Prothrombin Complex Concentrate (Human) Lyophilized Powder (Kcentra)
By William T. Elliott, MD, FACP, and
James Chan, PharmD, PhD
Dr. Elliott is Chair, Formulary Committee, Northern
California Kaiser Permanente; and Assistant Professor
of Medicine, University of California, San Francisco.
Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA
Drs. Elliott and Chan report no financial relationships relevant to this field
A new product has been approved for the urgent reversal of warfarin or other vitamin K antagonists anticoagulation in the setting of acute bleeding. This human plasma-derived product contains vitamin K-dependent coagulation Factors II, VII, IX, and X as well as antithrombotic Protein C and Protein S. It is heat-treated and viral filtered. Prothrombin complex concentrate (PCC) is manufactured by CSL Behring GmbH in Germany and marketed by CSL Behring LLC as Kcentra. The product has been licensed in Germany since 1996.
PCC is indicated for the urgent reversal of acquired coagulation factor deficiency induced by vitamin K antagonist (e.g., warfarin) in adults with acute major bleeding.1
The dose of PCC is individualized based on the patient’s INR value and body weight, and is given as a single dose.1 The dose is 25 units/kg of Factor IX for INR from 2-4, 35 units/kg for 4-6, and 50 units/kg if INR is > 6. Vitamin K should be given concurrently. PCC is available as single-use vials.
Compared to frozen plasma, PCC does not require blood group typing or thawing, and therefore can be administered more quickly in the setting of acute bleeding. It is also given at a significantly lower volume for a shorter time, and there is a standardized dose of clotting factors indexed to factor IX.1,2
There appears to be a higher risk of thromboembolic events with PCC than plasma, particularly in patients with prior thromboembolic events or coronary, cerebrovascular, or peripheral vascular disease.1 PCC contains heparin and is contraindicated in patients with known heparin-induced thrombocytopenia.1
The approval of PCC was based on a prospective, open-label (blinded assessor), active-controlled, non-inferiority randomized study.1 Subjects (n = 216) who required urgent replacement of their vitamin K-dependent clotting factors to treat acute bleeding were randomized to a single dose of PCC or plasma along with intravenous vitamin K. Efficacy endpoint was hemostatic efficacy as assessed by a blinded, independent board using standard clinical assessments. This was based on vital signs, hemoglobin measurements, and CT assessments depending on the type of bleed. Treatment outcomes were categorized as "effective" or "not effective." Efficacy endpoint was assessed in the first 24 hours and the observation period lasted for 90 days. An additional endpoint was the reduction of INR to 1.3 or less at 30 minutes after the end of infusion. Success rate was 72.4% for PCC and 65.4% for plasma meeting the criteria for non-inferiority (absolute difference of -10%) but not superiority. PCC was superior to plasma in the reduction of INR (62.2% vs 9.6%). Results from a post-hoc analysis by the FDA suggested that plasma may be more effective than PCC in patients with gastrointestinal bleeding.2 The 45-day, all-cause mortalities were nine in the PCC group and five in the plasma group (risk ratio, 1.91; 95% confidence interval, 0.66, 5.50).3 Subjects randomized to PCC with prior history of thromboembolic events (TE) had numerically higher frequency of TE compared to those without prior history [9/69 (13%) vs 1/34 (2.9%)].3 This did not reach statistical difference. The corresponding frequencies for plasma were 3/79 (3.8%) and 3/30 (10%).
PCC provides a new option to plasma to reverse vitamin K antagonist anticoagulation therapy in patients with acute major bleeding. It is more convenient to use than plasma. On the other hand, the risk of thromboembolism may be higher, particularly in patients with a prior TE history. To help address this risk, the FDA has required the sponsor to conduct a retrospective, case-control study as well as a randomized, controlled study to evaluate a lower dose of PCC.2
1. Kcentra Prescribing Information. King of Prussia, Pa: CSL Behring LLC; April 2013.
2. http://www.fda.gov/downloads/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/LicensedProductsBLAs/FractionatedPlasmaProducts/UCM352142.pdf. Accessed June 21, 2013.
3. http://www.fda.gov/downloads/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/LicensedProductsBLAs/FractionatedPlasmaProducts/UCM352573.pdf. Accessed June 21, 2013.