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no retreat, no reversal…

the case.

a 79 year old female returns to ED with left sided chest pain & dyspnoea. She was recently admitted following a fall with rib fractures (including a flail segment) and a small haemothorax.

Her past medical history includes AF, IHD & ischaemic cardiomyopathy. She has an AICD insitu.

On examination she is in marked respiratory distress with a SaO2 of 86%. You hear very little air entry on the left-side so order this chest x-ray…

CXR on return

[DDET You review her films from her previous admission…]

initial CXR

httpv://youtu.be/4Xyo7Ke8Nj0

[/DDET]

[DDET Then you see her medication list…]

  • Metoprolol 50mg bd
  • Frusemide 40mg bd
  • Ramipril 5mg mane

… & Dabigatran 110mg bd – this was restarted upon discharge.

[/DDET]

[DDET Is this the likely culprit ?!?]

very likely….

Dabigatran.

  • A direct thrombin inhibitor.
  • Predictable pharmacokinetics.
    • Rapidly absorbed after oral administration
    • Peak plasma concentration & maximal anticoagulation effect within 2-3 hours !
    • 80% excreted through the kidneys unchanged.

Given that this drug is being used more and more, by general practitioners and cardiologists, we better get familiar with it !!

[/DDET]

[DDET Can we measure it’s effect?!?]

Measuring the effect of dabigatran.

  • INR: 
    • Response is inconsistent & insensitive.
    • May be prolonged by supratherapeutic levels of dabigatran.
  • APTT: 
    • Curvilinear dose response to increasing levels of plasma concentrations of dabigatran.
    • If the APTT is prolonged by 2-3x at trough –> higher risk of bleeding.
    • Time of last dose is important.
  • Thrombin time:
    • A measure of conversion of fibrinogen to fibrin (clot).
    • Displays a linear time response to increasing plasma concentrations of dabigatran.
    • Exquisitely sensitive to the presence of dabigatran.
      • a normal TT indicates an absence of dabigatran (can be used to exclude dabigatran as cause of haemorrhage)

[/DDET]

[DDET But what if she’s bleeding !!!]

Haemorrhage! (on dabigatran) Now what ?!?

Dabigatran Reversal.

There are currently no antidotes available to reverse dabigatran.

Resuscitation & Supportive Care.

    • Blood product replacement / Transfusion (1:1:1 ratio).
    • Maintain renal perfusion [aids in dabigatran elimination].

DagClearance & RenalFnt

Dialysis.

    • Plasma concentrations can reduced by 50-60% after 4 hours of dialysis.
    • Significant logistical implications.

Prothrombin Complex Concentrates.

    • Whilst not directly affecting the action of dabigatran; thought to provide more substrate to increase thrombin generation.
      • Some positive animal studies.

FEIBA.

    • Enables generation of thrombin, independently of Factor VIII.
    • Case report of use of low-dose FEIBA (Factor Eight Inhibitor Bypassing Activity).
      • 26 U/kg.
      • Caution: too much can lead to DIC.

Recombinant factor VIIa

    • Is able to directly activate factors IX & X resulting in burst thrombin generation.
      • Reduced bleeding time in rat-tail models.
      • Prolonged aPTT in healthy volunteers on dabigatran.
    • There is increased risk of thrombotic complications.
    • Utility is not firmly established.

Others…

    • Tranexamic Acid.
      • Inhibition of fibrinolysis.
      • Used as an adjunct for bleeding with dabigatran on-board
        • little evidence to support this use however.
    • Activated charcoal.
      • Recommended for dabigatran overdose (when ingestion is < 2 hours)

[/DDET]

[DDET What happened next ?!?]

  • NIV was applied and markedly improved her oxygenation & work of breathing.
  • Concern was raised due to her elevated INR & aPPT.
  • Decision made for HDU admission & NIV overnight for support, allowing some ‘time’ for her anticoagulant effect to wear off.
  • A left sided pig-tail catheter is placed on Day 2 of her re-admission with litres of blood stained fluid drained.

 

CXR01on the morning of drain insertion…

CXR02 CXR03 CXR04
progress is made…

CXR05and upon her discharge…

[/DDET]

[DDET References.]

  1. Connolly S, Ezekowitz M, Yusuf S, et al. the RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139–51.
  2. van Ryn J. Dabigatran etexilate – a novel, reversible, oral direct thrombin inhibitor: Interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost 2010; 103: 1116–1127.
  3. Alikhan R, et al. The acute management of haemorrhage, surgery and overdose in patients receiving dabigatran. Emerg Med J 2013
  4. Dager WE, Gosselin RC, Roberts AJ. Reversing dabigatran in life-threatening bleeding occurring during cardiac ablation with factor eight inhibitor bypassing activity. Crit Care Med. 2013 May;41(5):e42-6.
  5. Eerenberg ES et al. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation. 2011 Oct 4;124(14):1573-9
  6. Avecilla ST, et al. Plasma-diluted thrombin time to measure dabigatran concentrations during dabigatran etexilate therapy. Am J Clin Pathol. 2012 Apr;137(4):572-4.

and more on this from the #FOAMed community…

  1. Bleeding Patients on Dabigatran @ EMCRIT.org
  2. Bleeding in the Patient on Dabigatran @ hqmeded.com
  3. Dabigatran Toxicity: The Top 10 Questions @ ThePoisonReview

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