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NOACs (new oral anticoagulants): are we ready for a wide use after stroke? YES George Ntaios University of Thessaly, Larissa, Greece 2013 Joint meeting.

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Presentation on theme: "NOACs (new oral anticoagulants): are we ready for a wide use after stroke? YES George Ntaios University of Thessaly, Larissa, Greece 2013 Joint meeting."— Presentation transcript:

1 NOACs (new oral anticoagulants): are we ready for a wide use after stroke? YES George Ntaios University of Thessaly, Larissa, Greece 2013 Joint meeting BNS-BSC Leuven, Belgium 23/11/2013

2 Disclosures Support to attend conferences: Bayer; Sanofi-Aventis; Pfizer; Lundbeck; Boehringer-Ingelheim; Galenica; Elpen; Bristol Myers Squibb. Honoraria: Quintiles; CHUV; Medtronic. Speaker fees: Sanofi Scholarships: European Stroke Organization; Hellenic Society of Atherosclerosis. Participation in trials – National coordinator (Greece) for the ENOS trial. – Sub-investigator (AMGEN, ).

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4 Dont forget my INR !

5 Courtesy of Patrik Michel, adapted from Hylek et al. NEJM 1996; 335:540-6 INR Odds ratio Target INR 2.5 (range 2-3) Ischemic stroke Intracranial hemorrhage

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7 Baker W, et al. J Manag Care Pharm 2009;15:244-52

8 Reduced Vitamin K Oxidised Vitamin K Vitamin K oxide reductase WARFARIN SR CYP1A1 CYP1A2 CYP3A4 CYP2C9 Inactive precursor Active Clotting Factor - Diet Why is it so difficult ?

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10 Reduced Vitamin K Oxidised Vitamin K Vitamin K oxide reductase WARFARIN SR CYP1A1 CYP1A2 CYP3A4 CYP2C9 Inactive precursor Active Clotting Factor - Diet - Drugs

11 Abciximab Acetaminophen Alcohol (acute and chronic) Allopurinol Aminodarone Aminoglutethimide Amobarbital Anabolic steroids Aspirin Azathioprine Butabarbital Butalbital Carbamazepine Cefoperazone Cefotetan Cefoxitin Ceftriaxone Chenodiol Chloral hydrate Chloramphenicol Chlorpropamide Chlorthalidone Cholestyramine Cimetidine Ciprofloxacin Clarithromycin Clofibrate Corticotropin Cortisone Coumadin Cyclophosphamide Danazol Dextran Dextrothyroxine Diazoxide Diclofenac Dicloxaxillin Diflunsial Disulfram Doxycycline Erythromycin Ethacrynic acid Ethchlorvynol Fenoprofen Fluconazole Fluorouracil Gemfibrozil Glucagon Glutethimide Griseofulvin Haloperidol Halothane Heparin Ofloxacin Olsalazine Omeprazole Oxaprozin Oxymetholone Paraldehyde Paroxetine Penicillin G Pentobarbital Pentoxifylline Phenobarbital Phenylbutazone Phenytoin Piperacillin Piroxicam Prednisone Primidone Propafenone Propoxyphene Propranolol Propylthiouracil Phytonadione Quinidine Quinine Ranitidine Rifampin Ibuprofen Ifosamide Indomethacin Influenza virus vaccine Itraconazole Ketoprofen Ketorolac Levamisol Levothyroxine Liothyronine Lovastatin Mefenamic Meprobamate Methimazole Methyldopa Methylphenidate Methylsalicylate Miconzale Metronidazole Miconazole Moricizine HCl Nafcillin Nalidixic acid Naproxen Neomycin Norfloxacin Secobarbital Sertaline Simvastatin Spironolactone Stanozolol Streptokinase Sucralfate Sulfamethizole Sulfamethoxazole Sulfinpyrazone Sulfisoxazole Sulindac Tamoxifen Tetracycline Thyroid hormone Ticacillin Ticlopidine t-PA Tolbutamide Trazodone Trimethoprim- sulfamethoxazole Urokinase Valproate Vitamin C Vitamin E

12 Reduced Vitamin K Oxidised Vitamin K Vitamin K oxide reductase WARFARIN SR CYP1A1 CYP1A2 CYP3A4 CYP2C9 Inactive precursor Active Clotting Factor - Diet - Drugs - Polymorphisms

