When Risk Becomes Reality Antithrombotic Reversal in Hemorrhagic Stroke Matthew P. Lillyblad, PharmD, BCPS-AQ Cardiology Clinical Pharmacy Coordinator - Cardiology & Critical Care Abbott Northwestern Hospital, Minneapolis, MN

Disclosure No current or recent financial relationships with pharmaceutical or medical device companies exist No potential conflicts of interest exist The use of medications outside of their FDA approved indication will be included in this presentation

Management of Hemorrhagic Stroke ICH Blood Pressure ICP Seizure Blood Glucose PPX Correct Na AC Reversal

Antithrombotic Associated ICH Antithrombotics are commonly used to treat or decrease the risk of thrombosis/embolism Oral Anticoagulants (Warfarin, DOACs) Parenteral (UFH, LMWH, Fondaparinux) Antiplatelets (Aspirin, P2Y12s, etc.) Thrombolytics (tPA, tenecteplase, etc.) Use is expected to rise Antithrombotics exacerbate spontaneous/ traumatic bleeding  hematoma expansion ↑ Mortality and ↓ Functional Outcomes 0.3-1.2% Warfarin 0.33-0.8% Anti-Xa 0.3% Oral DTI ≤0.1% Heparin 0.4% Aspirin 0.4-7% tPA Location Intracerebral: 46-86% Subdural: 13-45% Subarachnoid: 1-8%

Approach to Antithrombotic (AT) Reversal Stop AT and Determine Time + Amount of Last Dose Baseline Laboratory Evaluation Prompt Treatment with Reversal Agent Follow-up Laboratory + Clinical Assessment Additional Reversal Agent Treatment As Needed

2016 Guidelines for Antithrombotic Reversal

Vitamin K Antagonists (VKAs)

VKA Treatment and ICH ICH and INR 2-3 0.3-0.5 1 3.1-3.5 0.6 1.4 Warfarin (Coumadin®, Jantoven®) Others: acenocoumarol, phenprocoumon, dicoumarol, tecarfarin, and fluindione ↓Coagulation factors II, VII, IX, X Many indications VKA use has ↑4x over the last decade 2x+ the risk of spontaneous ICH Monitored with INR increases with increasing INR most occur within the recommended therapeutic range [11, 20–25]. ICH = 90 % of all VKA-related deaths Mortality rates + functional outcomes from ICH worse with VKA ICH and INR INR Per 100 Person-Years RR 2-3 0.3-0.5 1 3.1-3.5 0.6 1.4 3.6-3.9 0.4 4.6 >4 2.7-9.4 8.8

First-line Reversal of Warfarin ICH INR Baseline Lab(s) Vitamin K 10 mg IV infused >10 minutes 4-Factor PCC Dosed by Weight and INR Treatment 15–60 min after PCC Serially 6–8 h for the next 24–48 h. Follow Up Lab(s) INR >1.3 (<24 hrs): FFP vs. 4-fPCC INR >1.3 (>24 hrs): Vit K 10 mg + FFP/PCC Re-Treatment

Role of Vitamin K in Warfarin Reversal Indicated for all VKA reversals Should be given IV infusion Dose = 10 mg No high quality studies for improving outcomes Corrects INR Vitamin K alone was associated with a ↑50 % incidence hemorrhage growth https://emcrit.org/emcrit/reversal-head-bleeds/ Br J Haematol. 2001 Oct;115(1):145-9.

Role of 4-fPCC in Warfarin Reversal Multiple products Kcentra® is the only US approved Contain inactive coagulation factors II, VII, IX, X; proteins C, S, and Z; and heparin Distinguished from 3-factor products by appreciable amounts of Factor VII Theoretical hemostatic advantage Weight-based dosing of PCC more effective than fixed-dose Max 24 hr dose: 50 units/kg or 5000 U? Caution in patients with acute arterial thrombus, DIC, or other coagulopathies INR Dosing 1.4-1.9 10-25 units/kg Max: 2500 units 2.0-3.9 25 units/kg 4.0-6.0 35 units/kg Max: 3500 units >6 50 units/kg Max: 5000 units

Benefits of 4-fPCC in Warfarin Reversal Outcome PCC vs. FFP Preparation Time Volume Overload TRALI/TACO Risk of Infection Hematoma Expansion Severe Disability Mortality Thromboembolic Events 60-70% achieve an INR <1.4 at 30 minutes Circulation. 2013;128:1234-1243.

