NEW ORAL. François Mullier, Jonathan Douxfils, Anne Spinewine, Bernard Chatelain, Christian Chatelain, Jean-Michel Dogné. CORATA June 9 th, 2011

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1 NEW ORAL ANTICOAGULANTS François Mullier, Jonathan Douxfils, Anne Spinewine, Bernard Chatelain, Christian Chatelain, Jean-Michel Dogné CORATA June 9 th, 2011

2 Content Introduction - Overview of blood coagulation - Targets for anticoagulation - Disadvantages and limits of current anticoagulants - «Ideal» new anticoagulant - Potential indications of two new oral anticoagulants dabigatran and rivaroxaban Focus on the development of Dabigatran (Pradaxa ) - Pharmacology: Pharmacodynamic and pharmacokinetic profile - Studies and approved indications - Other studies - Monitoring - Why? Situations at risk? - When? - How? What about Rivaroxaban (Xarelto ) Conclusions

3 Cell-based model of coagulation AG Turpie; C Esmon. Thromb Haemost 2011; 105:

4 Targets for anticoagulation AG Turpie; C Esmon. Thromb Haemost 2011; 105:

5 Main disadvantages of current anticoagulants Heparin and its derivatives, as well as fondaparinux, must be administered parentally, making self administration both challenging and less desirable. Unfractionated heparin and, to a lesser extent, the LMWH can cause heparin induced thrombocytopenia (HIT).

6 Main disadvantages of current anticoagulants Many patients do not receive satisfactory anticoagulant therapy or stop it too early. Medical need: ideal anticoagulant

7 Properties of «ideal» anticoagulant Proven efficacy (non inferior to current anticoagulant therapy) Oral administration No requirement for routine blood monitoring and dose adjustment Wide therapeutic window Rapid onset of action Predictable pharmacokinetics and pharmacodynamics (good oral availability) Minimal interaction with food and other drugs Ability to inhibit and clot-bound coagulation factors Low non-specific binding Reversibility Availability of an antidote No unexpected toxicities (low bleeding risk, no hepatic toxicity) Acceptable costs Adapted from T. Mavrakanas, H. Bounameaux / Pharmacology & Therapeutics 2011 and J.Steffel and E.Braunwald European Heart Journal March 2011

8 I.Ahrens et al.thromb Haemost 2010; 104: 49 60

9 New anticoagulant agents Dabigatran etexilate Rivaroxaban 9

10 Indications of new oral anticoagulants Prevention of venous thromboembolism -Total hip/knee replacements - Medical ill patients Prevention of stroke and systemic embolism in adult patients with nonvalvular atrial fibrillation Treatment of venous thromboembolism Acute coronary syndrome

11 Content Introduction - Overview of blood coagulation - Targets for anticoagulation - Disadvantages and limits of current anticoagulants - «Ideal» new anticoagulant - Potential indications of two new oral anticoagulants dabigatran and rivaroxaban Focus on the development of Dabigatran (Pradaxa ) - Pharmacology: Pharmacodynamic and pharmacokinetic profile - Studies and approved indications - Other studies - Monitoring - Why? Situations at risk? - When? - How? What about Rivaroxaban (Xarelto ) Conclusions

12 Pharmacology - Pharmacodynamic Primary pharmacodynamic Synthetic, non-peptide, competitive, rapidly acting and reversible inhibitor of active site of thrombin. Inhibits Free thrombin (Ki of 4.5 nm) Fibrin bound thrombin (observed in a blood clot) Thrombin induced platelet aggregation Secondary pharmacodynamic low affinity (Ki>3.5 µm) towards the serine proteases factor Xa, factor XIa, factor VIIa/tissue factor complex, plasma kallikrein, plasmin, urokinase, tissue-type plasminogen activator, activated protein C, granulocyte elastase and C1 esterase. inhibits trypsin with a Ki of 50.3 nm,

