7/6/ ANNUAL MEETING CURRENT REVERSAL STRATEGIES FOR ORAL ANTICOAGULANTS AND A LOOK AT NEW REVERSAL AGENTS PHARMACY TECHNICIAN OBJECTIVES

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1 PHARMACY TECHNICIAN OBJECTIVES Identify brand/generic names of medications used for oral anticoagulation CURRENT REVERSAL STRATEGIES FOR ORAL ANTICOAGULANTS AND A LOOK AT NEW REVERSAL AGENTS PRESENTED BY: RUBEN SANTIAGO, PHARMD, BCPS EMERGENCY DEPARTMENT PHARMACY SPECIALIST JACKSON MEMORIAL HOSPITAL Describe the different classes of medications used for oral anticoagulation List treatment options for the management of bleeding due to oral anticoagulation DISCLOSURE I do not have a vested interest nor am I affiliated with any corporate organization offering financial support or grant monies for this continuing education activity, or have any affiliation with an organization whose philosophy could potentially bias my presentation PATIENT CASE 70 year old male Headache for three days Atrial fibrillation on anticoagulation (warfarin) Vital Signs HR 125 Temperature (C o ) 36.8 Respiratory Rate 18 Oxygen Saturation 98% Blood Pressure 178/ / PT INR PHARMACIST OBJECTIVES Review the mechanism of action of oral anticoagulant agents and identify laboratory parameters that may be used to assess the presence of these medications Discuss emergent reversal strategies and evaluate the current literature for the management of life threatening hemorrhage due to vitamin K antagonists and direct oral anticoagulants Identify future treatment options and assess their potential role in clinical practice for the reversal of hemorrhage due to oral anticoagulation 1

2 SCOPE OF PROBLEM Prevalence of atrial fibrillation (AF) in the United States (US) in 2010 ranged from 2.7 million to 6.1 million Expected to rise to 12.1 million in 2030 Estimated annual incidence of venous thromboembolism (VTE) 900,000 3 million people in the US on warfarin Use of antithrombotics expected to increase in future years Mozaffarian D. Circulation. 2015; 132: Heit J. Arterioscler Thromb Vasc Biol. 2008; 28(3): Sarode R. J Neurosurg. 2012; 116: DOACS FACTOR Xa INHIBITORS Rivaroxaban (Xarelto ) FDA Approval November 2011 Apixaban (Eliquis ) FDA Approval December 2012 Edoxaban (Savaysa ) FDA Approval January 2015 MOA: Prevents factor Xa mediated conversion of prothrombin to thrombin Indications: Treatment or secondary prevention of VTE Nonvalvular AF Dager W. Am J Health-Syst Pharm. 2016; 73 (suppl 2):S ORAL ANTICOAGULANTS (VITAMIN K ANTAGONISTS) WARFARIN (COUMADIN ) Sweet clover disease Mechanism of action (MOA): Inhibits vitamin K-dependent γ-carboxylation of clotting factors II VII IX X Protein C and S Weitz J. Chapter 30. Blood coagulation and anticoagulant, fibrinolytic, and antiplatelet drugs. 12 th ed Adams R. Nephrology. 2009; 14: Scaglione F. Clin Pharmacokinet. 2013; 52: Frontera J. Neurocrit Care. 2016; 24(1): 6 46 Edoxaban Nutescu E. Am J Health-Syst Pharm. 2013; 70(Suppl 1): S3 11. DIRECT ORAL ANTICOAGULANTS (DOACS) DIRECT THROMBIN INHIBITOR Medication Pharmacokinetic Parameters of Oral Anticoagulants (Adapted from Table 2) Warfarin (Coumadin ) Dabigatran (Pradaxa ) Rivaroxaban (Xarelto ) Apixaban (Eliquis ) Edoxaban (Savaysa ) Dabigatran (Pradaxa ) FDA approval October 2010 MOA: Competitive direct inhibition of thrombin (factor IIa) including thrombin-mediated platelet activation and aggregation Indications: Treatment or secondary prevention of venous thromboembolism (VTE) Stroke prevention in nonvalvular AF Dager W. Am J Health-Syst Pharm. 2016; 73 (suppl 2):S Mechanism of Action Elimination Inhibits vitamin-k clotting factors II, VII, IX, and X Hepatic metabolism; 92% renal elimination Competitive direct inhibition of thrombin (factor IIa) including thrombinmediated platelet activation > 80% renal Prevents factor Xa-mediated conversion of prothrombin to thrombin 66% renal; 28% fecal Majority fecal; 27% renal 50% renal Half-life (hours) (varies in renal disease) Impairment affects excretion (Renal/Hepatic) Yes/Yes Yes/No Yes/Yes Yes/Yes Yes/Yes Dialyzable No Yes (57% over 4 hours) No Minimal No 2

