Initial Experience with 4-Factor PCC for the Reversal of Warfarin: Patterns of Use and Safety Outcomes

Major bleeding among patients receiving oral anticoagulants is common and is reported to occur in up to 6.5% of patients per year. Vitamin K antagonists (VKA) remain the most frequently prescribed class of anticoagulants for conditions such as atrial fibrillation, mechanical heart valves and venous thromboembolism. The products used for the reversal of VKA-associated coagulopathy include Vitamin K, fresh frozen plasma (FFP), activated recombinant factor VII (rFVIIa), and Prothrombin Complex Concentrates (PCC).

Kcentra® (CSL Behring Gmbh, Marburg, Germany) is a 4-factor PCC that contains all of the vitamin K-dependent proteins (Factors II,VII, IX, X, Protein C and S). While Kcentra® has been in use in Europe and other parts of the world for several years, it was only recently approved in the United States for warfarin reversal during acute major bleeding (April, 2013) or when there is a need for an urgent invasive procedure (December 2013).

We conducted a retrospective study to evaluate the use of 4-factor PCC in a community-based tertiary care center. The efficacy and safety of PCCs has been established in large multi-center trials. However, there is limited data from outside of carefully conducted clinical trials. In particular, there is a paucity of data regarding the use of 4-factor PCC in the community setting, specifically from the United States. We developed protocols for the reversal of warfarin for life-threatening bleeding and emergent surgery. All patients get vitamin K and they receive Kcentra® if the INR is ≥ 2. If the INR is < 2 they receive plasma. The dose of Kcentra® is based on pre-treatment INR (25 u/kg for INR 2 to < 4, 35 u/kg for INR 4-6 and 50 u/kg for INR >6).

We identified 33 patients from July 2013 to April 2014 that were treated with 4-factor PCC (18 males and 15 females). The mean age was 71.06 +/- 14.04 years (Range 42-94). Kcentra® was used appropriately, per our institutional protocol for VKA reversal, in 28/33 (84.35%) cases. Four of the patients, who were treated inappropriately, did not have a drug history on admission and were subsequently found to have an elevated INR due to liver dysfunction. The leading indications for PCC use were intracranial hemorrhage (49%), reversal of elevated INR prior to surgery (21%) and gastrointestinal bleeding (15%). 73% of patients had a pre-reversal INR in the range of 2-4, 12% had INR of 4-6 and15% of patients presented with an INR of >6. The indications for warfarin use included atrial fibrillation (50% patients), prosthetic valve (21.4%) and prior deep vein thrombosis and pulmonary embolism in 18% patients. 40% patients were also receiving concomitant antiplatelet therapy.

The mean administered dose of Kcentra® was 2461 +/- 825 units (Range 1375-4715). Among patient treated for reversal of VKA-related coagulopathy, the pre-treatment INR was 4.6 (range 2-17) and mean post-treatment INR was 1.32 (range 1.1-1.9). Post-treatment INR of ≤ 1.5 was attained in 24/33 (73%) patients. Post-treatment INR was not available for one patient. There was only one case of thrombosis within 72 hours of treatment (myocardial infarction). 28/33 patients (85%) were alive at 24 hours.

Based on experience from our limited number of patients, we have found Kcentra® to be effective in the rapid reversal of INR in the setting of VKA associated coagulopathy. Kcentra® was successfully used for a wide variety of indications in our patient population. Arterial and venous thromboembolic complications have previously been reported in patients receiving 4-factor PCC. We found a low complication rate in our patients with only one patient developing a thrombotic phenomenon (acute coronary event) within 72 hours of administration of Kcentra®. In conclusion, based on our experience, we have found Kcentra® to be a safe and effective agent for reversal of VKA associated coagulopathy.