Presentation Details
| A Phase 3, Randomized, Active-Control Study of Four-Factor Prothrombin Complex Concentrate Versus Frozen Plasma in Bleeding Adult Cardiac Surgery Patients Keyvan Karkouti1, 2, Jeannie Callum3, 4, Kenichi Tanaka5, Deep Grewal2, Cristina Solomon6, Sigurd Knaub6, Sylvia Werner7, Gita Pezeshki7, Jerrold H.Levy8. 1University of Toronto, Toronto, ON, Canada.2University Health Network, Toronto, ON, Canada.3Queen’s University, Kingston, ON, Canada.4Kingston Health Sciences Centre, Kingston, ON, Canada.5University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.6Octapharma AG, Lachen, Switzerland.7Octapharma USA, Paramus, NJ, USA.8Duke University School of Medicine, Durham, NC, USA |
Abstract
Background: After cardiac surgery, patients frequently develop coagulopathic bleeding. The etiology of coagulopathy is multifactorial, including anticoagulation, hemorrhage, hemodilution and consumptive losses following tissue injury and during cardiopulmonary bypass (CPB). Reduced thrombin generation caused by coagulation factor deficiency is an important contributor to post-CPB bleeding. Prothrombin complex concentrate (PCC; off-label) and frozen plasma (FP) are administered for coagulation factor replacement during or after surgery; however, the efficacy-safety balance of PCCs in cardiac surgery is unknown, with limited studies in this setting. Objective: The LEX-211 (FARES-II) study will determine if four-factor PCC (4F-PCC, Octaplex, Octapharma) is clinically non-inferior to FP regarding hemostatic efficacy in patients undergoing cardiac surgery with coagulation factor deficiency. Methods: LEX-211 (FARES-II; NCT05523297) is a Phase 3, multicenter, randomized, active-control, prospective trial, conducted at 13 hospitals in Canada and the United States. Patients ≥18 years old undergoing cardiac surgery with CPB, requiring coagulation factor replacement due to bleeding and known or suspected coagulation factor deficiency, are eligible. Exclusion criteria include heart transplant, insertion/removal of ventricular assist devices, expected survival of <24 h, severe right heart failure, heparin contraindications, thromboembolic events in the past 3 months, and IgA deficiency. When the blood bank receives the first order for coagulation factor replacement, patients will be randomized to receive 4F-PCC or FP (Figure 1). For 4F-PCC dosing, patients ≤60 kg will receive 1,500 international units (IU), and those >60 kg will receive 2000 IU. For FP, patients ≤60 kg will receive 3 U, and patients >60 kg will receive 4 U. Patients will receive a maximum of 2 doses of 4F-PCC/FP, according to their assigned group, within the 24-h treatment period. If further treatment is necessary, both groups will receive FP. The primary endpoint is the hemostatic response to 4F-PCC vs. FP, rated ‘effective’ if no additional hemostatic intervention (systemic hemostatic agents, i.e., platelets, cryoprecipitate, other coagulation factor products, a second dose of study drug, or surgical re-opening for bleeding) is required within 60 min–24 h following administration of the first dose. Secondary and safety endpoints are detailed in Table 1. An unblinded interim analysis (100 evaluable patients/group) is planned for futility or sample size re-estimation, if necessary. Non-inferiority of the primary endpoint ‘hemostatic response’ between 4F-PCC and FP will be assessed using a Farrington-Manning score test with a 0.10 non-inferiority margin at a one-sided alpha level of 2.5%. If non-inferiority is determined, the superiority of 4F-PCC with respect to the primary endpoint will be considered. Results: LEX-211 (FARES-II) was initiated in Q4 2022 and is currently in progress. At present, >250 evaluable patients have been included in the study. Interim decisions will be available at the time of presentation. The overall sample size will be ≥410 evaluable patients with completion expected in Q4 2024. Conclusions: The study findings have the potential to improve clinical approaches to bleeding management in cardiac surgery patients. Optimizing the management of bleeding related to coagulation factor deficiency may reduce the need for allogeneic blood products and has the potential to improve outcomes in surgical patients.
No part of this publication may be reproduced, distributed, or transmitted in any form or by any means, including photocopying, recording, or other electronic or mechanical methods, without the prior written permission of the author.
No part of this publication may be reproduced, distributed, or transmitted in any form or by any means, including photocopying, recording, or other electronic or mechanical methods, without the prior written permission of the author.