ΠΑΡΑΚΟΛΟΤΘΗΗ ΚΑΙ ΓΙΑΥΔΙΡIΗ ΣΩΝ ΝΔΩΝ ΑΝΣΙΘΡΟΜΒΩΣΙΚΩΝ ΠΑΡΑΓΟΝΣΩΝ

ΠΑΡΑΚΟΛΟΤΘΗΗ ΚΑΙ ΓΙΑΥΔΙΡIΗ ΣΩΝ ΝΔΩΝ ΑΝΣΙΘΡΟΜΒΩΣΙΚΩΝ ΠΑΡΑΓΟΝΣΩΝ Δξ Ειεπζεξία Λεπθνύ Αηκαηνιόγνο Δπηκειήηξηα Β Ιππνθξάηεην ΓΝΘ Δμεηδηθεπζείζα ζηελ Αηκόζηαζε-Θξόκβσζε ζην St Thomas Hospital, London, UK

Πξνεπηζθόπεζε Παξνπζίαζεο Εηζαγσγή: Πνηα είλαη ε αλάγθε γηα λεώηεξα αληηπεθηηθά? Μέξνο 1ν: Καηεγνξίεο λεώηεξσλ αληηζξνκβσηηθώλ θαξκάθσλ Κατηγορία A: Άμεςοι αναςτολείσ του παράγοντα Xa Υποδόρια: Fondaparinux Per os: Rivaroxaban, Apixaban, Edoxaban)(DU-176b, LY517717, YM150,, Betrixaban-Idraparinux Κατηγορία Β: Άμεσοι αναστολείς της θρομβίνης Dabigatran etexilate (Pradaxa) Μέξνο 2ν: Εξγαζηεξηαθέο κέζνδνη γηα ηελ παξαθνινύζεζε ησλ ΝΑΤΑ Μέξνο 3ν: Δηαρείξηζε ΝΑΤΑ- Απαληήζεηο ζε ζπρλά πξνβιήκαηα θαη ζηα 4 W Επίινγνο-Σπκπεξάζκαηα

Δηζαγσγή Τπάξρεη αλάγθε γηα λεώηεξα αληηπεθηηθά?

Ανταγωνιστές της βιταμίνης Κ-Μειονεκτήματα Παξελέξγεηεο Narrow Therapeutic Genetic variation Drug interactions Food interactions Απαηηνύλ monitoring Αηκνξξαγηθόο θίλδπλνο Αξγή έλαξμε δξάζεο Protein Half Life (Hours) Prothrombin (II) 60-100 Factor VII 6-8 Factor IX 20-30 Factor X 24-40 Protein C 8-10 Protein S 40-60 Is this the perfect anticoagulant? Dipiro: Pharmacotherapy: a Pathophysiologic Approach, 2008

Safe Effective Oral Easy (No monitoring) No major complicationscontradictions No interactions Reversible CHEAP

Factor Xa Thrombin Dipiro: Pharmacotherapy: a Pathophysiologic Approach, 2008

Μέξνο 1ν Καηεγνξίεο λεώηεξσλ αληηζξνκβσηηθώλ θαξκάθσλ Κατηγορία A: Άμεςοι αναςτολείσ τησ θρομβίνησ Per os: Dabigatran etexilate (Pradaxa) Κατηγορία B: Άμεςοι αναςτολείσ του παράγοντα Xa Υποδόρια: Fondaparinux (Arixtra) Per os: Rivaroxaban, Apixaban, LY517717, YM150, DU-176b, Betrixaban-Idraparinux

Κατηγορία A: Άμεςοι αναςτολείσ τησ θρομβίνησ Dabigatran etexilate Pradaxa Boehringer Ingelheim Pharmaceuticals

Dabigatran Dipiro: Pharmacotherapy: a Pathophysiologic Approach, 2008

Direct inhibition of thrombin Dabigatran IIa Άκεζα αλαζηέιιεη ηόζο ηελ ειεύζερε όζο θαη ηε ζσλδεδεκέλε ζηο ζρόκβο ζροκβίλε, κε κεγάιε εηδηθόηεηα θαη ζσγγέλεηα.

