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Direct Oral Anticoagulants & Reversing Them
Roya Zolnoor Caloia, DO, MPH, FACEP, FAAEMJuly 30, 2018
Michigan Emergency Medicine Assembly
Disclosures
I have none.
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Monday Morning 7am
Room 13- 80 y/o Female fall from standing, on Xarelto
Room 10- 56 y/o Male, worst headache of his life, on Eliquis
Room 25- 62 y/o Female, not acting right, on Coumadin
Room 13
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Room 10
Room 25
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Seriously?
–Hippocratic Oath
“Primum non nocere.”
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–Me, 805am
“What did that throw-away journal say???”
The Anti-Coagulation Pathway in Heavy Detail
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Just kidding. This is only a 15 minute talk.
–UpToDate search on reversing anticoagulants, Me, 810am
Mortality rates after anticoagulant-associated intracerebral hemorrhage (April 2018)
Intracerebral hemorrhage (ICH) is the most feared complication of anticoagulation. Compared with warfarin, the direct oral
anticoagulants (DOACs) have been demonstrated to have a lower risk of ICH and a lower overall mortality. ”
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What is a DOAC?
Direct Oral Anti-Coagulants
Also known as NOACs (Novel (or Newer) Oral Anti-Coagulants, Non-vitamin K antagonist Oral Anti-Coagulants)
Factor Xa Inhibitors
Direct Thrombin Inhibitors
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What are the indirect ones?
fondaparinux (Arixtra)
enoxaparin (Lovenox)
heparin
warfarin (Coumadin)
Factor Xa Inhibitors
rivaroXaban (Xarelto)
apiXaban (Eliquis)
edoXaban (Lixiana, Savaysa)
betriXaban (Bevyxxa)
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Direct Thrombin Inhibitors
dabigatran (Pradaxa)
argatroban (IV)
bivalirudin (Angiomax) (IV)
When To Reverse Emergently
Any life-threatening bleed
The Expert Review of Hematology, in 2016, proposes: “symptomatic bleeding in a critical area of origin, such as intracranial, intraspinal, intraocular, retroperitoneal, or intramuscular with compartment syndrome, and/or bleeding causing a fall in the hemoglobin of 2.0g/l or more, leading to a transfusion of two or more units of blood.”
Someone requiring immediate surgical intervention
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So There is a Life-Threatening Bleed in Someone on Anticoagulants, Then
What?
Find out exactly what they are taking
Find out exactly when they took the last dose
Cross your fingers when they can’t answer any of your questions and say, “can I have my dilaula?”
Apply pressure (if possible)
Transfuse if you need to
What are the Options Available?
It depends..
What are you dealing with?
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Coumadin
Good ol' Vitamin K1 (aka phytonadione aka Mephyton)+ PCC (FEIBA(activated) or KCentra(inactivated)) or FFP (if no PCC available) +/- DDAVP +/- tranexemic acid
Heparin & Lovenox
Protamine
1mg protamine for every 100u heparin in previous 8 hrs
1mg protamine for every mg of lovenox if in previous 8hrs (max 50mg)
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Direct Thrombin Inhibitors
For the IV direct thrombin inhibitors: turn off the infusions
For the oral direct thrombin inhibitor, dabigatran (Pradaxa)- an antidote: idarucizumab (Praxbind) 5g IV +/- charcoal if within 2 hours +/- dialysis if severe renal impairment
Xa Inhibitors
Some new stuff.
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FDA Approved
andexanet alfa
factor Xa decoy protein
draws factor Xa inhibitors away from Xa allowing the coagulation cascade to keep going
Xa activity dropped fast immediately after infusion but started to rise again 2 hours after infusion
Things to Know
One study performed: ANNEXA-4
67 patients
Overall, 5% mortality, 18% of pts had a thrombotic event
needs reconstitution, refrigeration and a LOT of vials
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In the Process of FDA Approval
ciraparantag
water soluble molecule that binds everything-heparin, enoxaparin, fondaparinux, NOACs
so far so good, in 80 pts- no thrombotic events, onset 10 min, lasts 24 hrs
A Cool One Also in the Works
FXa
Mutant form of factor Xa
Amino acid substitution at position 16
Circulates inactively until encounters activated factor V or damaged cell surfaces and restores hemostasis at the site
Has been shown to work reversing rivaroxaban and dabigatran in vitro in human plasma
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What if your Hospital Says Adenexablessyou for Factor Xa
Reversal?
4 factor PCC (Kcentra)
aPCC (FEIBA- factor eight inhibitor bypassing activity)
It really depends on your hospital formulary
Other options: TXA, charcoal, FFP
Kcentra
Single use vial
Coagulation factors II, VII, IX, X, and antithrombotic proteins C & S
No great human studies showing efficacy in DOAC reversal
*MAY* be slightly less prothrombotic
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FEIBA
NON-activated factors II, IX, X, and activated factor VII
No good studies to prove efficacy in DOAC reversal
*MAY* be slightly more prothrombotic because of the activated factor
TXA
May help.
May not.
Won’t hurt.
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TXA
Prevents fibrinolysis by inhibiting binding of plasma to fibrin
Any clots already formed can’t break down
Not 100% sure what happens to patients on anticoagulants
Charcoal
IF the patient can swallow
IF the patient has an NG tube and is intubated and can safely have charcoal
IF the dose was within 2 hours
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FFP
You need a LOT to get the amount of factor in Kcentra or FEIBA
Be weary of older folks with CHF and fluid overloading and TRALI
(It may be the least of their problems but primum non nocere)
Room 13
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-Pharmacist and Neurosurgeon
“FEIBA.”
Room 10
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–Neurosurgeon
“Transfer.”
–Pharmacist and Neurosurgeon
“Just kidding. FEIBA.”
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Room 25
-Pharmacist and Neurosurgeon
“You again?”
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–Neurosurgeon, Pharmacist and Me
“Vitamin K. FEIBA. Prayers.”
References
http://www.emdocs.net/reversing-noacs-updates-emergency-physicians/
https://www.uptodate.com/
Frontera JA, et al, Guideline for reversal of antithrombotics in intracranial hemorrhage: A statement for healthcare professionals. Neurocrit Care. 2016; 24(1): 6-46
fda.gov. Prothrombin Complex Concentrate labeling. https://www.fda.gov/ucm/groups/fdagov-public/@fdagov-bio-gen/documents/document/ucm350239.pdf. Accessed 6/20/2018
fda.gov. Factor Eight Inhibitor Bypassing Activity label. https://www.fda.gov/downloads/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/licensedproductsBLAs/fractionatedPlasmaProducts/UCM221749.pdf. Accessed 6/27/2018
Yutthakasemsunt S, et al. Tranexamic acid for patients with traumatic brain injury: a randomized doubt-blinded, placebo-controlled trial. BMC Emerg Med. 2013; 13:20.
Ansel JE, et al. Use of PER977 to reverse anticoagulant effect of edoxaban. N Engl J Med. 2014; 371(22): 2141-2142.
Connolly SJ, et al. Adexanet Alfa for acute major bleeding associated with Factor Xa inhibitors. N Engl J Med. 2016; 375 (12):1131-1141.
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THANK YOU!