Will Coolidge PharmD BCCCP Critical Care/Emergency Medicine

Pharmacy Specialist Avera McKennan Hospital and University

Health Center

I have nothing to disclose

Discuss the mechanism of action and indication of oral anticoagulants

Explain the indications for emergent anticoagulation reversal

Identify the appropriate reversal agents for anticoagulants

Create a plan for the emergent reversal of anticoagulants

Warfarin has been used for > 60 years

Direct oral anticoagulants approval ◦ Dabigatran 2010

◦ Rivaroxaban 2011

◦ Apixaban 2012

◦ Edoxaban 2015

Why use the Direct Oral Anticoagulants (DOACs) ◦ AKA:

TSOAC: Target Specific Anticoagulants

Non-vitamin K oral antagonists

Atrial Fibrillation Guidelines VTE Guidelines

Guideline AHA/ACC/HRS

ACCP ESC ACCP ESC

General Recs

VKA (1A) or DOAC (1B)

OAC (1A)

OAC (1A)

AC (1B) DOAC (2B) VKA (2C)

Parenteral AC 1C) or OAC (1B)

Drug Preference

N/A DOAC (2B)

DOAC (1A)

DOAC (2B) N/A

Cicci.CCSAP.2017

Meta-analysis of 12 RCT comparing DOACs with VKAs with target INR 2-3: ◦ Statistically significant reduction in: Major bleeding:

RR : 0.72, NNT: 156

Fatal bleeding

RR: 0.53, NNT 454

Intracranial bleeding

RR: 0.43, NNT185

Clinically relevant non major bleeding:

RR: 0.78;NNT 99

Total bleeding:

RR 0.76;NNT 18

Major GI Bleeding

No significant reductions overall

Chai-Adisaksopha. Blood.2014

Systematic Review and Meta-analysis 13 RCT comparing DOACs vs warfarin ◦ Case fatality rate of major bleeding: DOAC: 7.57%

Warfarin: 11.04%

◦ Rate of fatal bleeding: DOAC: 0.16 per 100 patient-years

Warfarin: 0.32 per 100 patient-years

◦ Statistically significant reduction DOACs vs warfarin Fatal bleeding

Cardiovascular death Afib

All Cause Mortality

Chai-Adisaksopha.J Thromb Haemost.2015

XIIa XII

XI XIa

IX IXa

VIII VIII

X Xa

V Va

II IIa

Fibrinogen Fibrin

Intrinsic Pathway

Extrinsic Pathway

Tissue Factor

VII VIIa

Warfarin

Nutescu.AJHP.2013

Emergent reversal

Urgent reversal (1-24 hours)

Non-urgent reversal (>24 hours)

Cicci.CCSAP.2017

Is the Patient on an Oral Anticoagulation

Yes No Exit

Algorithm

Is the Patient

Bleeding

Is Emergent Reversal Needed

Yes No

Emergent Reversal < 1

hr

No

Does Patient Need Invasive Procedure

Yes No

Urgent (< 1

Hr)

Yes No

Yes

Other Considerations

Gulseth. AJHP.2016.

Is the Patient on an Oral Anticoagulation

Yes No Exit

Algorithm

Is the Patient

Bleeding

Is Emergent Reversal Needed

Yes No

Emergent Reversal < 1

hr

No

Does Patient Need Invasive Procedure

Yes No

Urgent (< 1

Hr)

Yes No

Yes

Other Considerations

Gulseth. AJHP.2016.

Indication for reversal

What anticoagulant

Indication for anticoagulation

Level of anticoagulation

Pharmacokinetics ◦ Half-life

◦ Renal function

Patient’s wishes

Gulseth. AJHP.2016.

Is the Patient on an Oral Anticoagulation

Yes No Exit

Algorithm

Is the Patient

Bleeding

Is Emergent Reversal Needed

Yes No

Emergent Reversal < 1

hr

No

Does Patient Need Invasive Procedure

Yes No

Urgent (< 1

Hr)

Yes No

Yes

Other Considerations

Gulseth. AJHP.2016.

Hold anticoagulant

Indication for anticoagulation

Risk of thromboembolic events

Need for bridge anticoagulant therapy

Bleeding risk/thrombosis risk for procedure

Laboratory tests

Is the Patient on an Oral Anticoagulation

Yes No Exit

Algorithm

Is the Patient

Bleeding

Is Emergent Reversal Needed

Yes No

Emergent Reversal < 1

hr

No

Does Patient Need Invasive Procedure

Yes No

Urgent (< 1

Hr)

Yes No

Yes

Other Considerations

Gulseth. AJHP.2016.

