC and 77.7% of those receiving the control 4F-PCC. Drug-related TEAEs occurred in 1 patient in each study group. The most frequently occurring adverse reactions among participants who received the investigational 4F-PCC were asthenia, anemia, and catheter site–related reaction.
TEAEs with a fatal outcome occurred in 5 patients in the investigational group and 1 patient in the control group. TEEs occurred in 3 patients in the investigational group and none in the control group.
Disclosure: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.
Sarode R, Goldstein JN, Simonian G, Milling TJ Jr. A phase 3, prospective, randomized, double-blind, multicenter, non-inferiority study comparing two four-factor prothrombin complex concentrates for reversal of vitamin K antagonist-induced anticoagulation in patients needing urgent surgery with significant bleeding risk. Presented at ASH 2022. December 10-13, 2022. Abstract 144.