Κατηγορία Β: Άμεςοι αναςτολείσ του παράγοντα Xa Υποδόρια Fondaparinux (Arixtra) Από του ςτόματοσ Rivaroxaban (Xarelto) Apixaban (Eliquis) Edoxaban -DU176b (Lixiana) LY517717 YM150 DU-176b Betrixaban-Idraparinux Eribaxaban TAK-442

Rivaroxaban directly inhibits Factor Xa Rivaroxaban Dipiro: Pharmacotherapy: a Pathophysiologic Approach, 2008 J Thromb Haemost. 2006 Jan;4(1):121-8

Selective binding of rivaroxaban on the active site of FXa Focus on the active site showing the key interaction between rivaroxaban and Tyr228 in the S1 pocket Perzborn et al ArteriosclerThrombVascBiol. 2010;30:376-381

Part 2: Laboratory methods for NATA monitoring Classic assays Global tests

Dabigatran-Pradaxa Monitoring

Pradaxa θαη Activated partial thromboplastin time-aptt To APTT εκθαλίδεη κίαs θακππιόγξακκε δνζνεμαξηώκελε απάληεζε ζην dabigatran κε κηα απόηνκε αύμεζε ζε ρακειέο ζπγθεληξώζεηο θαη γξακκηθόηεηα πάλσ από ζπγθέληξσζε 400 ng / ml. ηε δόζε ησλ 150 mg x2 ε κέζε αύμεζε ηνπ ΑΡΣΣ είλαη πεξίπνπ 2πιάζηα από ην control. 12 ώξεο κεηά ηελ ηειεπηαία δόζε ε αύμεζε είλαη πεξίπνπ ζην 1,5 ζε ζρέζε κε ην control, κε <10% αζζελώλ λα έρνπλ 2πιαζηα αύμεζε. Σε δνζνινγία 2 θνξέο/κέξα, αύμεζε ΑΡΤΤ>80 sec, 10-16ώξεο κεηά ηελ ηειεπηαία δόζε, ζπλδέεηαη κε απμεκέλν αηκνξξαγηθό θίλδπλν. Σε δνζνινγία 1/κέξα, αύμεζε ΑΡΤΤ>45 sec 20-24 ώξεο κεηά ηελ ηειεπηαία δόζε ζπλδέεηαη κε απμεκέλν αηκνξξαγηθό θίλδπλν. Educational Material as part of the EMA Risk Minimisation Plan- approved by German and Dutch authorities)

ΠΡΟΟΥΗ! Τν APTT επεξεάδεηαη από ην είδνο ηνπ πεθηνινγηθνύ αλαιπηή θαη ησλ αληηδξαζηεξίσλ πνπ ρξεζηκνπνηνύληαη, αιιά παξαηεξείηαη γεληθώο ινγηθή ζπκθσλία αλεμαξηήησο ηνπ ελεξγνπνηεηή ή θσζθνιηπηδίνπ (Lindahl et ατ, 2011) κε ηα απνηειέζκαηα ζπλήζσο εληόο 10% κίαο κέηξεζεο αλαθνξάο (van Ryn et al, 2010).

ΡΣ ζηελ παξαθνινύζεζε ηνπ Pradaxa? -To PT δελ είλαη επαίζζεην ζην dabigatran (van Ryn et al, 2010;Lindahl et al, 2011). - ηε δόζε ησλ 100 ng/ml ην PT βξίζθεηαη ηππηθά κέζα ζηα θπζηνινγηθά όξηα (Lindahl et al, 2011). -Τπάξρεη ηεξάζηηα απόθιηζε ζηελ επαηζζεζία ησλ PT αληηδξαζηεξίσλ (Lindahl et al, 2011).

Thrombin time- Pradaxa Ο ρξόλνο ζξνκβίλεο (TT) παξνπζηάδεη γξακκηθή ζπζρέηηζε ηεο απάληεζεο ζην dabigatran (van Ryn et al, 2010; Lindahl et al, 2011), ηα απνηειέζκαηα όκσο είλαη πνιύ εμαξηώκελα από ην είδνο ηνπ αληηδξαζηεξίνπ θαη ηνπ αλαιπηή πνπ ρξεζηκνπνηήζεθε. Σα πεξηζζόηεξα αληηδξαζηήξηα είλαη πνιύ επαίζζεηα. Η ρξεζηκόηεηα ηνπ ΤΤ είλαη γηα λα καο δείμεη εάλ ππάξρεη νπνηνδήπνηε επίπεδν ηνπ θαξκάθνπ, γεγνλόο πνπ κπνξεί λα απνθιεηζηεί όηαλ ππάξρεη θπζηνινγηθό ΤΤ.

