Will Coolidge PharmD BCCCP Critical Care/Emergency ... · Gulseth M. Overview of direct oral...
Transcript of Will Coolidge PharmD BCCCP Critical Care/Emergency ... · Gulseth M. Overview of direct oral...
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: [email protected]
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