DOAC's and their Reversal: “ The Slippery Slope”
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Transcript of DOAC's and their Reversal: “ The Slippery Slope”
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DOAC’s and their Reversal: “ The Slippery Slope”
William Dager, Pharm.D., BCPS (AQ Cardiology) FCSHP, FCCP, FCCM, FASHP, MCCM
Pharmacist Specialist : U C Davis Medical Center
Clinical Professor of Pharmacy, UC San Francisco School of Pharmacy
Clinical Professor of Medicine, UC Davis School of Medicine
Clinical Professor of Pharmacy, Touro School of Pharmacy
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Direct Oral Anticoagulants (DOACs)
Dabigatran Rivaroxaban Apixaban Edoxaban
Target for activity Thrombin (II) Anti-Xa Anti-Xa Anti-Xa
Prodrug Yes No No No
Bioavailability 6% (> 80% capsule opened) > 80% > 50% 62%
Time to peak Cp 2 hr (Delayed by food) 3 hr (Delayed by food) 3 hr 1.5 hr
Half-life 14-17 hr 5-9 hr (Elderly 11-13hr) 9-14 hr 8-10 hr
Dosing interval Once or twice daily Once daily Twice daily Once daily
Renal excretion 80% 36% 25% 35%
Dialyzable Yes No No No
Drug interactions P-gp inhibitors or inducers,
PPI
CYP 3A4
P-gp modifiers
CYP 3A4;
P-gp modifiers
P-gp modifiers
Gross PL et al. Arterioscler Thromb Vasc Biol. 2008; 28:380-6.
Plitt A et al. J Cardiovasc Pharmacol Ther. 2014; 19:409-16.
CYP - cytochrome P450; P-gp - P glycoprotein; PPI - proton pump inhibitors; hr – hours; Cp = peak plasma concentration
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Bleeding? Scan patient Site: risk of a complication
Assess Urgency of Situation Eminent life threatening vs
some time
Level of anticoagulation Laboratory assay Antiplatelet agents?
Keep in mind – need to restart anticoagulation
Assess the Situation
Assessing Risk
Bleeding
Thrombosis
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Look at the Big Picture – What path will we take?
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Is the situation CLEAR
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Depends on setting (ED, OR, ICU, Cardiac Cath Lab) and urgency
Hold Anticoagulation
Bleeding? • Site and severity – may influence outcomes
Mechanical Intervention (Surgery)
Pharmacological intervention • Topical Agents
• Neutralize the drug
• Reverse the effects of the drug independently
Replace losses
Optimize management of co-morbid situations
Anticoagulant “Reversal” Strategy
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Prior to procedure: Anticoagulant “Lowering Intensity or Reversal” Strategy
Bleeding Risk Assessment
• Site and severity – may influence outcomes
Create a plan and request necessary follow up
• Stop or slow it to locate and treat
Pre-Operative
Intra-Operative: Mechanical Intervention (Surgery)
Post-Operative
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Assessing intensity of Oral anticoagulation effects
Note: INR/aPTT - Potential for normal values at trough/active levels
Warfarin Dabigatran Rivaroxaban/Apixaban/Edoxaban
Drug Present INR/PT
Clotting Factor
(II and X)
Thrombin Time ? Chromogenic anti-Factor Xa
(Calibrated to the drug?)
? Anti-factor Xa (calibrated to UFH
or LMWH)
Quantative Test INR/PT
Clotting Factor
(II and X)
? Dilute thrombin
time (dTT) or
Chromogenic ECT
Chromogenic anti-factor Xa
Sensitivity:
PT vs aPTT (Reagent Dependent)
aPTT > PT
(Point-of-Care INR >
Central Lab)
PT > aPTT
No/Limited
effect
aPTT, anti-factor
Xa activity
anti-factor Xa activity ECT, TT
Lindhoff-Last E Ther Drug Monit 2010; Lindahl TL Thromb Haemost 2011; van Ryn Am J Med 2012;
van Ryn Thromb Haemost 2010
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Effects of Dabigatran on PT, aPTT and Thrombin Time
Dager W et al Ann Pharmacotherapy 2012
Thrombin Time
aPTT INR
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Potential INR response with higher DOAC serum concentrations
Serum Concentration
INR
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CLARITY
Determining a Course
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12
Reversing Newer Oral Anticoagulants: Bleeding Patients
‒ Activated charcoal if recent ingestion
‒ Concentrated clotting factor may depend on what is available – Reassess 5-10 min post administration - If time available, start with lower doses and repeat if necessary
Dabigatran Rivaroxaban/Apixaban/Edoxaban
No rush, minor
bleeding
• Monitor – re-check labs • Monitor – re-check labs
Expedited (1-24
hr), major
bleeding
• Idarucizumab 5gm
• Consider PCC4 (25 units/kg) or low dose
factor VIII inhibitor bypassing activity
(aPCC)
• Evaluate if PCC needed. Consider
PCC4 or PCC3 if clinically
necessary
• Option: low dose aPCC (8-12
units/kg)
Emergent (< 1
hr), major
bleeding
• Idarucizumab 5gm
• Option - Add: aPCC 10-25 units/kg, have
next dose ready (or PCC4 25-50 units/kg) or
TXA (bolus + Infusion)
• aPCC 25 - 50 units/kg or
• PCC4 or PCC3 25-50 units/kg
Nutescu EA et al. Am J Health-Syst Pharm. 2013; 70:1914-29;
https://www.ucdmc.ucdavis.edu/anticoag/pdf/AnticoagReversal.pdf
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Concentrated Blood Factor Products in USA
rFVIIa 3-Factor PCC
(PCC3)
4-Factor
PCC (PCC4)
aPCC
Brand
Names
Novo-
Seven®
Bebulin VH®
Profilnine SD®
Kcentra®
FEIBA®
Factors
Provided
VII II, IX, X
(Some VII)
II, VII, IX, X II, VII, IX, X
Activated? Yes No No Yes
Some PCC’s (Kcentra)
contain Heparin
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In-Vitro Data and Ex Vivo observations vary and depends on parameter measured - Results inconsistent
Independently drives hemostasis – does not remove anticoagulant
Doses variable (8 – 100 units/kg)
Single doses and low doses in GI Bleeds have worked
Rare need to repeat doses; Onset seems to be rapid.
