2. Overview
• Pharmacokinetic properties of
anticoagulants
• Rationale for reversal
• Therapeutic options
– Classical agents
– Target-specific oral anticoagulants
• Current guidelines
• Future avenues
3. Pharmacodynamic Considerations
• For warfarin:
– INR between 2.0 and 3.0 correlates with
decreased coagulation factors II, VII, IX and X
– Factor II level thought to be the major
determinant of anticoagulation
• Half-life=60-72 hrs
• INR initially prolongs secondary to rapid decrease in
FVII (half-life=6 hrs)
4. Vitamin K Dependent Coagulation
Factors on Warfarin
*Lind, SE et al. Blood Coagul Fibrinolysis 1997.
50 patients
on chronic therapy
(INR 2.68,
range 1.7-5.1)
5. Parameter Warfarin IV UFH Enoxaparin Fondaparinux
Tmax 5-7 days Immediate 3-5 hrs 2-3 hrs
Half-life 20-60 hrs 1-2 hrs 4.5-7 hrs 17-21 hrs
Elimination Hepatic RES Renal Renal
Holding Time 5 days 6 hours 24 hours 3 days
Pharmacokinetic Properties
6. Pharmacokinetic Properties
Parameter Dabigatran Rivaroxaban Apixaban Edoxaban
Tmax 2 h 2.5–4 h 3 h 1–2 h
Half-life 12–17 h 9–13 h 8–11 h 10–14 h
Elimination 80% renal; 20%
biliary; no liver
metabolism
33% renal
(unchanged);
33% renal
(inactive); 33%
liver-dependent
metabolism
25% renal
(mostly
unchanged); 55%
fecal
(metabolites);
15% liver
metabolism
50% renal
unchanged
Holding
Time
CrCl<50 ml/min:
3-5 days
CrCl≥50 ml/min:
1-2 days
At least 24 hours
(usually 48
hours)
24-48 hours At least 24 hours
(usually 48
hours)
Modified from Mantha S et al, Clin Pharmacol Ther 2013.
7. Indications for Reversal
• INR above the target range on warfarin
• Upcoming invasive procedure
– Bridging
• Bleeding
8. Universal Considerations for Reversal
• How urgent is reversal?
– Faster methods often have drawbacks
• What is the expected “drug effect” half-life
of the agent administered?
• Is drug excretion impaired?
• What is the risk of thrombotic event off
anticoagulation?
– Absolute Risk = Rate X Time
10. Reversal of Warfarin
• Choices of antidote:
– Vitamin K
– FFP
– Prothrombin complex concentrate (PCC)
– Recombinant activated factor VII (rFVIIa)
11. Reversal of Warfarin
• Vitamin K
– Oral administration results in correction by
24 hours
– IV administration is marginally faster
• Small risk of anaphylaxis
– SC route is unreliable
• Not faster than oral
• Poor bioavailability
12. IV vs Oral Vitamin K
*Lubetsky A et al, Arch Intern Med 2003.
13. Reversal of Warfarin
• FFP
– Each mL contains 1 U of factors II, VII, IX
and X
– Need large volume for meaningful
correction:
dose = (target factor activity – actual level) X body weight
eg: 20% desired increase X 70 kg = 1400 U or 1.4 l or 5-6 bags of
FFP
14. Reversal of Warfarin
• PCC
– 3-factor concentrate contains only II, IX and
X
– 4-factor version was just approved in the US*
• CSL Behring Kcentra/Beriplex
• At least equivalent to FFP for stopping major
bleeding at 24 hrs (72.4% vs 65.4%)
• Superior for INR reduction (≤1.3) at 30 min (62.2%
vs 9.6%)
• Less volume (105 mL +/-37 mL versus 865 mL +/-
269 mL)
*www.cslbehring.com
15. Kcentra: Time to International
Normalized Ratio (INR) Correction
*Sarode R et al, Circulation 2013.
17. Reversal of Warfarin
• Kcentra dosing*:
*www.cslbehring.com
Pre-treatment INR 2-3.9 4-6 >6
Dose of Kcentra (units
of Factor IX / kg body
weight)
25 35 50
Maximum dose (units
of Factor IX)
Not to exceed
2500
Not to exceed
3500
Not to exceed
5000
18. Reversal of Warfarin
• rFVIIa
– Approved indications include hemophilia A
or B with inhibitor, congenital factor VII
deficiency and acquired hemophilia
– “Bypassing” effect helps sustain coagulation
in the absence of FVIII or FIX
– Does not correct deficit in factors II, IX and
X
– (deceptively) corrects the INR
– Doses used have varied (20-90 mcg/kg)
19. Guidelines for Warfarin Reversal
• ACCP 2012 Guidelines for warfarin
overanticoagulation (NO bleeding)
– INR <4.5
• Decrease the dose of warfarin
– INR 4.5-10.0
• Hold warfarin
• Can administer small dose of vitamin K (not
routinely)
– INR >10.0
• Administer oral vitamin K
20. Guidelines for Warfarin Reversal
• ACCP 2012 Guidelines for warfarin
reversal (major bleeding present)
– IV vitamin K
– First choice for immediate reversal (over FFP):
• 4-factor PCC
21. Reversal of IV UFH
• Protamine
– Binds heparin chains
– Administer 1 mg of protamine per 100 U of
circulating heparin:
Time Elapsed Dose of Protamine (mg) to Neutralize 100 units of Heparin
Immediate 1-1.5
30-60 min 0.5-0.75
>2 h 0.25-0.375
22. Reversal of IV UFH
• Protamine
– Excess amount acts as a mild anticoagulant
– Risk of infusion reaction:
• Hypotension/circulatory collapse
• Pulmonary edema
• Pulmonary hypertension
23. Reversal of LMWH
• Protamine
– Neutralizes about 60-75% of activity
– Consider half-life of enoxaparin
• Enoxaparin administered ≤8 hours prior: give 1 mg
of protamine per mg of enoxaparin.
