Over the past several years a new era for patients requiring anticoagulation has arrived. The approval of the first DOAC reversal agent in 2015 and the continuing development of at least two additional reversal agents present both new opportunities and challenges. Direct thrombin inhibitor - Dabigatran (Pradaxa®) . Kcentra ®, Prothrombin Complex Concentrate (Human), is a blood coagulation factor replacement product indicated for the urgent reversal of acquired coagulation factor deficiency induced by Vitamin K antagonist (VKA—eg, warfarin) therapy in adult patients with acute major bleeding or the need for urgent surgery or other invasive procedure. The 1 st annual Rebellion in EM Clinical Conference took place in San Antonio, TX on May 11 th – 13 th, 2018. How much factor is in a vial of PCC versus a unit of FFP? Anti-Xa: Apixaban, Rivaroxaban, Edoxaban 4. Fixed Dose 4-factor Prothrombin Complex Concentrate for the Emergent Reversal of Warfarin: A Retrospective Analysis J Thromb Thrombolysis. Our experts recommend not stopping the DOAC in this case, ... Beriplex, Kcentra) at a dose of 50 IU/kg up to 2,000 units. If the bleeding does not resolve in an appropriate amount of time, this dose may be repeated. Kcentra is a four factor prothrombin complex concentrate that was FDA approved in 2013 and is used as an antidote to treat people with bleeding associated with taking warfarin. I would like to ask you about Kcentra dosing for non-coumadin related indications. GUIDELINES FOR REVERSAL OF ANTICOAGULANTS NAMES ELIMINATION HALF-LIFE REMOVED BY HD STRATEGIES TO REVERSE OR MINIMIZE DRUG EFFECT apixaban (UWMedicine: (Eliquis) 8-15 hours (longer in renal impairment) NO Drug activity can be assessed with anti-factor Xa activity assay apixaban assay [APIXN1]) If ingested within 2 hours, administer activated charcoal Consider 4-factor PCC (KCentra… Role of laboratory testing . ... (Beriplex/Kcentra) may normalize PT more effectively than 3-factor PCC (Profilnine), but it had less of an effect on normalizing thrombin generation. It contains clotting factors II, VII, IX and X derived from donated blood and could be effective in reversing the anticoagulation effects of the factor Xa inhibitor, apixaban. PCCs contain factors II, VII, IX and X and proteins C and S, along with heparin and human albumin. At the same time, the reversal of warfarin is not performed effectively or consistently across institutions. To reverse vitamin K antagonists (e.g., warfarin), use of 5-10 mg intravenous vitamin K is appropriate for major bleeding events, while 2-5 mg of oral or intravenous vitamin K can be used for nonmajor bleeding events that require hospitalization. The only DOAC with an actual reversal agent approved by the FDA is the direct thrombin inhibitor dabigatran. Four factor PCC (Kcentra) is dosed on the amount of factor IX. 11/6/2013 24 FEIBA ®and Kcentra ®Cautions • Increase risk of thromboembolism • Reversal is OFF-LABEL • Weigh risk/benefit • Blood products • Kcentra ®contains heparin Roadmap for today • Characteristics of novel anticoagulants • Approach to the bleeding patient • Specific reversal agents • UCSF guidelines. Idarucizumab was approved in 2015 (US and Europe) [18,19 •FDA Indications: VKA reversal in patients with acute major bleeding or need for urgent surgery/invasive procedure Labeled dosing: Pre-treatment INR Dose Maximum Dose 2 - < 4 25 units/kg 2,500 units 4-6 35 units/kg 3,500 units >6 50 units/kg 5,000 units Kcentra® (prothrombin complex concentrate human) [prescribing information]. Dabigatran may be reversed by giving 5 grams of idarucizumab by rapid IV administration. Dec 22, 2015 12:18pm. Kcentra Reversal of DOAC Overdose. 