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Jason Williamson, PharmD, BCPS Clinical Pharmacy Specialist – Drug Use Policy and Education THROUGH THICK AND THIN: APPROACHES TO ANTICOAGULANT REVERSAL The speaker has no actual or potential Conflict of Interest in relation to this presentation. Genesys Regional Medical Center OBJECTIVES - PHARMACIST Given a patient case, identify the appropriate dosing regimen of a reversal agent or factor product utilized to reverse the ef fects of a direct-acting oral anticoagulant (DOAC). Given a patient case, select appropriate monitoring parameters after the utilization of a reversal agent or factor product for the reversal of a DOAC. Discuss the benefits of blood factor/anticoagulant reversal agent stewardship programs on patient care and on health care expenditures. OBJECTIVES – PHARMACY TECHNICIAN Distinguish between reversal agents and factor products utilized in DOAC reversal. Select appropriate steps in the administration of idarucizumab for the reversal of dabigatran. Identify adverse ef fects associated with available reversal agents and factor products. AUDIENCE POLLING QUESTION Which of the following best describes your experience with blood factor products and anticoagulant reversal agents? A. I have extensive experience with blood factor products and anticoagulant reversal agents (e.g., involved in everyday practice) B. I have some experience with blood factor products and anticoagulant reversal agents (e.g., involved with a case requiring a blood factor or reversal agent every so often) C. I have minimal to no experience with blood factor products and anticoagulant reversal agents (e.g., very few cases in practice, I usually hand off to another pharmacist) D. I have some experience with these medications but have great difficulty keeping up with the rapid changes in evidence -based reversal strategies STRATEGIES FOR REVERSAL OF DIRECT-ACTING ORAL ANTICOAGULANTS DIRECT ACTING ORAL ANTICOAGULANTS (DOAC’S) Includes four unique agents that were developed to improve upon the shortcomings of warfarin Apixaban (Eliquis) Dabigatran (Pradaxa) Edoxaban (Savaysa) Rivaroxaban (Xarelto) Despite some improvements to these shortcomings (e.g., lack of dietary concerns with use, relatively fewer drug interactions, etc), an issue with the use of DOAC’s arose Lack of specific reversal agent/antidote (until recently) How do practitioners manage bleeding episodes associated with the DOAC’s? How to practitioners manage patients treated with a DOAC who require an emergency surgery/urgent procedure? Direct-Acting Oral Anticoagulants as a Class – Indications and PK/PD Characteristic Indications Renal elimination of unchanged drug (%) Half-life (hr) Protein binding (%) Dialyzable? Apixaban NVAF DVT/PE treatment DVT/PE prophylaxis after TKA/THA Dabigatran NVAF DVT/PE treatment DVT/PE prophylaxis after THA Edoxaban NVAF DVT/PE treatment Rivaroxaban NVAF DVT/PE treatment DVT/PE prophylaxis after TKA/THA 27 80 50 36 8-15 12-14 10-14 5-9 87 35 55 92-95 Unlikely Yes Unlikely Unlikely Selected Direct-Acting Oral Anticoagulants– Major Bleeding and GI Bleeding Drug Endpoint Major Bleeding GI Bleeding Apixaban vs warfarin Prevention of stroke or systemic embolism in patients with NVAF 2.13% vs 3.09% 0.76% vs 0.86% Dabigatran vs warfarin Prevention of stroke or systemic embolism with NVAF 3.11% vs 3.36% 1.51% vs 1.02% Dabigatran vs warfarin Prevention of recurrent VTE in patients with acute VTE 1.6% vs 1.9% 4.2% vs 2.8% Rivaroxaban vs warfarin Prevention of stroke and systemic embolism in patients with NVAF 3.6% vs 3.4% No data Rivaroxaban vs warfarin Prevention of recurrent VTE in patients with PE 1.1% vs 2.2% No data Selected Direct-Acting Oral Anticoagulants – Intracranial Hemorrhage and Fatal Bleeding Drug Endpoint Intracranial Hemorrhage Fatal Bleeding Apixaban vs warfarin Prevention of stroke or systemic embolism in patients with NVAF 0.33% vs 0.8% No data Dabigatran vs warfarin Prevention of stroke or systemic embolism with NVAF 0.3% vs 0.74% 1.45% vs 1.8% Dabigatran vs warfarin Prevention of recurrent VTE in patients with acute VTE 0% vs 0.2% 0.08% vs 0.08% Rivaroxaban vs warfarin Prevention of stroke and systemic embolism in patients