Abstract
Background and Significance: Four-factor prothrombin complex concentrates (4F-PCCs) are approved for rapid reversal of acquired coagulation factor deficiency induced by vitamin K antagonist (VKA) therapy in adult patients presenting with major bleeding or requiring urgent surgery. In addition to this approved use, 4F-PCCs are increasingly being used in other settings, including the management of direct oral anticoagulant (DOAC)-associated bleeding when specific DOAC antidotes are unavailable. The LEX-210 study aims to investigate the efficacy and safety of two dosing strategies for the 4F-PCC Balfaxar/Octaplex (Octapharma) in patients with DOAC-associated major bleeding (currently off-label in the US). Despite the increasing use of DOACs, including factor Xa inhibitors (FXaIs), millions of patients in the US continue to receive VKA therapy. The LEX-212 study aims to assess the safety of Balfaxar vs. a comparator 4F-PCC (Kcentra/Beriplex, CSL Behring) for the urgent reversal of VKA-induced anticoagulation in real-world surgical settings, complementing evidence from clinical trials.
Study Design and Methods: LEX-210 (NCT04867837) is a Phase 3, multicenter, prospective, double-blinded, group-sequential, parallel-group, adaptive design study with a preplanned interim analysis for potential sample size modification. Approximately 260 patients aged ≥18 years with acute major bleeding while on FXaI therapy will be randomized 1:1 to receive low-dose (15 IU/kg) or high-dose (50 IU/kg) 4F-PCC, with the aim to include at least 91 evaluable patients in each group in the full analysis set (FAS). Enrollment may continue as planned, be increased, or stopped based on an unblinded interim analysis from the first 30 evaluable patients in each group. Patients must have known or suspected baseline DOAC-specific anti-FXa activity of ≥100 ng/mL. Key exclusion criteria are patients with acute trauma for which reversal of FXaI alone would not be expected to control bleeding, and thromboembolic events (TEEs) within the prior 3 months. The primary endpoint is the proportion of patients in whom 4F-PCC demonstrates hemostatic effectiveness within 24 hours after treatment, assessed by an Independent Data Monitoring and Endpoint Adjudication Committee using a binary outcome of ‘effective’ (rating of excellent or good) or ‘non-effective’ (rating of poor/none). The primary endpoint will be compared between groups using a one-sided z-test, adjusted for baseline anti-factor Xa activity as determined retrospectively by the central laboratory. Secondary endpoints include endogenous thrombin potential, TEEs, all-cause mortality, and adverse events through 30 days.
LEX-212 (NCT06429787) is a post-marketing, multi-site, observational study enrolling an estimated 3,574 patients aged ≥18 years who received either Balfaxar or Kcentra for reversal of VKA-induced anticoagulation within 48 hours before urgent surgery or invasive procedure. Exclusion criteria are history of TEEs within 90 days before receiving VKA reversal therapy, and treatment with VKA reversal therapy but not undergoing urgent surgery or invasive procedure. Data will be obtained from electronic healthcare records of individual health systems, linked with administrative claims data as necessary. The primary endpoint, defined as the proportion of patients with TEEs within 45 days after treatment with either 4F-PCC, will be compared between groups using a Farrington-Manning test for relative risk, with a one-sided type I error of α = 0.025 and power of 1−β = 0.9. Secondary endpoints include TEE rates within 7 and 14 days, median time to TEE, and all-cause mortality within 7, 14, and 45 days post-treatment. Both studies comply with the Declaration of Helsinki.
LEX-210 commenced in Q3 2021 and is ongoing at ~60 sites in North America and Europe, with more than 80 patients enrolled and treated to date; the study is expected to conclude in Q4 2026. LEX-212 is conducted in the US; the study started in Q1 2025 and has one site initiated and 14 patients enrolled so far, with the study end expected in Q2 2032. These studies will expand the understanding of 4F-PCCs in the context of anticoagulation reversal, with specific emphasis on hemostatic effectiveness in the currently off-label use of DOAC-associated bleeding (LEX-210) and rates of TEEs in the well-established indication of VKA reversal (LEX-212).