3 Laboratory Monitoring Dabigatran (Pradaxa ) (Adapted from Dager W, Hellwig T. Am J Health-System Pharm. 2016; 73(suppl 2): S14 26.) ROLE OF LABORATORY MONITORING Warfarin Advantages of DOACs Limitations of DOACs Therapeutic efficacy monitored via International Normalized Ratio (INR) Doses adjusted based on INR Administered as fixed doses Do not require routine laboratory monitoring Dosing based on renal function (dabigatran, rivaroxaban, and edoxaban) Dosing based off a combination of renal function, age, and body weight for apixaban Laboratory approaches to quantitate the amount of DOAC are being explored, not universally available Lack of standardized calibrators and assays sanctioned by the FDA for DOACs Cuker A. J Thromb Thrombolysis. 2016; 41: Dager W. Am J Health-Syst Pharm. 2016; 73(suppl 2): S Assay Sensitivity Utility Thrombin Time (TT) PT/ INR aptt Dilute Thombin Time (dtt) Ecarin Clotting Time (ECT) Very sensitive; detects lower levels of dabigatran but rapidly reaches maximum levels limiting ability to differentiate high serum concentrations Relatively insensitive More sensitive than PT/INR Less sensitive than ecarin clotting assay (ECA) at lower dabigatran levels depending on calibrator used Sensitive at all concentrations Sensitivity limits utility in quantifying anticoagulation Not ideal. Elevated values may suggest presence of drug. Higher values may signal potentially excessive drug if no other causes are present Availability and sensitivity support use, cannot be used for quantitative assessment Limited availability, lacks FDA approval, and may be difficult to interpret without prior experience Limited availability; lacks FDA approval INDICATIONS FOR OBTAINING LABORATORY MEASUREMENTS IN THE PRESENCE OF DOACS Treatment failure Obesity Renal hyperfunction Malabosrption Drug interaction(s) Bleeding Overdose Renal insufficiency Low body weight Advanced age Trauma Surgery Thrombolysis THROMBOELASTOGRAPHY (TEG) Measures the mechanical resistance of an indicator rod in clotting whole blood or plasma Measures the formation and degradation of a fibrin clot in time in whole blood or plasma Provides information on clot formation, propagation, stabilization, and dissolution Questionable use in guiding therapy Cuker A. J Thromb Thrombolysis. 2016; 41: Brinkman H. Thrombosis Journal. 2015; 13: 9. Laboratory Monitoring Factor Xa Inhibitors (Adapted from Dager W, Hellwig T. Am J Health-System Pharm. 2016; 73(suppl 2): S14 26.) Assay Sensitivity Utility TITLE AND CONTENT LAYOUT WITH LIST Widespread availability. PT useful to suspect high More sensitive at higher concentrations Add your first bullet point here levels if notably elevated. Results vary depending (rivaroxaban and apixaban); more sensitive on thromboplastin reagent used, making Prothrombin Time Add than your aptt second but bullet insufficient point sensitivity here at low ontherapy drug levels (edoxaban). Reagent standardization difficult and using an INR (PT)/INR increases this variability. Elevated values may Add dependent your third bullet and inconsistent point herebetween suggest presence of drug. Higher values suggest