with NVAF 0.5% vs 0.7% 0.2% vs 0.5% Rivaroxaban vs warfarin Prevention of recurrent VTE in patients with PE <0.1% vs 0.4% <0.1% vs 0.1% COAGULATION ASSAYS AND DOAC’S Routine monitoring of coagulation assays is typically not required for the DOAC’s Extenuating Circumstances Major bleeding Surgery Reversal of anticoagulation Suspicion of overdose COAGULATION ASSAYS aPTT Intrinsic pathway Chromogenic Anti-factor Xa Functional test which assesses plasma factor Xa concentrations Ecarin clotting time (ECT) Specific assay for thrombin production Direct measure of direct thrombin inhibitor activity (e.g., dabigatran) PT-INR Extrinsic and common pathway Thrombin clotting time (TT) Directly assesses activity of thrombin USEFULNESS OF COAGULATION ASSAYS Factor IIa inhibitors (e.g., dabigatran) ECT > TT > aPTT > PT/INR Factor Xa inhibitors (e.g., apixaban, edoxaban, rivaroxaban) Chromogenic anti-factor Xa > PT/INR > aPTT Despite these depictions of the optimal coagulation assays for each type of DOAC, many health systems lack an ability to utilize these tests or have to send out specimens for analysis by another laboratory NON-PHARMACOLOGIC MANAGEMENT OF BLEEDING Discontinue the anticoagulant involved Target hemostasis at the bleeding site Fluid resuscitation/hemodynamic support Transfusion Further intervention with factor products/reversal agents is often required PHARMACOLOGIC MANAGEMENT OF BLEEDING Activated charcoal May be effective if given within 1-2 hours of last DOAC dose Hemodialysis May be considered in patients treated with dabigatran due to low plasma protein binding May decrease drug levels by at least 50% after a 4 hour session Multiple factor products may be used for DOAC reversal Hospital formulary restrictions typically play a factor in which factor products are selected for use Thromb Haemost. 2013;109:596-605. SELECTED FACTOR PRODUCTS 3 Factor PCC Brand Name Bebulin VH Dose based on 4 Factor PCC Profilnine SD Kcentra Units of factor IX activity Factor II 24-38 IU/mL 150IU/100 fIX IU 0.76 -1.6 units/unit Factor VII < 5 IU/mL* < 35 IU/100 fIX IU* 0.4-1 unit/unit Factor IX 24-38 IU/mL 100 IU 0.8-1.24 units/unit Factor X 24-38 IU/mL 100 IU/100 fIX IU 1-2.04 units/unit Unfractionated heparin 0.15 IU per 1 IU fIX None 0.016-0.08 unit/unit Other components - - Protein C, Protein S, Anti-thrombin III * denotes products with non-therapeutic levels of factor VII SELECTED FACTOR PRODUCTS aPCC rFVIIa Brand Name Feiba NF NovoSeven RT Dose based on Units of factor VIII inhibitor bypassing activity Units of recombinant factor VIIa Factor II 1.3 IU/IU - Factor VII 0.9 IU/IU X 1000-8000 mcg X Factor IX 1.4 IU/IU - Factor X 1.1 IU/IU - Unfractionated heparin None None Other components - - X denotes products with activated factor VII THROMBOGENICIT Y ASSOCIATED WITH FACTOR PRODUCT ADMINISTRATION Use of factor products as part of a patient -specific DOAC reversal strategy may confer an increased risk of a pro thrombotic state Specific factor component involvement has not been clearly defined Products containing protein C, protein S, and other anticoagulants may preclude excessive thrombin production Providers must carefully balance the benefits of anticoagulant reversal with the risks of thrombosis after reversal or seek alternate methods of reversal “Targeted anti-anticoagulants” or agent -specific antidotes of fer less risk for thrombogenicity than factor product counterparts IDARUCIZUMAB (PRAXBIND) Approved in October 2015 for the reversal of the anticoagulant ef fects of dabigatran for emergency surgery/urgent procedures or in life-threatening or uncontrolled bleeding Mechanism of action: humanized monoclonal antibody fragment that binds to dabigatran and its acylglucuronide metabolites with an af finity for dabigatran ~ 350 times greater than thrombin IDARUCIZUMAB DOSING AND ADMINISTRATION 5 gm IV (given as 2 separate 2.5 gm doses no more than 15 minutes apart) May be given as IV push or as IV infusion Give within 1 hour of removing from the vial if IV push selected Infuse no longer than 5 to 10 minutes if IV infusion selected No reconstitution required If specific coagulation parameters are re -elevated and clinically relevant bleeding occurs OR if a second emergency