Kcentra Reversal of DOAC Overdose

Kcentra Reversal of DOAC Overdose
Dec 22, 2015 12:18pm

From Gabor Varadi, MD, Albert Einstein Cancer Center, Philadelphia.

I would like to ask you about Kcentra dosing for non-coumadin related indications. This would be for treating life threatening bleeding or urgent reversal prior to surgery for patients receiving targeted anticoagulants. This would only apply to the direct oral Xa antagonists, not dabigatran. Do you think 25u/kg is appropriate for these patients, allowing for a one time re-dose up to a max of 50u/kg if needed?


Hello, Dr. Varadi, and thank you for your question. Kcentra, trademarked Bebulin in Europe, is a four-factor PCC that has been available several years in Europe and was approved April, 2013 by the US FDA for reversal of bleeding that results from Coumadin overdose. Kcentra dosing ranges from 25–50 u/kg body weight depending on the patient’s INR and on the coagulation factor IX concentration provided on the product label. It is administered IV with vitamin K. Kcentra is called four-factor PCC because it provides factor VII activity levels equivalent to factors II, IX, and X, whereas standard PCC preparations provide little factor VII.

Though I’ve recently heard presentations describing Kcentra’s efficacy in reversing hemorrhage caused by overdose of the anti-Xa DOACs rivaroxaban and apixaban, these are off-label applications that the manufacturer does not support. I have attached two articles below that provide DOAC-induced bleeding reversal data and algorithms. They appear to recommend dosing patterns similar to those employed for Coumadin-induced bleeding. As this is an off-label application, please do not accept these citations as a Fritsma Factor recommendation.

Fortunately, two potentially effective agents are under development for reversal of the direct anti-Xa anticoagulants. One are Portola’s Andexanet Alfa, an inactive factor Xa analog currently submitted for FDA accelerated approval. Andexanet Alfa also reverses bleeding caused by low molecular weight heparin and fondaparinux overdose. The second is Perosphere’s Ciraparantag, a small molecule in early human trials that appears to reverse the effects of all DOACs.

While I am on the subject, Boehringer-Ingelheim’s idarucizumab (Praxbind) was FDA-approved October, 2015 for reversal of dabigatran-associated bleeding. Dabigatran is a DOAC that works through direct thrombin inhibition.

I hope this is helpful, it does appear that we will soon have several reversal options, and I hope these will be paralleled by FDA approval of DOAC laboratory assays, several of which have been developed and submitted. The article links appear below:

/sites/default/files/pcc_doac_reversal_thromb_j_2014.pdf

/sites/default/files/pcc_doac_reversal_biomed_res_intl_2014.pdf

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From Gabor Varadi, MD, Albert Einstein Cancer Center, Philadelphia.

I would like to ask you about Kcentra dosing for non-coumadin related indications. This would be for treating life threatening bleeding or urgent reversal prior to surgery for patients receiving targeted anticoagulants. This would only apply to the direct oral Xa antagonists, not dabigatran. Do you think 25u/kg is appropriate for these patients, allowing for a one time re-dose up to a max of 50u/kg if needed?


Hello, Dr. Varadi, and thank you for your question. Kcentra, trademarked Bebulin in Europe, is a four-factor PCC that has been available several years in Europe and was approved April, 2013 by the US FDA for reversal of bleeding that results from Coumadin overdose. Kcentra dosing ranges from 25–50 u/kg body weight depending on the patient’s INR and on the coagulation factor IX concentration provided on the product label. It is administered IV with vitamin K. Kcentra is called four-factor PCC because it provides factor VII activity levels equivalent to factors II, IX, and X, whereas standard PCC preparations provide little factor VII.

Though I’ve recently heard presentations describing Kcentra’s efficacy in reversing hemorrhage caused by overdose of the anti-Xa DOACs rivaroxaban and apixaban, these are off-label applications that the manufacturer does not support. I have attached two articles below that provide DOAC-induced bleeding reversal data and algorithms. They appear to recommend dosing patterns similar to those employed for Coumadin-induced bleeding. As this is an off-label application, please do not accept these citations as a Fritsma Factor recommendation.

Fortunately, two potentially effective agents are under development for reversal of the direct anti-Xa anticoagulants. One are Portola’s Andexanet Alfa, an inactive factor Xa analog currently submitted for FDA accelerated approval. Andexanet Alfa also reverses bleeding caused by low molecular weight heparin and fondaparinux overdose. The second is Perosphere’s Ciraparantag, a small molecule in early human trials that appears to reverse the effects of all DOACs.

While I am on the subject, Boehringer-Ingelheim’s idarucizumab (Praxbind) was FDA-approved October, 2015 for reversal of dabigatran-associated bleeding. Dabigatran is a DOAC that works through direct thrombin inhibition.

I hope this is helpful, it does appear that we will soon have several reversal options, and I hope these will be paralleled by FDA approval of DOAC laboratory assays, several of which have been developed and submitted. The article links appear below:

/sites/default/files/pcc_doac_reversal_thromb_j_2014.pdf

/sites/default/files/pcc_doac_reversal_biomed_res_intl_2014.pdf

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