laboratory methods and for the different potentially excessive drug if no other causes are agents present. Activated Partial Thromboplastin Time (aptt) Chromogenic Anti-FXa Low sensitivity (rivaroxaban and apixaban); low sensitivity particular at low doses (edoxaban) High sensitivity and accuracy (rivaroxaban, apixaban, edoxaban); greater than PT (apixaban) Not ideal; widely available Most promising assay. Best results occur if assay calibrated to the agent. No FDA approved calibrators available. Variable results occur between labs that different reagents and either an LMWH or a heparin calibrator MANAGEMENT OF BLEEDING ENHANCED ELIMINATION Activated charcoal May be given within 2 hours of last DOAC administration Contraindicated in patients with a gastrointestinal (GI) bleed, risk of GI perforation, intestinal obstruction, unprotected airway Hemodialysis Dabigatran (Pradaxa ) only ~2/3 removed over 2 hours Low dose factor products (e.g., FEIBA) may be given immediately before insertion of dialysis catheter Monitor coagulation parameters ; Sajkov D. Clinical Medicine Insights: Case Reports. 2015; 8: 57 Wang X. Am J Cardiovasc Drugs. 2014; 14: ; van Ryn J. Thromb Haemost. 2010; 103: Chang D. Am J Kidney Dis. 2013; 61(3):

4 MANAGEMENT OF BLEEDING REVERSAL AGENTS Provides necessary substrate for clotting factors 10 mg IV used in emergent reversal Onset of action 6 8 hours Anaphylactoid reactions (3 in 10,000 doses) Vitamin K Kalus J. Am J Health Syst Pharm. 2013; 70 (Suppl 1): S Straznitskas A. AACN. 2014; 25(1): Fresh Frozen Plasma (FFP) Clotting Factors Need for ABO blood type Time to thaw and prolonged infusion duration Large volume of administration [low] Risk of transmission of infectious diseases Transfusion related reactions Hypersensitivity Fast preparation and reconstitution time Rapid INR reversal Small volume Lower risk of infection compared to FFP ABO blood type not required Composition of Prothrombin Complex Concentrates Adapted from Kalus J. Am J Health-Syst Pharm. 2013; 70 (Suppl 1): S ; Kcentra [package insert]. Kankakee, IL: CSL Behring LLC; ; Product Factor II Factor VII Factor IX Factor X Protein C Protein S 3F-PCCs: Bebulin 3F-PCCs: Profilnine SD 4F-PCC: Kcentra apcc - FEIBA NMT 150 units/100 factor IX units <5 NMT 35 units/100 factor IX units unit/ 1.4 units/ FEIBA FEIBA unit unit* 1.3 units/ FEIBA unit NMT 100 units/100 factor IX units Antithrombin III Heparin <0.15 (IU per 1 U IX) units/ Kcentra 500 unit units/ Kcentra 500 unit 4 30 units/ Kcentra 500 unit 8 40 units/ Kcentra 500 unit 1.1 units/ FEIBA unit EFFECT OF VARIOUS THERAPIES ON INR FOR WARFARIN REVERSAL Adapted from Dager W. Am J Health-Syst Pharm. 2013; 70 (Suppl 1): S Use of vitamin K antagonists (VKA) more than doubles the risk of spontaneous intraparenchymal hemorrhage (IPH) VKAs associated with 12 14% of all IPH IPH occurs in % of patients on VKA therapy and accounts for 3500 IPHs per year INR > 4 > 65 years of age History of gastrointestinal bleed Renal/Hepatic Impairment Risk Factors for Bleeding Hypertension Malignancy Cerebrovascular disease Anemia Trauma Genetic factors Drug interactions Reversal of hemorrhage: May improve outcomes Reduce mortality Limit hemorrhage expansion Frontera J. Neurocrit Care. 2016; 24(1): 6 46 Nutescu E. Am J Health-Syst Pharm. 2013; 70(Suppl 1): S3 11. COMPARISON OF CLOTTING FACTOR CONCENTRATES Brand Name Factor Presence rfviia NovoSeven RT* 3-Factor Prothrombin Complex Concentrates (PCC) Bebulin* Profilnine SD* 4-Factor PCC Beriplex (Kcentra*) Cofact Kaskadil Octaplex Activated-PCC (apcc) FEIBA NF* VII II, IX, X II, VII, IX, X II, VII, IX, X Activated Yes No No *FDA approval in the United States Contains factor VII in an activated form Kalus J. Am J Health-Syst Pharm. 