surgery/urgent procedure is needed and the patient elevated coagulation parameters, an additional 5 gm dose may be considered (supported by limited data) IDARUCIZUMAB PK/PD In general, this agent neutralizes the anticoagulant ef fects of idarucizumab within minutes of administration Median time of hemostasis restoration = 11 .4 hours Duration of at least 24 hours Half-life elimination 47 minutes (initial); 10.3 hours (terminal) Metabolized to small peptides and amino acids; also excreted in the urine IDARUCIZUMAB STORAGE/STABILIT Y Store intact vials at 36 – 46 o F; do not freeze Do not shake; do not tube (monoclonal antibody) Can be stored in original packaging at room temperature Up to 48 hours if in original packaging (protected from light) Up to 6 hours if exposed to light WARNINGS/PRECAUTIONS WITH IDARUCIZUMAB Coagulation parameter re -elevation may occur in some patients (limited number in clinical trials). If clinically relevant bleeding occurs in conjunction with elevated coagulation parameters, consider an additional dose of idarucizumab. Hypersensitivity may occur from administration Due to the underlying risk of thromboembolism associated with reversed the ef fects of dabigatran, labeled dosing information recommends restarting dabigatran or an alternative anticoagulant when appropriate. Hereditary fructose intolerance? EVIDENCE FROM REVERSE-AD TRIAL Purpose: determine the safety of 5 gm IV idarucizumab and its capacity to reverse the anticoagulant ef fects of dabigatran in patients who had a serious bleed or required an urgent procedure Primary endpoint: maximum percentage reversal of dabigatran within 4 hours after administration of idarucizumab Pre-dose test result [s]–minimum post-dose test result [s]) (Pre-dose test result [s]–upper limit of the normal range [s])×100 Secondary endpoint: restoration of hemostasis N Engl J Med. 2015;373(6):511-20. EVIDENCE FROM REVERSE-AD TRIAL Idarucizumab rapidly and completely reversed the anticoagulant activity of dabigatran in 88% to 98% of patients with elevated clotting times at baseline There were no safety concerns among the 90 patients involved in this study Includes patients given idarucizumab on clinical grounds but were later found to have had normal results on clotting tests at baseline N Engl J Med. 2015;373(6):511-20. IN THE PIPELINE: ANDEXANET ALFA Presently studied but not yet approved for factor Xa inhibitor reversal (e.g., rivaroxaban, apixaban, edoxaban, fondaparinux) Currently being studied in phase 4 trials (ANNEXA -4), and phase 3 trials (ANNEXA - A and ANNEXA -R) were released in 2015 Purported mechanism of action : recombinant modified human factor Xa decoy protein that is catalytically inactive but retains the ability to bind factor Xa inhibitors in the active state at a high af finity, restoring the activity of endogenous factor Xa EVIDENCE FROM ANNEXA -A AND ANNEXA-R TRIALS Phase III, randomized, double -blind, placebo-controlled clinical trials from March 2014 – May 2015 involving 2 clinical sites Inclusion criteria – age 50 – 75 years Exclusion criteria – history of: Abnormal bleeding, active bleeding, or risk factors for bleeding Thrombosis or risk factors for thrombosis Adult asthma or use of inhaled medication Primary study endpoint: percent change in anti -factor Xa activity (examined nadir associated with bolus and with infusion) N Engl J Med. 2015;373(25):2413-24. EVIDENCE FROM ANNEXA -A AND ANNEXA-R TRIALS Percent change in anti-factor Xa activity (mean SD) Bolus Bolus + Infusion Study Andexanet Placebo P-value ANNEXA-A 942% 219% < 0.001 ANNEXA-R 9211% 1815% < 0.001 ANNEXA-A 923% 336% < 0.001 ANNEXA-R 972% 4512% < 0.001 N Engl J Med. 2015;373(25):2413-24. OTHER REVERSAL AGENTS IN THE PIPELINE Aripazine (PER977; ciraparantag) – reversal of all DOAC’s presently on the market May additionally work against heparin and LMWH N Engl J Med. 2014;371(22):2141-2. STRATEGIES FOR REVERSAL OF WARFARIN ADVANCES IN THE MANAGEMENT OF WARFARIN REVERSAL Phytonadione (vitamin K) is the antidote to warfarin, but this agent by itself may not be suf ficient for acute major bleeding issues or where rapid reversal of anticoagulation prior to an emergency surgery is required Four factor prothrombin complex