Reversal of Direct Oral Anticoagulants. Why are we now seeing so many patients on DOACs? Objectives. DOAC: Recurrent VTE. DOAC: Intracranial Bleeding

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1 Reversal of Direct Oral Anticoagulants Cameron D Griffiths, MD, FRCPC Clinical Assistant Professor Division of Hematology UBC Objectives Review efficacy and safety data for Direct Oral Anticoagulants (DOACs) Identify important factors to consider when managing DOAC related bleeding Outline supportive, local and non-specific measures to control bleeding Review data for DOAC antidotes and discuss availability in Victoria DOAC: Recurrent VTE Why are we now seeing so many patients on DOACs? van Es. Blood DOAC: Major Bleeding DOAC: Intracranial Bleeding Lim et al. Thrombosis & Hemostasis Lim et al. Thrombosis & Hemostasis

2 DOAC: Fatal Bleeding Lim et al. Thrombosis & Hemostasis ACCP Guidelines 2016 Apixaban Dabigatran Rivaroxaban Edoxaban Dose 10mg PO BID x 7d -> 5mg PO BID 150mg PO BID 15mg PO BID x21d -> 20mg PO OD 60mg PO OD* LMWH Lead In Mechanism of Action Factor Xa Inhibitor Direct Thrombin Inhibitor Factor Xa Inhibitor Factor Xa Inhibitor Drug interactions CYP3A4 CYP3A4 Half Life ~12 hours hours 5-13 hours hours Onset of Action 1-3 hrs 1-3 hrs 1-3 hrs 1-3 hrs Renal Clearance ~25% ~85% ~35% ~50% WARFARIN APIXABAN RIVAROXABAN EDOXABAN 2

3 Are Laboratory Measures Helpful? Dabigatran Variable effect on PTT/INR Normal values do NOT rule out clinically relevant drug levels DABIGATRAN Most sensitive test = Thrombin Time Normal thrombin time likely excludes clinically relevant Dabigatran Possibly too sensitive Siegal. Blood Are Laboratory Measures Helpful? Apixaban/Rivaroxaban/Edoxaban Variable effect on PT/INR Normal values do NOT rule out clinically relevant drug levels Anti-Xa level most appropriate test to determine drug levels No safe levels determined for surgery/procedures Siegal. Blood Cuker. JACC Medication Interactions inhibitors ( DOAC Levels) Cyclosporine Azoles Tacrolimus Ritonavir Imatinib inducers ( DOAC Levels) Carbamazepine Dexamethasone Phenobarbitol Phenytoin Rifampin CYP3A4 inhibitors ( DOAC Levels) Azoles Amiodarone Erythromycin Fluconazole Verapamil CYP3A4 inducers ( DOAC Levels) Phenytoin Trazadone Clarithromycin Pioglitazone St John s Wart Step 1: Stop Anticoagulation STOP THE DRUG 3

4 Step 2: Supportive Measures Determine hemodynamic stability Establish IV access and airway (if applicable) Reverse hypothermia, acidosis, and electrolyte imbalances RBC transfusion +/- platelets +/- plasma Liaise with blood bank if massive transfusion protocol expected Possible monitoring in ICU Step 3 : Are relevant drug levels present? Determine which drug has been taken, at what dose and at what time the lost dose was administered Assess renal function Determine if other drugs could be leading to higher/lower than expected drug levels STAT lab measures if available Thrombin time (Dabigatran) Anti-Xa level (Riva/Apixa/Edoxa) Step 4: Local Measures Step 5: Non-specific Measures You need to have a hole to bleed from Rapidly aim to achieve local control of bleed: Topical pressure/sutures/glue Endoscopies (GI/GU/Bronchoscopy) Surgery Fresh Frozen Plasma * Tranexamic Acid* Prothrombin Concentrate Factor VIIa* Oral charcoal * Dialysis DDAVP * * No clinical data Prothrombin Concentrate Blood product containing factors: II,VII,IX,X Commonly used to reverse warfarin Very limited data for reversal of DOACs Goal is to overwhelm inhibitors Eerenberg. Circulation

5 Dialysis Step 6: Specific Measures Dabigatran is both the most dependent on renal excretion and least protein bound Studies have shown transient reduction in drug concentration (52-77%) rebound effect due to drug redistribution Dabigatran: Idarucizumab Apixaban/Edoxaban/Rivaroxaban: Andexanet Alfa Singh. Clin J Neph Trial Design 503 patients who were receiving Dabigatran and: Had life threatening bleeding (Group A) Needed Surgery within 8hrs (Group B) All patients received 5g of Idarucizumab 1 Outcome: Reversal of Dabigatran based on clotting times (dilute thrombin time) Clinical Outcomes Severity of Bleeding Peri-procedural Hemostasis Patient Characteristics 95% of patients were receiving Dabigatran for Atrial Fibrillation Median age = 78yrs 60% of patients were receiving 110mg BID dose Median GFR 52.6 ml/min Median time from last dose to antidote: Group A = 14.6 hrs Group B = 18.0 hrs 5

6 Results Group A: Median maximum reversal = 100% Median time to stop bleeding = 2.5 hrs Group B: Median time to OR = 1.6 hrs Hemostasis deemed normal in 93.4% of patients during procedure *Thrombotic events occurred in 4.8% of patients Trial Design Results 67 patients presenting with major bleeding within 18hrs of taking: Apixaban Rivaroxaban Edoxaban Enoxaparin Andexanet given as a bolus followed by a 2 hours infusion dose depended on timing since last dose 1 outcomes: Change in anti-xa activity Hemostatic efficacy 6

7 When can we restart Anticoagulation? Establish if anticoagulation is truly needed Ongoing VTE risk factors CHADS 2 score Ensure cause of bleeding has been definitively managed Consider risk of further bleeding Are these risks modifiable? Recall that all DOACs have rapid onset of action Summary Step 1: Stop the drug Step 2: Supportive measures Step 3: Determine if relevant drug level present Step 4: Local control of bleeding Step 5: Non-specific hemostatic reversal Step 6: Specific antidotes Step 7: Careful reconsideration of anticoagulation indication Correct information is paramount: Drug(s) Dose Timing of last dose Renal function Summary Supportive care and local measures are extremely important not all bleeding is DOAC related! Various non-specific agents have been tried with limited clinical data Specific antidotes are now studied and Idarucizumab is available in VIHA Only restart anticoagulation if hemostasis is achieved and it is truly indicated 7