2013; 70 (Suppl 1): S PCC TO REVERSE WARFARIN-INDUCED COAGULOPATHY IN PATIENTS WITH INTRACRANIAL BLEEDING Methods Retrospective case-series review of patients treated with an institution-approved warfarin reversal protocol Inclusion Criteria Objective Acute intracranial bleeding, INR > 1.4 associated with warfarin therapy Evaluate safety and efficacy of a PCC-based protocol in patients with warfarinassociated intracerebral hemorrhage, subdural hematoma, or subarachnoid hemorrhage Cabral K. Clinical Neurology and Neurosurgery. 2013; 115:

5 PCC TO REVERSE WARFARIN-INDUCED COAGULOPATHY IN PATIENTS WITH INTRACRANIAL BLEEDING EFFICACY AND SAFETY OF A 4-FACTOR PCC IN PATIENTS ON VKA PRESENTING WITH MAJOR BLEEDING Primary Endpoints Hemostatic effect of intervention (4F PCC or plasma) Rapid INR reduction 1.3 at 0.5 hour after the end of infusion Results Effective hemostasis achieved in 72.4% (71/98) (patients in the 4F PCC group versus 65.4% (68/104) in the plasma group Rapid INR reduction achieved in 61/98 patients (62.2%) in 4F PCC group versus 9.6% (10/104) in the plasma group Conclusions 4F PCC is superior to plasma for INR reduction but non inferior to plasma for hemostatic efficacy Cabral K. Clinical Neurology and Neurosurgery. 2013; 115: Sarode R. Circulation. 2013; PCC TO REVERSE WARFARIN-INDUCED COAGULOPATHY IN PATIENTS WITH INTRACRANIAL BLEEDING FFP VERSUS PCC IN PATIENTS WITH INTRACRANIAL HEMORRHAGE RELATED TO VKAS (INCH) Results INR 1.7 in all patients (30) at 240 minutes No patients INR increased by more than 0.3 over 72 hours 3 thrombotic events Ischemic stroke PE (5 weeks post hospital admission) MI (60 days post discharge) Conclusions Routine use of 3F-PCC resulted in rapid and sustained INR reversal and low incidence of thrombotic events Methods Investigator- initiated, multicentre, prospective, randomised (1:1), openlabel, blinded-endpoint study Primary endpoint INR 1.2 or lower at 3 hours after the start of treatment Inclusion Criteria 18 years of age Intracerebral hemorrhage diagnosed via CT within 12 hours of symptom onset or after last seen well Receiving VKA treatment INR > 2 Exclusion Criteria Traumatic or secondary ICH Glasgow Coma Score < 5 Acute ischemic events Congestive heart failure Thrombotic events within 30 days Liver failure Moderate-to-severe premorbid disability Intervention FFP 20 ml/kg 4F-PCC (Octaplex ) 30 IU/kg Cabral K. Clinical Neurology and Neurosurgery. 2013; 115: Steiner T. Lancet Neurol. 2016; 15: EFFICACY AND SAFETY OF A 4-FACTOR PCC IN PATIENTS ON VKA PRESENTING WITH MAJOR BLEEDING Methods Prospective, randomized (1:1), open-label, active-controlled, non-inferiority IIIb trial Inclusion Criteria 18 years of age VKA therapy; INR 2 within 3 hours Acute major bleeding event Exclusion Criteria Acute trauma for which reversal of VKA alone would not be expected to control or resolve the acute bleeding event History of thrombotic event, myocardial infarction, DIC, CVA, TIA, unstable angina pectoris, severe PVD at 3 months of enrollment Dose of Study Treatment per Baseline INR Baseline INR 4F-PCC Dose per kg Body Weight Plasma Dose ml per kg Body Weight 2 to < > Sarode R. Circulation. 2013; FFP VERSUS PCC IN PATIENTS WITH INTRACRANIAL HEMORRHAGE RELATED TO VKAS (INCH) Results Primary Outcome FFP (n = 23) PCC (n = 27) p value INR (9%) 18 (67%) Time until INR 1.2 (minutes) Hematoma expansion (ml) at 3 hours Hematoma expansion (ml) at 24 hours 1482 ( ) 40 ( ) 0.05 PCC superior to FFP at normalizing INR within 3 hours and has less hematoma expansion at 3 and (28.4) 9.7 (20.9) hours compared to FFP 22.1 (27.1) 8.3 (18.3) Deaths at day 90 8 (35%) 5 (19%) 0.14 Steiner T. Lancet Neurol. 2016; 15:

6 Society (Year) Europe 4 th ed. (2016) NCS and SCCM (2015) Vitamin K (IV) 10 mg 1.4 Guideline Recommendations for Warfarin Reversal INR Correction Associated w/ hemorrhage emergency reversal AHA (2015) 5 10 mg ICH and elevated INR Australian (2013) 5 10 mg 1.5 Prothrombin Complex Concentrate (Dose) 4F-PCC (manufacturer) 4F-PCC over 3F-PCC (based on weight and INR) Consider over FFP (not stated) 3F PCC (50 IU/kg for life threatening bleed; clinically significant bleeding based on INR and weight) Fresh Frozen Plasma Use if PCC not available Yes (dose not stated) ml in addition to 3F-PCC 15 ml/kg if 3F-PCC unavailable rviia Not recommended Not recommended EFFECT OF NON-SPECIFIC REVERSAL AGENTS ON ANTICOAGULANT ACTIVITY OF DABIGATRAN AND RIVAROXABAN Methods: Randomized, cross-over, ex vivo study in 10 healthy volunteers Dabigatran 150 mg Rivaroxaban 20 mg Agents used for reversal Washout period of 15 days 4F-PCC (Kanokad), apcc (FEIBA), rviia (Novoseven) Receive other anticoagulant ACCP (2012) 5 10 mg INR associated w/major bleeding British (2012) 5 mg 4F-PCC > plasma Yes (dose not stated) 4F-PCC (25 50 units/kg) Use if PCC not available Not recommended Marlu R. Thromb Haemost. 2012; 108: REVERSING DOACS EFFECT OF NON-SPECIFIC REVERSAL AGENTS ON ANTICOAGULANT ACTIVITY OF DABIGATRAN AND RIVAROXABAN In vitro and ex vivo investigations suggest FFP not effective Dabigatran 150 mg Rivaroxaban 20 mg Comparisons of rfviia and PCCs from in vitro or ex vivo not conclusive Ideal agent and dose to reverse anticoagulation effects of DOACs remains unclear Dager W. Am J Health-Syst Pharm. 2016; 73(suppl 2): S Marlu R. Thromb Haemost. 2012; 108: apcc and PCC corrected ETP-AUC rviia and apcc corrected altered lag time Venous blood 2 hours post one dose of drug administration PCC corrected ETP-AUC rfviia modified the kinetic parameters apcc corrected both ETP- AUC and kinetic parameters Use of Hemostatic Factors in Reversal of DOACs in Healthy Volunteers (Adapated from Aronis K, Hylek E. J Thromb Thrombolysis. 2016; 41: ) Easy administration Predictable response Onset offset meet the profile of anticoagulant reversed Reference Study Design DOAC Intervention Comparison Results Erenberg E, et. al. Circulation. 2011; 124: Randomized, double blind, placebocontrolled Rivaroxaban 20 mg BID Dabigatran 150 mg BID PCC 50 units/kg Placebo (saline) PCC reversed PT, ETP in rivaroxaban treated patients PCC did not restore aptt, ECT, TT in dabigatran treated patients Low risk of adverse events Optimal Reversal Strategy Ability to reinitiate anticoagulation when feasible Dager W. Am J Health-Syst Pharm. 2016; 73(suppl 2): S Levi M, et. al. J Thromb Haemost. 2014; 12(9): Zahir H, et. al. Circulation. 2015; 131(1): Randomized, open-label, placebocontrolled Randomized, double-blind, placebocontrolled crossover Rivaroxaban 25mg BID Edoxaban 60 mg QDaily 3F-PCC 50 units/kg 4F-PCC 50 units/kg 4F-PCC (10, 25, 50 units/kg) Placebo (saline) Placebo (saline) 3F-PCC reduced PT by s 4F-PCC reduced PT by s 3F PCC reversed changes in TG more than 4F-PCC 4F-PCC reduced bleeding duration and increased ETP in a dosedependent manner Complete reversal of bleeding and ETP at 50 units/kg 6