Hemoclot Thrombin Inhibitor Assay Hemoclot : Tξνπνπνηεκέλε πνζνηηθή κέζνδνο ΣΣ εηδηθή θαη πνιύ επαίζζεηε γηα ην Pradaxa. Μπνξεί λα καο δώζεη πιεξνθνξίεο θαη γηα ηελ επαθξηβή ζπγθέληξσζε ηνπ ζην πιάζκα

Ecarin clotting time (ECT) Ο ρξόλνο εθαξίλεο είλαη ρξήζηκνο επίζεο γηα ηελ κέηξεζε ηνπ dabigtran

Effect of dabigatran on clotting tests in patients with AF Van Ryn et al Thromb Haemost 2010

Effect of dabigatran on clotting assays in patients with AF Pharmacodynamics of dabigatran following a single dose oral dose of 200 mg Distribution of patients according to mean trough aptt after oral administration of dabigatran etexilate twice daily Van Ryn et al Thromb Haemost 2010

Ηemoclot and Pradaxa

Dabigatran-Pradaxa The APTT can be used with most reagents for urgent determination of the relative intensity of anticoagulation due to dabigatran. The APTT cannot be used to determine the drug level. A normal TT means the level of dabigatran must be very low.

Rivaroxaban-Xarelto Monitoring

ΑPTT ζηελ παξαθνινύζεζε ηνπ Xarelto Σν ΑΡΣΣ δείρλεη επίζεο κία θακππιόγξακκε απάληεζε ζην rivaroxaban αιιά είλαη ιηγόηεξν επαίζζεηε ζε ρακειέο ζπγθεληξώζεηο θαξκάθνπ ζε ζύγθξηζε κε ην dabigatran. Σα απνηειέζκαηα APTT επεξεάδνληαη από ηνπο αλαιπηέο θαη ηα αληηδξαζηήξηα θαη κεξηθά αληηδξαζηήξηα δελ είλαη θαζόινπ επαίζζεηα κε απνηέιεζκα λα κεο εκθαλίδεηαη παξάηαζε ηνπ APTT αθόκε θαη ζε κέγηζηα επίπεδα (Hillarp et al, 2011).

ΡΣ ζηελ παξαθνινύζεζε ηνπ Xarelto Ο ρξόλνο πξνζξνκβίλεο (ΡΤ) είλαη πην θαηάιιεινο από ηνλ ΑΡΣΣ γηα ηελ εθηίκεζε ηεο έληαζεο ηεο αληηπεθηηθήο ζε αζζελείο πνπ ιακβάλνπλ rivaroxaban. Τπάξρεη κία γξακκηθή δνζνεμαξηώκελε- απάληεζε, κε κεγάιε κεηαβιεηόηεηα αλάινγα κε ην ρξεζηκνπνηεκέλν αληηδξαζηήξην. (Samama et al, 2010; Hillarp et al, 2011). Tν INR (International Normalized Ratio-International Sensitivity Index) δελ πξέπεη λα ρξεζηκνπνηείηαη ζηελ παξαθνινύζεζε ηνπ rivaroxaban.

Influence of rivaroxaban on prothrombin time

Thrombin time-δcarin time Xarelto To Rivaroxaban δελ έρεη θαλέλα απνηέιεζκα ζηνλ TT,ή ζην ΔCT.

Σπγθέληξσζε Rivaroxaban ζην πιάζκα Υξήζηκε ζεσξεηηθά Ηigh-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) ηελ πξάμε δύζθνια λα βξεζεί θαη ρξεηάδεηαη 2-4 εκέξεο γηα ηα απνηειέζκαηα.

Anti-factor Xa chromogenic assay for the measurement of rivaroxaban plasma concentrations using calibrators and controls Anti-factor Xa assays are sensitive to rivaroxaban. By using rivaroxaban calibrators and controls, the anti-factor Xa chromogenic method is suitable for measuring a wide range of rivaroxaban plasma concentrations (20 660 ng/ml), which covers the expected rivaroxaban plasma levels after therapeutic doses (Samama et al, 2010, 2012) (Samama et al, 2010, 2012; Asmis et al, 2012).

