AOD moins dangereux que AVK? P Albaladejo Pôle Anesthésie Réanimation CHU de Grenoble France

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1 AOD moins dangereux que AVK? P Albaladejo Pôle Anesthésie Réanimation CHU de Grenoble France DCI: Bayer Healthcare, Boehringer Ingelheim, BMS-Pfizer, Sanofi, Daiichi Sankyo, LFB, CSL Behring, Octapharma, Portola

2 Anticoagulants Oraux Directs Agent Classe ½ vie Tmax Biodisponibilité Elimination Dabigatran anti-iia Rivaroxaban anti-xa Apixaban anti-xa 14-17h 0,5 à 2 h 6-8% 80% rein 20% foie 7-13h 2-4h >80% 33% rein (inchangée) 33% rein (metabolites inactifs) 33% foie 8-15h 3-4h 50-85% 25% rein 75% foie Edoxaban anti-xa 10-14h 1,5h 65% 35% rein

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 Europace. 2015;17:

6 RCTs=

7 Ruff Lancet 2014

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10 À haut risque de saignement? ATCD de saignement? Cockroft? Bleeding scores? Comédication? Aspirine AINS

11 ATRIA HAS-BLED HEMORR 2 HAGES Anemia 1 3 Hypertension 4 1 Severe renal disease 2 3 Abnormal Renal 5 or 1 Liver function 6 1 Hepatic 10 or 1 Renal disease 2 1 Ethanol abuse 1 Age 75 yrs 2 Stroke 1 Malignancy 1 Any prior hemorrhage 1 Bleeding 1 Older Age (>75 yrs) 1 Hypertension 3 1 Labile INR 8 1 Reduced platelet number or function 11 1 Elderly (>65 yrs) 1 Rebleeding 12 2 Drugs 9 or Alcohol 1 1 Hypertension 4 1 Anemia 13 1 Genetic factors 14 1 Excessive fall risk 15 1 Stroke 1

12 Davidson B L et al.jama Intern Med. 2014;174(6):

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17 Schéma posologique Dose recommandée 60 mg en 1 seule prise par jour Dose recommandée chez les patients présentant un ou plusieurs des caractéristiques cliniques suivants Insuffisance rénale Poids faible Inhibiteurs de la P-gp Modérée ou sévère (ClCr de 15 à 50 ml/min) 60 kg Ciclosporine, dronédarone, érythromycine, kétoconazole 30 mg en 1 seule prise par jour Haut risque hémorragique?

18 RCTs

19 RCTs Real life

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21 Dabigatran and rivaroxaban new users were matched to VKA new users by the use of 1:2 matching on the propensity score. Patients were followed for up to 90 days until outcome, death, loss to follow-up, Circulation 2015; 132:

22 Dabigatran and rivaroxaban new users were matched to VKA new users by the use of 1:2 matching on the propensity score. Patients were followed for up to 90 days until outcome, death, loss to follow-up, Circulation 2015; 132:

23 Interactions médicamenteuses?

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

25 Europace. 2015;17:

26 Europace. 2015;17:

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32 Absence de surveillance biologique Absence de test biologique

33 NOACs and coagulation assays

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

35 Samama MM, Thromb Haemost 2010

36 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:

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

38 Brinkman Thrombosis Journal (2015) 13:9

39 Thrombosis Research 2014;134:

40 Le patient saigne sous AOD

41 Hémorragie sous AOD Toujours: Traitements non spécifiques Compression chirurgie Embolisation Remplissage Transfusion Antifibrinolytiques Facteurs de coagulation PFC, Plaquettes Fibrinogène

42 Stratégie de réversion Options: Pharmacocinétique Temps Antidotes Dialyse (dabigatran) Charbon activé Agents hémostatiques CCP CCPa (rfviia)

43 Ann Fr Anesth Reanim (2013),

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45 Bleeding 41 centres (included 1-60 patients) 18 months GIHP-NACO Observatory 349 patients admitted and hospitalised for major bleeding while on DOAs

46 Bleeding GIHP-NACO Observatory

47 Bleeding GIHP-NACO Observatory

48 Bleeding GIHP-NACO Observatory

49 Bleeding GIHP-NACO Observatory

50 Major bleeding (ISTH)= 74.2% GIHP-NACO Observatory % GIHP-NACO (n=349) Rocket AF (n=395) Rely (n=627) EPAHK (AVK) (n=822) GI Intracranial (spont) Intracranial (trauma) Epistaxis Muscular hematoma Multiple Trauma Hemoptysis Intraperitoneal Pericardial Hemarthrosis Hemothorax (unpublished data, December GIHP working group)

51 Bleeding % (unpublished data, December GIHP working group)

52 aptt ratio Saignements n=219 Dabigatran (n=32) 3,2 3 2,8 2,6 2,4 2,2 2 1,8 1,6 1,4 1,2 1 0,8 (2 points out of range) ,8 3,2 3 2,8 2,6 2,4 2,2 2 1,8 1,6 1,4 1,2 1 NOAC concentration determined in 46% Rivaroxaban (n=68) PT ratio 3,2 3,2 (3 points out of range) 3 3 2,8 2,8 2,6 2,6 2,4 2,4 2,2 2, ,8 1,8 1,6 1,6 1,4 1,4 1,2 1, ,8 0, ng/ml ng/ml (Observatoire GIHP-NACO, données non publiées)

53 Bleeding GIHP-NACO Observatory

54 Bleeding GIHP-NACO Observatory

55 Bleeding GIHP-NACO Observatory Did the bleeding stop after administration of these clotting factors? Yes, completely 42.7 % Yes, partially 39.7% No 17.7% (unpublished data, December GIHP working group)

56 Outcome GIHP-NACO (30 days) EHPAK (Crit Care 2014) (7 days Major bleeding in dabigatran studies (Majeed, Circulation 2013) Major bleeding in rivaroxaban studies (Piccini, Eur Heart J 2014) Cardiovascular events 9.1 % Pulmonary oedema 5.0 % Cardiogenic shock 1.8 % Acute coronary syndrome 1.8 % 2.6 Stroke 0.9 % 4.7 VTE 0.9 % Mortality (Hart et al, Stroke 2012) (Majeed et al Circulation 2013) (Hankey, Stroke 2014) (Piccini et al Eur Heart J 2014) All cause 14.6 % 13 % D= 9.1 % W = 13% R = 20.4 % w = 26% Intracranial bleeding (Spont) Intracranial bleeding (Trauma) 31.8 % 33 % D = 37.5 % 12.5 % D = 27.3% R= 49 % (unpublished data, May GIHP working group)

57 Conclusion Les AOD n ont pas l air plus dangereux que les AVK

58 Conclusion Les AOD n ont pas l air plus dangereux que les AVK Les AOD n ont pas l air aussi dangereux que les AVK

59 Conclusion Les AOD n ont pas l air plus dangereux que les AVK Les AOD n ont pas l air aussi dangereux que les AVK De là à dire que c est moins dangereux