concentrate (Kcentra) is now approved for the reversal of warfarin in specific patients PROTHROMBIN COMPLEX CONCENTRATE (KCENTRA) Contains factors II, VII, IX, and X as well as protein C and S (a.k.a. 4 factor PCC) Indicated for the urgent reversal of acquired coagulation factor deficiency induced by vitamin K antagonist (e.g., warfarin) therapy in patients with acute major bleeding or a need for an urgent surgery/invasive procedure Dose depends on pretreatment INR and on patient weight DOSING 4 FACTOR PCC Pre-treatment INR 2-<4 4–6 >6 Dose (units of factor IX)/ kg body weight 25 35 50 Maximum dose (units of factor IX) Not to exceed 2500 Not to exceed 3500 Not to exceed 5000 Dose based on actual potency as stated on the car ton, which varies from 20-31 factor IX units/mL af ter reconstitution. Nominal potency is 500 units or 1000 units per vial (25 units/mL af ter reconstitution). NOTABLE WARNINGS/PRECAUTIONS WITH 4 FACTOR PCC Increased risk for thromboembolic events (Boxed Warning in the US) As patients treated with vitamin K antagonists have an underlying risk of or a diagnosed thromboembolic disease state, administration of PCC may predispose the patient to a thromboembolic complication Formulations contain heparin and are products or human plasma (may contain infectious agents) 4 factor PCC products contain factor VII ad should not be confused with other products that contain low or nontherapeutic levels of factor VII (e.g., Profilnine) Hypersensitivity reactions may occur from administration EVIDENCE FOR 4 FACTOR PCC PRODUCTS Numerous prospective interventional trials and retrospective observational studies have been published supporting use Notable publications Sarode et al. Circulation. 2013;128(11):1234-43. Pabinger et al. Journal of Thrombosis and Haemostasis. 2008;6(4):622-31. Preston et al. British Journal of Haematology. 2002;116(3):619-24. Open-label, randomized, multicenter phase III soon to be published comparing 4 factor PCC to plasma in patients requiring urgent surgery (N = 176) FACTOR PRODUCT/ REVERSAL AGENT STEWARDSHIP PROGRAMS STEWARDSHIP PROGRAM FOR FACTOR PRODUCTS/REVERSAL AGENTS University of North Carolina Medical Center (UNCMC) Innovative pharmacist-led program to improve prescribing, dosing, and monitoring of clotting factor therapy Pharmacist assigned to round with hematologists daily, recommending treatment plan modifications and dose adjustments as necessary Am J Health Syst Pharm. 2015;72(18):1579-84. STEPS TO PROGRAM DEVELOPMENT/IMPLEMENTATION Selection of one formulary product within each clotting factor class Establishment of guidelines on blood factor prescribing, order review, compounding, and administration Initial and ongoing education of pharmacy, nursing, and medical staff Am J Health Syst Pharm. 2015;72(18):1579-84. RESULTS OF UNCMC PROGRAM Contributed both to cost savings and improved outcomes Increase in patients receiving clotting factors by 22%, but reduction of doses dispensed by 45% overall Reduction in readmissions associated with bleeding episodes for patients with hemophilia A Cost-savings estimated to exceed $4 million annually (from 4 year program period) Numerous opportunities for improvement contributed to reduction of doses dispensed Conversion of patients with hemophilia A or B from intermittent infusions of factors VIII and IX to continuous infusion therapy Change in product selection for patients with hemophilia A Review of factor concentrate doses ordered beyond initial dose by designated pharmacist team member Am J Health Syst Pharm. 2015;72(18):1579-84. APPLYING THIS ARTICLE TO ANTICOAGULATION REVERSAL Despite many specific roles with blood factor use with inherited bleeding disorders, a designated team of pharmacists could be formed to optimize the utilization of blood factor and reversal agent products within a variety of health systems Specific institutional guidelines should be developed and utilized to guide factor product and reversal agent selection, dosing, and subsequent monitoring An interdisciplinary approach would likely result in the greatest improvements in patient care as well as cost savings DESIGN FOR FACTOR PRODUCT/REVERSAL AGENT STEWARDSHIP Pharmacist Chair and Physician Chair