The Grand Master vs. New Kids on the Block

Transcription

1 Hong Kong Pharmacy Conference 2013: Therapeutic Debate - Session 1 The Grand Master vs. New Kids on the Block Should warfarin or new oral anticoagulants (NOACs) claim the throne as 1st line agent for stroke prevention in patients with Non-valvular Atrial Fibrillation in the 21 st Century?

2 Conflict of Interest Disclosure The speakers have no conflict of interest to declare

3 Context Landmark clinical trials for NOACs RE-LY: Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361: ROCKET-AF: Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365: ARISTOTLE: Granger CB, Alexander JH, McMurray JJV, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365:

4 Context Evidence based Guidelines on Anticoagulation 2012 focused update of the ESC Guidelines for the management of atrial fibrillation: An update of the 2010 ESC Guidelines for the management of atrial fibrillation. Developed with the special contribution of the European Heart Rhythm Association. European Heart Journal (2012) 33, Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines

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6 Guidelines ACCP Chest 9 ESC focused update

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8 Net Clinical Benefit Banerjee et al. Net clinical benefit of new oral anticoagulants (dabigatran, rivaroxaban, apixaban) versus no treatment in a 'real world' atrial fibrillation population: a modelling analysis based on a nationwide cohort study. Thromb Haemost Mar;107(3):584-9.

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10 Net Clinical Benefit CHADS 2 1 or CHA 2 DS 2 -VASc 2: Net clinical benefit of NOAC > Warfarin regardless of risk of bleeding

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12 Guidelines o Guidelines based on landmark trials o Applicability of landmark trials

13 Landmark Trials

14 Landmark trials o Non-inferiority study comparing difference in side effect profiles too o Side effects mainly reported as bleeding but not other fatal side effects, o e.g. liver injury of the previous trial agent, Ximelagatran o Different findings on efficacy o Superior for Dabigatran and Apixaban o Non-inferior for Rivaroxaban

15 Landmark trials o Dose determination, struggle between safety and efficacy o Renal dose determined by extrapolating pharmacokinetic data o Efficacy good enough to replace warfarin as first line treatment? o Risk justified?

16 Clinical application of warfarin o More than 50 years of clinical experience o Local guidelines & expert experience in monitoring & managing side effects o Experience in different clinical scenario o Laboratory data to support decision o System & multi-disciplinary team support the safe use of Warfarin

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18 Life Style 50 years of experience Life style is important! Hard to comply with the warfarin-style Dietary restriction Routine blood draw Complicated dosing regimen

19 1/3 AF warfarin candidates not started on warfarin 67% of eligible patients

20 AVERROES Study Connolly et al. Apixaban in Patients with Atrial Fibrillation. N Engl J Med 2011; 364:

21 TTR < 60% Mean TTR = 55%

22 Discontinued once started Within 1yr after warfarin initiation, 26.3% discont despite few hospitalisations for haemorrhage (2.3%)

23 Life style drug Clinical benefit of a drug that is not used NOACs save trouble! more patients may be willing to get anticoagulated

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25 Over- & Under- anticoagulation o INR monitoring for warfarin o TTR as an indicator for performance, but no similar monitoring for NOAC o No valid & reliable monitoring for NOAC o No information about over- or underanticoagulation until stroke or bleeding

26 Compliance Issue o No indicator to monitor compliance for NOAC o T 1/2 of NOACs generally short. Poor compliance can affect efficacy o Brief interruption of Dabigatran VTE & bleeding complication o Interruption of Rivaroxaban & Apixaban VTE o Financial toxicity