Graph of Response Over Time PCC Vitamin K

Alternative Reversal Agents 3-factor PCC Alternative to 4f-PCC Less data than 4-factor Rec’d over FFP May add FFP for more FVII FFP 10-15 mL/kg Preferred if no PCC Considered if need reversal after full dose PCC aPCC No recs from guidelines 500-1000 U ↓INR ↑thrombosis rates rFVIIa ↓INR but only from ↑FVII Short t1/2 *Vitamin K should be administered with all alternatives

Direct Oral Anticoagulants (DOACs)

Semin Hematol. 2014 Apr;51(2):98-101. DOAC Treatment and ICH Oral Direct Factor Xa Inhibitors Apixaban (Eliquis®) Betrixaban (Bevyxxa®) Edoxaban (Savaysa®) Rivaroxaban (Xarelto®) Oral Direct Thrombin (IIa) Inhibitors Dabigatran (Pradaxa®) Associated with a risk of intracranial hemorrhage ↓ ICH compared to warfarin in AF Apixaban 5 mg BID (HR 0.42) Dabigatran 150 mg BID (HR 0.40) Edoxaban 60 mg daily (HR 0.54) Rivaroxaban 20 mg daily (HR 0.67) ↓ ICH severity Semin Hematol. 2014 Apr;51(2):98-101.

First Line Reversal of Dabigatran ICH Guide primarily by bleeding not lab testing Can check aPTT and/or Diluted Thrombin Time Baseline Lab(s) Idarucizumab (Praxbind®) 5 g IV in two divided doses Treatment Can check aPTT and/or Thrombin Time Follow Up Lab(s) Idarucizumab (Praxbind®) 5 g IV Hemodialysis Re-Treatment

Considerations Prior to Reversal Assess time/amount of last ingested dose, renal function, and drug interactions to estimate exposure T1/2: 12-17 hrs  28 hrs Reversal should be guided primarily by bleeding and not primarily by lab testing Administer activated charcoal (50 g) to intubated patients with enteral access or those at low risk of aspiration who present within 2 h of ingestion J Thromb Haemost. 2016 Nov;14(11):2194-2201.

Idarucizumab in Dabigatran Reversal ↓ aPTT to normal ↓ dTT to normal Bleeding Cessation by 24 hrs = 67.7% Median Time to Hemostasis = 2.5 hrs Thrombosis = 4.8% 5 g of idarucizumab IV 2 x 50-ml bolus infusions of 2.5 g No more than 15 minutes apart calculated to reverse the total body load of dabigatran that was associated with the 99th percentile of the dabigatran levels measured in the RE-LY trial 33% ICH Am J Med. 2016 Nov;129(11S):S64-S72. N Engl J Med 2017;377:431-41.

Alternative Reversal Agents Hemodialysis Consider in ongoing bleeding or no Idaruciz iHD (4 hr) or CVVHDF at high rates of 200–400 ml/min Watch for rebound PCC/aPCC Animal, In- vitro, Healthy data Only if idarucizumab unavailable 50 U/kg of either aPCC likely more thrombotic FFP Little data Not thought to be enough clotting factors Use as part of massive transfusion protocol(s) rFVIIa Limited data Not recommended *Vitamin K is ineffective for DOACS

First Line Reversal of Xa Inhibitor ICH Guide primarily by bleeding not lab testing Can check PT and/or heparin anti-Xa Baseline Lab(s) 4-fPCC (50 U/kg) or aPCC (50 U/kg) Andexanet Alfa (Andexxa®) Treatment Follow Up Lab(s) Unclear, no recommendations Re-Treatment

Considerations Prior to Reversal Assess time/amount of last ingested dose, renal/hepatic function, and drug interactions to estimate exposure Reversal should be guided primarily by bleeding and not primarily by lab testing Administer activated charcoal (50 g) to intubated patients with enteral access or those at low risk of aspiration who present within 2 h of ingestion J Thromb Haemost. 2016 Nov;14(11):2194-2201.

4-fPCC/aPCC in Factor Xa Inhibitor Reversal aPCC 50 U/kg 4-fPCC 50 U/kg 50 U/kg IV one time Thromb Res. 2014 Apr;133(4):671-81. Circulation. 2011; 124:1573–9.