Hold anticoagulation and use mechanical interventions

Full or partial reversal Short and long term risks for thrombosis

and bleeding Laboratory tests Reversal agents ◦ Fresh frozen plasma (FFP) ◦ Prothrombin complex concentrate (PCC) ◦ Antidotes ◦ Vitamin K ◦ Lady Luck!!

Gulseth. AJHP.2016.

https://www.hindawi.com/journals/ijvm/2012/753596.fig.002c.jpg

Vitamin K antagonist: ◦ Decreases factors II, VII, IV, X, protein C

and protein S in the liver

Dose: Patient specific

Onset: 24-72 Hours

Full Effect: 5-14 days

Monitoring: PT/INR, CBC

Adverse effects

Dager.AJHP.2015 Micromedex.Warfarin.2017

Vitamin K

Fresh Frozen Plasma (FFP)

Prothrombin Complex Concentrate (PCC) ◦ 3 Factor (Profilnine)

◦ 4 Factor (Kcentra)

Dager.AJHP.2013

Promotes formation of activated clotting factors II, VII, IX, X

Dose: 5-10 mg IV or PO

Must use with FFP or PCC

Tsu.Ann Pharmacother.2012. Holbrok.CHEST.2012.

Clotting factors: II, VII, XI, X

Dose: 10-20 ml/kg

Must be thawed

Must get type and crossmatch

Risk of transfusion reactions, fluid overload, infection transmission

Nutescu.AJHP.2013 FFP.Medscape.2017

Factors II,VII,IX,X, Protein C, Protein S, Heparin

Must give with vitamin K

Do not use if heparin allergy or history of HIT

Reversal in 30 minutes

INR Dose:

2-3.9 25 units/kg (Max 2500 units)

4-5.9 35 units/kg (Max 3500 units)

> 6 50 units/kg (Max 5000 units)

Gulseth.AJHP.2016.

Effective Hemostasis at 24 hours achieved in 72.4% of 4F-PCC vs 65.4% in FFP

Superior INR reduction ≤ 1.3 at 30 minutes after infusion completion ◦ 62.2% in 4F-PCC vs 9.6% FFP

Safety profile similar between groups

Sarode.Circulation.2013

Effective hemostasis achieved in: ◦ 4F-PCC: 90%

◦ FFP: 75%

Rapid INR reduction: ◦ 4F-PCC: 55%

◦ FFP: 0%

INR ≤ 1.3 at 60 min (p < 0.001)

◦ 4F-PCC: 54%

◦ FFP: 0%

Similar rate of any adverse events

Goldstein.Lancet.2015

Adverse Effects: ◦ 4F-PCC: 60.2% vs FFP: 62.9%

SAE: ◦ 4F-PCC: 28.3% vs FFP: 24.9%

Deaths: ◦ 4F-PCC: 6.8% vs FFP: 6.6%

Fluid Overload: ◦ 4F-PCC: 4.7% vs FFP: 12.7%

Milling. AEM.2016

Major/Life Threatening Bleeding ◦ Stop Warfarin!

◦ Hemodynamic support, blood, fluids

◦ 4F-PCC + Vitamin K 5-10 mg IV

◦ Alternative options:

3F-PCC + FFP 10-15 ml/kg + Vitamin K IV

FFP 10-15 ml/kg + Vitamin K IV

Holbrook.CHEST.2012

Dabigatran (Pradaxa)

Rivaroxaban (Xarelto)

Apixaban (Eliquis)

Edoxaban (Savaysa)

MOA: Direct thrombin inhibitor

Half-life: 12-17 hr

Lab Monitoring: ◦ Thrombin Time, Diluted thrombin time, ecarin

clotting time, aPTT

Dager. AJHP. 2016 Micromedex.2017

Idarucizumab (Praxbind) ◦ Humanized monoclonal antibody fragment

Smythe.AJHP.2016

Ongoing multicenter, prospective cohort study

2 patient groups ◦ Serious bleeding (51 patients)

◦ Urgent surgery (39 patients)

Study Drug: ◦ 2.5 g IV bolus x 2 doses

Primary end point: ◦ Max percentage reversal of dabigatran

anticoagulant effect within 4 hours of the second 2.5 mg dose

Pollack C. N Engl J Med.2015 Smythe M. AJHP.2016

Maximum percentage anticoagulation reversal of 100% in both groups

Clotting times normalized

Dabigatran levels decreased to < 20 ng/ml

Normal intraoperative hemostasis achieved 92% of emergent procedure patients

Overall all mortality rate of 20%

Pollack C. N Engl J Med.2015 Smythe M. AJHP.2016

Urgent and Emergent: ◦ Hold dabigatran

◦ 50 g activated charcoal (last dose < 2 hours)