13 Pharmacology - Pharmacodynamic Multiple actions of thrombin JTB Crawley et al.. J Thromb Haemost 2007; 5 (Suppl.1):

14 Pharmacology - PK Doubts about the non requirement of «drug monitoring» H 3 C O O Oral prodrug N N O CH 3 N N HN O NH 2 N O CH 3 PRADAXA = Dabigatran etexilate Gastrointestinal absorption HO O Active metabolite in plasma N N O CH 3 N N HN NH 2 NH Dabigatran

15 Pharmacology - PK Low with a very large interindividual variability of PK parameters (Cmax, AUC). the interindividual variability of Cmax and AUC expressed as CV was high i.e. approximately 80%. In healthy volunteers the intraindividual variability was close to 30%. E Nutescu et al. ; J Thromb Thrombolysis 2011; 31:

16 Pharmacology - PK Low with a very large interindividual variability of PK parameters (Cmax, AUC). Risks of underdosage (thrombosis) or overdosage (bleeding) E Nutescu et al. ; J Thromb Thrombolysis 2011; 31: Importance of monitoring and individual follow-up

17 Pharmacology - PK E Nutescu et al. ; J Thromb Thrombolysis 2011; 31: moderate renal insufficiency (CrCL between ml/min): 2.7-fold AUC increase Pradaxa should be used with caution A close clinical surveillance (looking for signs of bleeding or anemia) recommended dose is 150 mg taken once daily as 2 capsules of 75 mg (in stead of 220 mg: 2x110mg)

18 Pharmacology - PK Severe renal deficiency (CrCL between ml/min): 6-fold AUC increase => CONTRA-INDICATED E Nutescu et al. ; J Thromb Thrombolysis 2011; 31:

19 Pharmacology - PK Plasma concentrations of dabigatran might be elevated when co-administered with strong P-gp inhibitors: verapamil, amiodarone. This may increase the risk of bleeding and these patients should be closely Clinically monitored (looking for signs of bleeding and anaemia) E Nutescu et al. ; J Thromb Thrombolysis 2011; 31:

20 Pharmacology - PK P- glycoprotein inhibitors: Caution should be exercised with strong P- glycoprotein inhibitors. The P- glycoprotein inhibitor quinidine is contraindicated. P- glycoprotein inducers: Potent P- glycoprotein inducers such as rifampicin or St John s wort (Hypericum perforatum), may reduce the systemic exposure of dabigatran. Caution is advised when coadministering these medicinal products.

21 E Nutescu et al. ; J Thromb Thrombolysis 2011; 31:

22 Studies and approved 18/03/2008 indications (EMA) Prevention of Venous Thromboembolism (VTE) in patients following elective knee or hip replacement surgery

23 Studies and approved indications (EMA) Total arthroplasty Three phase III studies were conducted. All were randomised, double-blind, parallel group. All phase III studies were non-inferiority studies. T. Galanis et al. J Thromb Thrombolysis 2011; 31: 310:320

24 Studies and approved indications (EMA) Total arthroplasty T. Galanis et al. J Thromb Thrombolysis 2011; 31: 310:320 -The proposed therapeutic doses (150 or 220 mg q.d.) were found to be non-inferior to enoxaparin in terms of efficacy in the pivotal studies. -There is a trend to higher efficacy of DAB 220mg compared with enoxaparin, associated with an increased bleeding risk. - On the opposite, with DAB 150mg, there is a trend to lower efficacy compared with enoxaparin, associated with a lower bleeding risk risk, which might be useful for some at risk populations (patients with moderate renal impairment, elderly) which have increased DAB exposure.

25 Studies and approved indications (EMA) Total arthroplasty Bleeding Risks -The safety data was based on 7942 subjects who received at least one dose of DE, 6976 of these in the VTE prevention trials. -For any bleeding event, there was no statistical difference between DE 150 mg and enoxaparin and between DE 220 mg and enoxaparin. -A clear dose response with respect to bleeding was seen for DAB.