Andexanet Alfa for Factor Xa Inhibitor Reversal 79% of patients had good or excellent hemostasis at 12 hours 18% experience thrombotic events during 30 days follow-up N Engl J Med 2016;375:1131-41. Last Dose < 8 hours or Unknown ≥ 8 hours Apixaban ≤ 5 mg 400 mg bolus + 4 mg/min Apixaban > 5 mg 800 mg bolus + 8 mg/min Rivaroxaban ≤ 10 mg Rivaroxaban > 10 mg Am J Med. 2016 Nov;129(11S):S80-S88.

Alternative Reversal Agents Hemodialysis No role due to high protein binding FFP Little data Not thought to be enough clotting factors Use as part of massive transfusion protocol(s) rFVIIa Limited data Not recommended given alternatives available and thrombotic risk *Vitamin K is ineffective for DOACS

Heparins (UFH and LMWH)

Treatment with Heparins and ICH Unfractionated Heparin (UFH) Low Molecular Weight Heparins (LMWH) Enoxaparin (Lovenox®) Dalteparin (Fragmin®) MOA Indirectly inhibits Factor Xa and Factor IIa via antithrombin LMWHs have more predictable pharmacokinetics and bioavailability than UFH Typically used for short courses intraprocedurally (PCI) or as bridge to oral anticoagulation with warfarin Reversal not recommended for prophylactic doses N Engl J Med 1997; 337:688-699

First Line Reversal of Heparin ICH Guide primarily by bleeding not lab testing Can check aPPT or heparin anti-Xa Baseline Lab(s) Protamine: 1 mg for every 100 units of heparin in the last 2–3 h (max 50 mg) Treatment aPPT or heparin anti-Xa Follow Up Lab(s) Protamine 0.5 mg per 100 units of UFH Re-Treatment NO ACT since not specific

Protamine for Heparin (UFH) Reversal Protamine 1 mg for every 100 units of heparin in the last 2–3 h (max 50 mg per 10 min) 1 mg of protamine neutralizes 80–120 units UFH UFH has a t1/2 is 60–90 min Administer at a rate ≥20 mg/min Adverse reactions: anaphylaxis, hypotension, bradycardia, and bronchoconstriction Excessive dose can exacerbate bleeding Risk factors for ADEs Prior exposure, use of NPH insulin, vasectomy, or allergy to fish Can lead to antibodies against protamine sulfate Considered pre-treating with corticosteroids and histamines Protamine sulfate is a basic protein derived from fish sperm. half-life of protamine is approximately 7 min Dose and rate dependent Little data to support the reversal of prophylactic SC doses Consider if prolongs the aPTT

Alternative Reversal Agents rFVIIa Efficacy in reversing UFH in animal studies and case reports Not explicitly recommended in the guidelines

First Line Reversal of LMWH ICH Guide primarily by bleeding not lab testing Can check LMWH anti-Xa Baseline Lab <8 hrs or 3-5x T1/2: 1 mg of protamine per 1 mg of enoxaparin or per 100 anti-Xa units of other LMWH 8-12 hrs: 0.5 mg of protamine per 1 mg of enoxaparin Treatment Follow Up Lab 0.5 mg of protamine per 100 anti-Xa units of LMWH or per 1 mg of enoxaparin Re-Treatment

Protamine for LMWH Reversal Enoxaparin and dalteparin are FDA approved Lack of inhibitors for complete reversal Little data specifically in ICH Protamine is widely utilized Neutralizes the anti-IIa activity and only partially effective at reversing anti-Xa Enoxaparin exposed plasma: reversed 64 % of anti-IIa effect and 35 % of the anti-Xa Same risks as UFH reversal apply Dosing (max dose 50 mg) <8 hrs for enoxaparin or 3-5x T1/2 for dalteparin: 1 mg of protamine per 1 mg/100 anti-Xa units 8-12 hrs: 0.5 mg of protamine per 1 mg of enoxaparin

Alternative Reversal Agents Hemodialysis Depends on their molecular size and other drug specific factors Not recommended at this time rFVIIa Limited data May have some efficacy Reserved contraindication to protamine or refractory bleeding

Other Parenteral Anticoagulation Other Parenteral Anticoagulation . (Fondaparinux, Bivalirudin, Argatroban)

