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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!