1. 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

2. 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

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

4. 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 %
Warfarin %
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%

5. 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

6. 2016 Guidelines for Antithrombotic Reversal

7. Vitamin K Antagonists (VKAs)

8. 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 1
0.6
1.4
0.4
4.6
>4
8.8

9. 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

10. 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
Br J Haematol Oct;115(1):145-9.

11. 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
10-25 units/kg
Max: 2500 units
25 units/kg
35 units/kg
Max: 3500 units
>6
50 units/kg
Max: 5000 units

12. 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:

13. Graph of Response Over Time
PCC
Vitamin K

14. 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
U ↓INR
↑thrombosis rates
rFVIIa
↓INR but only from ↑FVII
Short t1/2
*Vitamin K should be administered with all alternatives

15. Direct Oral Anticoagulants (DOACs)

16. 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 Apr;51(2):

17. 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

18. Considerations Prior to Reversal
Assess time/amount of last ingested dose, renal function, and drug interactions to estimate exposure
T1/2: 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 Nov;14(11):

19. 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 Nov;129(11S):S64-S72.
N Engl J Med 2017;377:

20. 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

21. 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

22. 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 Nov;14(11):

23. 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 Apr;133(4):
Circulation. 2011; 124:1573–9.

24. 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:
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 Nov;129(11S):S80-S88.

25. 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

26. Heparins (UFH and LMWH)

27. 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:

28. 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

29. 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

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

31. 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

32. 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

33. 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

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

35. Other Parenteral Anticoagulants and ICH
Pentasaccharides
Fondaparinux (Arixtra®)
Long T1/2: 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: 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

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

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

38. 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

39. Alternative Reversal Agents

40. Antiplatelets

41. Antiplatelet Treatment and ICH
Several classes of FDA- approved antiplatelet agents exist
Reversible Inhibitors  platelet function restored after 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 Apr;32(4):

42. 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

43. Platelet Transfusion for Antiplatelet Reversal
Lancet Jun 25;387(10038):
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

44. 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 Apr;1(4):682-9.

45. 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

46. Thrombolytics

47. 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

48. 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

49. 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

50. 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

51. 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
units/kg, not to exceed 2500 units
units/kg, not to exceed 2500 units
units/kg, not to exceed 3500 units
> 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
units/kg
> 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

52. 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

53. 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 Feb;24(1):
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 Nov;14(11):
Pollack CV Jr et al. Idarucizumab for Dabigatran Reversal - Full Cohort Analysis. N Engl J Med Aug 3;377(5):
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 ;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 ;133:671–81.
Connolly SJ et al. Andexanet Alfa for Acute Major Bleeding Associated with Factor Xa Inhibitors. N Engl J Med Sep 22;375(12):
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 Jun 25;387(10038):