Other Parenteral Anticoagulants and ICH Pentasaccharides Fondaparinux (Arixtra®) Long T1/2: 17-21 hrs Affected by renal function Reversal not recommended for prophylactic doses Intravenous Direct Thrombin Inhibitors (DTIs) Bivalirudin (Angiomax®) Short T1/2: 25 min Affected by renal function: ESRD ~3.5 hrs Argatroban (Acova®) Short T1/2: 39-51 min Affected by renal and hepatic function Typically used for short courses intraprocedurally (PCI) or as bridge to oral anticoagulation with warfarin Data for reversal based on animal, in vitro, and cases/case series J Pharmacogenom Pharmacoproteomics 2011, 2:2

First Line Reversal of Fondaparinux ICH No monitoring parameters available Baseline Lab aPCC: 20 IU/kg Treatment Follow Up Lab No recommendations Re-Treatment

Alternative Reversal Agents Protamine Not effective rFVIIa If aPCC is contraindicated or not available 90 mcg/kg

First Line Reversal IV DTIs in ICH Guide primarily by bleeding not lab testing May check an aPTT Baseline Lab aPCC 50 units/kg or 4-factor PCC 50 units/kg Treatment Follow Up Lab No recommendations Short T1/2 with normal end organ function Re-Treatment

Alternative Reversal Agents

Antiplatelets

Antiplatelet Treatment and ICH Several classes of FDA- approved antiplatelet agents exist Reversible Inhibitors  platelet function restored after 3-5 T1/2 Irreversible Inhibitors  must wait for new platelet turnover Controversial whether antiplatelet agents influence intracranial hemorrhage expansion or neurologic outcome Utility of reversal agents is unknown Diabetes Care. 2009 Apr;32(4):531-40.

First Line Reversal Antiplatelets in ICH Platelet function testing prior to platelet transfusion if possible Baseline Lab(s) Consider DDAVP 0.4 mcg/kg IV (one time) if bleed associated with aspirin or ADP receptor inhibitors Treatment Platelet function testing if further platelet transfusion if possible Follow Up Lab(s) Platelet transfusion if undergoing neurosurgical procedure Re-Treatment

Platelet Transfusion for Antiplatelet Reversal Lancet. 2016 Jun 25;387(10038):2605-2613. Suggest against platelet transfusion who will not undergo a neurosurgical procedure, lack of substantive data to suggest that platelet transfusion improves outcome Platelet transfusion recommend for: Those who will undergo a neurosurgical procedure AND Aspirin- or ADP inhibitor- associated hemorrhage AND (IF POSSIBLE) Platelet dysfunction on testing Initial dose: 1 single-donor apheresis unit  platelet function testing prior to repeat Platelet transfusion is associated with serious risks  14–16 % increase in AEs transfusion-related acute lung injury, thrombosis, disseminated intravascular coagulopathy, hemolytic transfusion reactions, and transfusion-associated sepsis, among others

Desmopressin for Antiplatelet Reversal Promotes platelet adhesion to the endothelium through: Increases the endothelial release of large factor VIII:vWF multimers Increase platelet membrane glycoprotein expression Demonstrated efficacy in restoration of platelet function in antiplatelet treated patients Desmopressin (DDAVP): 0.4 mcg/kg IV If associated with aspirin/COX-1 inhibitors or ADP receptor inhibitors Can used in addition to platelet transfusion those undergoing a neurosurgical procedure (Rare) Side effects include: facial flushing, hypervolemia, decreased urine output, and hyponatremia J Thromb Haemost. 2003 Apr;1(4):682-9.

Alternative Reversal Agents Cryoprecipitate/FFP In-vitro data suggests improved aggregation of GP IIb/IIIa inhibitor treated platelets No recommendation rFVIIa Improves hemostasis in genetic GP IIb/IIIa deficiencies No data with GP IIb/IIIa inhibitors

Thrombolytics

Thrombolytics and ICH Plasminogen activators convert plasminogen to plasmin, which can degrade fibrinogen and fibrin and cause thrombolysis Fibrin-non-selective: urokinase and streptokinase Fibrin-selective: alteplase, reteplase, and tenecteplase Can low serum fibrinogen levels Alteplase 100 mg  ↓16–36 % Strong predictor of ICH Short T1/2s but coagulopathy can persist beyond 24 hrs Can also produce an antiplatelet effect Leads to hematoma expansion in up to 40 % of patients and mortality up to 61 % at 3 months https://usmle.biochemistryformedics.com

First Line Reversal Lytics and ICH Guide primarily by bleeding not lab testing May check fibrinogen Baseline Lab Cryoprecipitate: 10 units Treatment Fibrinogen Follow Up Lab Additional cryoprecipitate Re-Treatment