26 Studies and approved indications (EMA) Total arthroplasty Conclusions of Prevention of VTE in THR (10d) and TKR (35d) -Non inferior efficacity -Same risk of bleeding compared to the LMWH -No hepatoxicity, no increased ACS - Start first dose 1-4 hour after surgery mg/day or 150 mg/day if Renal impairment (Creat Cl 30-50ml/min) Amiodarone (P-gp inhibitor), Old patients (>75y)

27 Studies and approved 14 April 2011 indications (EMA) CHMP adopted the new indication as follows: Prevention of stroke and systemic embolism in adult patients with nonvalvular atrial fibrillation with one or more of the following risk factors: Previous stroke, transient ischemic attack, or systemic embolism (SEE) Left ventricular ejection fraction < 40 % Symptomatic heart failure, New York Heart Association (NYHA) Class 2 Age 75 years Age 65 years associated with one of the following: diabetes mellitus, coronary artery disease, or hypertension

28 Studies and approved Atrial fibrillation indications (EMA) PETRO Study: Ezekowitz M. et al, Dabigatran With or Without Concomitant Aspirin Compared with Warfarin Alone in Patients with Nonvalvular Atrial Fibrillation (PETRO Study). Am J Cardiol, 2007, 100, RE-LY study: Connolly S.J. et al, Dabigatran versus Warfarin in Patients with Atrial Fibrillation. N Engl J Med, 2009, 361,

29 Studies and approved indications (EMA) Atrial fibrillation RE-LY study N = patients at risk of stroke Noninferiority trial Fixed doses of dabigatran-110 mg twice daily blinded Fixed doses of dabigatran 150 mg twice daily Adjusted-dose warfarin (INR ). The median duration of the follow-up period was 2.0 years. The primary outcome was stroke or systemic embolism. unblinded

30 Studies and approved indications (EMA) Atrial fibrillation RE-LY study T. Galanis et al. J Thromb Thrombolysis 2011; 31: 310:320

31 Studies and approved Atrial fibrillation RE-LY study indications (EMA) Dabigatran given at a dose of 110 mg was associated with rates of stroke and systemic embolism that were similar to those associated with warfarin, as well as lower rates of major hemorrhage. Dabigatran administered at a dose of 150 mg, as compared with warfarin, was associated with lower rates of stroke and systemic embolism but similar rates of major hemorrhage.

32 Other studies J.Steffel and E.Braunwald European Heart Journal March 2011

33 Monitoring Situations requiring a biological monitoring Who said no monitoring? Biological monitoring or clinical monitoring? How to monitor?

34 Situations requiring a biological monitoring PK and PD data showing a high variability Narrow therapeutic window Drug interactions Compliance Particular clinical situations (elderly, hepatic disorders, renal disorders) Off label use Abuse or misuse Dabigatran

35 Situations requiring a biological monitoring Interest of biological monitoring of dabigatran Risk of overdose Bleedings Risk of underdose Lack of effectiveness!!! Thrombosis

36 Situations requiring a biological monitoring Interest of biological monitoring of dabigatran Clinical trials Safe and protected environment Real world Monitoring not necessary

37 Situations requiring a biological monitoring Interest of biological monitoring of dabigatran Clinical trials Safe and protected environment Real world Monitoring not necessary Monitoring to minimize the risks of bleedings and identify non responders (lack of effectiveness)

38 Who said no monitoring? EMA public assessment report: Pradaxa in the prevention of Venous Thromboembolism (VTE) in patients following elective knee or hip replacement surgery Conclusion on balance benefit-risk in the indication It is important to underline that the PK characteristics of DAB i.e low bioavailability (6.5%) with a very large interindividual variability, the concentration-effect relationship and the bleeding risks strongly suggest that drug monitoring is needed. Based on the above balance the benefits associated with the proposed use of DE are considered to outweigh the risks.

39 Who said no monitoring? EMA public assessment report: Pradaxa in the prevention of Venous Thromboembolism (VTE) in patients following elective knee or hip replacement surgery Follow-up measure The possibility of drug monitoring would be valuable, especially for these patients at risk and commercially available TT test kits will be developed for measurement of TT following administration of DTIs. A cross-validation of chronometric TT measurements at local laboratories will be performed as part of the FUM. Commercially available TT test kits developed for measurement of TT following administration of DTIs (i.e. hirudin) will be validated for measurement of TT of DAB.

