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FDA approved Kcentra for urgent reversal of anticoagulation
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The FDA has approved the use of Kcentra for the urgent reversal of vitamin K antagonist anticoagulation in adults with acute major bleeding.
Kcentra (CSL Behring) is used in conjunction with the administration of vitamin K to reverse the anticoagulation effect and stop bleeding. Acute bleeding may be a complication for patients receiving chronic anticoagulation therapy with warfarin and other vitamin K antagonist anticoagulants to prevent blood clotting in conditions such as atrial fibrillation or the presence of an artificial heart valve.
Plasma is the only other FDA-approved product for this use in the United States. Unlike plasma, Kcentra can be administered rapidly because it does not require blood-type grouping or thawing. Kcentra is made from the pooled plasma of healthy donors and is processed to minimize risk for transmitting viral and other diseases, according to the FDA press release.
FDA approval of Kcentra was based on a study of 216 patients who received vitamin K antagonist anticoagulation and who had acute major bleeding and a clotting test value indicating use of anticoagulants. Results demonstrated Kcentra was similar to plasma in terms of stopping acute major bleeding, according to the release.
“The FDA’s approval of this new product gives physicians a choice when deciding how to treat patients requiring urgent reversal of vitamin K antagonist anticoagulation,” Karen Midthun, MD, director of the Center for Biologics Evaluation and Research at the FDA, stated in the release. “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 vitamin K antagonist anticoagulation.”
Kcentra is associated with the occurrence of venous thromboembolism when used as indicated, and both fatal and nonfatal arterial and venous thromboembolic complications were reported during clinical trials and postmarketing surveillance. It carries a boxed warning regarding this risk.
Perspective
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Bruce Evatt, MD
Vitamin K antagonists (VKA) such as warfarin are often used to treat patients who require anticoagulation therapy. VKA prevent carboxylation of coagulation factors II, VII, IX and X (vitamin K dependent factors) and antithrombotic factor Protein C and its cofactor Protein S during synthesis of these molecules by the liver. The missing carboxyl group is critical for proper membrane binding and function of these factors during the coagulation process.
Although both coagulation factors and antithrombotic factors are affected, the result shifts the balance of the clotting system toward bleeding, and the patient is considered anticoagulated. Many environmental factors — including diet and other medications — affect the response of individual patients to VKA, necessitating frequent monitoring of patients with laboratory tests and adjustments to the VKA dose to keep the patient within a narrow, safe therapeutic range.
When a patient’s coagulation system anticoagulation exceeds the therapeutic range and he becomes at increased risk for bleeding, he is normally managed by reducing or temporarily suspending VKA therapy or by giving small doses of vitamin K. If he develops bleeding, he is managed more aggressively. With severe bleeding, the response to vitamin K may be too slow to prevent severe complications. Under these conditions, reversal of effects of VKA becomes urgent. In the past, the physician had the option of reversing the effects of VKA with plasma that replaces the defective clotting factors or by the off label use of prothrombin complex concentrates, which contain varying amounts of the various vitamin K-dependent factors depending on brand. The use of plasma requires blood typing and may require volume overload if large volumes are needed to replace the factors.
Prothrombin complex concentrate, human (Kcentra, CSL Behring) was recently licensed by the FDA to reverse the effects of VKA in patients with urgent acute bleeding. The ruling was based on clinical studies that showed the effectiveness of Kcentra in this situation. Unlike plasma, Kcentra treatment does not require blood typing and does not create the potential volume overload problem seen with the use of plasma. Kcentra contains vitamin K-dependent factors reduced by VKA (ie, II, VII, IX and X, as well as Protein C and Protein S. Because it is manufactured from donor plasma, Kcentra cannot be guaranteed to be completely free of risk of transmitting infectious agents (eg, viruses or variant Creutzfeldt-Jakob disease), although it has been manufactured using techniques of proven effectiveness for blood-borne agents.
Perspective
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Harry S. Jacob, MD, FRCPath(Hon)
Keep tuned for an upcoming FDA approval of a new modified Factor X congener that blocks activity of anti-Factor Xa anticoagulants, yet lacks intrinsic thrombotic capability of its own. It may be a game-changer in providing a much-needed antidote for bleeding patients being treated with newer oral anticoagulants.
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