New anticoagulants Focus on dabigatran and rivaroxaban

Transcription

1 New anticoagulants Focus on dabigatran and rivaroxaban Jean-Michel Dogné, Jonathan Douxfils, Anne Spinewine, Christian Chatelain, Bernard Chatelain, François Mullier. February,

2 Commonly used anticoagulants Parenteral anticoagulants Unfractionated heparin Low molecular weight heparins Indirect Factor Xa inhibitor (fondaparinux( fondaparinux) Oral anticoagulants Vitamin K antagonists Geerts WH et al. Chest 2008;133:381S 453S 2

3 Traditional anticoagulants: drawbacks UFH 1 Parenteral administration Monitoring and dose adjustment required Risk of HIT LMWH 1 Parenteral administration Weight-adjusted dosing Oral VKAs 2 Narrow therapeutic window Interaction with food and drugs Frequent monitoring and dose adjustment required 1. Hirsh J et al. Chest 2008;133;141S 159S; 2. Ansell J et al. Chest 2008;133;160S 198S 3

4 (R)evolution in anticoagulant therapy AG Turpie; C Esmon. Thromb Haemost 2011; 105:

5 Main disadvantages of current anticoagulants Many patients do not receive satisfactory anticoagulant therapy or stop it too early. Medical need: ideal anticoagulant 5

6 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

7 Potential 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 7

8 The promise of new oral anticoagulants Simplified dosing regimen No dietary restrictions Predictable anticoagulation and no need for routine coagulation monitoring Can be given at fixed doses Reduced potential for food and drug interactions Less labour-intensive Less impact on patients daily life Improved compliance Reduced administrative costs Improved quality of life Improved efficacy and safety 1. Raghaven N et al. Drugs Metab Dispos 2009;37:74 81; 2. Shantsila E & Lip GY. Curr Opin Investig Drugs 2008;9: ; 3. Mueck W et al. Clin Pharmacokinet 2008;47: ; 4. Mueck W et al. Thromb Haemost 2008;100: ; 5. Mueck W et al. Int J Clin Pharmacol Ther 2007;45:

9 I.Ahrens et al.thromb Haemost 2010; 104:

10 First new anticoagulant agents Dabigatran etexilate Rivaroxaban 10

11 First new anticoagulant agents Dabigatran etexilate Rivaroxaban Pradaxa Xarelto Competitive, reversible direct thrombin inhibitor EMA authorized: 18/03/2008 Highly selective direct factor Xa inhibitor EMA authorized: 30/09/

12 Rivaroxaban: : total arthroplasty T. Galanis et al. J Thromb Thrombolysis 2011; 31: 310:320 12

13 Dabigatran: : total arthroplasty T. Galanis et al. J Thromb Thrombolysis 2011; 31: 310:320 13

14 Dabigatran: : total arthroplasty -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. T. Galanis et al. J Thromb Thrombolysis 2011; 31: 310:320 14

15 Knee replacement surgery Rivaroxaban Hip replacement surgery 10 mg rivaroxaban taken orally once daily. The initial dose should be taken 6 to 10 hours after surgery a treatment duration of 2 a treatment duration of 5 weeks is recommended weeks is recommended 15

16 Dabigatran Knee replacement surgery Hip replacement surgery 220 mg once daily taken as 2 capsules of 110 mg Treatment should be initiated orally within 1 4 hours of completed surgery with a single capsule and continuing with 2 capsules once continuing with 2 capsules daily thereafter for once daily thereafter for a total of 10 days a total of days 16

17 OACs and other indications VTEx PE Pulmonary embolism (PE) 500,000 deaths per year in Europe Ischemic Stroke 15% due to atrial fibrillation SPAF Deep venous thrombosis (DVT) 1 event every 12 seconds DVT VTEp Elective hip replacement surgery DVT risk: 42 57% Elective knee replacement surgery DVT risk: 41 85% Unstable angina and myocardial infarction 1 death every 17 seconds ACS 17