Support Pharmacists Drug Use Policy/ Formulary Management Pharmacy and Health System Administration CONCLUSIONS A variety of factor products and reversal agents (e.g., agent specific antidotes) are available or in the pipeline for the reversal of anticoagulation Pharmacy staf f members can assist with vital roles associated with the use, dosing, administration, and patient monitoring of medications used in anticoagulant reversal Factor and reversal agent stewardship programs have the potential to improve patient care as well as contain health care costs DISCUSSION/QUESTIONS PATIENT CASE - PHARMACIST Patient LK presents to the MICU with a new onset GI bleed. Upon reviewing the patient’s medication profile, you discover that the home medication list includes multiple blood thinners. Among these blood thinners, dabigatran 150 mg PO BID was prescribed for this patient for their NVAF. The patient weighs 89 kg, is 87 years old, and is presently receiving hemodialysis for their end stage renal disease. Hematology/oncology is consulted and decides to hold anticoagulation and initiate idarucizumab for reversal. As the pharmacist, hem/onc seeks your input for this patient’s care about the overall reversal strategy. QUESTION 1 - PHARMACIST What’s the most appropriate dosing regimen of idarucizumab to utilize for this patient case? A. 2.5 gm IV push X 2 doses (no more than 15 minutes apart) B. 5 gm IV push X 1 dose C. 2.5 gm as an IV infusion X 2 doses D. A and C QUESTION 2 - PHARMACIST During administration of the idarucizumab, the prescribing physician wants your suggestions about further monitoring of the patient. What information do you provide the physician? A. There is no further monitoring required. B. Monitor for re-elevation of coagulation parameters (e.g., aPTT) along with signs and symptoms of clinically relevant bleeding or thrombosis. C. Monitor the aPTT but there’s no need to monitor for bleeding or thrombosis signs and symptoms. D. Check an INR 4 hours and 8 hours after idarucizumab has been administered. QUESTION 3 - PHARMACIST Patient RK is a 78 year old male weighing 114 kg who presents to the ER after falling at home. The medication history indicates that he was taking warfarin 10 mg PO daily at home, but RK cannot recall his last “Coumadin level.” Upon checking the INR in ER, you find it is supratherapeutic at 8.5. Additionally, after examining the patient, the ER physician is concerned about reversing the effects of the warfarin due to clinical evidence of a subdural hematoma. The physician orders Kcentra and vitamin K 10 mg IV per your health system’s reversal protocol, but looks to you as the pharmacist for Kcentra dosing recommendations. What dose of Kcentra do you recommend for RK? A. 3500 units B. 3990 units C. 5000 units D. 5700 units QUESTION 4 - PHARMACIST Considering the factor stewardship program implemented at the University of North Carolina Medical Center, which of the following best depicts the potential benefits of a factor product/anticoagulant reversal agent stewardship program? A. Optimization of factor product/reversal agent dosing B. Evidence-based guideline approaches to care for bleeding patients C. Reduced health care expenditures D. All of the above QUESTION 1 - TECHNICIAN Which of the following is best described as a factor product? A. Idarucizumab (Praxbind) B. Andexanet alfa C. aPCC (Feiba NF) D. Aripazine QUESTION 2 - TECHNICIAN Which of the following is best described as a “targeted anti anticoagulant”, not a factor product? Kcentra Andexanet alfa NovoSeven Profilnine SD QUESTION 3 - TECHNICIAN Concerning the administration of idarucizumab, which of the following statements is true? A. Appropriate administration may include IV push or IV infusion. B. Light protection is a concern for this medication, and the medication can be stored for up to 6 hours at room temperature if exposed to light. C. Idarucizumab should be administered over no longer than 5 to 10 minutes if IV infusion selected. D. All of the above are true QUESTION 4 - TECHNICIAN True or False: thromboembolic risk after drug administration is perhaps the most concerning risk associated with Kcentra, and this concern is described in a boxed warning for the medication.
