Critical bleeding events in patients receiving warfarin anticoagulation poses significant morbidity and mortality risk (1). The annual incidence of major bleeding associated with warfarin reported in a pooled analysis of three clinical trials comparing warfarin to novel oral anticoagulants (NOACs) in atrial fibrillation patients was 3.09%-3.57%, with intracerebral hemorrhage (ICH) and gastrointestinal (GI) bleeding having a reported incidence of 0.70%-0.80% and 0.86%-1.02%, respectively (2). When critical bleeding occurs, rapid reversal of the anticoagulant effects of warfarin can slow or arrest progression of the bleed and allow for treatment interventions to correct the cause and source of the bleed.
The International Normalized Ratio (INR) is the currently recommended laboratory assessment used to determine reversal of warfarin anticoagulation (1). Traditional strategies for reversal of warfarin’s anticoagulation effects and the lowering of INR include discontinuation of warfarin, administration of vitamin K to promote hepatic biosynthesis of vitamin K-dependent clotting factors II, VII, IX, and X (3), and fresh frozen plasma (FFP) to replace functional clotting factors (4). These strategies, while effective, are limited because the time to reverse the INR is delayed over several hours (5). The onset of action of intravenous (IV) vitamin K to lower the INR is one to two hours, and longer when given orally (PO) (3, 6). Fresh frozen plasma requires time for thawing and blood group matching and is administered in large volumes, usually over 30 minutes (4). Risks associated with administration of FFP, including transfusion reactions, transmission of infections, transfusion related lung injury, and the risk of complications associated with volume overload secondary to the large fluid volume of FFP (4).
Recent strategies to rapidly reverse warfarin anticoagulation include the administration of prothrombin complex concentrate (PCC), also known as factor IX complex, in the setting of critical bleeding or emergent surgery. These products can be administered more quickly and normalize the INR more rapidly than FFP (7). Prothrombin complex concentrate products are derived from pooled human plasma and are free of viral contaminants. They vary in composition and amount of clotting factors (1). All PCC products contain factors II, IX, and X, but 3-factor PCC (PCC3) products differ in that they contain low amounts of factor VII. Four factor PCC products contain higher concentrations of factor VII (7). Several recent guidelines recommend PCC4 (along with vitamin K), as a first line agent for emergent warfarin reversal (EWR). Plasma is recommended as an alternative if PCC4 is not available (1, 4, 8–13). Prior to 2013, only PCC3 products were available in the United States (US). These products were used off-label and with no guidance for dosing for EWR. In April 2013, the US Food and Drug Administration (FDA) approved a PCC4 product for warfarin reversal that contains clotting factors II, VII, IX, and X, as well as the anticoagulant proteins C and S, heparin, antithrombin III, and human albumin. This product was approved based on randomized, noninferiority, plasma-controlled studies that found more rapid reversal of the INR with PCC4 (14–16).
Given the compositional differences in the PCC products, it is important to know if there are differences in clinical response for effective and safe use of these products. Studies evaluating the comparative effects of PCC3 and PCC4 head-to-head for EWR with the outcome of INR lowering response and/or clinical outcomes are few (17–23). The inclusion criteria for these studies vary, but all were in adult patients needing reversal of warfarin for bleeding, surgical intervention, and/or trauma associated bleeding. These studies did not control for pre-defined times between dose and INR measurements, thus allowing for varied durations of time for coagulation reversal from PCC and other reversal agents. The only systematic review and meta-analysis compares separate studies of PCC3 and PCC4 from various institutions rather than head-to-head comparisons (24).
The aim of this study is to describe and characterize the differences in efficacy of INR lowering between PCC4 and PCC3 in patients who required EWR. To maximize our analysis reflecting the response of PCC on INR while minimizing effects of external factors, we restricted our patient inclusion to those who received PCC within 6 hours of the baseline INR and the pre- and post-PCC INR measurement to be no greater than 12 hours. Our primary outcome is achieving an INR of 1.5 or less after the first dose of PCC. Additionally, we explored the change in INR, thromboembolic events (TE), death during hospital stay and length of stay between the PCC3 and PCC4 groups.