This document discusses anticoagulation reversal. It describes the therapeutic intervals for various anticoagulants including warfarin and heparin. It discusses considerations for reversing anticoagulation including urgency and drug half-life. It provides guidelines for reversing warfarin with vitamin K, FFP, PCC or rFVIIa depending on the urgency and presence of bleeding. It also discusses reversing heparin with protamine and options for reversing newer oral anticoagulants like dabigatran and rivaroxaban.

1. Anticoagulation Reversal
Simon Mantha, MD, MPH
Memorial Sloan-Kettering Cancer Center
May 2013

2. Overview
• Therapeutic interval on anticoagulation
• PK/PD considerations
• Approach to reversal and bridging
– Rationale
– Therapeutic options
– Current guidelines
– Future avenues

3. Therapeutic Interval on
Anticoagulation
• Best evidence exists for warfarin
• Thrombotic complications more common
with INR<2.0
– Atrial fibrillation
– VTE
• Bleeding complications more common
with INR>3.0

4. Risk of Complication According
to INR in Atrial Fibrillation
*Singer DE et al, Circ Cardiovasc Qual Outcomes 2009.

5. Risk of Bleeding with
Overanticoagulation
• Relatively low for short periods in patients
on warfarin
– 1% risk of major bleeding at 30 days if INR
5.0-9.0 in one study*
*Garcia et al, J Am Coll Cardiol 2006.

6. Risk of Thrombotic Complications
off Anticoagulation
• Low for AF and low-risk CHADS2 score
– Stroke risk off warfarin is about 2.5%/year
(0.007%/day)
• Higher for AF in the presence of artificial
heart valve
• Significant for recent VTE episode
– Highest with first month after event
– Decreases over the following 2 months

7. Therapeutic Interval on
Anticoagulation
• Less data is available for IV unfractionated
heparin
– Subtherapeutic PTT in the first 24 hrs of VTE
treatment is associated with a higher risk of
recurrent event*
– Ideal “upper end” of the target range unclear
*Raschke RA et al, Ann Intern Med 1993.

8. Therapeutic Interval on
Anticoagulation
• Other commonly used anticoagulants not
dosed according to levels:
– LMWH/fondaparinux
– Dabigatran
– Rivaroxaban
– Apixaban

9. Therapeutic Interval on
Anticoagulation
• Distribution of blood levels available from
landmark trials
– Observed values
– Not used for dosing in the original studies
• Retrospective data
– Not a “guarantee of outcome”
– Should not be used routinely to guide therapy

10. PK/PD 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)

11. 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)

12. PK/PD Considerations
Parameter Warfarin IV UFH Enoxaparin Fondaparinux Dabigatran Rivaroxaban
Tmax of effect 5-7 days Immediate 3-5 hrs 2-3 hrs 2 hrs 2.5-4 hrs
Half-life of
drug
20-60 hrs 1-2 hrs 4.5-7 hrs 17-21 hrs 12-17 hrs 9-13 hrs
Elimination Hepatic RES Renal Renal Mostly
renal
Mostly
hepatic

13. Indications for Reversal
• INR above the target range on warfarin
• Upcoming invasive procedure
– Bridging
• Bleeding

14. 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

15. Reversal of Warfarin
• Choices of antidote:
– Vitamin K
– FFP
– Prothrombin complex concentrate (PCC)
– Recombinant activated factor VII (rFVIIa)

16. 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

17. IV vs Oral Vitamin K
*Lubetsky A et al, Arch Intern Med 2003.

18. 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

19. 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

20. 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

21. 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)

22. 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

23. 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

24. Guidelines for Warfarin Bridging
• ACCP 2012 Guidelines
– High thrombotic risk: bridge
– Moderate thrombotic risk: use clinical
judgement (consider risk of bleeding)
– Low thrombotic risk: do not bridge

25. Risk of Thrombotic Complications
off Anticoagulation
Risk Stratum Indication for Anticoagulation
Atrial Fibrillation Venous Thromboembolism
High thrombotic
risk
CHADS2 score of 5 or 6
Recent (within three months)
stroke or transient ischemic
attack
Rheumatic valvular heart
disease
Recent (within three months)
VTE
Severe thrombophilia (eg,
deficiency of protein C, protein
S, or antithrombin;
antiphospholipid antibodies;
multiple abnormalities)
*ACCP Guidelines (9th
Edition), Chest 2012.

26. Risk of Thrombotic Complications
off Anticoagulation
Risk Stratum Indication for Anticoagulation
Atrial Fibrillation Venous Thromboembolism
Moderate
thrombotic risk
CHADS2 score of 3 or 4 VTE within the past 3 to 12
months
Nonsevere thrombophilia (eg,
heterozygous factor V Leiden
or prothrombin gene mutation)
Recurrent VTE
Active cancer (treated within
six months or palliative)
*ACCP Guidelines (9th
Edition), Chest 2012.

27. Risk of Thrombotic Complications
off Anticoagulation
Risk Stratum Indication for Anticoagulation
Atrial Fibrillation Venous Thromboembolism
Low thrombotic
risk
CHADS2 score of 0 to 2
(assuming no prior stroke or
transient ischemic attack)
VTE >12 months previous and
no other risk factors
*ACCP Guidelines (9th
Edition), Chest 2012.

28. Guidelines for Warfarin Bridging
• ACCP 2012 Guidelines
– Last dose of warfarin 5 days before the
surgery
– Parenteral anticoagulant:
• Last dose of LMWH should be 24 hours before the
surgery
• D/C IV UFH be 4-6 hours before the surgery
• Restart 24-72 hours
– Restart warfarin 12-24 hours after the
procedure

29. 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

30. Reversal of IV UFH
• Protamine
– Excess amount acts as a mild anticoagulant
– Risk of infusion reaction:
• Hypotension/circulatory collapse
• Pulmonary edema
• Pulmonary hypertension

31. 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.

32. 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

33. 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.

34. Reversal of Dabigatran
• Thrombin generation in a patient with ICH
on dabigatran:

35. Reversal of Rivaroxaban
• 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.

36. Future Avenues
• Monoclonal antibody directed against
dabigatran showed efficacy in murine
model*
• “decoy” Xa drug neutralizes the effect of
enoxaparin and fondaparinux in rats†
– Inactive mimetic binds the anticoagulant
*Schiele F et al, Blood 2013.
†Lu G et al, Nat Med 2013.

37. Ideal Anticoagulant
• Orally administered
• Not reliant on renal or hepatic clearance
• Predictable PK/PD
– One size fits all
• No drug interactions
• Minimal effect on normal hemostasis
• Can turn on/off effect at will

38. Summary
• For INR ≤10.0 holding warfarin is often all
that is required
• Oral vitamin K can be used in non-
bleeding patients
– SC administration should not be used
• 4-factor PCC is probably the best choice
for warfarin-associated ICH

39. Summary
• Protamine has limited efficacy for reversal
of enoxaparin
• Dabigatran can be dialyzed
– aPCC (FEIBA) is another option
• PCC might reverse rivaroxaban effect
– Minimal data

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