Ecarin = highly puridied metalloprotease isolated from the venom ot Echis carinatus.

Transcription

1 Atlernative Ecarin Clotting Time Ecarin = highly puridied metalloprotease isolated from the venom ot Echis carinatus. Generation of meizothrombin (Ecarin + prothrombin), insensitive to heparin. Able to transform fibrinogen into fibrin. Ecarin Chromogenic Assay --> meizothrombin is measured using a specific chromogenic substrate. Douxfils J, Muller F et al, Thomb Haemost 2012 May 2;107(5):985-97

2 Douxfils J, Muller F et al, Thomb Haemost 2012 May 2;107(5): Limitations of aptt No reflect of circulating concentrations of dabigatran No demonstrated link with the bleeding risk Influence of the reagents and instruments : we need more specific recommendations. More studies are needed. Prolonged aptt indicates a supratherapeutic concentration but should be interpreted with caution because of the anticoagulant effect could be underestimated. A normal aptt exclude probably an anticoagulant effect from dabigatran Calibrations and controls are essential

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4 Protocol Results in the therapeutic range «Result in the therapeutic range, defined on in vitro data» Infratherapeutic results «Result under the therapeutic range, defined on in vitro data. It is important to check drug interactions and compliance». Supratherapeutic results «Result above the therapeutic range, define on in vitro data. It is imporant to check drug interactions and renal/liver functions.

5 Dose individualisation

6 According to european guidelines

7 Rivaroxaban (Xarelto )

8 In practice... Rivaroxaban PT for the monitoring of Rivaroxaban as a screening test. Chromogenic anti-xa tests (i.e. Biophen DiXaI or Liquid Anti-Xa) Rivaroxaban + FXaexcess --> Riva-FXa + FXaresidual FXaresidual + chromogenic molecule --> 405 nm Result in ng/ml of rivaroxaban

9 Limitations of PT No reflect of the rivaroxaban s circulating concentration No demonstrated link with the bleeding risk Reagents and instruments influence : more studies need to be done to suggest more specific recommendations INR is not valid! A normal PT (with sensitive reageant) excludes a significative anticoagulant effect from rivaroxaban Calibrations and controls are essentials

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12 Protocol Results in the therapeutic range «Result in the therapeutic range, defined on in vitro data» Infratherapeutic results «Result under the therapeutic range, defined on in vitro data. It is important to check drug interactions and compliance». Supratherapeutic results «Result above the therapeutic range, define on in vitro data. It is imporant to check drug interactions and renal/liver functions.

13 Clinical cases

14 N 1 (23/01/1951), (M) AF Prostate cancer COPD III Pancreatitis 2007 Renal fuction : Creat. 1,19 mg/dl, CG 59 ml/min Liver function : OK (GGT 115 UI/L (15-73)) Pulmonary embolism 2009 Peptic ulcer Atheromatosis Thrombophilia : FVIII ++ and heterozygous for prothrombin mutation

15 N 1, monitoring Xarelto 15 mg/d 27/07/ min : 71,03 ng/ml --> therapeutical trough 120 min : 399,13 ng/ml --> supra-therapeutic 180 min : 449,84 ng/ml --> supra-therapeutic For 20 mg/d Ctrough Cmax Douxfils J et al, Thromb. Res. 2012, Sep.21

16 CYP450 and P-gp? N 1 - Traitements Simvastatine Esomeprazole Cordarone Spiriva, Inuvair Durogesic Xarelto 15 mg Duovent Rivotril drops Oxygenotherapy Zestril Montelukast Medrol

17 CYP450 and P-gp? N 1 - Traitements Cordarone Substrate CYP3A4 Inhibitor YP2C9, 3A4, 2D6, P-gp Simvastatine Substrate CYP3A4 Inhibitor P-gp Esomeprazole Substrate CYP3A4 Inhibitor CYP2C19 Durogesic Substrate CYP3A4 et P-gp Xarelto 15 mg Spiriva, Inuvair Duovent Rivotril drops Substrate CYP3A4 Zestril Medrol Montelukast Inhibitor CYP2C8

18 Durg interactions Substrate CYP3A4 Inhibitor YP2C9, 3A4, 2D6, P-gp Amiodarone --> Flécaïnide? (CYP2D6). Taken for AF post-embolia. Paroxystic, re-evaluation? Simvastatine : strong substrate of CYP3A4 (competition?), principal metabolic pathway --> Pravastatine?... In case of overdose, check the drug interactions! Often, polymedicated patients!