Global test for monitoring NATA Thrombin Generation Assays The Tail Thromboelastography [TE] and Rotational Elastometry [ROTEM]

Thrombin generation tests Οη θιαζηθέο δνθηκαζίεο κέηξεζεο ησλ ρξόλσλ ηεο πήμεο κεηξνύλ κόλν ηελ αξρηθή θάζε ηνπ ζρεκαηηζκνύ ηεο ζξνκβίλεο, ελώ δε ιακβάλνπλ ππόςε ην πνζό ηεο παξαγόκελεο ζξνκβίλεο θαη ην ρξόλν πνπ απηή παξακέλεη ελεξγνπνηεκέλε. Αθόκε θαη κεηά ην ζρεκαηηζκό ζξόκβνπ, πνιιέο από ηηο δξάζεηο ηεο ζξνκβίλεο κόιηο αξρίδνπλ. Σα ηεζη ηεο παξαγσγήο ζξνκβίλεο κεηξνύλ ηε ζπγθέληξσζε ηεο ζξνκβίλεο ζην πιάζκα πνπ είλαη ζε δηαδηθαζία πήμεο Αληηθαηνπηξίδνπλ ηε θπζηνινγηθή δηαδηθαζία ηνπ αηκνζηαηηθνύ κεραληζκνύ Μεηξνύλ ηόζν ηνλ ζξνκβσηηθό, όζν θαη αηκνξξαγηθό θίλδπλν

Thrombin Generation Assay Is Superior to Traditional Coagulometric and Chromogenic Assays to Monitor New Oral Anticoagulants François Mullier 1*, Jonathan Douxfils 2*, Christian Chatelain 3, Bernard Chatelain 4 and Jean-Michel Dogné 5* ASH 2012 Thrombin generation assay (TGA) which measures the entire thrombin generation process could be used to better discriminate the inhibitory profile of the NOACs in patients. OBJECTIVES: To study the impact of dabigatran and rivaroxaban in patients by thrombin generation assay compared to other traditional coagulometric and chromogenic assays. MATERIALS AND METHODS: Five patients under dabigatran and 5 patients under rivaroxaban for atrial fibrillation were included in this study. Conclusion: Thrombin generation assay could be superior to traditional coagulometric and chromogenic assays to monitor new oral anticoagulants in terms of prediction of bleeding or thrombosis risk.

Θξνκβνειαζηνγξαθία- (ΤΕG-ROTEM) Γεκηνπξγήζεθε πεξηζζόηεξν από 55 ρξόληα πξηλ, αιιά ε αμία ηνπ ζηελ κειέηε ηεο in vivo αηκόζηαζεο κόιηο πξόζθαηα έγηλε γεληθά παξαδεθηή Η θιαζηθή ζξνκβνειαζηνγξαθία παξαθνινπζεί θαη θαηαγξάθεη ηνλ ξπζκό ζρεκαηηζκνύ θαη ηελ πνηόηεηα ηεο δεκηνπξγίαο ηνπ ζξόκβνπ, ρξεζηκνπνηώληαο νιηθό αίκα ζε αληηπεθηηθό Έρεη πνιιά πιενλεθηήκαηα όπσο όηη είλαη ζρεηηθά γξήγνξε <30 ιεπηά θνξεηή ζπζθεπή δίλεη πνιιέο πιεξνθνξίεο ζρεηηθά κε ηε δεκηνπξγία θαη ηε ιύζε ηνπ ζξόκβνπ θαη γηα νιόθιεξε ηελ αηκόζηαζε, από ηα αξρηθά ζηάδηα, ηα αηκνπεηάιηα, ηελ πήμε έσο θαη ηελ ηλσδόιπζε

Δίδε ζξνκβνειαζηνγξάθνπ TEG, ROTEM δηαθέξνπλ κόλν ζην πην κέινο ηνπ κεραλήκαηνο πεξηζηξέθεηαη

TEG Απνηειέζκαηα-Κιηληθή ζεκαζία

Influence of Rivaroxabanfondaparinux and dabigatran on TF-triggered whole bloodt hromboelastometry Rivaroxaban Dabigatran

http://www.thrombosis.gr Γ. Γεροηδηάθας, Αλ. θαζεγεηής Αηκαηοιογίας Παλεπηζηεκίοσ Pierre et Marie Curie (Paris VI)

Part III New drugs, new problems 1. 2. 3. Surgery Bridging with anti-vitamin K, LMWH Antidote? Management of bleeding

Xarelto

Interrupting rivaroxaban for interventions with a bleeding risk Rivaroxaban: A Practical Guide 6/7/2012, Belgium *Thromboprophylaxis with rivaroxaban low dose (10mg OD) only recommended in case of THR and TKR surgery.