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28 Clinical Issues Interactions Drug interactions with warfarin Level of Causation Antiinfectives Cardiovascular Analgesics, Antiinflammatories, and Immunologics CNS Drugs GI Drugs and Food Herbal Supplements Other Drugs Potentiation Highly probable Ciprofloxacin Cotrimoxazole Erythromycin Fluconazole Isoniazid Metronidazole Miconazole Oral Gel Miconazole Vag Supp Voriconazole Amiodarone Clofibrate Diltiazem Fenofibrate Propafenone Propranolol Sulfinpyrazone (biphasic with later inhibition) Phenylbutazone Piroxicam Alcohol (if concomitant liver disease) Citalopram Entacapone Sertraline Cimetidine Fish oil Mango Omeprazole Boldofunugreek Quilinggao Anabolic steroids Zileuton Probable Amoxicillin/ clavulanate Azithromycin Clarithromycin Itraconazole Levofloxacin Ritonavir Tetracycline Aspirin Fluvastatin Quinidine Ropinirole Simvastatin Acetaminophen Aspirin Celecoxib Dextropropoxphene Interferon Tramadol Disulfiram Chloral hydrate Fluvoxamine Phenytoin (biphasic with later inhibition) Grapefruit Danshen Don quai Lycium Barbarum l PC-SPES Fluorouracil Gemcitabine Levamisole/ fluorouracil Paclitaxel Tamoxifen Tolterodine Possible Amoxicillin Amoxicillin/tranexamic rinse Chloramphenicol Gatifloxacin Miconazole Topical Gel Nalidixic Acid Norfloxacin Ofloxacin Saquinavir Terbinafine Amiodarone-induced toxicosis Gemfibrozil Metolazone Celecoxib Disopyramide Propoxphene Rofecoxib Sulindac Tolmetin Topical salicylates Felbamate Indomethacin Leflunomide Orlistat Danshen/ methyl salicylates Acarbose Cyclophosphamide/ methotrexate/ fluorouracil Curbicin Danazol ifosphamide Trastuzumab Highly improbable Cefamandol Cefazolin Sulfisoxazole Bezafibrate Heparin Levamisole Methyl- prednisolone Nabumetone Fluoxetine/ diazepam Quetiapine Etoposide/carboplatin Levonorgestrel Inhibition Highly probable Griseofulvin Nafcillin Ribavirin Rifampin Cholestyramine Mesalamine Barbiturates Carbamazepine Food with vit k / enteral feeds Avocado Mercaptopurine Probable Dicloxacillin Ritonavir Bosentan Azathioprine Chlordiaze- poside Soy milk Sucralfate Ginseng Chelation therapy Influenza vaccine Multivitamin supp. Raloxifene HCL Possible Terbinafine Telmisartan Sulfasalazine Sushi containing seaweed Highly improbable Cloxacillin Natcillin/ dicloxacillin Teicoplanin Furosemide Propofol Green tea Cyclosporine Etretinate Ubidicaremone

29 Clinical Issues Drug interactions with NOACs - P-gp and 3A4 inhibitor/ inducer - antithrombotics - antiplatelets Rivaroxaban Apixaban Dabigatran

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31 Clinical Issue o NOACs Drug Interaction: limited knowledge Dabigatran: A New Oral Anticoagulant. John R. Horn, Philip D. Hansten. Pharmacy Times P Retrieved on March 22, 2013

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33 Clinical Issues - Monitoring Routine monitoring not necessary Predictable PK/PD Only in emergency situations: Hemorrhage Overdose Surgery Invasive procedures

34 Clinical Issues - Monitoring Dabigatran Rivaroxaban Apixaban PT /- /- /- aptt /- /- TCT - - ECT - - Hemoclot assay - - Anti-factor Xa actvity Clot-based Chromogenic no data

35 Clinical Issues - Monitoring Role of routine coagulation assays Qualitative information Normal TCT/ aptt (Dabigatran), PT (Rivaroxaban), anti-xa activity (Apixaban) very low drug level + intact haemostatic function

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37 Monitoring Well validated INR for both efficacy & toxicity Don t have to wait for an event to know the problem Quantitative enough Especially useful in emergency situation

38 Clinical Issue o Bleeding Management Vitamin K for warfarin FFP PCC Agent for NOAC?

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40 Clinical Issues Bleeding No antidote bleed to death Short T 1/2 Antidotes under development Management strategy available

41 Clinical issues Bleeding FFP: no human data; mice: ICH but ~ mortality RVIIa: no effect/ partial lab correction in various studies

42 Clinical issues Reversal PCC: healthy volunteers: PT due to rivaroxaban but ~ aptt due to dabigatran, improved thrombin generation for apixaban patients; mice: intracranial haematoma expansion & 24 hr mortality (dabigatran); rabbit: partial correlation of lab, but not bleeding

43 Clinical issues Reversal apcc: animal model: correct anticoagulant effect; in vitro: reduced clot initiation time; healthy volunteer: corrected thrombin generation

44 Pt on NOAC initial assessment Minor bleeding Local hemostatic measures w/h NOAC Moderate bleeding General measures: w/h NOAC, compression, monitor HD status, vol replacement, def interv. Severe bleeding General measures + blood product transfusion: ICU, HD support, 4 factor CC 50u/kg; activated PCC 80u/kg Blood product transfusion: RBC (anemia), FFP, plt Adj therapies: charcoal if ingestion within 2h, HD (Dabigatran), desmopressin, transamine

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46 Q & A Let s hear what our audience say

47 Conclusion Get the RIGHT person to be anticoagulated at the RIGHT intensity with the RIGHT agent

48 Conclusion NOACs may be viable 1 st option if: Patient preference! Problems with FU or INR test schedule Labile INR while on VKA Noncompliance to Dietary Restrictions

49 Conclusion Points to consider about NOACs Longer term efficacy/safety data? Dosing of NOACs available for CrCL<30ml/min Bleeding Management/Specific antidotes Early signals of NOACs safety issues Cost-benefit analysis Warfarin vs. NOACs

50 THANK YOU!