1. Pharmacology of Anticoagulants
Nathan Culver, PharmD, BCPS

2. anticoagulant Medication Classes
Direct Thrombin Inhibitors (DTI)
Argatroban
Bivalrudin
Dabigatran (Pradaxa®)
Betrixaban (Bevyxxa®)
Factor Xa Inhibitors
Enoxaparin
Fondaparinux
Rivaroxaban (Xarelto®)
Apixaban (Eliquis®)
Edoxaban (Savaysa®)
Vitamin K antagonists
Warfarin (Coumadin®, Jantoven®)

3. Citation: Antithrombotics, Hoffman RS, Howland M, Lewin NA, Nelson LS, Goldfrank LR. Goldfrank's Toxicologic Emergencies, 10e; Available at: Accessed: October 05, 2018
Copyright © 2018 McGraw-Hill Education. All rights reserved

4. Warfarin
Dabigatran
Rivaroxaban
Apixaban
Edoxaban
Mechanism of action
Inhibition of II, VII, IX, X
Selective, competitive, direct inhibition of activated Factor II (thrombin)
Selective, competitive, direct inhibition of activated Factor X
Pro-drug No
Yes
Half-life 32
12 -14
9-12 12
8-10
Bio-availability
98%
6.5%
>80%
>50%
>45%
Excretion
Liver
Renal (80%)
Renal (66%)
Renal (25%)
Renal (35%)

5. Laboratory monitoring

6. Dabigatran Laboratory Monitoring
In patients receiving dabigatran 150mg bid
Observed Serum concentrations1
Peak values
64 – 443 ng/ml
Trough values
31 – 225 ng/m
Dabigatran Laboratory Monitoring
Thrombin Time (TT) and diluted Thrombin Time (dTT) – Quantitative and specific
The TT test measure will depend on the coagulometer and on the thrombin lot used for the measurement. It is therefore advisable to use the calibrated Hemoclot®Thrombin Inhibitor assay (a diluted TT [dTT] assay) with dabigatran standards to calculate the concentration of Pradaxa rather than to determine TT.
A TT measure with the calibrated Hemoclot® Thrombin Inhibitor assay (HYPHEN BioMed, Neuville-sur-Oise, France) of >200 ng/mL dabigatran plasma concentration (approximately >65 seconds) prior to the next drug intake after 150 mg twice-daily dosing (trough measure, i.e. 10−16 hours after the previous dose) is associated with a higher risk of bleeding
A normal TT measure indicates no clinically relevant anticoagulant effect of Pradaxa
Activated Partial Thromboplastin Time (aPTT) - semi-quantitative, not specific
An aPTT test may be useful in determining an excess of anticoagulant activity, despite aPTT being less sensitive to the activity of Pradaxa above therapeutic levels. Please note: in the first 2–3 days after surgery, false prolonged measures may be detected.
An aPTT 2–3 fold of control at trough (when the next dose is due) is associated with a higher risk of bleeding
Ecarin clotting time (ECT) - Quantitative and specific
ECT provides a direct measure of the activity of direct thrombin inhibitors
Approximately 3−4 times elevated ECT over control prior to the next drug intake of Pradaxa (at trough) is associated with a higher risk of bleeding

7. Rivaroxaban Laboratory Monitoring
Anti-Xa activity
High degree of correlation when calibrated for rivaroxaban
In the absence of a drug-specific calibration curve, use of a curve calibrated for unfractionated or low molecular weight heparin is a reasonable surrogate for excluding drug levels ≥ 25–30 ng/mL.
Prothrombin Time (PT)
Rivaroxaban prolongs the PT in a concentration-dependent manner.
PT reagents vary markedly in their sensitivity to rivaroxaban.
The PT has insufficient sensitivity to exclude on-therapy levels of rivaroxaban. In a study of ex vivo samples from patients taking rivaroxaban 20 mg daily at steady state, 19% to 93% of samples at trough had a normal PT, depending on the reagent.
Activated Partial Thromboplastin Time (aPTT)
Less sensitive than PT, not useful clinically
Other
Urinary assays 5-15 times higher than blood levels
Stroke Prevention in AF
(20mg daily)
VTE Treatment
VTE Prevention
(10mg daily)
Peak values
160 – 360 ng/ml
175 – 360 ng/ml
91 – 196 ng/ml
Trough values
4 – 96 ng/ml
19 – 60 ng/ml
1.3 – 38 ng/ml