◦ Prolonged HD (> 2 hr)

Emergent reversal ◦ Idarucizumab 5 g IV

◦ Hemodynamic support, blood products, FFP

Gulseth.AJHP.2016 Smythe.AJHP.2016

Pharmacokinetics of Direct Oral Anticoagulants

Characteristic Rivaroxaban

Apixaban

Edoxaban

Tmax(hr)

2-3 3-4 2-3.5

T1/2(hr)

6-9 8-15 9-10

Renal Elimination (%)

36 25-29 35

Lab monitoring:

Anti-Xa assays

PT

Gulseth.AJHP.2016

No FDA approved specific reversal agent

Consider: ◦ Fresh frozen plasma

◦ 4F-PCC (Kcentra)

◦ 3F-PCC (Profilnine)

◦ Activated factor VII

◦ aPCC (FEIBA)

Antidotes in studies ◦ Andexanet alfa

◦ Ciraparantag

Dager.AJHP.2016

4 small studies in, young, healthy subjects with no bleeding ◦ Rivaroxaban: 2 Studies

◦ Apixaban: 1 study

◦ Edoxaban: 1 study

4F-PCC dose: ◦ 50 IU/kg

PT and endogenous thrombin potential (ETP) normalized

Whole blood clotting time reversed

◦ Dose ≤ 37.5 IU/kg not effective

Urgent and Emergent ◦ Stop drug

◦ Activated Charcoal (Last dose < 2 hours) and repeat 6 hours later

◦ Hemodynamic support, fluids, FFP

Emergent: ◦ 4F-PCC: 50 IU/kg x 1, MAX dose 5000 units IV

x 1

◦ Hemodynamic support with fluids, blood products, FFP

Gulseth.AJHP.2016 Smythe.AJHP.2016

Factor Xa-Inhibitor Antidotes

Andexanet Alfa

Ciraparantag

Andexanet alfa ◦ Recombinant, modified human factor Xa decoy

protein

Smythe. AJHP.2016

Parallel, randomized, double-blind, placebo-controlled studies

Healthy volunteers 50-75 years (N = 145)

Part 1: study bolus dose of andexanet alfa

Part 2: study bolus dose plus 2 hour infusion

Siegel.NEJM.2015

Antifactor-Xa activity decreased by > 90%

Thrombin generation restored

Significant decrease in apixaban and rivaroxaban concentrations after andexanet alfa

Rebound in ETP levels with peak at 3 hours post dose

No serious or severe adverse events

Siegel.NEJM.2015

Multicenter, prospective, open-label, single group study of patients with acute major bleeding

2 dosing regimens

Primary outcomes: ◦ Percent change in anti-factor Xa activity

◦ Rate of excellent or good hemostatic efficacy 12 hours after infusion

Connolly.NEJM.2015

Significant decrease in anti-FXa activity from baseline to end of bolus

Anti-FXa activity was still > 30% below baseline 4 hours after infusion

79% of patients with excellent to good hemostasis 12 hours after end of infusion

12 patients (18%) with thrombotic events

Connolly.NEJM.2015

Appropriate dose and duration for each factor-Xa inhibitor to be determined

Patients on chronic therapy that are bleeding will have different body loads and renal function

Relationship of timing of last dose of factor Xa inhibitor and andexanet dose

Laboratory test to determine degree of anticoagulation

When to restart anticoagulation

Smythe.AJHP.2016

Smythe.AJHP.2016.

Small studies with escalating doses of ciraparantag

Edoxaban 60 mg dose

Whole blood clotting time decreased after administration of ciraparantag dose > 100 mg

Immediate reversal that last ~24 hours

Ansell.NEJM.2014

Ideal characteristics for anticoagulation reversal

Whole blood clotting time as biomarker for anticoagulant effect and reversal

Utility during procedures

24 hour duration of reversal

Phase 3 studies to be completed ◦ Effectiveness in bleeding patients

Restarting anticoagulation

Smythe.AJHP.2016

Use 4F-PCC and idarucizumab for warfarin and dabigatran reversal

Reversal agents halt or blunt medication effect on anticoagulation

Reversal of anticoagulation is not without risk

Limited data on anticoagulation reversal with cessation of bleeding

No perfect reversal agent

Email: William.Coolidge@avera.org

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