18 OACs in AF New OACs approved or in phase III clinical development for stroke prevention in AF Direct thrombin inhibitors: Ximelagatran (withdrawn): SPORTIF III (complete) + V (complete) Dabigatran: : RE-LY (complete) Direct Factor Xa inhibitors: Apixaban: : AVERROES (complete), ARISTOTLE (complete) Edoxaban: : ENGAGE AF-TIMI 48 (ongoing) Rivaroxaban: : ROCKET AF (complete) 18

19 Non-valvular atrial fibrillation Atrial fibrillation is the most common sustained cardiac rhythm disorder and affects more than 6 million people in Europe. People with AF are at a five-fold fold increased risk for stroke compared with the general population, and about one-third of them will suffer a stroke. 19

20 Rivaroxaban: : Non-valvular atrial fibrillation The approval of rivaroxaban for the prevention of AF-related stroke is based on the important clinical benefits demonstrated in ROCKET AF, Double-blind blind global Phase III study that compared once-daily rivaroxaban with warfarin in more than 14,000 patients. The results from the ROCKET AF trial were published in the New England Journal of Medicine (NEJM) in August

21 ROCKET AF Atrial fibrillation Risk factors Stroke, TIA or systemic embolism OR CHF Hypertension Age 75 Diabetes At least 2 or 3 required* Rivaroxaban 20 mg od (15 mg od for CrCl ml/min) Randomized double blind/ double dummy Warfarin INR target: 2.5 ( inclusive) Monthly monitoring Adherence to standard-of-care guidelines Primary endpoint: stroke or non-cns systemic embolism *Enrolment of patients without prior stroke, TIA or systemic embolism and only two factors capped at 10% Patel MR et al. N Engl J Med 2011;365:

22 ROCKET AF: primaryp efficacy outcome 6 Cumulative event rate (%) HR 0.79 (0.66, 0.96) p<0.001 (non-inferiority) Warfarin Rivaroxaban Days since randomization Number of subjects at risk Rivaroxaban 6,958 6,211 5,786 5,468 4,406 3,407 2,472 1,496 Warfarin 7,004 6,327 5,911 5,542 4,461 3,478 2,539 1,538 Per-protocol population as treated Patel MR et al. N Engl J Med 2011;365:

23 ROCKET AF: bleeding analysis Rivaroxaban (N=7,111) Warfarin (N=7,125) HR Parameter n (% per year) n (% per year) (95% CI) Principal safety endpoint 1,475 (14.9) 1,449 (14.5) 1.03 (0.96,1.11) HR and 95% CIs Major bleeding 395 (3.6) 386 (3.4) 1.04 (0.90,1.20) Haemoglobin drop 305 (2.8) 254 (2.3) 1.22 (1.03,1.44)* ( 2 g/dl) Transfusion 183 (1.6) 149 (1.3) 1.25 (1.01,1.55)* Critical organ bleeding 91 (0.8) 133 (1.2) 0.69 (0.53,0.91)* Intracranial 55 (0.5) 84 (0.7) 0.67 (0.47,0.93)* haemorrhage Fatal bleeding 27 (0.2) 55 (0.5) 0.50 (0.31,0.79)* Non-major clinically relevant bleeding 1,185 (11.8) 1,151 (11.4) 1.04 (0.96,1.13) Major bleeding from gastrointestinal site (upper, lower and rectal): rivaroxaban = 224 events (3.2%); warfarin = 154 events (2.2%); p<0.001* Safety population on-treatment analysis. *Statistically significant Favours Favours rivaroxaban warfarin 23

24 ROCKET AF: most frequent treatment-emergent emergent adverse events 24

25 Rivaroxaban: : Non-valvular atrial fibrillation Based on the prespecified primary efficacy outcome: A once-daily fixed-dose dose regimen of rivaroxaban was non-inferior to warfarin for prevention of stroke or non-cns systemic embolism Safety: Similar overall incidence of bleeding and adverse events Increase in gastrointestinal bleeds but fewer intracranial haemorrhages and less fatal bleeding with rivaroxaban Implication: Rivaroxaban,, administered once daily, has demonstrated non-inferiority to warfarin in the prevention of stroke or systemic embolism, with similar overall bleeding and fewer intracranial haemorrhages and fatal bleedsb 25

