The Food and Drug Administration has approved a new agent – Kcentra (Prothrombin Complex Concentrate, Human) – for the urgent reversal of vitamin K antagonist (VKA) anticoagulation in adults with acute major bleeding.
Kcentra, manufactured by CSL Behring of *King of Prussia, Pa., is a nonactivated 4-factor prothrombin complex concentrate (PCC). It contains the coagulation factors that are low in warfarin-treated patients: factors II (prothrombin), VII, IX, and X. The product also contains antithrombotic proteins C and S. Fresh frozen plasma is the only FDA-approved product for reversing warfarin-induced acute bleeding. Like plasma, Kcentra is used with administration of vitamin K to reverse the anticoagulation effect and stop bleeding. Unlike plasma, Kcentra can be given quickly because it does not require thawing or determination of blood type.
"The FDA’s approval of this new product gives physicians a choice when deciding how to treat patients requiring urgent reversal of VKA anticoagulation," Dr. Karen Midthun, director of the FDA’s Center for Biologics Evaluation and Research, said in a statement. "Kcentra is administered in a significantly lower volume than plasma at recommended doses, providing an alternative for those patients who may not tolerate the volume of plasma required to reverse VKA anticoagulation."
The American College of Chest Physicians endorsed use of PCC for rapid reversal of VKA-associated bleeding in its 2012 consensus guidelines on anticoagulant therapy (CHEST 2012;141(Suppl):e152S-e184S).
"Kcentra has been shown to restore the decreased vitamin K–dependent clotting factors significantly faster than plasma in patients on warfarin," Dr. Ravi Sarode, the coordinating investigator for the pivotal Kcentra trial and director of transfusion medicine and hemostasis reference laboratory at the University of Texas Southwestern Medical Center, said in a statement issued by CSL Behring.
According to the company, 3-4 million people in the United States each year receive warfarin to prevent clots after a stroke, heart attack, heart valve surgery, or deep vein thrombosis/pulmonary embolism, or for atrial fibrillation. Severe bleeding is possible, however, because of the warfarin-induced clotting factor deficiency. CSL Behring said that some 29,000 emergency department visits annually are for warfarin-associated bleeding.
The FDA said that Kcentra will carry a boxed warning on the risk of blood clots. Patients should be monitored for signs and symptoms of thromboembolic events. "Both fatal and nonfatal arterial and venous thromboembolic complications have been reported in clinical trials and postmarketing surveillance," said the FDA. The warning further states that Kcentra was not studied in subjects who had a thromboembolic event, myocardial infarction, disseminated intravascular coagulation (DIC), cerebral vascular accident, transient ischemic attack, unstable angina pectoris, or severe peripheral vascular disease within the prior 3 months, and as such might not be suitable in patients who had any of those events in the 3 months before starting therapy.
Kcentra, made from pooled plasma of healthy donors, is processed to minimize risk of transmitting viral and other diseases, the agency said. It is marketed as Beriplex or Confidex in 25 countries.
Dr. Sarode received compensation as coordinating principal investigator of the study.
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*Clarification (5/2/13): A previous version of this story said that the manufacturer of Kcentra, CSL Behring, was based in Marburg, Germany. Kcentra will be manufactured in the Marburg facility.