How to switch from VKA to rivaroxaban? Rivaroxaban: A Practical Guide 6/7/2012, Belgium

How to switch from LMWH to rivaroxaban? Rivaroxaban: A Practical Guide 6/7/2012, Belgium

Αληηκεηώπηζε αηκνξξαγίαο από ηα ΝΑΤΑ

Αηκνζηαηηθά παξάγσγα ζηελ Αληηκεηώπηζε ηεο αηκνξξαγίαο Hemostatic agent Recommendations PCC: 4 factor concentrate PPSB S.D. (flacon 20 ml - FIX 400IE) Confidex (flacon 20 ml - FIX 500IE) Octaplex (flacon 20 ml - FIX 400 à 620IE), BERIPLEX CSL-Boehring Desmopressin Minirin Amp (4 κg/ml) for iv. use Tranexamic Acid Transamin The administration of Prothrombin Complex Concentrate (PCC) is suggested in case of life-threatening bleeding. After an initial administration of 25U/kg of the available PCC we recommend to clinically re-evaluate the need for a repeat administration of PCCs*. Desmopressin can be considered in case of associated coagulopathy or thrombopathy**. A standard dose scheme for bleeding disorders is 0,03 κg/kg with a maximum of 20 κg. Tranexamic acid associated to direct anti-xa (antithrombinindependent) oral anticoagulants was effective in reducing postoperative blood loss, improving hemoglobinemia at 5 days and reducing transfusion rates.21 apcc: activated prothrombin concentrate (Feiba S-Tim 4 ) This writing group does not recommend the use of Feiba S- Tim 4 for life-threatening bleedings in patients treated with rivaroxaban. Recombinant human FVIIa (Novoseven ) There is no clinical experience with rhfviia in rivaroxaban treated subjects. Due to the short half-life of rhfviia, a repeat dose may be needed. This writing group does not recommend the use of Novoseven for life-threatening bleedings in patients treated with rivaroxaban.

Thrombosis &Haemostasis 2010

Πξνζνρή! ε αζζελείο πνπ ιακβάλνπλ Pradaxa ε ηηκή ηνπ ηλσδνγόλνπ κπνξεί λα είλαη ςεπδώο ρακειή. ε ζπλδπαζκό κε ηελ παξάηαζε ηνπ ΑΡΣΣ, κπνξεί λα δηαγλσζηεί σο ΓΔΠ. Γηαθνξά: Σα ΝΑΣΑ δελ επεξεάδνπλ ηα d-dimers!

Αληηκεηώπηζε αηκνξξαγίαο από Xarelto Rivaroxaban: A Practical Guide 6/7/2012, Belgium

Μέιινλ Άιινη ζηόρνη- Λνηπέο θαηεγνξίεο ΝΑΤΑ ππό αλαπηπμε Ultra-low-molecular-weight heparins (semuloparin ) Vitamin K antagonists (Tecarfarin) Factor (TF) VIIa complex (Nematode anticoagulant proteins) Factors V and VIII Factor IXa Oral: oral direct Factor IXa inhibitor, TTP889 Intravenous and subcutaneous formulations of an aptamerbased Factor IXa inhibitor

πκπεξαζκαηηθά Tα λεώηεξα αληηπεθηηθά θάξκαθα είλαη κία από ηηο κεγαιύηεξεο αλαθαιύςεηο ηνπ αηώλα καο. Πξηλ ηα ζπληαγνγξαθήζνπκε πξέπεη λα μέξνπκε πώο λα ηα παξαθνινπζήζνπκε θαη πώο λα ηα δηαρεηξηζηνύκε. Κάζε εξγαζηήξην πξέπεη λα είλαη ελήκεξν ηεο επαηζζεζίαο ηνπ αληηδξαζηεξίνπ PT θαη APTT πνπ ρξεζηκνπνηεί ζην dabigataran θαη ζην rivaroxaban.

