Everything You Always Wanted to Know About NOACs-DOA-TSOACs

Transcription

1 Everything You Always Wanted to Know About NOACs-DOA-TSOACs before a surgery, before a regional anesthesia, being on call in ICU or in the OR P Albaladejo, MD, PhD Department, of anesthesia and intensive care Grenoble University Hospital France Disclosures: Bayer Healthcare, Boehringer Ingelheim, BMS-Pfizer, Sanofi, Daiichi Sankyo, LFB, CSL Behring, Octapharma, BBraun, Sandoz, Portola

2 NOACs-DOA-TSOACs Elimination ½ life Tmax Bio-availability Elimination Dabigatran anti-iia Rivaroxaban anti-xa Apixaban anti-xa 14-17h 0,5 à 2 h 6-8% 80% renal 20% hepatic 7-13h 2-4h >80% 33% renal (unchanged) 33% renal (inactive metabolites) 33% hepatic 8-15h 3-4h 50-85% 25% renal 75% hepatic Edoxaban anti-xa 10-14h 1,5h 65% 35% renal

3 VTE prevention in major orthopedic surgery Dabigatran 75 mg then 150 mg OD 110 mg then 220 mg OD Rivaroxaban 10 mg OD Apixaban 2,5 mg BID Edoxaban (not approved)

4 (non valvular) Atrial fibrillation - VTE treatment Dabigatran Atrial fibrillation 110 mg BID 150 mg BID VTE treatment 150 mg BID Rivaroxaban Atrial fibrillation 15 mg/j (Cockcroft ml/min) 20 mg/j (Cockcroft > 50 ml/min) VTE treatment 15 mg BID for 3 weeks 15 or 20 mg OD (Cockcroft) Apixaban Atrial fibrillation 5 mg BID 2.5 mg BID (if bleeding risk factors) VTE treatment 10 mg BID for 7 days 5 mg or 2.5 mgbid Edoxaban Atrial fibrillation 60 mg OD 30 mg OD (if bleeding risk factors) VTE treatment 60 mg OD 30 mg OD (if bleeding risk factors)

5 Ruff et al. Lancet 2014; 383:

6 Variability

7 Europace. 2015;17:

8 P-Glyprotein and/or CYP450 Europace. 2015;17:

9 Europace. 2015;17:

10 Europace. 2015;17:

11 Factors that may affect bleeding risks while on NOACs Cockcroft= Age + Weight + Creatinine Verapamil/dronedarone Macrolids -Azole -Navir Rifampicin Immunosuppressive drugs And aspirin, clopidogrel Etc Never, Never, Never..overlap with other anticoagulants

12 NOACs and coagulation assays

13 Cmax (150mgx2) Cmin (150mgx2) Van Ryn J, Thromb Haemost 2010

14 Samama MM, Thromb Haemost 2010

15 PT ratio PT ratio 3,3 3,2 3,1 Neoplastin CI 3,0 2,9 Excel 2,8 2,7 PT-Fibrinogen 2,6 2,5 Neoplastin CI+ 2,4 2,3 Thromborel S 2,2 2,1 Innovin 2,0 1,9 Excel S 1,8 1,7 1,6 1,5 1,4 1,3 1,2 1,1 1, Apixaban (ng/ml) Thromb Haemost 2014; 111:

16 Diluted Thrombin Time ng/ml Specific antixa activity Dabigatran Rivaroxaban Van Ryn J, Thromb Haemost 2010 Freyburger G. Thrombosis Research 2011

17 Brinkman Thrombosis Journal (2015) 13:9

18 Thrombosis Research 2014;134:

19 Brinkman, Thrombosis Journal (2015) 13:9

20 Is the lab useful? Lab monitoring is not required. Lab monitoring may be useful in difficult cases Urgent surgery Bleeding Specific assays are not available everywhere, everytime. PT and/or aptt may be normal despite high plasma concentration (but still useful) ROTEM may be helpful.all depends on the question.