Cryoprecipitate for Lytic Reversal Cryoprecipitate: 10 units in all patients who have received a thrombolytic agent in the previous 24 h Cryoprecipitate contains fibrinogen (200 mg/unit), Factor VIII, fibronectin, factor XIII, and von Willebrand Factor. 10 units of cryoprecipitate will raise fibrinogen levels by roughly 70 mg/dL in a 70 kg patient Fibrinogen level targets >100 mg/dL and >150 mg/dL have been used Fibrinogen as a marker for continued administration of cryoprecipitate may be useful https://www.sigmaaldrich.com

Alternative Reversal Agents Antifibrinolytics Limited data Recommended if cryoprecipitate is contraindicated or not timely Tranexamic acid 10–15 mg/kg IV over 20 min or e-aminocaproic acid 4–5 g IV FFP Contains fibrinogen Larger volume needed due to low concentrations Platelets Unclear if useful Recommended by AHA/ASA guidelines

Implementing Recommendations into Practice Received warfarin  phytonadione (VITAMIN K) IV   ONE TIME, Intravenous, Dose: 10 mg  prothrombin complex concentrate (PCC) (KCENTRA) IV ONE TIME, Intravenous, Dose: [ ] mg Comments: Dose according to patient weight and INR INR KCentra Dose 1.4-1.9 25 units/kg, not to exceed 2500 units 2-3.9 25 units/kg, not to exceed 2500 units 4-6 35 units/kg, not to exceed 3500 units >6 50 units/kg, not to exceed 5000 units  anti-inhibitor coagulant complex (FEIBA VH) IV – if PCC (KCENTRA) unavailable or patient has history of heparin induced thrombocytopenia Comments: Dose according to patient INR INR PCC Dose 1.5-3 15 units/kg > 3 25 units/kg  Fresh Frozen Plasma (FFP) – for patient at high risk for thrombotic complications (LVAD, DIC) ONE TIME, Dose: 20 mL/kg  Protime-INR 30 min after PCC dose Q6 hrs x 6 occurrences If on subsequent checks, INR is > 1.4 correct with FFP

Summary and Conclusions Intracranial hemorrhage and hemorrhagic stroke is associated with significant morbidity and mortality Concomitant antithrombotic therapy worsens outcomes Reversal of antithrombotic induced coagulopathy is an important component of patient care There is no universal reversal agent for all antithrombotics therefore treatment must of tailored to the patients current medications Establishing institution guideline and/or order sets will help facilitate safe and effective ordering

References Frontera JA et al. Guideline for Reversal of Antithrombotics in Intracranial Hemorrhage: A Statement for Healthcare Professionals from the Neurocritical Care Society and Society of Critical Care Medicine. Neurocrit Care. 2016 Feb;24(1):6- 46. Watson HG, et al. A comparison of the efficacy and rate of response to oral and intravenous Vitamin K in reversal of over- anticoagulation with warfarin. Br J Haematol. 2001;115:145–9. Sarode R 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, phase IIIb study. Circulation. 2013;128:1234–43. Testa S et al. Poor comparability of coagulation screening test with specific measurement in patients receiving direct oral anticoagulants: results from a multicenter/multiplatform study. J Thromb Haemost. 2016 Nov;14(11):2194-2201. Pollack CV Jr et al. Idarucizumab for Dabigatran Reversal - Full Cohort Analysis. N Engl J Med. 2017 Aug 3;377(5):431- 441. Eerenberg ES, Kamphuisen PW, Sijpkens MK, Meijers JC, Buller HR, Levi M. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation. 2011;124:1573–9. Perzborn E, Heitmeier S, Laux V, Buchmuller A. Reversal of rivaroxaban-induced anticoagulation with prothrombin complex concentrate, activated prothrombin complex concentrate and recombinant activated factor VII in vitro. Thromb Res. 2014;133:671–81. Connolly SJ et al. Andexanet Alfa for Acute Major Bleeding Associated with Factor Xa Inhibitors. N Engl J Med. 2016 Sep 22;375(12):1131-41. Baharoglu MI et al. Platelet transfusion versus standard care after acute stroke due to spontaneous cerebral haemorrhage associated with antiplatelet therapy (PATCH): a randomised, open-label, phase 3 trial. Lancet. 2016 Jun 25;387(10038):2605-2613.