40 Biological monitoring or clinical monitoring? Summary of characteristics of the Product No references about «biological» monitoring But references to «clinical monitoring» «monitoring» «Caution»

41 Biological monitoring or clinical monitoring? Summary of characteristics of the Product «clinical monitoring», «caution» With strong P-gp inhibitors (e.g. verapamil, amiodarone). This may increase the risk of bleeding and these patients should be closely clinically monitored (looking for signs of bleeding and anaemia). Patients with moderate renal impairment have an increased exposure to dabigatran. Limited data is available in patients < 50 kg and the elderly (see sections 4.2 and 5.2). In these situations, Pradaxa should be used with caution and a close clinical surveillance (looking for signs of bleeding or anemia) is required throughout the treatment period.

42 Biological monitoring or clinical monitoring? Summary of characteristics of the Product «close monitoring» A close monitoring should be exercised when dabigatran etexilate is combined with clarithromycine.

43 How to monitor? APTT: Activated Partial Thromboplastin Time PT: Prothrombin Time dpt:dilute Prothrombin Time TT: Thrombin Time PiCT: Prothrombinase induced Clotting Time ECT: Ecarin Clotting Time ECA-T: Ecarin Chromogen Assay ACT: Activated Clotting Time Hemoclot Thrombin Inhibitor assay (Hyphen BioMed) HepTest antixa chromogenic assays (StaChrom and Rotachrom/ Liquid anti Xa) Thrombin Generation test (TGT) Thromboelastogram (TEG) 43

44 aptt Van Ryn TH 2010 aptt (ratio) CK prest (sta) Cephascreen (sta) Actin FS (BCS) PTTA (STA) Synthasil (ACLTOP) Influence of dabigatran on aptt [dabigatran] µg/ml -A curvilinear relationship -Sensibility at therapeutic concentrations? (50-200/400 ng/ml) -Variability among reagents => qualitative indication of anticoagulant activity, but it may not be suitable for the precise quantification of anticoagulant effect 44

45 PT expressed as INR Van Ryn TH Linear relationship between plasma concentration and INR (<2.0) -BUT: modest INR increase at supratherapeutic doses =>low sensibility! => high variability! => INR is not considered a suitable tool for monitoring the anticoagulanteffects of DE 45

46 Ecaring Clotting Time (ECT) Not of current practice in clinical laboratories Specific assay for thrombin generation. The activator of the assay, ecarin, is a snake venom that specifically activates prothrombin resulting in the generation of meizothrombin, an unstable precursor of thrombin. As DTIs are able to inhibit the thrombin-like activity of meizothrombin, the ECT test provides a direct measure of the activity of DTIs. Reagent : Ecarin 50UI/vial 46

47 Ecaring Clotting Time (ECT) Van Ryn TH Linear relationship with drug plasma concentrations over the full range of Concentrations -Did not plateau at higher concentrations -more sensitive to DAB than aptt -BUT: -Not standardized! -Not current practice ECT may provide a more accurate measurement of DAB anticoagulation than the other PD parameters. Routine use not recommended 47

48 Thrombin time (TT) Van Ryn TH linear relationship with plasma concentration with a high level of sensitivity. -BUT: 1. too sensitive to DAB plasma concentrations in the clinically relevant plasma concentration range. 2. At DAB concentrations greater than 600 ng/ml, the TT frequently exceeded the maximum measurement time of the coagulometer 3. Reagents used for determining TT at different laboratories are not standardized. TT assay is only presented as a sensitive method for determining if any DAB is present. Should be adapted : Hemoclot 48

49 Hemoclot TT assay Not of current practice in clinical laboratories Sensitive diluted TT assay which allows for quantitative measurement of DTI activity in plasma, based on inhibition of a constant and defined concentration of thrombin. Diluted test plasma (1:8 to 1:20) is mixed with normal pooled human plasma clotting is then initiated by adding a constant amount of highly purified humanα-thrombin. Calibrators and controls available since december