19 Cytochromes P450 - Hemoproteins particularly implicated in Xenobiotics metabolism. - Localisation in the liver, but also in the gastrointestinal tract. - Substrates - Inducers - Inhibitors Major durgs interactions mechanism

20 P- glycoprotein «Multi-Drug Resistance Pump» Rejection in the GI tract Rivaroxaban and Dabigatran Absorption Inducers + Substrates - Inhibitors - Rifampicine - Phenytoïn - Dexaméthasone - Millepertuis - Ciclosporine, Tacrolimus - Amiodarone - Simvastatine - Clarithromycin - Ketoconazole - Phenytoïn - Ritonavir - Ciclosporine - Amiodarone - Verapamil - Ketoconazole - Ritonavir - Tamoxifène - Grapefruit juice

21 Common drug interactions Rifampicine Before NOACs administration, drug anamnesis is mandatory! Ketoconazole Verapamil Clarithromycin (particularly in patients with renal impairment) Millepertuis (Hypercium perforatum) Carbamazepin or phenytoïn Ciclosporine, Tacrolimus

22 N 2, 23/07/1957 (F) 1m61, 108 kg (BMI = 42) after diet! AF Renal and liver functions : ok No response to VKA! acenocoumarol (Sintrom) : to 15 mg/d with INR = 1 warfarine (Marevan): to 5 mg/d with INR = 1 phenprocoumone (Marcoumar) «Resistance» to clonazepam, hydroxizine and zolpidem Stroke on AF, supra-ventricular tachycardia,... By pass!

23 N 2, 23/07/1957 (F) Rivaroxaban 20 mg (no dabigatran because of the extreme weight) Switch Clexane --> Rivaroxaban Last Clexane intake : 17 august, 9h00 First dose of Rivaroxaban : 18 august, 10h05 Complete PK J0, J6 and J56 : 0min, 30min, 1h, 1h30, 2h, 3h, 4h et 6h Genotyping : CYP3A4, CYP2C9, VKORC1,...

24 VKA metabolism AVK AVK Cofactor γ-carboxylation

25 Phenprocoumone Warfarine Acénocoumarol Rivaroxaban? CYP450 and anticoagulants Other genes can be involved...

26 Genotyping? CYP2C9 VKORC1 CYP3A4 CYP3A5 ABCB1 TaqMan, Luminex, Genechip, MLPA, Sequencing,...

27 N 2, 23/07/1957 (F) No detection of common mutations for CYP2C9 or VKORC1! We only find what we are looking for! Sequencing? CYP3A4*22 negative (Haufroid et al) CYP3A5 positive! (20% population) --> increase in CYP3A activity Part in VKA resistance? African population is more resistant to VKA and CYP3A5 is more expressed... (-->?) PPAR-A, POR*28,..., under investigation

28 Assay PT values are not similar for the different plasmatic concentrations Anti-Xa assays (chromogenics) give similar results 0 min, 30min, 1h, 1h30, 2h, 3h, 4h et 6h Cmax 2-4h after intake

29 N 3 : N.J, 17/02/1924 (F) Femoral neck fracture, accidental fall --> 23/10/2012 in Mont-Godinne Dabigatran 110 mg bd, AF Last intake : 22/10 at 22h15 Renal function with CG : 34,8 ml/min Coagulation assays 23/10 : aptt = 64,4 sec (26,0-38,0), TT > 120 sec

30 N 3 : N.J, 17/02/1924 (F) Recommandations : with Clcreat ml/min --> stop for 4 days before surgery (26/10?) monitoring 25/10 morning + switch to Clexane 40 2x/d? Monitoring dabigatran 25/10 --> 0 ng/ml (Hemoclot), aptt 29,9 sec, TT 23,4 sec. Surgery the 25/10