8. Apixaban Laboratory Monitoring
Apixaban dose
Observed Peak Concentration
Observed Trough Concentration
VTE Prophylaxis
2.5mg bid
ng/ml
ng/ml
VTE Treatment
5mg bid
10mg bid
ng/ml
ng/ml
 ng/ml
11-90 ng/ml
ng/ml
ng/ml
Stroke Prevention in AF
ng/ml
ng/ml
ng/ml
ng/ml
Apixaban Laboratory Monitoring
Anti-Xa activity
High degree of correlation when calibrated for rivaroxaban
In the absence of a drug-specific calibration curve, use of a curve calibrated for unfractionated or low molecular weight heparin is a reasonable surrogate for excluding drug levels ≥ 25–30 ng/mL
Prothrombin Time (PT)
Less sensitive for apixaban than rivaroxaban or edoxaban
Most PT reagents are inadequately sensitive to detect not only on-therapy, but even above on-therapy levels of apixaban with minimal change in values up to concentrations of 200 ng/mL in both patient and spiked sampl
Activated Partial Thromboplastin Time (aPTT)
Levels > 500 ng/ml only marginally increase aPTT
Other
Urinary assays 5-15 times higher than blood levels

9. Edoxaban Laboratory Monitoring
Anti-Xa activity
Commercial product newly available
Data with Anti-Xa correlated to heparin shows sensitivity
Prothrombin Time (PT)
Some effect but limited correlation available
Activated Partial Thromboplastin Time (aPTT)
Limited sensitivity and conflicting data
Other
No urine screen

13. References
2017 ACC Expert Consensus Decision Pathway on Management of Bleeding in Patients on Oral Anticoagulants: A Report of the American College of Cardiology Task Force on Expert Consensus Decision Pathways. J Am Coll Cardiol2017;Dec 1
Zehnder JL. Drugs Used in Disorders of Coagulation. In: Katzung BG. eds. Basic & Clinical Pharmacology, 14e New York, NY: McGraw-Hill; .  October 09,
Buxton IO. Pharmacokinetics: The Dynamics of Drug Absorption, Distribution, Metabolism, and Elimination. In: Brunton LL, Hilal-Dandan R, Knollmann BC. eds.Goodman & Gilman's: The Pharmacological Basis of Therapeutics, 13e New York, NY: McGraw-Hill; .  October 10,
Clinical/Images/Tools%20and%20Practice%20Support/Mobile%20Resources/ManageAnticoag/B18120_ManageAnticoag_App_Fact_Sheet.p df

14. Reversal

15. DOAC: Reversal Travis Gatesman, pharmd
Clinical pharmacy specialist, neurology
October 10, 2018

16. objectives
Introduce factor Xa inhibitors (FXa) & direct thrombin inhibitors (DTI)
Guideline recommendations
Reversal agents
Anticoagulant reversal PowerPlan
Future agents

17. Factor Xa Inhibitor Reversal

18. Factor Xa inhibitors Apixaban (Eliquis®) Rivaroxaban (Xarelto®)
T½ = 12 hours
Removal by HD ≈ 14% over 4 hours
Rivaroxaban (Xarelto®)
T½ = 5 hours
Not dialyzable
Edoxaban (Savaysa®)
T½ = hours
Apixaban. Lexi-Comp OnlineTM, Hudson, Ohio: Lexi-Comp, Inc.; Accessed August 2018
Rivaroxaban. Lexi-Comp OnlineTM, Hudson, Ohio: Lexi-Comp, Inc.; Accessed August 2018
Edoxaban. Lexi-Comp OnlineTM, Hudson, Ohio: Lexi-Comp, Inc.; Accessed August 2018

19. Guidelines: Neurocritical Care & ICH
≤ 2 hours of ingestion
(No intracranial hemorrhage)
Activated charcoal 50g (intubated or low aspiration risk)
Intracranial hemorrhage
Within 3-5 terminal T1/2 (normal hepatic fx)
PCC (50 Units/kg)
Frontera JA, et al. Neurocrit Care 2016;24(1):6-46
Hemphill JC, et al. Stroke 2015;46:

20. Prothrombin Complex Concentrate (Kcentra®)
Mechanism
Factors II, VII, IX, & X. It also contains protein C and S
Dosing
50 Units/kg if ICH occurred within 3-5 terminal T1/2 [timing may be altered in setting of renal (DTI) or hepatic impairment (FXa)]
PK Parameters
Onset = rapid (within 10 min)
t1/2 = hours depending on which factor
Duration = 6-8 hours
Side Effects
Clotting events (1%)
Monitoring
Signs of thrombosis
PCC 4 factor. Lexi-Comp OnlineTM, Hudson, Ohio: Lexi-Comp, Inc.; Accessed August 2018

21. Direct Thrombin Inhibitors Reversal

22. Direct Thrombin Inhibitors
Argatroban
Bivalirudin (Angiomax®)
Dabigatran (Pradaxa®)
T½ = hours (≤34 in severe renal impairment)
Removal by HD ≈ 65% over 4 hours
Idarucizumab (Praxbind®)
Dabigatran. Lexi-Comp OnlineTM, Hudson, Ohio: Lexi-Comp, Inc.; Accessed August 2018

23. Guidelines: Neurocritical Care
Activated charcoal 50g (intubated or low aspiration risk)
≤ 2 hours of ingestion
(no intracranial hemorrhage)
Idarucizumab
If none available then PCC (50 Units/kg)
Ongoing bleeding then idarucizumab and/or HD
Intracranial hemorrhage
Within 3-5 terminal T1/2 (normal GFR)
If none available then HD
Renal insufficiency or overdose
Frontera JA, et al. Neurocrit Care 2016;24(1):6-46

24. Idarucizumab (Praxbind®)
Mechanism
Humanized monoclonal antibody that binds specifically to dabigatran and its acylglucuronide metabolites
Dosing
2.5 grams IV every 15 mins x 2 doses (5 grams total)
May repeat if clinically indicated (more bleeding, re-elevation, urgent surgery)
PK Parameters
Onset = effects observed within “minutes” (median hemostasis 11.4 hours)
t1/2 = 47 min (terminal 10.3 hours)
Duration ≤ 24 hours
Side Effects
Common = headache, constipation, nausea (5%)
Uncommon = clotting events (<1%)
Monitoring
aPTT & signs of bleeding,
Dabigatran Overdose = 2 hours after exposure, then q12h till aPTT normalize
Idarucizumab. Lexi-Comp OnlineTM, Hudson, Ohio: Lexi-Comp, Inc.; Accessed August 2018

25. Idarucizumab: Efficacy
Study
Design
Results
Conclusion
Limitations
Idarucizumab for Dabigatran Reversal 2015 (RE-VERSE AD)
-Multicenter, prospective cohort
-Primary outcome: Maximum reversal of dTT or ECT
-Randomized 90 pts
Primary: dTT – 22 pts normal prior to treatment, 68 treated = normal in 98% (group A) & 93% (group B). ECT – 9 pts normal prior to treatment, 81 treated = 89% (group A) & 88% (group B)
Among patients receiving dabigatran who develop serious bleeding or need an urgent invasive procedure, idarucizumab reverses the anticoagulant effects of dabigatran within minutes of administration
-For most clinically relevant bleeds it’s hard to say when exactly the bleeding stopped
- Giving idarucizumab did not prevent majority of pts from going to sgy
->80 y/o excluded
-Selection bias w/ who needed reversal and timing of Sgy
->80% white
->60% pts on 110mg
--No control group
Idarucizumab for Dabigatran Reversal – Full Cohort Analysis 2017 (RE-VERSE AD)
-Same as initial
-Randomized 503 pts
-median reversal was 100% with respect to dTT or ECT
-median bleeding cessation time was 2.5 hrs (group A) & 1.6 hrs (group B)
In emergency situations, idarucizumab rapidly, durable, and safely reversed the anti-coagulant effect of dabigatran
Pollack CV, et al. NEJM. 2015; 373(6):511-20
Pollock CV, et al. NEJM. 2017; 377:431-41

26. Reversal PowerPlan

27. Anticoagulant reversal powerplan

28. Factor Xa Reversal PowerPlan

29. Factor Xa Reversal PowerPlan

30. Direct Thrombin Inhibitors PowerPlan

31. Future reversal agents

32. Future Agents Andexanet alfa (Andexxa®) – Factor Xa reversal agent
Ciraparantag (PER977) – “Universal” reversal agent