Pharmacokinetics Prodrug Rapid absorption Time to peak: 1-2 hours Half-Life: 12-17 hours Longer in renal impairment Monitoring: aptt Qualitative not Quantitative TT (Thrombin Time) Linear dose relationship Not as readily available -Haemoclot -Global assays (Thrombin generation, TEG, ROTEM) Dabigatran, Package Insert

Pradaxa

Σύλνςε Xarelto- Pharmacokinetics and Monitoring Pharmacodynamics Peak 2.5-4 hours Half Life: 3.2 22 hours Metabolized via CYP3A4 Monitoring PT More sensitive Varies with different reagents Cannot be standardized aptt Anti-Xa Modified Anti-Xa being developed Global assays (Thrombin generation, TEG, ROTEM) Br J Clin Pharmacol. 2011 Oct;72(4):593-603 Thromb Haemost. 2010 Apr;103(4):815-25

Summary- NATA Effects on PT Dabigatran Causes PT/INR elevations False elevations of INR have been reported Relatively insensitive and variable We do not yet know what INR elevations mean in relation to levels of anticoagulation with Dabigatran Has not proven useful in hemorrhagic emergencies Rivaroxaban Prolongs PT in a concentration dependent fashion Only has a weak effect at therapeutic concentrations, more profound at higher concentrations Converting to INR appears to increase variability of results May be useful in hemorrhagic emergencies Apixaban Prolongs PT in a concentration dependent fashion Converting to INR appears to increase variability of results May be useful in hemorrhagic emergencies

Summary- NATA Effects on aptt Dabigatran aptt more sensitive and less variable than PT Supratherapeutic doses prolog aptt in (curvi) linear fashion -Response curve may flatten at very high concentrations No relationship established yet with outcomes Could be useful in hemorrhagic emergency Rivaroxaban Concentration dependent prolongation Minimal variability between reagents PT appears to be more sensitive compared to aptt Less useful than aptt in hemorrhagic emergency Apixaban Prolongs aptt in dose dependent manner High degree of variability between reagents PT is much more sensitive than aptt Less useful than aptt in hemorrhagic emergency

Low dose acetylsalicylic acid to rivaroxaban Considering the increased bleeding risk with combined therapy of acetylsalicylic acid (ASA) and rivaroxaban, the need for concomitant low-dose ASA after initiating rivaroxaban needs to be carefully evaluated. In the absence of a specific indication for continuing ASA, ASA should no longer be administered after initiating rivaroxaban

How to switch from rivaroxaban to VKA? Rivaroxaban: A Practical Guide 6/7/2012, Belgium

How to switch from rivaroxaban to LMWH? Rivaroxaban: A Practical Guide 6/7/2012, Belgium

How to switch from rivaroxaban to intravenous UFH? Rivaroxaban: A Practical Guide 6/7/2012, Belgium

How to switch from rivaroxaban to dabigatran? Rivaroxaban: A Practical Guide 6/7/2012, Belgium

How to switch from dabigatran to rivaroxaban based on patient s renal function? Rivaroxaban: A Practical Guide 6/7/2012, Belgium Caution is advised when considering a treatment switch from dabigatran to rivaroxaban 15 mg od for patients with severe renal impairment (15-29ml/min CrCL)

Acetylsalicylic acid and NATA Considering the increased bleeding risk with combined therapy of acetylsalicylic acid (ASA) and NATA, the need for concomitant low-dose ASA after initiating rivaroxaban needs to be carefully evaluated. In the absence of a specific indication for continuing ASA, ASA should no longer be administered after initiating NATA.

Standard coagulation test Impact of rivaroxaban PT aptt PT-based coagulation factors (II, V, VII, X) Time prolonged ++ (may vary depending on the reagents used) Time prolonged + Limited decrease- aptt-based coagulation factors (VIII, IX, XI) Limited decrease - POC test for INR measurement aptt Thrombin Generation Assay Activated Clotting Time Thrombo-elastogram Fibrinogen (Clauss method) D-Dimer Thrombin time Ecarin clotting time Not influenced Lupus anticoagulants (DRVVT) Antithrombin anti-xa based Antithrombin anti-iia based Unpredictable Decreased/Influenced (depending on the parameter used) Unpredictable In vitro data only, all parameters influenced (R, K, Angle, MA) Not influenced Not influenced Not influenced Not influenced False positive results expected Increase with appr.10%/100κg/l rivaroxaban Not affected