7 ADMINISTRATION OF 4F-PCC AS AN ANTIDOTE FOR INTRACRANIAL BLEEDING IN PATIENTS TAKING DIRECT FACTOR Xa INHIBITORS Study Dumkow et. al. 2012* Age (Years) 85 Case Studies Describing the use of PCCs and apccs for Dabigatran Reversal (Adapted from Grottke O. Critical Care. 2016; 20:115.) Case Presentation Treatment Results Upper GI bleeding with acute kidney and liver failure and anemia 2000 units 3F PCC 16 units FFP Hemoglobin concentration stabilized and bleeding ceased Methods Retrospective chart review Inclusion Criteria Pre-injury use of direct factor Xa inhibitors Spontaneous ICH or blunt TBI with ICH Exclusion Criteria FFP for anticoagulation reversal Primary Objective Evaluate the safety and efficacy of 4F- PCC for reversal of rivaroxaban and apixaban induced coagulopathy in patients with ICH Javedani et. al Schulman et. al Acute ischemic stroke SDH post fall 84 TT 127s, aptt 46s, INR 1.2 Hemorrhage in left basal ganglia; 81 TT > 150s, aptt 48s Penetration of pacemaker lead into 85 pericardium 4520 units Patient discharged after 7 days on aspirin and 3F PCC warfarin 1 mg rfviia TT normalized after 3 days 50 units/kg apcc Received craniotomy Discharged on day 4 Mild increase in hematoma, no further progression of 42 units/kg apcc symptoms 100 units/kg apcc Bleeding ceased but TT remained elevated for 3 days 83 Upper GI bleeding 50 units/kg apcc 3 units RBCs Clinical condition stablaized Grandhi R. World Neurosurg. 2015; 84(6): Masotti et. al GI bleeding 25 units/kg x 2 4F PCC Tranexamic Acid Recovered Doses ranged from 75 mg twice daily to 150 mg twice daily *Patient expired ADMINISTRATION OF 4F-PCC AS AN ANTIDOTE FOR INTRACRANIAL BLEEDING IN PATIENTS TAKING DIRECT FACTOR Xa INHIBITORS Results 18 patients 16 Rivaroxaban, 2 apixaban 8/18 Trauma 8/18 Spontaneous intracranial hemorrhage 1/18 Subarachnoid hemorrhage 1/18 Tumor hemorrhage 1/18 hematoma expansion on CT 6/18 in hospital mortality Conclusion 4F-PCC reversed coagulopathy secondary to rivaroxaban and apixaban in ICH and appears to be safe and may reduce hemorrhagic complications and hematoma expansion Grandhi R. World Neurosurg. 2015; 84(6): Society (Year) Europe 4 th ed. (2016) NCS and SCCM (2015) Guideline Recommendations for Reversal of Direct thrombin Inhibitors (Dabigatran) Lab Parameters Dabigatran levels (TT or aptt as alternative) Renal function Reversal guided by bleeding and not labs First Line Treatment of Hemorrhage Idarcizumab Idarcizumab Alternative PCC or apcc (25 50 units/kg) combined with TXA 15 mg/kg (or 1 g) apcc or 4F-PCC (50 units/kg) Fresh Frozen Plasma Not recommended rviia Not recommended AHA (2015) aptt apcc, other PCCs May be considered Australian (2014) aptt, TT, dabigatran level 3F-PCC (25 50 units/kg) or apcc (50 units/kg) or TXA mg/kg IV ± infusion Use if concerned about dilutional coagulopathy Guideline Recommendations for Reversal of Direct Factor Xa Inhibitors Society (Year) Lab Parameters First Line Treatment of Hemorrhage Alternative Fresh Frozen Plasma rviia IDARCIZUMAB (PRAXBIND ) Europe 4 th ed. (2016) NCS and SCCM (2015) Plasma levels of specific anti-fxa agent Alternative consult expert hematologist Management guided by bleeding, not primarily lab testing TXA 15 mg/kg (or 1 g) with PCC or apcc (25 50 units/kg) 4F-PCC or apcc at 50 units/kg No data 4F-PCC or apcc > rviia due to lower risk of thrombotic events AHA (2015) PT apcc, other PCCs May be considered Australian (2014) PT anti-xa level 3F-PCC (25 50 units/kg) or apcc (50 units/kg) or TXA mg/kg IV ± infusion Use if concerned about dilutional coagulopathy Dabigatran reversal FDA approved October 2015 Humanized monoclonal antibody fragment (Fab) that binds dabigatran and rapidly neutralizes the anticoagulant effect Affinity ~350 times stronger for dabigatran Dose 5 g IV given as bolus infusions of 2.5 g each within 15 minutes Smythe M. Am J Health-Syst Pharm. 2016; 73(suppl 2):S