21 Reversal strategies

22 NOAC reversal with PCC DOA Preclinical Healthy volunteers Patients Dabigatran Ø 1 ; +/ Ø ; +/ Insufficient data Rivaroxaban +/ Ø 23 ; +/++ 19,20,24 27 Insufficient data Edoxaban ++ 14, ,28,29 No data Apixaban Ø 16 +/++ 21,30,31 No data DOA, direct oral anticoagulant; PCC, prthrombin complex concentrate; Ø, no reversal; +, partial reversal; ++, complete reversal 1. Schaefer et al. J Cereb Blood Flow Metab 2014; 34: 870 5; 2. Hoffman et al. Anesthesiology 2015; 122: ; 3. Zhou et al. Stroke 2011; 42: ; 4. van Ryn et al. Anesthesiology 2014; 120: ; 5. Herzog et al. Thromb Res 2014; 134: ; 6. Pragst et al. J Thromb Haemost 2012; 10: ; 7. Grottke et al. Crit Care 2014; 18: R27; 8. Honickel et al. Thromb Haemost 2015; 113 [Epub]; 9. Lambourne et al. J Thromb Haemost 2012; 10: ; 10. Zhou et al. Stroke 2013; 44: 771 8; 11. Perzborn et al. Thromb Haemost 2013; 110: ; 12. Herzog et al. Thromb Res 2015; 135: ; 13. Godier et al. Anesthesiology 2012; 116: ; 14. Herzog et al. Anesthesiology 2015; 122: ; 15. Fukuda et al. Thromb Haemost 2012; 107: 253 9; 16. Martin et al. Int J Cardiol 2013; 168: ; 17. Solbeck et al. Int J Cardiol 2014; 176: 794 9; 18. Solbeck et al. Scand J Clin Lab Invest 2014; 74: 591 8; 19. Eerenberg et al. Circulation 2011; 124: ; 20. Marlu et al. Thromb Haemost 2012; 108: ; 21. Dinkelaar et al. Clin Chem Lab Med 2014; 52: ; 22. Lindahl et al. Thromb Res 2015; 135: 544 7; 23. Korber et al. Clin Appl Thromb Hemost 2014; 20: ; 24. Perzborn et al. Thromb Res 2014; 133: ; 25. Escolar et al. Circ J 2015; 79: 331 8; 26. Levi et al. J Thromb Haemost 2014; 12: ; 27. Dinkelaar et al. J Thromb Haemost 2013; 11: ; 28. Zahir et al. Circulation 2015; 131: 82 90; 29. Halim et al. Thromb Res 2014; 134: ; 30. Escolar et al. PloS one 2013; 8: e78696; 31. Martin et al. J Thromb Haemost 2015; 13: ; 32

23 PCC VKA Replace missing factors NOACs Overwhelm the inhibition of FIIa or FXa and???? DOA, direct oral anticoagulant; F, factor; PCC, prothrombin complex concentrate; VKA vitamin K antagonist

24 How to manage a RABBIT treated with dabigatran, with a kidney trauma, admitted to the ER? Pragst et al. J Thromb Haemost 2012; 10:

25 Anesthesiology December 2015

26 Rivaroxaban Dabigatran Marlu et al, Thromb Haemostasis 2012

27 Zahir et al, Circulation 2015; 131: 81-90

28 Brinkman, Thrombosis Journal (2015) 13:9

29 PCC and apcc seem to be efficient at high doses

30 Management of NOACs Regional anesthesia? Elective surgery? Urgent surgery? Bleeding while on NOACs?

31 Management of NOACs Regional anesthesia? Elective surgery? Urgent surgery? Bleeding while on NOACs?

32 ! Lowest dose of NOACs

33

34 Rivaroxaban The plasma half-life of rivaroxaban is 5 9 h and is not significantly prolonged in patients with moderate renal impairment, but according to the manufacturer it is prolonged to h in the elderly. A time interval of h between the last dose of rivaroxaban (10 mg) and catheter withdrawal is thus required (Class IIa, level C). After catheter withdrawal the next dose of rivaroxaban may be given after 4 6h (Class IIb, level C). Available experience with neuraxial blockade is very limited. Extreme caution is therefore recommended when using rivaroxaban in the presence of neuraxial blockade (Class IIb, level C).

