Post-ISTH review: Thrombosis-I New Oral Anticoagulants 臺 大 醫 院 內 科 部 血 液 科 周 聖 傑 醫 師

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1 Post-ISTH review: Thrombosis-I New Oral Anticoagulants 臺 大 醫 院 內 科 部 血 液 科 周 聖 傑 醫 師

2 The antithrombotic efficacy is limited but the risk of bleeding is indefinite Fuster V et al. Circulation 2011;123:e269-e367

3 A new and better anticoagulant found?

4 Dabigatran is worse than warfarin in mechanical valve patients Thrombotic event Bleeding event N Engl J Med 2013;369:

5 Every anticoagulant has its own place, and not single one is always better Do not use it because it s new; Do use it because it s the most suitable for this individual patient.

6 Facts about new oral anticoagulants

7 General aspects of NOAC vs. warfarin Drug Warfarin Dabigatran Rivaroxaban Apixaban Target VKORC1 IIa Xa Xa Prodrug No Yes No No Bioavailability >95% 6.5% 80% 66% T(max) hr 2 hr 2-3hr 3-4hr Half-life 20-60hr 12-17hr 5-9 hr 12hr Elimination - 80% renal 20% hepatic 33% renal 33% hepatic 33% inactive 27% renal 73% hepatic Semin Hematol, 2014, 51: Curr Opin Crit Care 2015, 21:

8 Suggested dosing Drug Warfarin Dabigatran Rivaroxaban Apixaban Half-life 20-60hr 12-17hr 5-9 hr 12hr Interactions So many! P-gp CYP3A4 p-gp Dosing Af INR adjusted (varied largely) 150/110 mg bid 20/15mg qd Dosing DVT 15mg bid X 21 days then 20mg qd CYP3A4 p-gp 5mg bid Semin Hematol, 2014, 51: Curr Opin Crit Care 2015, 21:

9 Conditions that you can use NOACs Prophylaxis of atrial fibrillation related thromboembolism Prophylaxis of surgery related thromboembolism Fresh (or first in lifetime) DVT and PE

10 Conditions that you should NOT use NOAC Poor renal / liver function Patients with mechanical valve(s) Taking (multiple) interfering drug(s) Poor GI condition Poor compliance Pregnancy Extreme body weight (>120kg or <40 kg)

11 Special patient populations that lack of evidence to use NOAC Cancer patients drug interactions, GI problems, bleedings APS patients recurrence, bleedings Recurrent VTE

12 Use of NOAC in APS Rivaroxaban in APS (RAPS trial) Population: APS patients stable on warfarin Randomized: Rivaroxaban 20mg/d (n=57) vs. stay VKA (n=59) End point: ETP, VTE recurrence, safety ETP: higher in rivaroxaban group P<0.001 d-dimer: no difference no VTE/bleeding event ISTH 2015 LB003

13 Laboratory issue

14 Laboratory data are messed up Coagulation tests Dabigatran Rivaroxaban /Apixapan PT/INR aptt TT -- Anti-Xa assay -- PT-based factor level (II, V, VII, X) aptt-based factor level (VIII, IX, XI, XII) Mixing test Incomplete correction drvvt false positive false positive ASH 2012 education program

15 Expected PT/aPTT in NTUH (2015 Apr) Drug Dabigatran Rivaroxaban Apixaban Concentration PT/INR (Dade Innovin ) aptt (Actin FSL ) Trough (~50 μg/l) 1.03 ± ± 4.9 sec Peak (~200 μg/l) 1.24 ± ± 6.1 sec Trough (~25 μg/l) 1.03 ± ± 3.6 sec Peak (~200 μg/l) 1.46 ± ± 6.3 sec Trough (no data) - - Peak (~100 ng/ml) 1.0 Ratio 1.1 J Thromb Haemost 2011; 9: Thromb Haemost 2011; 105: Thromb Haemost 2014; 111:

16 PT/aPTT in NOACs patients NOT for drug adjustment NOT for compliance check NOT for cause of treatment failure/recurrence Possible overdose if it s too high

17 What if we REALLY want to monitor it?

18 HemoClot (diluted thrombin time) for dabigatran monitoring

19 Specific anti-xa assay for apixaban/rivaroxaban Reagent: Factor Xa and it substance (factor II) Assay factor IIa (the product of factor Xa function) Anti-Xa for heparin/lmwh is different to anti- Xa for rivaroxaban/apixaban (some how diluted )

20 Real world monitoring in dabigatran users JTH 2015; 13:

21 Should NOAC be monitored? Lancet 2015; 385:

22 Bleeding and management

23 Major bleeding is not very rare Drug/dose Tiral Major bleeding rate Comparator Dabigatran 110mg bid Dabigatran 150mg bid RELY 2.71% 3.31% 3.36% (warfarin) Rivaroxaban 20mg qd Apixaban 5mg bid ROCKET-AF 3.6% ARISTOTLE 2.1% 3.45% (warfarin) 3.09% (warfarin) Semin Hematol, 2014, 51:

24 Meta-analysis of NOAC efficacy and safety Lancet 2014; 383:

25 Bleeding under new anticoagulants Surgical intervention/ local control of bleeding General managements Stop the drug + Supportive care and monitoring Charcol gastric lavage (within 2-6 hour) Transfusion of FFP Life threatening condition Dialysis only for dabigatran Non specific reversal agents (off-labeled): rfviia, PCC, or apcc Antidotes in clinical trial phase 2-3 J Thromb Thrombolysis (2013) 35:

26 Evidence of using non-specific, off labelled reversal agents

27 PCC for rivaroxaban reversal in therapeutic dose (in vivo) J Thromb Haemost 2014; 12:

28 Thrombin generation assay for apixaban effects

29 Reversal agents in apixaban 700ng/mL (ex vivo) J Thromb Haemost 2015; 13:

30 PCC for reversal of endoxaban (in vivo) Healthy volunteers take endoxaban 60mg Randomized and double-blinded 4 factor PCC (50, 25, 10 IU/kg)vs placebo Puncture biopsy (5mm depth, 5mm diameter) on the back of thigh Test bleeding volume, bleeding duration, ETP and PT Circulation.2015;131:82-90

31 PCC reversal of endoxaban result-1 Circulation.2015;131:82-90

32 PCC reversal of endoxaban result-2

33 Developing specific antidotes

34 NEJM, 2015 Jul 22 [online] Idarucizumab: dabigatran specific RE-VERSE AD study reversal agents Idarucizumab for dabigatran reversal Population: A: severe bleeding (n=51) B: need emergent surgery (n=39) 5g IV infusion (2.5g X 2, <15 min apart)

35 NEJM, 2015 Jul 22 [online] Idarucizumab: dabigatran specific reversal agents Diluted thrombin time Unbound dabigatran

36 Anti-Xa reversal agent: Andexanat-alpha Nature Medicine 19, (2013)

37 Anti-Xa reversal agent: Andexanat-alpha Andexanet vs. placebo in health adult Healthy subject age take apixaban 5mg bid X4 days Andexanet-alpha vs. placebo 400mg bolus + 4mg/min infusion Total and immediate neutralized anti-xa level return to normal PK in 2hr after stop infusion ISTH 2015 LB004

38 Take home message New oral anticoagulants are not perfect Indications: not in MV or catheter related VTE Monitoring: maybe, but need more data Bleeding is not very rare Antidotes is in development