26 RE-LY: dabigatran vs warfarin Randomized, phase III, single-blind, non-inferiority study Nonvalvular AF plus at least 1 additional risk factor* N=18,113 R Dabigatran 110 mg bid Dabigatran 150 mg bid Open-label warfarin (target INR range 2 3) End of treatment Follow-up Primary efficacy: composite of all-cause stroke or systemic embolism Major safety: major bleeding Excludes: patients with severe renal impairment (CrCl 30 ml/min) *Previous stroke or TIA, NYHA Class II HF, LVEF <40%, age 75 years, age 65 with either a history of coronary artery disease, hypertension or diabetes mellitus Connolly SJ et al. N Engl J Med 2009;361:

27 Dabigatran: : Non-valvular atrial fibrillation Among patients with AF: Dabigatran 110 mg bid was associated with: Stroke/systemic embolism rate similar to warfarin A lower rate of major bleeding Dabigatran 150 mg bid was associated with: A lower stroke/systemic embolism rate versus warfarin A similar rate of major bleeding 27

28 Dabigatran: : Non-valvular atrial fibrillation Indication approved by the EMA (April 2011) 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

29 Dabigatran: : Non-valvular atrial fibrillation Indication approved by the EMA (April 2011) Doses: Pradaxa is taken at a dose of 300 mg (as one 150 mg capsule twice a day) ) and should be taken long term. A lower dose is used in patients with moderate kidney problems who w are at high risk of bleeding, patients aged over 80 years and in patients also taking verapamil. A lower dose may also be used in patients aged 75 to 80 years who are at high risk of bleeding. All patients considered to be at risk r of bleeding should be monitored closely and the dose of Pradaxa lowered at the discretion of the doctor. 29

30 Apixaban in AF AVERROES Among patients with AF for whom VKA therapy was unsuitable, apixaban: Reduced the risk of stroke or systemic embolism versus ASA Did not increase the risk of major bleeding or intracranial haemorrhage ARISTOTLE In patients with AF, compared with warfarin, apixaban: Was superior in preventing stroke or systemic embolism Caused less bleeding Resulted in lower mortality compared with warfarin Granger CB et al. N Engl J Med 2011;365:

31 Other indications VTEx PE Pulmonary embolism (PE) 500,000 deaths per year in Europe Ischemic Stroke 15% due to atrial fibrillation SPAF Deep venous thrombosis (DVT) 1 event every 12 seconds DVT VTEp Elective hip replacement surgery DVT risk: 42 57% Elective knee replacement surgery DVT risk: 41 85% Unstable angina and myocardial infarction 1 death every 17 seconds ACS 31

32 Rivaroxaban: Other indications Treatment of deep vein thrombosis (DVT) Prevention of recurrent DVT and pulmonary embolism (PE) following an acute DVT in adults 32

33 VTE Phases of the Disease and Conventional Treatment with Anticoagulants 33

34 Rivaroxaban: : phase III studies in VTE treatment EINSTEIN DVT/PE 1,2 Treatment period of 3, 6 or 12 months Confirmed acute symptomatic DVT without symptomatic PE Confirmed acute symptomatic PE with or without symptomatic DVT N=3,449 R Rivaroxaban 15 mg bid Rivaroxaban 20 mg od Estimated Enoxaparin 1.0 mg/kg bid for at least 5 days, followed N=4,000 by VKA to start 48 hours, target INR range 2 3 Day 1 Day 21 EINSTEIN EXT 1 Treatment period of 6 or 12 months 30-day observation period Confirmed symptomatic DVT or PE completing 6 or 12 months of rivaroxaban or VKA N=1,197 R Day 1 Rivaroxaban 20 mg od Placebo 30-day observation period 1. The EINSTEIN Investigators. N Engl J Med 2010;363: ; 2 EINSTEIN PE. Trial ID: NCT Accessed 10 June

35 EINSTEIN DVT: conclusions In patients who had acute symptomatic proximal DVT, without symptomatic PE, rivaroxaban showed: Non-inferiority to LMWH/VKA for efficacy: HR=0.68 (95% CI ); p<0.001 for non-inferiority Similar findings for principal safety outcome: HR=0.97 (95% CI ); p=0.77 Consistent efficacy and safety results irrespective of age, body weight, gender, creatinine clearance and cancer No evidence for liver toxicity Oral rivaroxaban 15 mg bid for 3 weeks followed by rivaroxaban 20 mg od,, could provide clinicians and patients with a simple, single-drug approach for the acute and continued treatment of DVT that potentially improves the benefit risk profile of anticoagulation 35

