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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