Minimising and Managing bleeding with the NOACs. Dr Frances Akor Imperial College Healthcare NHS Trust

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1 Minimising and Managing bleeding with the NOACs Dr Frances Akor Imperial College Healthcare NHS Trust

2 Key CharacterisEcs of Warfarin Onset Slow NOACs Half- life Long ~ 40 hours Rapid Dosing Variable Fixed Food effect Yes No InteracEons Many Few Inactive factor Monitoring Yes No Offset Reversibility Long Vitamin K Shorter No Specific AnEdote Active factor

3 Reference: Garcia, D. Crowther, M. Reversal of Warfarin: Case- Based PracEce RecommendaEons. Circula(on 2012: 125:

4 INR reversal by PCC 7-27u/kg Yasaka 2003

5 The NOACs target specific enzymes in the common pathway of the coagula;on cascade. Soff G A Arterioscler Thromb Vasc Biol 2012;32:

6 Pharmacology of NOACs Dabigatran 1-3 Rivaroxaban 4,5 Apixaban 6,7 Mode of action Factor II Factor X Factor X Half life hrs 7-11 hrs 12 hrs Dosing B.D. O.D. B.D. Metabolism Esterase catalysed hydrolysis CYP P450 dependant and independent mechanisms CYP P450 Excretion 85% Renal 1/3 Renal 2/3 Hepatic 1/4 Renal 3/4 Non Renal Form Capsule Tablet Tablet Dose 150 mg 110 mg (>80 yrs, verapamil or increased bleeding risk) 20 mg 15 mg (CrCL ml/min) 5 mg 2.5 mg (2 or more: >80yr; weight <60 kg; Cr >1.5 mg/dl) 1. Ezekowitz MD et al. Am Heart J 2009;157:805 10; 2. Connolly SJ et al. N Engl J Med 2009;361: ; 3. Connolly SJ et al. N Engl J Med 2010;363: ; 4. Rocket Investigators. Am Heart J 2010;159: ; 5. Patel MR et al. NEJM 2011;365:883 91; 6. Lopes et al. Am Heart J 2010;159:331-9; 7. Granger et al. N Eng J Med 2011;365:

7 Key points - NOACs Direct inhibitors RelaEvely short t1/2 Quick onset /offset of aceon Renal dependency Predictable pharmacokineecs No specific anedote Measurement less widely available

8 AF: Major, Intracranial and GI bleeding Miller CS., Grandi SM., et al. Meta- Analysis of Efficacy and Safety of New Oral AnEcoagulants (Dabigatran, Rivaroxaban, Apixaban) Versus Warfarin in PaEents with Atrial FibrillaEon. Am J Cardiol. 2012;110:

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10 Remember. NOACs Half life of effect is relaevely short (10-15 hours Aher 24 hours negligible levels (cf warfarin) Once NOAC is cleared full complement of cloing factors present (cf warfarin)

11 Management of bleeding Further Reading: BCSH: Guideline on the management of bleeding in pa(ents on an(thrombo(c agents (2012)

12 General measures Stop / delay NOAC (at least one dose) Assess renal and hepaec funceon, FBC, coagulaeon screen and obtain drug level May need to esemate likely drug level When was last dose taken Renal, hepaec, other drugs AcEvated charcoal last dose < 2hrs ago 50% reduceon last dose < 6hrs ago 27% reduceon IdenEfy bleeding point and apply pressure if possible Resuscitate as necessary UElise endoscopic, radiological or surgical assistance.

13 CoagulaEon Screen Some measures may be prolonged in presence of anecoagulaeon (parecularly overdose): APTT, ECT, TT dabigatran PT Xa inhibitors Crude measures Should not be solely relied upon for assessment Measures can be normal at therapeuec levels of anecoagulaeon

14 Measuring NOAC Should now be available in laboratories Standard coagulaeon sample in citrate Timing of samples is criecal for interpretaeon Dabigatran Haemoclot Modified thrombin Eme Rivaroxaban and Apixaban Use an ane- Xa assay Must use a drug- specific calibrator (not heparin) Should be able to order from lab as drug assay

15 Managing Bleeding Minor bleeding Consider conenuing anecoagulaeon (risks vs. benefits) Moderate bleeding DisconEnue drug Tranexamix acid SupporEve measures inc transfusion Severe/life threatening bleeding Surgical, procedural interveneon Procoagulant therapy PCC APCC rviia (last resort) Dialysis for dabigatran

16 PCC (50u/kg) reverses rivaroxaban effect Corrects bleeding Eme in rat model Eerenberg E S et al. Circulation. 2011;124:

17 Cloing factors Evidence base sell growing PCC and APCC can correct some measures of anecoagulaeon in vitro ane- Xa but less so ane- IIa Results with PCC in animal models are variable. rfviia can correct some effects of ane- Xa in vitro but limited on ane- IIa rfviia was ineffeceve in animal models. Consider severity of bleeding and current anecoagulant level. Including drug and renal effects Consider underlying thromboec risk

18 Dialysis for dabigatran Khadzhynov T&H :596

19 On the Horizon

20 Idarucizumab: a specific ane- dabigatran Ab Humanised Fab fragment of murine anebody dtt (sec) DE + placebo DE + placebo (n=9) DE + 1 g idarucizumab (day 4) (n=9) DE + 2 g idarucizumab (day 4) (n=9) DE + 4 g idarucizumab (day 4) (n=8) Normal upper reference limit (n=86) Mean baseline (n=86) Dabigatran Antidote Time after end of infusion (hr) Data from BI 2014

21 FX A specific anedote for ane- Xa agent (R- anedote) FX- dummy Gla AcEvaEon site S419A HaemostaEcally inaceve recombinant Fxa Per977 Small molecule Binds to oral thrombin, Xa inhibitors, LMWH and UFH Nat Med. 2013; 19:

22 Minimising and Managing bleeding with the NOACs Dr Frances Akor Imperial College Healthcare NHS Trust