Reversal of warfarin and other NOACs

Recently, FDA has approved idarucizumab as the reversal agent in dabigatran induced bleeding. Well, it will not be available because it’s too freaking expensive. Read this: http://www.jwatch.org/fw110754/2015/10/20/dabigatran-reversal-agent-price-set

Onto our topic….

The (damn) clotting pathway

Capture

Warfarin

  • Blocks vitamin K activation by inhibiting vitamin K oxide reductase
  • No vitamin K, no synthesis of factor 7,10,2 and 9.

NOACs

  • Dabigatran (Factor IIa inhibitor)
  • Rivaroxaban and apixaban (Factor IXa inhibitor)

https://s-media-cache-ak0.pinimg.com/736x/07/fc/df/07fcdf0ab15af7906337885719afc488.jpg

Reversal of anticoagulants induced bleeding

In general, patients using warfarin with abnormal INR

  • Without active bleeding
    – INR <4: hold warfarin and monitor.
    – INR 4-10: hold warfarin, consider vitamin K 2mg PO in high risk
    – INR > 10: hold warfarin, vitamin K 2mg PO
  • With bleeding
    – Vitamin K 10 mg IV SLOWLY (over 30 minutes) + something

With-holding warfarin will correct the coagulopathy but only in 3-5 days (warfarin effective half life is about 20-60 hours)

IV vitamin K has anaphylaxis risk, so only use in very high risk/bleeding state.

  • IV form lowers the INR quicker than oral, but at 24 hours the rate of correction is the same.
  • S/C form has less efficacy than oral form, so do not use it.

What’s the something?

FFP

  • Can be used, but at least 4 units are needed. More likely need 8-10 units (= up to 2L), This is a risk for TACO.
  • Choice if patient has hypovolemic shock (eg massive GIB). But if intracranial bleed, would not be a good choice.
    – You would not bleed to death in ICB.
  • FFP has an intrinsic INR of 1.5, so INR would not get beyond that.

PCC

  • 3 factors (factor II, IX and X), 4 factors (3 factors + unactivated factor VII), FEIBA (3 factors + activated factor VII)
    – FEIBA = Factor Eight Inhibitor Bypass Activity
  • 3 factors lack factor VII, so will not improve INR, but bleeding time does improve.
    – A little (~2 units) FFP can be added if needed to complete the reversal.
  • 4 factors will reverse bleeding and INR.
  • Is the ideal choice, contains all the required factors (especially 4 factors and FEIBA), and uses LESS volume to achieve the same effect as FFP
    – In powder form, no need to thaw before use, just reconstitute in water (FFP needs to be thawed for 45 minutes)
  • Less risk of viral infection and no need for ABO incompatibility
    – Undergo viral inactivation and purification
  • Thrombosis risk of <5% (approx ~2%)
  • Dose: 25-50 U/kg has been replaced by dosing according to initial and target INR (15-50 U/kg)
    – INR < 4 and goal INR is 2   –> 20 U/kg is a good dose to start (15-25 U/kg)
    – INR 4-10 and goal INR is 2 –> 30 U/kg
    – INR > 10 and goal INR is 2 –> 40 U/kg

Factor VIIa

  • Will improve INR, but because it does not replace Factor IIa and Factor IXa, bleeding is not reversed.
  • Not preferred for routine use for warfarin reversal.
  • Thrombosis risk of 10-20% reported.

If patient has mechanical valve, can you still reverse?

  • Yes, risk of thromboembolism is 4/100 per year. The risk is low as long as you restart the a/c after the INR reaches the goal and patient stops bleeding after 1-2 days.

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What about NOACs?

Dabigatran

  • Affects factor IIa, so affect aPTT. A normal aPTT makes very unlikely.
  • PCC could help.
  • Hemodialysis could help, BUT if the patient does not have access to h/d, it will be nightmare trying to get it.

Dabigatran is dialysable drug, other drugs include I STUMBLED

  • Isopropanol
  • Salicyclate acid
  • Theophylline
  • Uremia
  • Methanol
  • Barbiturates
  • Lithium
  • Ethylene glycol
  • Depakine and Dabigatran

Factor Xa inhibitors should also be reversed with PCC (since it replaces it)

Summary:

  1. Use FFP for volume + replacement, use PCC for replacement ONLY
  2. For NOACs, PCC is favoured. Dabigatran is dialysable if access is present.

Periprocedural reversal of warfarin and other NOACs

Warfarin

  • 5 days
  • Preop vitamin K 1 mg PO can be given if INR is not <1.5 24 hours before the surgery.
  • Can restart 1 day after op if hemostasis is achieved.

Dabigatran

  • Depends on CrCl and bleeding risk of the operation
  • CrCl > 50
    – Low bleeding risk: 1-2 days
    – High bleeding risk: 3 days
  • CrCl < 50
    – Low bleeding risk: 4 days
    – High bleeding risk: >5 days
  • Restart postop
    – Low bleeding risk: 12-24 hours (~1 day) after op if hemostasis is achieved
    – High: 2-3 days after op if hemostasis is achieved

Rivaroxaban and apixaban

  • Depends on CrCl and bleeding risk of the operation
  • CrCl > 50
    – Low bleeding risk: 1 day
    – High bleeding risk: 2 days
  • CrCl < 50
    – Low bleeding risk: 2 days
    – High bleeding risk: 3 days
  • Restarting after operation: same as dabigatran

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Reference

  1. David A. Garcia, MD; Mark A. Crowther, M. Reversal of Warfarin. Case-Based Practice Recommendations.
    Circulation 2012;125:2944-2947
  2. Meena Zarah, BS, Andrew Davis, BS, Sean Hernderson, MD. Reversal of warfarin induced hemorrhage in emergency department. Western Journal of Emergency Medicine 2011;12(4):386-92
  3. David A. Garcia, MD; Mark A. Crowther, MD. Reversal of Warfarin. Case-Based Practice Recommendations. Circulation. 2012;125:2944-2947
  4. Periprocedural Anticoagulation – Adult – Inpatient and Ambulatory–Clinical Practice Guideline. http://www.uwhealth.org/files/uwhealth/docs/anticoagulation/Periprocedural_Anticoagulation_Guideline.pdf
  5. http://lifeinthefastlane.com/ccc/warfarin-reversal/
  6. http://www.emdocs.net/sinaiemcrit-ed-critical-care-conference-recap/
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