33. Anticoagulants Reversal Site of Action
Tiffany YH, et al. Vasc Health Risk Manag. 2016; 12:35-44

34. Andexanet Alfa (Andexxa)
Mechanism
Binds and sequesters the factor Xa inhibitors; inhibits the activity of Tissue Factor Pathway Inhibitor, increasing tissue factor-initiated thrombin generation
Dosing
High Dose: mg/min x 2 min, then 8 mg/min for up to 120 min
Low Dose: mg/min x 2 min, then 4 mg/min for up to 120 min
PK Parameters
Onset = Rapid
T1/2 = 5-7 hours
Side Effects
Most common = Infusion site (18%), DVT (6%), Stroke (5%), MI (3%)
Monitoring
Signs of bleeding, signs of thrombotic event
Andexant. Lexi-Comp OnlineTM, Hudson, Ohio: Lexi-Comp, Inc.; Accessed August 2018

35. Andexanet Alfa: Dosing
Andexant. Lexi-Comp OnlineTM, Hudson, Ohio: Lexi-Comp, Inc.; Accessed August 2018

36. Andexanet Alfa: Efficacy
Study
Design
Results
Conclusion
Limitations
Andexanet for reversing Xa inhibitors 2015 (ANNEXA)
-RPCT, DB, intention-to-treat
-Primary outcome: Change in anti-Xa activity
-Randomized 145
Primary:
ANNEXA-A1: 94 vs 21% (P<0.001)
ANNEXA-A2: 92 vs 33% (P<0.001)
ANNEXA-R1: 92 vs 18% (P<0.001)
ANNEXA-R2: 97 vs 45% (P<0.001)
Secondary: ≥80% reversal
100 vs 0% (P<0.001)
Andexanet effectively reverses the anticoagulant effects of factor Xa inhibitors apixaban and rivaroxaban within minutes of administration
-Different doses are required depending on the factor Xa inhibitor used. ? Challenging hx
-Patients who require urgent reversal were excluded
Andexanet for reversing Xa inhibitors – Interim Analysis 2016 (ANNEXA-4)
-MC, Pro, Open label, single group
-evaluated 67 pts
-rivaroxaban activity decreased by 89% (95% CI, 58 to 94)
-apixaban activity decreased by 93% (95% CI, 87 to 94)
-12 hours after andexanet infusion, hemostasis was excellent or good in 37 of 47 pts in efficacy group (79%; 95% CI, 64 to 89)
In this interim analysis, andexanet demonstrated that it has reduced anti factor Xa activity and achieve hemostasis in 79% of patients
-Thrombosis rate 18% during 30 day F/U
-Interim analysis
-No edoxaban data
-Single group so no comparison
-Severe bleeding was excluded
Siegal DM, et al. NEJM. 2015; 373(25):
Connolly SJ, et al. NEJM. 2016; 375(12):

37. Ciraparantag Mechanism Dosing
It inactivates anticoagulants via noncovalent hydrogen binding, which blocks the binding to the target sites of factor IIa and Xa (It does not bind to coagulation factors or other plasma proteins)
Dosing
Single mg IV Once (Still under investigation)
Miling, TJ, Kaatz S. Am J Med. 2016; 129(11 suppl):S80-88
Tiffany YH, et al. Vasc Health Risk Manag. 2016; 12:35-44

38. Ciraparantag: Efficacy
Study
Design
Outcomes
Conclusion
Safety/efficacy of escalating doses of PER977 alone and following one dose of edoxaban (Phase I)
-RCT
-8:2 to PER977 or placebo
-Randomized 80 pts
Primary:
To evaluate the safety, tolerability, and plasma and urinary pharmacokinetics of a range of single IV dose of PER977
Secondary: Pharmacodynamics
Achieved baseline hemostasis within 10–30 minutes following administration (whole-blood clotting time); effects sustained for 24 hours
PER977 Administered to Subjects With Steady State Edoxaban Dosing and Re-anticoagulation With Edoxaban (Phase II)
-Randomized 4:1 to PER977 or placebo
-Randomized 69 pts
Not yet published
ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US) Feb Identifier NCT Phase I trial; April 2013
ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US) Feb Identifier NCT Phase II trial; September 2015

39. Conclusion DOAC Reversal New Agents to come! Questions?
Inside of 2 hours (non-life threatening) = Activated Charcoal?
Inside 3-5 terminal T1/2 = PCC (50 Units/kg) or idarucizumab
New Agents to come!
Questions?