36 EINSTEIN Extension Primary objective to evaluate whether rivaroxaban is superior to placebo in the long-term prevention of recurrent symptomatic VTE in patients with symptomatic DVT or PE who completed 6 or 12 months of treatment with a VKA or rivaroxaban Study Design Multicentre, randomized, double-blind, blind, placebo- controlled, event- driven, superiority study for efficacy 36

37 EINSTEIN Extension Randomized, double-blind, placebo-controlled, event-driven (n=30), superiority study Confirmed symptomatic DVT or PE completing 6 or 12 months of rivaroxaban or VKA in EINSTEIN VTE programme Confirmed symptomatic DVT or PE completing 6 or 12 months of VKA ~53% N=1,197 ~47% Day 1 R Treatment period of 6 or 12 months Rivaroxaban 20 mg od Placebo 30-day observation period The EINSTEIN Investigators. N Engl J Med 2010;363:

38 EINSTEIN Extension Primary efficacy outcome* Symptomatic recurrent VTE, i.e. composite of recurrent DVT, non fatal PE or fatal PE, or unexplained death where PE cannot be excluded Principal safety outcome* Major bleeding, defined as overt bleeding associated with: A fall in haemoglobin of 2 g/dl or more, or A transfusion of 2 or more units of packed red blood cells or whole blood, or Occurrence at a critical site: intracranial, intraspinal,, intraocular, pericardial, intra-articular articular,, intramuscular with compartment syndrome, retroperitoneal, or Death *Adjudicated by the Central Independent Adjudication Committee The EINSTEIN Investigators. N Engl J Med 2010;363:

39 EINSTEIN Extension: primary efficacy outcome analysis time to first event 39

40 EINSTEIN Extension: major bleeding 40

41 EINSTEIN Extension: conclusions In patients who had completed 6 or 12 months of anticoagulation, rivaroxaban showed: An 82% relative risk reduction in the recurrence of VTE (HR=0.184;( p<0.001) Absolute risk reduction 5.8%, hence 15 patients need to be treated ed to prevent one recurrent VTE event Low incidence of major bleeding (0.7%; p=0.11; NNH approximately 139) Efficacy and safety results were consistent irrespective of bodyweight and creatinine clearance Modest increase in non-major clinically relevant bleeding (5.4% versus 1.2%; p<0.01) No signal for liver toxicity Oral rivaroxaban 20 mg od could provide clinicians and patients with a simple and effective option for continued anticoagulant treatment 41

42 Rivaroxaban December, 2011: oral anticoagulant Xarelto (rivaroxaban)) has been approved by the European Commission (EC) for use in two new indications, making it the only new oral anticoagulant approved in three indications across all 27 EU member states: Prevention of stroke and systemic embolism in adult patients with non- valvular atrial fibrillation (AF) with one or more risk factors Treatment of deep vein thrombosis (DVT( DVT) ) and prevention of recurrent DVT and pulmonary embolism (PE) following an acute DVT in adults The prevention of VTE in adult patients undergoing elective hip or knee replacement surgery 42

43 Rivaroxaban: : other indications? Rivaroxaban for long-term secondary prevention after ACS? 43

44 ATLAS ACS 2 TIMI 51 44

45 ATLAS ACS 2 TIMI 51: summary Compared with placebo, rivaroxaban (2.5 or 5 mg bid) on top of ASA or ASA plus clopidogrel showed: Significant reductions in the rates of death, MI, and stroke Benefits in all types of ACS patients (UA, NSTEMI and STEMI ) More than a 30% reduction in risk of both CV and all-cause mortality (2.5 mg bid) No increase in fatal bleeding and fatal ICH A non-bleeding safety profile similar to placebo The addition of anticoagulation with rivaroxaban may represent a new treatment strategy in patients after recent ACS 45