1. Case-based examples for application to practice Objectives . Specific reversal agents are enzymatically inactive and abrogate the effect of DOACs by direct binding, reducing the concentration of the anticoagulant in the blood. Written by Salim Rezaie REBEL EM Medical Category: Hematology and Oncology 3 Comments. Kcentra is for intravenous use only. 4-factor PCC/Kcentra is approved for urgent reversal of acquired coagulation factor deficiency induced by vitamin K antagonist therapy in patients with acute major bleeding or a need for an urgent surgery/invasive procedure. Reversal Strategies for NOACs accidental ingestion Activated Charcoal ... Kcentra Feiba® NF NovoSeven® RT Dose based on Units of factor IX activity Units of factor IX activity Units of factor IX activity Units of factor VIII inhibitor bypassing activity Units of recombinant factor VIIa dose Administrationtime Max 2 ml/min Max 10 ml/min Max 8.4 ml/min Max 2 units/kg/min Bolus over 2-5 … Four‐factor prothrombin complex concentrate (4F‐PCC) has emerged as the preferred option for emergent reversal of vitamin K antagonists (VKAs); however, the optimal dosing strategy is unknown. August 2017. 2018 Feb;45(2):300-305. doi: 10.1007/s11239-017-1586-x. Overview of reversal agents . Generally recommended as mainstay of reversal (with in vitro evidence and some clinical data). Despite these benefits, DOAC reversal has proven difficult. In 2015, idarucizumab was approved by the FDA for the reversal of direct thrombin inhibitor dabigatran. Aspirin 8. of Factor Xa Inhibitor-Associated Intracranial Hemorrhage . The reversal strategy depends on the urgency of the situation; presence, site, and severity of bleeding; DOAC involved; and comorbid conditions. Reversal of DOAC therapy may be required in patients with or at risk for bleeding because of trauma or a need for an invasive procedure (e.g., decision making about the approach used to reverse the anticoagulant effects of DOACs. Dabigatran reversal. Two specific reversal agents are now available: idarucizumab for dabigatran , and andexanet alfa for apixaban and rivaroxaban . This would be for treating life threatening bleeding or urgent reversal prior to surgery for patients receiving targeted anticoagulants. This effect can be measured by anti-Xa assays, in the case of FXa … The efficacy of 25 to 50 U/kg of four-factor PCC (Kcentra) for reversal of elevated INR in warfarin patients has recently received FDA approval. One vial of PCC also contains factors II, VII, IX, X, Proteins C and S, Antithrombin III and a small amount of heparin. Factor Xa inhibitors - Rivaroxaban (Xarelto®) - Apixaban (Eliquis®) - Edoxaban (Savaysa®) DOAC lineup . George Fritsma. From Gabor Varadi, MD, Albert Einstein Cancer Center, Philadelphia. As PCCs are the most commonly used DOAC reversal agents, it is important to compare their mechanism of action with those of the specific reversal agents. Despite the advantages of DOAC therapy, the lack of a reversal agent is sometimes perceived as limiting their broader use 22. Neither PCC product corrected anti-Xa activity. Warfarin and Prothrombin Complex Concentrate (PCC) 2. Andexxa® vs. Kcentra® for Reversal . TM A TRADEMARK OF ALLINA HEALTH SYSTEM. Clinical Controversies in DOAC Reversal Karen Berger, PharmD, FCCM, BCPS, BCCCP Neurocritical Care Clinical Pharmacist NewYork-Presbyterian Hospital/Weill Cornell Medical Center. Unlike VKA reversal, DOAC reversal has, until recently, been a clinical challenge due to limited availability of/access to specific reversal agents . If you missed out in 2018, the Rebellion is coming back June 28 th – 30 th, 2019. 3 Direct Oral Anticoagulants (DOACs) Guide S414386A 281375 0517 ©2017 ALLINA HEALTH SYSTEM. Kcentra ®, Prothrombin Complex Concentrate (Human), is a blood coagulation factor replacement product indicated for the urgent reversal of acquired coagulation factor deficiency induced by Vitamin K antagonist (VKA—eg, warfarin) therapy in adult patients with acute major bleeding or the need for urgent surgery or other invasive procedure. Heparin and Low Molecular Weight Heparin 5. Fondaparinux 7. Kcentra is a 4-factor PCC, indicating it provides therapeutic levels of factors II, VII, IX, and X, whereas current PCCs provide little VII. Generally works for ~6-8 hours. However, reversal of factor Xa inhibitors remains challenging due a lack of specific antidote. Direct Thrombin Inhibitors: Argatroban and Bivalirudin 6. In