8 REVERSAL EFFECTS OF IDARCIZUMAB ON ACTIVE DABIGATRAN (RE-VERSE AD) Methods Inclusion Criteria Study End Points Ongoing, phase III, multicenter, prospective cohort study 18 years of age Currently taking dabigatran Group A overt, uncontrollable or life-threatening hemorrhage Group B Required surgery that could not be delayed for at least 8 hours and normal hemostasis required Maximum percentage of reversal of the maximum effect of dabigatran based on dtt or ECT Group A extent of bleeding and hemodynamic stability Group B hemostasis during intervention classified by physician as normal or as mildly, moderately, or severely abnormal Smythe M. Am J Health-Syst Pharm. 2016; 73(suppl 2):S Pollack C. N Engl J Med. 2015; 373: ANDEXANET ALFA FOR THE REVERSAL OF FACTOR Xa INHIBITOR ACTIVITY Methods Randomized, double-bind, placebo-controlled study ANNEXA-R Rivaroxaban 20 mg once daily for 4 days in healthy volunteers Andexanet 800 mg bolus or 800 mg bolus followed by continuous infusion at 8 mg/minute (total dose 960 mg) ANNEXA-A Apixaban 5 mg twice daily for 3.5 days in healthy volunteers Andexanet 400 mg bolus or 400 mg bolus followed by continuous infusion at 4 mg/minute (total dose 480 mg) Primary outcome percentage change in FXa activity All participants achieved >80% reversal anti-fxa activity Concerns Siegel D. N Engl J Med. 2015; 373: REVERSAL EFFECTS OF IDARCIZUMAB ON ACTIVE DABIGATRAN (RE-VERSE AD) - RESULTS Normalization dtt 98% 93% Normalization of ECT 89% 88% 20% (18/90) mortality rate 6% (5/90) patients with thrombotic events Median time to cessation of bleeding 11.4 hours Conclusion Immediate and safe reversal of dabigatran and normal hemostasis achieved in 90% of patients undergoing procedures Concerns Group A (n = 51) Smythe M. Am J Health-Syst Pharm. 2016; 73(suppl 2):S Pollack C. N Engl J Med. 2015; 373: Group B (n = 39) ANDEXANET ALFA (PRT064445, R-ANTIDOTE) Target: Oral FXa, LMWH, fondaparinux reversal Not FDA approved Recombinant modified FXa protein Competitively binds to direct FXa inhibitors CIRAPARANTANG (PER977, ARIPAZINE) Target oral FXa inhibitors, direct thrombin inhibitors (dabigatran), unfractionated heparin, LMWH Not FDA approved Synthetic small, water-soluble molecule Strong, physical, noncovalent bonds Promising Phase I/II clinical trials Smythe M. Am J Health-Syst Pharm. 2016; 73(suppl 2):S Smythe M. Am J Health-Syst Pharm. 2016; 73(suppl 2):S

9 PATIENT CASE REVISITED Intubated REFERENCES Cuker A. Laboratory measurement of the non-vitamin K antagonist oral anticoagulants: selecting the optimal assay based on drug, assay availability, and clinical indication. J Thromb Thrombolysis. 2016; 41: Dager W. Developing a management plan for oral anticoagulant reversal. Am J Health-Syst Pharm. 2013; 70 (Suppl 1): S Vitamin K 10 mg IV x 1 Profilnine 2170 units IV x 1 (25 units/kg) 3% 250 ml IV x 1 Surgery right hemicraniectomy Initial Labs ~3 hours Post ~5 hours Post Initial INR Initial INR PT INR Kalus J. Pharmacologic interventions for reversing the effects of oral anticoagulants. Am J Health-Syst Pharm. 2013; 70 (Suppl 1): S Kcentra [package insert]. Kankakee, IL: CSL Behring LLC; Cabral K, Fraser G, Duprey J, Gibbons B, Hayes T, Florman J, et. al. Prothrombin complex concentrates to reverse warfarin-induced coagulopathy in patients with intracranial bleeding. Clinical Neurology and Neurosurgery. 2013; 115: Sarode R, Milling T, Refaai M. Mangione A, Schneider A, Durn B, et. al. Efficacy and safety of a 4-Factor prothrombin complex concentrate in patients on vitamin K antagonists presenting with major bleeding: A randomized, plasma-controlled, pharse IIIb study. Circulation. 