46 The NEJM heralds a new era in secondary prevention after ACS Roe and Ohman, NEJM, 2011: /NEJM Mega JL et al. N Engl J Med DOI: /NEJMoa

47 Rivaroxaban: : dosing across indications Indication Rivaroxaban dose Duration VTE prevention after orthopaedic surgery 10 mg od 2 weeks (total knee replacement) 5 weeks (total hip replacement) Stroke prevention in AF 20 mg od (15 mg od in patients with moderate As long as risk factors persist renal impairment*) VTE treatment 15 mg bid First 3 weeks 20 mg od (15 mg od in patients with moderate renal impairment*) As long as risk factors persist ACS 2.5 and/or 5 mg bid 47

48 Is there a significant difference in patient adherence to once-daily (od( od) ) and twice-daily (bid) dosing regimens across a range of chronic conditions? Main result of literature search (PubMed( PubMed; March ): 2011): A total of 44 publications were identified that either directly or indirectly indicated that patient adherence with od dosing is greater than (or in a few cases equal to) bid dosing No studies indicated that patients show better adherence to bid dosing regimens when compared with od dosing. 48

49 Practical management: switching drugs Switching from VKAs to rivaroxaban VKA treatment should be stopped and rivaroxaban should be initiated ted when the INR is 2.5 INR measurement is not appropriate to measure rivaroxaban and should not be used; treatment with rivaroxaban only does not require routine coagulation monitoring Switching from a parenteral anticoagulant to rivaroxaban Rivaroxaban should be started hours before the time of the next scheduled administration of the parenteral medicinal product (e.g. LMWH) or at the time of discontinuation of a continuously administered parenteral medicinal product (e.g. i.v. UFH) Switching from rivaroxaban to parenteral anticoagulants Give the first dose of parenteral anticoagulant at the time the next rivaroxaban dose would be taken Xarelto Summary of Product Characteristics 49

50 Practical management: dosing before and after invasive procedures Rivaroxaban should be stopped at least 24 hours before the intervention, if possible, and based on the clinical judgement of o the physician If the procedure cannot be delayed the increased risk of bleeding should be assessed against the urgency of the intervention Rivaroxaban should be restarted after the invasive procedure or surgical intervention as soon as possible, provided the clinical situation allows and adequate haemostasis has been established Xarelto Summary of Product Characteristics 50

51 Clinical utility of rivaroxaban for treatment of DVT and secondary prevention of VTE Does not require injection or routine coagulation monitoring Rapid anticoagulant effects (within hours) High oral bioavailability Low potential for drug drug or food drug drug interactions Enables single-drug approach versus LMWH plus warfarin/vka for the initial treatment of VTE and a convenient once-daily dosing for long-term treatment and prevention of VTE recurrence The EINSTEIN Investigators. N Engl J Med 2010;363: ; Xarelto Summary of Product Characteristics 51

52 Rivaroxaban vs Dabigatran Daily use Jean-Michel Dogné, Jonathan Douxfils, François Mullier, Christian Chatelain, Bernard Chatelain, 52

53 Pharmacokinetics properties E Nutescu et al. ; J Thromb Thrombolysis 2011; 31:

54 Pharmacokinetics properties Contraindicated in patient with hepatic disease associated with coagulopathy and an increase of bleeding risks. Is to be used with caution in cirrhotic patients with moderate hepatic impairment (Child Pugh B) if it is not associated with coagulopathy. Risk of hemorrhage. E Nutescu et al. ; J Thromb Thrombolysis 2011; 31:

55 Pharmacokinetics properties Mild renal impairment: (Cl Cr between 50 to 79ml.min -1 ) AUC increase by 44% Moderate renal impairment: (Cl Cr between 30 to 49ml.min -1 ) AUC increase by 52% Severe renal impairment: (Cl Cr <30ml.min -1 ) AUC increase by 54% No recommendation No recommendation, but care is to be taken in patient concomitantly receiving medicinal products which increase rivaroxaban plasma concentration Is to be used with caution and not recommended in patient with Cl Cr <15mL/min Risk of bleeding 55

56 Pharmacokinetics properties Not recommended in patient receiving concomitant systemic treatment with CYP3A4 inhibitors azole-anti-mycotics (ketoconazole, itraconazole, posaconazole and voriconazole) or protease inhibitor (e.g: ritonavir) => Risk of bleedings E Nutescu et al. ; J Thromb Thrombolysis 2011; 31:

57 Pharmacokinetics properties Strong CYP3A4 inducers (rifampicin, phenytoin, carbamazepine, phenobarbital or St. John s Wort) are to be administrated with caution. Reduction of plasma concentration of rivaroxaban Risk of thrombosis E Nutescu et al. ; J Thromb Thrombolysis 2011; 31:

58 Pharmacokinetics properties: Interactions E Nutescu et al. ; J Thromb Thrombolysis 2011; 31:

59 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:

60 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 60

61 Pharmacology - PK 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) E Nutescu et al. ; J Thromb Thrombolysis 2011; 31:

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

63 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:

64 Pharmacology - PK P- glycoprotein inhibitors: Caution should be exercised with strong P- glycoprotein inhibitors.. The P-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 co-administering these medicinal products. 64

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

66 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 effect relationship and the bleeding risks strongly suggest that drug monitoring is needed. Based on the above balance the benefits associated with the proposed osed use of DE are considered to outweigh the risks. 66

67 [ ] In patients at high risk of bleeding a reduction in dabigatran dose may be necessary. A diluted Thrombin Time test (dtt) is commercially available and can be used to identify patients at increased risk because of excessive exposure to dabigatran, e.g. when renal function could be impaired [ ]. 67

68 EMA and SmPC recommendations Pradaxa is contraindicated in patients who are bleeding, patients with severe renal impairment, and should be used with caution and at lower doses in elderly patients and patients with moderate renal impairment. The updated product information includes recommendations: that renal function be assessed in all patients before starting Pradaxa treatment; while on treatment, renal function should be assessed at least once a year in patients over 75 years of age and whenever a decline in renal function is suspected in patients of any age. 68

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

70 Availability of an antidote PCC contains: Factor II, VII,IX and X + protein C and S Was used at 50 U PCC/kg PCC may restore PT value at baseline compared with placebo. Elise S. Eerenberg, et al. Circulation 2011: 124;

71 Conclusion New oral anticoagulants: (r)evolution( in different clinical settings (venous and arterial diseases). Rivaroxaban is not dabigatran bid vs od Other parameters: liver, kidney, drug interactions, compliance, bleeding New oral anticoagulants: Developed with the intent not to require monitoring due to their predictable pharmacologic effects However this will be required in some specific settings: classic coagulation tests not adapted 71

72 Thank you for your attention! 72

73 Backup slides 73

74 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:

75 Dabigatran and elective surgery Faible risque hémorragique Faible risque hémorragique modéré ou élevé Arrêt 24h avant geste Reprise 24h après geste Arrêt à J-5 Reprise: -Disponibilité voie orale -Risque hémorragique post-opératoire chirurgical ou lié à la technique anesthésique + gestion risque thrombotique! Sié et al Recommendations GEHT et GIHP 75

76 Dabigatran and urgent surgery Heure de la dernière re prise à connaitre Chirurgie hémorragiqueh - Retarder au maximum l opl opération - 1 ou 2 demi-vies d éd élimination test biologique Pas de recommandations au niveau réversionr Anesthésie sie loco-régionale médullaire contre-indiqu indiquée Sié et al Recommendations GEHT et GIHP Gogarten et al

77 Which naive patient should be treated with dabigatran? Pengo et al. Thromb Haemost

78 In which patients should dabigatran be prioritised in replacing VKAs? Pengo et al. Thromb Haemost

79 In which patients should dabigatran be prioritised in replacing VKAs? Pengo et al. Thromb Haemost

80 In which patients should dabigatran be prioritised in replacing VKAs? Pengo et al. Thromb Haemost

81 In which patients should dabigatran be prioritised in replacing VKAs? Pengo et al. Thromb Haemost

82 In which patients should dabigatran be prioritised in replacing VKAs? Pengo et al. Thromb Haemost

83 In which patients should dabigatran be prioritised in replacing VKAs? Pengo et al. Thromb Haemost

84 In which patients should dabigatran be prioritised in replacing VKAs? Pengo et al. Thromb Haemost