this study, apixaban steady‐state PD effects were demonstrated by changes in several thrombin generation parameters, clotting time assessments, and AXA. Each vial has about 500 units of factor IX. Dabigatran 3. Repeat INR in 30 minutes after Kcentra *life-threatening GI bleed, retroperitoneal bleed, fall in Hg >= 2 g/dl or Hg = 8 g/dl if no baseline. With the approval of four-factor prothrombin complex concentrate (4F-PCC, Kcentra) for the reversal of vitamin K antagonist-associated bleeding in the US, it has become a relatively common practice for 4F-PCC to be used in an 'off-label' fashion to correct coagulopathy caused by direct oral anticoagulants (DOACs) such as anti-Xa inhibitors. Fixed Dose Kcentra for Warfarin Reversal; Weight = 100 kg or INR = 6 Weight > 100 kg or INR > 6 ; No CNS Bleed* 1500 units : 2000 units : CNS Bleed : 2000 units : 2500 units : Give all Kcentra doses with phytonadione 10 mg IVPB over 30 minutes. Rebellion in EM 2018 – DOAC Reversal by Scott Wieters, MD. Although several studies have attempted to determine the optimal dose of 4F‐PCC using a variety of dosing regimens, no dosing strategy has been found to be superior. Dosing consistent with prescribing information was used for most patients receiving 4F-PCC for warfarin reversal (313/415, 75.4%) and the remainder of patients (102/415, 24.6%) received a fixed-dosing approach of 500 to 1500 units . For reversal of other NOACs in cases of life-threatening bleeding, a four-factor prothrombin complex concentrate (PCC) such as Kcentra is an option. Depending on the pharmacology of the anti-Xa agent, the DOAC may out-last this, causing rebound bleeding. Non-steroidal Anti-inflammatory Drugs … MINNEAPOLIS HEART INSTITUTE® AND MHI ® ARE TRADEMARKS OF MINNEAPOLIS HEART INSTITUTE, INC. Thrombophilia and Anticoagulation Clinic, Minneapolis Heart Institute®, Abbott Northwestern Hospital. All increase the risk of thrombosis and are usually reserved for the most critical cases. The approval of new target specific oral anticoagulants offers practitioners several advantages over traditionally used vitamin K antagonist agents including predictable pharmacokinetics, rapid onset of action, comparable efficacy and safety, all without the need for routine monitoring. Contraindicated in patients with a history of heparin-induced thrombocytopenia (contains small amounts of heparin). To quickly view reversal recommendations for specific antithrombotic medications select hyperlink below. Discuss DOAC-reversal strategies for severe bleeding and for perioperative management . The use of fresh frozen plasma (FFP) has so far not been studied. PCC/Kcentra®) as described below. Note that if you highly suspect a Xa inhibitor intracranial bleed before obtaining a CT head, it is reasonable to give 1,500 units of 4 factor PCC on speculation. • PCC (Kcentra ®) to reverse rivaroxaban/apixaban. Tel: 612-863-6800 | Reviewed August 2016 Characteristics of DOAC-specific reversal agents. Kcentra is for intravenous use only. Median dose for DOAC reversal was 23.5 units/kg (IQR 23.5–26.5) or 2000 units (IQR 2000–5000). Would you reverse the DOAC? 11 While dabigatran targets thrombin, it is hypothesized that administration of factors may overcome dabigatran’s effects on the coagulation cascade, allowing for PCC to play a role in its reversal. Use of a reversal agent should be reserved only for patients with a life-threatening bleed or a major bleed in a critical site. Introduction. Though its use for neutralizing the direct oral anticoagulants (DOACs) is off-label, it appears to partially reverse rivaroxaban and apixaban overdose-generated bleeding per the attached meta-analysis, Kreuziger LMB, Keenan JC, Morton CT, Dries DJ. Ashley E. Lock, PharmD PGY2 Emergency Medicine Pharmacy Resident Department of Pharmacotherapy Services, University Health System Pharmacotherapy Division, The University of Texas at Austin College of Pharmacy Pharmacotherapy Education and Research Center, UT Health San Antonio September 13, …
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