Some failures
Unclear need to repeat dose if anticoagulant effects persist
Bleeding patients limited to case reports/series
Concentrated Clotting Factors with non-Vitamin K related oral anticoagulants
Dager WE et al AJHP in press
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Getting Drug to the patient
Patient Arrives
Situation assessed, Medication History, Labs
Decision to treat
Medications Ordered
Pharmacy Processes Order
Ordered Medications sent to patient
Medication Infused
• rFVIIa
• PCC 3or 4
• aPCC
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Idarcuizumab – Dabigatran Reversal
Humanized Fab fragment specific to dabigatran No evidence of prothrombotic effect
Rapid onset and dose dependent effect (aPTT, TT and ECT normalized)
Interim Phase III Analysis - RE-VERSE AD
Prospective – 5gm dose
Pollack CV et al. NEJM 2015;373:511-20
A (n=51) Serious Bleeding B (n=39) Urgent Procedure
Mean Dabigatran Cp = 132ng/ml Mean Dabigatran Cp = 114ng/ml
Reversed (Cp < 20ng/ml) in minutes Reversed (Cp < 20 ng/ml) in minutes
Hemostatic effect at 11.4 hr (median) Acceptable procedure hemostasis
Most remained reversed at 24 hours
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Idarucizumab: Duration of Dabigatran reversal
Pollack et al. N Engl J Med 2015;373:511-520
Bleeding Patient Surgical Patient
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Andexanet Factor Xa inhibitor Antidote PRT4445
Recombinant Protein structurally similar to Factor Xa
Acts as “decoy”, binding to Factor Xa inhibitors, thus limiting the effect of a Factor Xa inhibitor (Direct and Indirect)
Does not cleave prothrombin to thrombin
Ex-Vivo – Dose dependent inhibition, corrects clotting times
Lu G et al. Nat Med. 2013;19:446-51; Crowther Circulation 2014
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Andexanet: Reversing Apixaban and Rivaroxaban Activity
Siegal et al. NEJM 2015
Apixaban Rivaroxaban
Bolus Only
Bolus + 2 hr Infusion
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Ciraparantag “Universal”Factor Xa and IIa inhibitor Antidote: PER977
Synthetic small molecule directly binds and reverses heparins, direct factor Xa- and IIa-inhibitors. Does not bind to blood coagulation factors/other blood proteins.
Reverses anticoagulant activity as soon as 10-30 minutes after IV dose.
Effects last at least 24 hours in most cases
Dose dependent complete reversal of rivaroxban and apixaban anti-Xa activity ex vivo in human plasma. May reverse Enoxaparin and Fondaparinux
No evidence of prothrombotic effects
Laulicht B et al Circulation. 2012;126:A11395. Ansell J NEJM 2014; http://circ.ahajournals.org/cgi/
content/meeting_abstract/126/21_MeetingAbstracts/
A11395?sid=e9490841-a812-42d8-ab48-2d661cf7fccf
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Potential challenges with DOAC antidotes
Tissue rebound of either the anticoagulant or antidote
Need for emergent hemostasis – when is a hemostatic agent necessary, which agent and what dose
Rapid availability to patient; adaptable order sets
Ability to measure/assess when the antidote can be stopped
Prolonged infusion until bleeding stops as anticoagulant effects may be sustained for days
Neutralization of other anticoagulants that may be necessary for a emergent therapy (e.g. ECLS or cardiopulmonary bypass)
Availability, especially if the cost is high; Storage
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Restarting Anticoagulation Very Slippery and we may Slide
Assessment of Thrombosis vs Bleeding
↑Thrombosis Risk: Surgery, PCC, Acutely Ill
Will their be a change in the anticoagulant?
GIB and ICH: (Pts on warfarin) Higher long term survival and lower incidence of thrombosis with
minimal risk of recurrent bleeding events Potential Exceptions (CNS bleeds):
o Cerebral amyloid angiopathy (lobar) o Microvascular risk o Microbleeds on gradient-echo MRI o Indication: Primary prevention; Atrial fibrillation, low CHADS2 < 4 or CHA2DS2-
VASc < 5; Anticipated difficulty managing anticoagulation
Arch Intern Med 2012;172:1484-91; JAMA 2015;313:824-36; Am J Card 2014;113:662-68; CCJM
2010;77:791-99
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Gastrointestinal tract bleeding
Overall Mortality
Am J Card 2014;113:662-68
Adjusted HR= 0.67, 95% CI 0.56-0.81
Time of restarting
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Intracranial Hemorrhage
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The ability to managing anticoagulant bleeding