Anticoag Reversal

Anticoagulation Reversal
Lauren Goeser, PGY-1 Pharmacy Resident

lgoeser@iuhealth.org
Warfarin
2
Warfarin
 MOA: blocks function of vitamin K epoxide reductase, leading to decreased levels of vitamin K
dependent clotting factors: II, VII, IX, X, protein S and protein C
 Reversal agents:
 Vitamin K
 Prothrombin complex concentrate (PCC)
 Fresh frozen plasma (FFP)
3
Vitamin K
 MOA: vitamin K helps to synthesize the clotting factors II, VII, IX, and X
 Reduction of INR to < 1.4 may take up to 24 hours
4
PCC
 MOA: contain various amounts of factors II, VII, IX, X, protein C, protein S and Z, and heparin
 3 factor products: factors II, IX, X (i.e. Profiline)
 4 factor products: factors II, VII, IX, X (i.e. Kcentra)
INR PCC Dose Maximum

2 to < 4 25 U/kg 2,500 U
4 to 6 35 U/kg 3,500 U
>6 50 U/kg 5,000 U
Hemorrhage 1,000 to 2,000 U once
5
Direct Factor Xa Inhibitors
6
Direct Factor Xa Inhibitors
 Agents: rivaroxaban, apixaban, edoxaban
 Activated charcoal 50 g within 2 hours of ingestion
 PCC 50 units/kg IV
 Andexenat
7
Andexanet
 MOA: recombinant modified factor Xa protein
 Dose:
 < 8 hours since last dose of factor Xa inhibitor or higher dose of factor Xa inhibitor: bolus of
800 mg followed by infusion of 960 mg
 > 8 hours since last dose or lower dose of factor Xa inhibitor: 400 mg bolus followed by
infusion of 480 mg
8
Direct Thrombin Inhibitors
9
Direct Thrombin Inhibitors
 MOA: directly inhibit thrombin (factor IIa)
 Agent: dabigatran
 Activated charcoal 50 g within 2 hours of ingestion
 Idarucizumab 5 g IV
 PCC 50 units/kg IV
10
Idarucizumab
 MOA: humanized antibody fragment that binds to thrombin binding site of dabigatran and is
then cleared by the kidneys
 Dose: 5 g IV in two divided doses
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Heparin
12
Unfractionated Heparin
 MOA: potentiates action of antithrombin III to inactivate thrombin and prevent conversion of
fibrinogen to fibrin
 Reversal agent:
 Protamine: protein that can bind to heparin and form a stable salt
⎻ 1 mg IV for every 100 units of heparin administered in previous 2-3 hours
13
Low Molecular Weight Heparin - Enoxaparin
 MOA: potentiates action of antithrombin III to inactivate thrombin and inhibits factor Xa
 Reversal agent:
 Enoxaparin < 8 hours: protamine 1 mg IV per 1 mg of enoxaparin
 Enoxaparin > 8 hours: protamine 0.5 mg IV per 1 mg of enoxaparin
14
Meta-Analysis of Reversal Agents for Severe
Bleeding Associated with Direct Oral
Anticoagulants
Gomez-Outes, Antonio; et. al. Meta-Analysis of Reversal Agents for Severe Bleeding Associated with Direct Oral
Anticoagulants: Journal of American College of Cardiology. Vol. 77, No. 24, 2021. doi.org/10.1016/j.jac.2021.04.061
15
Meta-Analysis of Reversal Agents for Severe Bleeding Associated
with Direct Oral Anticoagulants
 Objective: examine clinical outcomes associated with the use of idarucizumab, andexanet, or 4-
factor prothrombin complex concentrate for reversal of severe DOAC associated bleeding
 Methods: systematic review and meta-analysis
 Eligibility criteria:
 Inclusion: studies evaluating 4PCC, idarucizumab, or andexanet for treatment of
severe/uncontrolled bleedinging
 Exclusion: subgroups who did not receive a reversal agent or treated with other reversal agents
16
 Outcome:
 Primary outcome: all-cause death
 Secondary safety outcome: total thromboembolism, effective hemostasis, rebleeding after
initial control of bleeding episode
 Study design: 60 studies included, 8,636 patients
 48 retrospective studies, 10 prospective studies, 2 clinical trials
 4,735 patients had severe bleeding related to DOAC
⎻2,688 treated with PCC
⎻1,111 treated with idarucizumab
⎻936 treated with andexanet
17
 Patient characteristics:
 Mean age 77
 57% males
 55% had intracranial hemorrhage
 82% had atrial fibrillation for reason for anticoagulation
 Results:
 17.7% mortality rate, higher in patients with intracranial hemorrhage (20.2%) compared with other
hemorrhages (15.4%)
 4.6% rate of thromboembolism, highest with andexanet (10.7%)
 Rate of effective hemostasis was 78.5%
 Rebleeding rate was 13.2% and 78% of those bleeds occurred after resuming anticoagulation
 Risk of death was significantly increased in the patients who failed to achieve hemostasis (RR 3.63)
18
 Conclusion:
 High rate of effective hemostasis with the reversal agents
 High rates of death
 > 3x increased risk of mortality in patients who did not achieve hemostatic efficacy
 Application: comparative studies are needed to determine if specific reversal agents are safer and
more effective than reversal with 4PCC
19
Case Example
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Case Example
 A 78-year-old with presents to the ED after a car accident. The patient is minimally response. The
patient’s wife reports the patient has a history of atrial fibrillation, hyperlipidemia, and
hypertension. She reports the patient is taking lisinopril, simvastatin, warfarin, and aspirin. A heat
CT shows intracranial hemorrhage. His INR is 6.2. The provider is asking how the warfarin
should be reversed.
 What would you recommend to the provider to reverse the warfarin?
21
References
 Gomez-Outes, Antonio; et. al. Meta-Analysis of Reversal Agents for Severe Bleeding Associated with Direct Oral
Anticoagulants: Journal of American College of Cardiology. Vol. 77, No. 24, 2021.
doi.org/10.1016/j.jac.2021.04.061
 Frontera, JA. Guideline for Reversal of Anti-thrombotics in Intracranial Hemorrhage. A Statement for Healthcare
Professionals from the Neurocritical Care Society and Society of Critical Care Medicine. Neurocrit Care (2016)
24:6-46. DOI 10.1007/s12028-015-0222-x.
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Anticoagulation Reversal
Lauren Goeser, PGY-1 Pharmacy Resident
lgoeser@iuhealth.org

Anticoag Reversal

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Anticoagulation Reversal

Lauren Goeser, PGY-1 Pharmacy Resident

INR PCC Dose Maximum

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