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

Introduction: The 4-factor prothrombin complex concentrates (4F-PCCs) are very effective in urgent reversal of vitamin K antagonist (VKA) anticoagulant therapy, including correction of the International Normalized Ratio (INR). This study (LEX-209) compared the hemostatic efficacy of an investigational 4F-PCC (Octaplex®; Octapharma) with a control 4F-PCC (Beriplex® P/N, also known as Kcentra®; CSL Behring).

Methods: Patients included were ≥18 years old, on VKA therapy, hospitalized for urgent surgery with a significant bleeding risk (≥50 mL) for which VKA withdrawal and intravenous vitamin K were considered to be insufficient, and had an INR ≥2.0. Patients received a single intravenous 4F-PCC dose of 25, 35, or 50 international units (IU)/kg body weight per baseline INR (2-<4, 4-6, >6, respectively); infusion rate was 0.12 mL/kg/min (~3 IU/kg/min) up to 8.4 mL/min (~210 IU/min). The primary endpoint was hemostatic efficacy rating at surgery end assessed by a blinded Independent Endpoint Adjudication Board using establised objective criteria. Secondary efficacy endpoints were the proportion of patients with INR ≤1.5, and changes in coagulation factor levels (FII, FVII, FIX, FX), at 30 (±15) minutes post-infusion. Safety endpoints included treatment-emergent adverse events (TEAEs), and thromboembolic events (TEEs) and mortality at 3, 21, and 45 days post-surgery. The Farrington-Manning test was used to assess the primary hypothesis that investigational 4F-PCC was non-inferior to control 4F-PCC (80% power, 15% non-inferiority margin). A pre-planned interim analysis was performed on the first 50% of randomized patients (≥185 patients).

Results: This Phase 3 study was performed at 24 sites in the USA and Europe from June 2017-November 2021 and randomized 208 patients to investigational 4F-PCC (N=105) or control 4F-PCC (N=103). Baseline characteristics with respect to age, sex, and baseline INR for patients included in the two groups were similar, and the most common location of the planned surgery was gastrointestinal. The pre-procedural estimated maximum blood loss ≥200 mL was also similar in both groups (67.6% vs. 67.0% patients, respectively). Median dose was 25 IU/kg in both groups (range: 16-50 IU/kg investigational 4F-PCC, 15-50 IU/kg control 4F-PCC). Median (range) duration of infusion was 12 (8-50) minutes and 13 (7-30) minutes, respectively.

The primary objective was met at the interim analysis and the study was stopped for non-inferiority. In the final analysis, investigational 4F-PCC was non-inferior to the control 4F-PCC, with effective hemostasis at surgery end achieved in 94.3% vs. 94.2% patients (Table 1). The proportion of patients achieving INR ≤1.5 was 78.1% with investigational 4F-PCC vs. 71.8% with control 4F-PCC (proportion difference 0.063; 95% confidence interval [CI] −0.056, 0.181; Figure 1). No patient had surgery cancelled for inadequate INR correction. Mean activities of coagulation factors (FII, FVII, FIX, FX) similarly increased in both groups.

Similar proportions of patients in the investigational and control 4F-PCC groups experienced TEAEs (81.9% vs. 77.7%) and drug-related TEAEs (both 1.0%). The most common adverse reactions observed in patients who received investigational 4F-PCC were asthenia, anemia, and catheter site related reaction. One death occurred <21 days post-surgery, in the control 4F-PCC group, which was considered unrelated to the product by the investigator. Two TEEs occurred <21 days post-surgery in the investigational 4F-PCC group (unstable angina on day 5, reported as possibly related).

Conclusions: The investigational 4F-PCC was non-inferior to control 4F-PCC for reversal of VKA in patients undergoing urgent surgery with significant bleeding risk. INR reductions and coagulation factor increases supported the primary endpoint. The safety profile was similar between treatment arms and consistent with previous studies.

Sarode:Siemens: Research Funding; Octapharma: Consultancy; VarmX: Consultancy; Cerus: Research Funding; CSL Behring: Consultancy; Takeda: Research Funding. Goldstein:Pfizer: Research Funding; Takeda: Research Funding; Octapharma: Research Funding; CSL Behring: Consultancy; AstraZeneca: Consultancy; Cayuga: Consultancy; NControl: Consultancy. Simonian:Octapharma: Consultancy. Milling Jr:CSL Behring: Consultancy; Octapharma: Consultancy; Genentech: Research Funding.