2013; Steiner T, Poli S, Griebe M, Husing J, Hajda J, Freiberger A, et. al.. Fresh frozen plasma versus prothrombin complex concentrate in patients with intracranial hemorrhage related to vitamin K antagonists (INCH): a randomised trial. Lancet Neurol. 2016; 15: Marlu R, Hodaj E, Paris A et. al. Effect of non-specific reversal agents on anticoagulant activity of dabigatran and rivaroxaban: a randomised crossover ex vivo study in healthy volunteers. Thromb Haemost. 2012; 108: CONCLUSIONS Patients on oral anticoagulation present unique challenges in the management of life-threatening hemorrhage 3F-PCC or 4F-PCC may be used in conjunction with vitamin K ± FFP to reverse coagulopathy induced by VKAs PCC, apcc may be used for DOAC reversal; however, data limited Specific antidotes on the horizon may aid in managing life-threatening hemorrhage REFERENCES Aronis K, Hylex E. Who, when, and how to reverse non-vitamin K oral anticoagulants. J Thromb Thrombolysis. 2016; 41: Grottke O, Aiseberg J, Bernstein R, Goldstein P, Huisman M, Jameison D, et. al. Efficacy of prothrombin complex concentrates for the emergency reversal of dabigatran-induced anticoagulation. Critical Care. 2016; 20: 115. Grandhi R, Newman C, Zhang X, Harrison G, Moran C, Okonkwo D, et. al. Administration of 4-factor prothombin complex concentrate as an antidote for intracranial bleeding in patients taking direct factor Xa inhibitors. World Neurosurg. 2015; 84(6): Smythe M, Trujillo T, Fanikos J. Reversal Agents for use with direct and indirect anticoagulants. Am J Health-Syst Pharm. 2016; 73(suppl 2):S Pollack C, Reilly P, Eikelboom J, Glund S, Verhamme P, Bernstein R, et. al. Idarcizumab for dabigatran reversal. N Engl J Med. 2015; 373: Siegal D, Curnutte J, Connolly S, Lu G, Conley P, Wiens B, et. al. Andexanet alfa for the reversal of factor Xa inhibitor activity. N Engl J Med. 2015; 373: REFERENCES Mozaffarian D, Benjamin E, Go A, Arnett D, Blaha M, Cushman M, et. al. Heart disease and stroke statistics 2016 update: a report from the American Heart Association. Circulation. 2015; 132: THANK YOU Heit J. The epidemiology of venous thromboembolism in the community. Arterioscler Thromb Vasc Biol. 2008; 28(3): Sarode R, Matevosyan K, Bhagat R, Rutherford C, Madden C, Beshay J. Rapid warfarin reversal: a 3-factor prothrombin complex concentrate and recombinant factor VIIa cocktail for intracerebral hemorrhage. J Neurosurg. 2012; 116: Frontera J, Lewin J, Rabinstein A, Aisiku I, Alexandrov A, Cook A, et. al. Guideline for reversal of antithrombotics in intracranial hemorrhage. Neurocrit Care. 2016; 24(1): Weitz J. Chapter 30. Blood coagulation and anticoagulant, fibrinolytic, and antiplatelet drugs. Goodman and Gilman s The Pharmacological Basis of Therapeutics, 12 th ed Adams R, Bird R. Review article: Coagulation cascade and therapeutics update: relevance to nephrology. part 1: overview of coagulation, thrombophilias and history of anticoagulants. Nephrology. 2009; 14: Scaglione F. New oral anticoagulants: comparative pharmacology with vitamin K antagonists. Clin Pharmacokinet. 2013; 52: Questions? Ruben.santiago@jhsmiami.org Dager W, Hellwig T. Current knowledge on assessing the effects of and managing bleeding and urgent procedures with direct oral anticoagulants. Am J Health-Syst Pharm. 2016; 73(suppl 2): S Nutescu E. Oral anticoagulant therapies: balancing the risks. Am J Health-Syst Pharm. 2013; 70(Suppl 1): S

10 CURRENT REVERSAL STRATEGIES FOR ORAL ANTICOAGULANTS AND A LOOK AT NEW REVERSAL AGENTS PRESENTED BY: RUBEN SANTIAGO, PHARMD, BCPS EMERGENCY DEPARTMENT PHARMACY SPECIALIST JACKSON MEMORIAL HOSPITAL 10