31 NOACs and renal impairment Dabigatran : ~80% renal elimination. Rivaroxaban : ~50% renal elimination. Renal impairment? Mild : no recommendation Moderate (ClCr ml/min) --> use with caution, clinical surveillance (bleeding,...). Severe (ClCr ml/min) : caution!... Not recommanded in patient with ClCr < 15 ml/min, risk of bleeding. European medicines agency ie : Dabigatran

32 23/02/2012 : depuis 48h, cordon induré sensible au niveau de la face interne de la jambe droite, notion de voyage en avion en Italie --> thrombophlébite de la veine saphène interne droite. Volumineux caillot visible à l échographie --> Fraxodi 1 ml 1x/jour. Cas n 3, 30 mai 1972, (M) Thrombose de la veine saphène droite en 1997 (à 25 ans) --> Fraxiparine. Bilan thrombophilie (FV Leiden muté, facteur VIII élevé (180%) (et IX)), antécédents de thromboses familiales. Enormes difficultés à être mis sous AVK , embolie pulmonaire. Arrêt AVK --> Fraxiparine Mis sous HBPM pendant quelques années, mais lui est pénible. Mise sous Pradaxa au Luxembourg (mutuelle luxembourgeoise), mi

33 Cas n 3, 30 mai 1972, (M) Pradaxa 110 mg 2co en une prise. 23/02/2012 : Monitoring, délais entre prise et prélèvement : 9h TCA Synthasil : 47,4 sec (26,0-38,0) TT > 120 sec Hemoclot Thrombin inhibitor 80 ng/ml. Patient dans la zone thérapeutique*. Bilan hépatique, rénal --> OK! Pas de co-médication particulière. * Douxfils J et al, Thrombosis and Haemostasis 107.5/2012

34 Cas n 3, 30 mai 1972, (M) 06/04/2012 : sous Pradaxa depuis 1 an, 2x110 mg 1x/jour. Report par le patient de l oubli d une dose, et survenue d un début de phlébite... Après confirmation, passage au Xarelto (a décidé qu il ne prendrait plus de Pradaxa) 23/10/2012 : oubli de prendre le médicament, survenue douleurs jambes et perturbations de la vue (30 min) --> rentré dans l ordre à la prise de Xarelto. Traitement à domicile : Xarelto 20 mg/jour Labo : Rivaroxaban, 20 mg 19/07/2012 : 0 min : 0 ng/ml 120 min : 190 ng/ml 180 min : 166 ng/ml 23/10/2012 : 0 min : 31 ng/ml 120 min : 203 ng/ml Cvallée et Cmax dans les intervalles thérapeutiques

35 Conclusion cas n 3 Manque de compliance? Le Sintrom n était pas gérable chez ce patient. «N en fait qu à sa tête...» Fraxiparine OK, mais pénible pour lui. Monitoring Pradaxa ok, mais pas évident d évaluer la compliance en faisant du monitoring (non rétrospectif). Aléas dans les prises, épisodes thrombotiques, le patient refuse de continuer à prendre le médicament. Passage au Xarelto, mieux supporté.

36 Conclusion A biological follow-up of NOACs is indicated in some situations In case of infra- or supra-therapeutic concentration, be careful to renal function, liver function, drug interactions and compliance. Knowledge for the laboratory of the impact of NOACs on routine coagulation assays! Physician-Biologist dialogue is of utmost importance! All this has to be well orchestrated!

37 Website NTHC (Namur Thrombosis and Hemostasis Center) Google --> NTHC (first website*) Practical Guide Rivaroxaban Practical Guide Dabigatran *

38 Thanks to... Ph. J. Douxfils, Pr. JM. Dogné Ph. AS Larock, Ph G.Remy, Pr. A. Spinewine Dr V. Mathieux, Pr. F. Mullier, Pr. B. Chatelain, Pr C. Chatelain Pr. V. Haufroid