50 Hemoclot TT assay Van Ryn TH 2010 Clinical practice needed 50

51 Thrombin generation Cmax (nm) Lagtime (min) Adaptation of S. Robert Focus conference november 17th

52 Thrombin generation Dabigatran: 10 nm nm nm 50 nm 100 nm 250 nm 500 nm 750 nm 1000 nm nm 10 nm 50 nm 100 nm 250 nm 500 nm 750 nm 1000 nm nm 10 nm 50 nm 100 nm 250 nm 500 nm 750 nm TF pathway induced active thrombin concentration (nm) TF and contact pathways induced active thrombin concentration (nm) Contact pathway induced active thrombin concentration (nm) Time (min) Time (min) Time (min) Dabigatran mainly delayed the initiation phase Strong dose-dependent increase of lag time and Tmax Slight dose-dependent decrease of Cmax and ETP Difficult to use in routine Should be standardized 52

53 Which test in clinical practice? Dabigatran Rivaroxaban Non-specific - ECT - PT test - Dilute TT - Thrombin generation test - Thrombin generation test Specific test Anti-IIa activity Anti-Xa activity

54 Content Introduction - Overview of blood coagulation - Targets for anticoagulation - Disadvantages and limits of current anticoagulants - «Ideal» new anticoagulant - Potential indications of two new oral anticoagulants dabigatran and rivaroxaban Focus on the deveolpment of Dabigatran (Pradaxa ) - Pharmacology: Pharmacodynamic and pharmacokinetic profile - Studies and approved indications - Other studies - Monitoring - Why? Situations at risk? - When? - How? What about Rivaroxaban (Xarelto ) Conclusions

55 Drug interactions: rivaroxaban E Nutescu et al. ; J Thromb Thrombolysis 2011; 31:

56 Drug monitoring required? (EMA, CHMP) Interest Who? Dabigatran etexilate CHMP: EMEA/174363/2008: low bioavailability+ high interindividual variability drug monitoring needed - Situations that may increase the hemorrhagic risk - Coadministration of strong P-gp inhibitors (e.g. verapamil, amiodarone). - Moderate renal impairment have an increased exposure to dabigatran. Limited data is available in patients < 50 kg and the elderly Rivaroxaban SmPC=signs of bleeding complications after initiation of treatment (regular physical examination of the patients, close observation of the surgical wound drainage and periodic measurements of haemoglobin) Any unexplained fall in haemoglobin or blood pressure should lead to a search for a bleeding site. enough? - severe renal impairment (creatinine clearance < 30 ml/min) -In cirrhotic patients with moderate hepatic impairment (classified as Child Pugh B), - strong inhibitors of CYP3A4 and P-gp :azole-antimycotics (such as ketoconazole, itraconazole, voriconazole and posaconazole) or HIV protease inhibitors (e.g. ritonavir).

57 Which test in clinical practice? Dabigatran Rivaroxaban Non-specific - ECT - PT test - Dilute TT - Thrombin generation test - Thrombin generation test Specific test Anti-IIa activity Anti-Xa activity

58 Conclusions New oral anticoagulants: potential role to play a significant role in a wide range of clinical settings. Developed with the intent not to require monitoring due to their predictable pharmacologic effects. However this will be (is?) required in some specific settings (liver, kidney, drug interactions, compliance, bleeding, recurrence). Monitoring to minimize the risks for both overdosage and underdosage. 58

59 Back up slides

60 Invasive procedures and management of bleedings JW. Eikelboom, JI. Weitz. BMJ 2011;342:

61 Management of bleedings on dabigatran Van Ryn et al. Dabigatran etexilate a novel, reversible, oral direct thrombin inhibitor: Interpretation of coagulation assays and reversal of anticoagulant activity.thromb.haemost 2010; 104: 49 60

62 Management of bleedings on dabigatran Van Ryn et al. Dabigatran etexilate a novel, reversible, oral direct thrombin inhibitor: Interpretation of coagulation assays and reversal of anticoagulant activity.thromb.haemost 2010; 104: 49 60