35 Dabigatran In the initial studies with dabigatran, neuraxial blockade was performed in approximately 70% of patients, however, all epidural catheters were removed at least 4-6 hours before the first dose of dabigatran, there is no experience with dabigatran and indwelling epidural catheters Possible time interval of 34 hours between the last dose of dabigatran and catheter withdrawal, however, the manufacturer advises against the use of dabigatran in the presence of neuraxial blockade (Class III, level C) Possible medicolegal consequences, if a spinal epidural haematoma occurs.

36 Apixaban Time interval of hours between the last dose of apixaban (2.5 mg) and catheter withdrawal and at least one dose should be omitted (Class IIb, level C) After catheter withdrawal the next dose of apixaban may be given after 4-6 hours (Class IIb, level C) Experience with neuraxial blockade is limited and most patients received only single-shot spinal anaesthesia. Extreme caution is therefore recommended when using apixaban in the presence of neuraxial blockade (Class IIb, level C)

37 accessed 12/11/2015

38 Reg Anesth Pain Med 2015;40:

39 Low doses («prophylactic») 2 half lives High doses («therapeutic») > 5 half lives Beware of elderly/renal insufficiency/low weight patients!!!!!!!! Check plasma concentration or try general anesthesia

40 Management of NOACs Regional anesthesia? Elective surgery? Urgent surgery? Bleeding while on NOACs?

41 Europace. 2015;17:

42 Low hemorrhagic risk High hemorrhagic risk Before the procedure No DOA the evening before and the morning of the procedure rivaroxaban apixaban edoxaban dabigatran Cockcroft 30 ml/mn Cockcroft 50 ml/mn Cockcroft ml/mn Last DOA on D-3 Last DOA on D-4 Last DOA on D-5 No bridging No dosage After the procedure Resumption at the usual time but at least 6h after the procedure «Prophylactic» dose of anticoagulant At least 6 hours after the procedure if venous thromboprophylaxis is indicated «Therapeutic» dose of anticoagulant as soon as the hemostasis allows it (between 24 and 72 hours)

43 Management of NOACs Regional anesthesia? Elective surgery? Urgent surgery? Bleeding while on NOACs?

44 Arch Cardiovasc Dis 2013;106:382-93

45 Management of NOACs Regional anesthesia? Elective surgery? Urgent surgery? Bleeding while on NOACs?

46 Bleeding in patients treated with NOACs Always consider: Symptomatic and supportive therapies Compression Surgery Embolisation Specific procedures Fluids Transfusion Clotting factors FFP PCCs

47 Reversal strategies Options: Alter the PK of the DOA Time Antidotes Dialysis (dabigatran) Charcoal!!! Clotting factors 4F-PCC apcc (rfviia) First-line First- or second-line

48 New oral anticoagulants, such as rivaroxaban and dabigatran, may increase surgical bleeding and ICH growth. We suggest that PCC, FEIBA or rfviia may be used as non-specific antagonists in life-threatening bleeding or ICH. 2C Kozek-Langenecker et al. Eur J Anaesthesiol 2013; 30:

49 Europace. 2015;17:

50 Non specific measures May be PCC in life threatening bleeding Wait for antidotes..

51 Antidotes?

52 Idarucizumab: PRAXBIND

53 Group A: Major bleeding Group B: Urgent procedures N Engl J Med. 2015;373:

54 Nature Medicine 2013

55 This article was published on November 11, 2015, at NEJM.org. DOI: /NEJMoa

56 NEJM 2014

57 French National Congress SFAR 2016 Mark your calendar! September 2016 Paris