• Enoxaparin administered > 8 hours prior: give 0.5
mg of protamine per mg of enoxaparin.
25. FDA Approval
Indication Dabigatran Rivaroxaban Apixaban Edoxaban
VTE
Prophylaxis
for
Orthopedic
Surgery
Atrial
Fibrillation
Treatment of
VTE
26. Reversal of Dabigatran
• Activated charcoal if ingestion <2 hours
prior
– In vitro testing confirmed binding
• Hemodialysis can help clear the drug
– Useful for patients with renal failure
– Case report data
– Entails risks associated with central line
placement
27. Reversal of Dabigatran
• 4-factor PCC:
– 12 healthy volunteers (in vivo); no correction of
hemostatic parameters*
• aPCC:
– 10 healthy volunteers (ex vivo); aPCC corrected
thrombin generation LT and ETP†
• rFVIIa:
– Partial correction of thrombin generation
*Eerenberg ES et al, Circulation 2011.
†Marlu R et al, Thromb Haemost 2012.
28. Reversal of Xa-TSOAC’s
• Activated charcoal if ingestion <2 hrs prior
• 4-factor PCC
– 12 healthy volunteers (in vivo); PT and thrombin
generation ETP normalized*
• aPCC
– 10 healthy volunteers (ex vivo); corrected thrombin
generation LT and ETP†
• rFVIIa:
– Partial correction of thrombin generation
*Eerenberg ES et al, Circulation 2011.
†Marlu R et al, Thromb Haemost 2012.
29. Recommendations for Reversal of
TSOAC’s in the Setting of Major
Bleeding
• Dabigatran:
– aPCC 80 U/kg*
– Consider activated charcoal and
hemodialysis
• Rivaroxaban, apixaban and edoxaban:
– 4-factor PCC 50 U/kg*
– Consider activated charcoal
*Adapted from Siegal DM et al, Blood 2014.
30. Quantification of Drug Activity with
TSOAC’s
• Quantification of drug levels can be useful
when bleeding/concern for bleeding arise
• Dosing of TSOAC’s in clinical trials not based
on drug activity/levels
• Typical drug levels (mean/distribution) known
– Unclear correlation with efficacy and safety
• Precise methods with short turnaround time
not widely available
31. Effect of Novel Oral Anticoagulants on
Coagulation Tests
*Adapted from Siegal DM et al, Blood 2014 and Cuker A et al, J Thromb
Thrombolysis 2015.
Anticoagulant PT aPTT TT ECT
Anti-Xa
Activity
Dabigatran ↑ or ↔ ↑ ↑ ↑ NA
Rivaroxaban ↑ or ↔ ↑ or ↔ NA NA ↑
Apixaban ↑ or ↔ ↑ or ↔ NA NA ↑
Edoxaban ↑ or ↔ ↑ or ↔ NA NA ↑
32. Effects of TSOAC’s on Coagulation
Testing: the MSK Experience
*Reilly PA et al, J Am Coll Cardiol 2014.
†Samama MM et al, Thromb J 2013.
33. Effects of TSOAC’s on Coagulation
Testing: the MSK Experience
*Reilly PA et al, J Am Coll Cardiol 2014.
†Samama MM et al, Thromb J 2013.
34. How to Estimate TSOAC Activity
• Dabigatran:
– Normal thrombin time rules out significant
drug activity
– TT or ECT-derived test can give precise level
• Rivaroxaban, apixaban and edoxaban:
– Assess sensitivity of local PT
– Specially calibrated chromogenic anti-Xa is a
promising tool for clinical use
– Absent anti-Xa means no remaining
anticoagulant effect
35. Future Avenues
• “Decoy” Xa drug neutralizes the effect of anti-Xa
agents*
– Inactive mimetic binds the anticoagulant
• Monoclonal antibody directed against dabigatran†
• Cationic small molecule “all purpose sponge”
– Binds UFH, LMWH, dabigatran, rivaroxaban,
apixaban and edoxaban‡
*Lu G et al, Nat Med 2013.
†Schiele F et al, Blood 2013.
‡Ansell JE et al, N Eng J Med 2014.
40. Summary
• For major bleeding in a patient on
warfarin:
– 4-factor PCC (Kcentra)
– IV vitamin K (expect response 12-24 hrs
later)
• Protamine has limited efficacy for
reversal of enoxaparin
41. Summary
• Dabigatran can be dialyzed
– aPCC (FEIBA) is another option
• PCC (Kcentra) might reverse
rivaroxaban, apixaban or edoxaban
effect
– Minimal data
• Promising antidotes to TSOAC’s being
developed