13 Estimated warfarin daily dose (mg) based on patient age and genotype Age (years) CYP2C9*1CYP2C9*2 CYP2C9*3 6.5 (2.9, 10.2) 6.3 (2.7, 9.9) 6.0 (2.5, 9.6) 5.8 (2.2, 9.3) 5.5 (2.0, 9.0) 5.3 (1.8, 8.8) 5.0 (16, 8.5) 4.8 (1.3, 8.2) 4.5 (1.1, 7.9) 4.3 (0.9, 7.7) 4.0 (0.6, 7.4) 3.8 (0.4, 7.2) 3.5 (0.9, 6.9) 3.3 (-0.2, 6.7) 3.0 (-0.5, 6.5) 5.8 (1.9, 9.8) 5.6 (1.8, 9.4) 5.3 (1.6, 9.0) 5.1 (1.5, 8.7) 4.8 (1.3, 8.3) 4.6 (1.1, 8.0) 4.3 (1.0, 7.7) 4.1 (0.8, 7.4) 3.8 (0.5, 7.1) 3.5 (0.3, 6.8) 3.3 (0.1, 6.5) 3.0 (-0.2, 6.3) 2.8 (-0.5, 6.0) 2.5 (-0.8, 5.8) 2.3 (-1.1, 5.6) 5.5 (1.3, 9.8) 5.3 (1.2, 9.4) 5.0 (1.1, 9.0) 4.8 (1.0, 8.6) 4.5 (0.8, 8.3) 4.3 (0.7, 7.9) 4.0 (0.5, 7.5) 3.8 (0.3, 7.2) 3.5 (0.1, 6.9) 3.3 (-0.1, 6.6) 3.0 (-0.3, 6.4) 2.8 (-0.6, 6.1) 2.5 (-0.8, 5.9) 2.3 (-1.1, 5.7) 2.0 (-1.5, 5.5) Thrombosis & Anticoagulation Research Group

14 … lower initiation doses should be considered for patients with certain genetic variations in CYP2C9 and VKORC1 enzymes … FDA 2007

15 Kimmel, et al. NEJM 2013, online early 45.2% 45.4%

16 Verhoef, et al. NEJM 2013, online early 61.6% 60.2%

17 Pirmohamed, et al. NEJM 2013, online early 67.4% 60.3%

18 Anti-VKAs limitations Narrow therapeutic window Frequent INR monitoring Frequent dose adjustments Unpredictable dose response Drug and food interactions Slow onset/offset of action

19 Baker W, et al. J Manag Care Pharm 2009;15:244-52

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21 Anti-VKAs limitations Narrow therapeutic window Frequent INR monitoring Frequent dose adjustments Unpredictable dose response Drug and food interactions Slow onset/offset of action

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23 Guigliano, et al. NEJM 2013, online first

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25 Acenocoumarol Warfarin Dabigatran Rivaroxaban Apixaban Edoxaban

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27 Ntaios G, et al. Stroke 2012; 43:

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36 NOACs limitations (?) Eerenberg, et al. Circulation 2011; 124: Patients with renal function impairment -Patients with mechanical valves -Can not monitor drug effect and titrate dose -No specific antidote -Their short half-life makes them dangerous in non-adherent patients -Not better than warfarin for high TTRs Majeed, et al. Circulation 2013; 128:

37 Wallentin L, et al. Lancet 2010; 376:975–83

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39 Baker W, et al. J Manag Care Pharm 2009;15:244-52

40 -Patients with renal function impairment -Patients with mechanical valves -Can not monitor drug effect and titrate dose -No specific antidote -Their short half-life makes them dangerous in non-adherent patients -Not better than warfarin for high TTRs -Bleeding rates in real-life were higher than in RCTs NOACs limitations (?)

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44 We believe that the large number of reported cases of bleeding associated with dabigatran provides a salient example of stimulated reporting. Bleeding rates associated with dabigatran are not higher than those with warfarin, a finding that is consistent with the results of RE-LY. Southworth M, et al. NEJM 2013; 368: We believe that dabigatran provides an important health benefit when used as directed.

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46 Novel oral anti- coagulants -Reduce stroke or systemic embolism -Reduce ICH -Reduce major hemorrhage -Steady dose -Limited drug & no food interactions -No INR monitoring NOACs limitations vs. Warfarin

47 NOACs (new oral anticoagulants): are we ready for a wide use after stroke? YES THIS IS ALREADY HAPPENING !

48 Kirley K, et al. Circ Cardiovasc Qual Outcomes. 2012;5:

49 Xu J, et al. CMAJ 2013

50 NOAC…


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