Θξνκβνειαζηνγξαθία- ΤΕG Εθαξκνγέο πνιπάξηζκεο όπσο: πξόβιεςε ηεο αηκνξξαγίαο θαηά ηε δηάξθεηα ηνπ ρεηξνπξγείνπ, βνεζώληαο κε ηνλ ηξόπν απηό πνιύ ζηελ νξζή ρξεζηκνπνίεζε ησλ παξαγώγσλ αίκαηνο παξαθνινύζεζε ηεο ζεξαπείαο κε αλαζπλδπαζέλν FVIIa παξαθνινύζεζε ηεο αληηαηκνπεηαιηαθήο ζεξαπείαο παξαθνινύζεζε ηεο ιεηηνπξγίαο ησλ αηκνπεηαιίσλ παξαθνινύζεζε ηεο ηλσδόιπζεο α. TEG β. ROTEM

What in case of an overdose with Xarelto without bleeding? Due to limited absorption of rivaroxaban at higher concentrations, a ceiling effect with no further increase in average plasma exposure is expected at supra-therapeutic doses of 50 mg rivaroxaban and above. The use of activated charcoal to reduce the absorption in case of a rivaroxaban overdose can be considered within the first 2 to 4 hours after intake. We propose to use in this case a suspension of 20g active charcoal / 240 ml H20, with a standard dosing scheme for adults of 30 to 50 g. Coagulation tests may help to estimate the plasma levels of rivaroxaban

Cardioversion in a rivaroxaban treated patient Anticoagulation should be maintained for at least 4 weeks after successful cardioversion, regardless of the baseline risk of stroke. Beyond 4 weeks, decisions on anticoagulation should be made in accordance with CHADS2 and CHA2DS2-VASC. For patients with AF of duration of 48h or less undergoing electrical or pharmacological cardioversion, anticoagulation should be started at presentation and maintained for at least 4 weeks after successful cardioversion. A similar scheme can be proposed for rivaroxaban but a TEE-based strategy, with exclusion of intra-cardiac thrombi immediately before cardioversion, ican be considered given absence of data and limited experience. Switching to appropriate treatment with VKA can be an alternative, until further prospective safety and efficacy data become available.

Oral Factor Xa inhibitor Not yet approved, no indications Apixaban awaiting FDA review Approval expected Apixaban reduced occurrence of stroke and systemic embolism compared to warfarin Apixaban associated with lower risk of bleeding compared to warfarin Dosing: 5 mg twice daily 2.5 mg twice daily with two of the following: Age > 80 years Weight < 60 kg SCr > 1.5 mg/dl

Acetylsalicylic acid and NATA Considering the increased bleeding risk with combined therapy of acetylsalicylic acid (ASA) and NATA, the need for concomitant low-dose ASA after initiating rivaroxaban needs to be carefully evaluated. In the absence of a specific indication for continuing ASA, ASA should no longer be administered after initiating NATA.

Which is the Best Target? Factor Xa Strategically located at junction of extrinsic and intrinsic pathway Gatekeeper of thrombin generation No effect on thrombin-mediated hemostatic mechanisms Few functions outside of coagulation Thrombin Final effector in coagulation Directly drives fibrin formation Induces feedback amplification of coagulation Potent platelet agonist

Rivaroxaban (Xarelto, Bayer)

Xarelto : pharmacodynamique Accumulation si : inhibiteur CYP3A4 (CI : ketoconazole, ritonavir ) grand âge, insuffisance rénale sévère, atteinte hépatique Absorption accrue si prise alimentaire concomitante Pas d interférence : inhibiteurs anti-acides aspirine et AINS digoxine amiodarone

Pradaxa-Pharmacokinetics Rapid absorpion Time to peak: 1-2 hours Prodrug 35% bound to plasma proteins Bioavailability: 6.5-7.2% Half-life of 12-17 hours. Longer in renal impairment Excreted predominantly in the feces. Elimination of dabigatran after hepatic activation occurs predominantly (up to 80%) in the kidneys: dose reduction in the setting of moderate renal dysfunction, and recommend against use with severe renal dysfunction.