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Warfarin and Novel Oral Anticoagulants Frances Akinwunmi PhD Consultant Pharmacist – Anticoagulation Imperial College Healthcare NHS Trust Warfarin Coagulation Cascade Synthesis of Clotting Factors: II, VII, IX & X is Vitamin K dependent Warfarin blocks recycling of Vit K Warfarin Inactive factor Active factor Warfarin Warfarin Adjusted dose warfarin compared with placebo or no treatment Initiation of warfarin anticoagulation 100% II 90 80 INR X 70 60 IX 50 VII 40 Protein C 30 20 0 1 3 5 Days 7 14 Narrow therapeutic range with VKA 20 Odds ratio 15 Stroke 10 Intracranial bleed 5 1 0 1 2 3 4 5 6 7 8 International Normalized Ratio (INR) Fuster V et al. Circulation 2006;114:e257–e354 6 http://source:82/news/notice_board/viewnotice.asp?noticeid=15279&fro m=email Pharmacokinetic metabolism interactions CYP2C9 inducer CYP2C9 inhibitor CYP3A4 inducer CYP3A4 inhibitor CYP1A2 inducer CYP1A2 inhibitor Ritonavir aprepitant carbamazepine phenobarbital phenytoin primidone rifampin rifapentine Ataznavir (ATZ) amiodarone chloramphenicol cimetidine clopidogrel cotrimoxazole delavirdine disulfiram efavirenz fenofibrate fluconazole fluorouracil fluoxetine fluvastatin fluvoxamine gemfibrozil imatinib isoniazid itraconazole ketoconazole leflunomide lovastatin metronidazole modafinil omeprazole paroxetine sertraline sulfonamides ticlopidine voriconazole zafirlukast Nevirapine (NVP) Efavirenz (EFV) aminoglutethimide aprepitant carbamazepine dexamethasone efavirenz ethosuximide garlic supplements glucocorticoids glutethimide griseofulvin modafinil nafcillin nevirapine oxcarbazepine phenobarbital phenytoin primidone rifabutin rifampin rifapentine St John’s wort Ritonavir Delavirdine (DLV) Efavirenz (EFV) Saquinavir (SQV) Indinavir (IDV) Nelfinavir (NFV) Amprenavir (APV) Ataznavir (ATZ) Fosamprenavir (FPV) acitretin amiodarone amprenavir aprepitant cimetidine ciprofloxacin clarithromycin cyclosporine danazol delavirdine diltiazem diethyldithiocarbamate efavirenz erythromycin ethinyl estradiol fluconazole fluoxetine fluvoxamine gestodene grapefruit indinavir imatinib isoniazid itraconazole Ritonavir carbamazepine charbroiled food lansoprazole omeprazole phenobarbital phenytoin primidone rifampin ritonavir smoking St John’s wort amiodarone cimetidine ciprofloxacin citalopram clarithromycin diltiazem enoxacin erythromycin ethinyl estradiol fluvoxamine isoniazid ketoconazole methoxsalen mexiletine nalidixic acid norethindrone norfloxacin omeprazole oral contraceptives paroxetine tacrine ticlopidine troleandomycin zileuton Haemorrhage Thrombosis Novel Oral Anticoagulants 2007 2008 2009 2010 Edoxaban (HOKUSAI VTE) Apixiban (ARISTOTLE - SPAF) Dabigatran (PCI) Rivaroxaban (ACS) Apixiban (APPRAISE- 2 ACS) Rivaroxaban (ROCKET - SPAF)22 Dabigatran (Long tern VTE Prophylaxis)4 Rivaroxaban (EINSTEIN – DVT Treatment)17 Apixiban (AVERROES –SPAF)21 Apixiban (ADVANCE 3 VTE) Apixaban (ADVANCE -2 ) 14 Dabigatran (RELY – SPAF) 20 Dabigatran (RE-COVER – DVT Treatment)16 Apixaban (ADVANCE-1 VTE 13 Rivaroxaban (RECORD – VTE Prophylaxis)5,6,7,8 Dabigatran (RE-NOVATE – VTE Prophylaxis)4 Ximelagatran (SPOERTIF I-IV – SPAF) Novel Oral Anticoagulants 2013 2011 This table provides a guide only to the variety of trials underway, the dates reported or license granted. Due to the large number of indications being reviewed and the continual changing landscape it is not intended to be comprehensive. Novel Oral Anticoagulants Rivaroxaban Apixaban Betrixaban Darexaban Edoxaban DU 176b Dabigatran Drug Dabigatran Etexilate Rivaroxaban Apixaban Edoxaban Mechanism of Action Direct thrombin inhibitor Factor Xa inhibitor Factor Xa inhibitor Factor Xa inhibitor Prodrug Yes No No No Pharmacokinetics Predictable Predictable Predictable Predictable Bioavailability ~6.5% >80% >50% ~50% Half life 12-17 hours 9 -13 hours 8 – 15 hours ~ 6 – 11 hours Max plasma concentrations 2 hours 2.5 – 4 hours 1-3 hours 1- 2 hours Onset of action Rapid Rapid Rapid Rapid Dosing frequency Fixed twice daily Fixed once daily Fixed twice daily Fixed once daily Blood clotting monitoring Not required Not required Not required Not required Protein Binding 35% 90% 87% ~40-59% Renal excretion 85% 66% 25% ~35-39% Interactions P-glycoprotein pump inhibitors /inducers CYP3A4 P-glycoprotein pump inhibitors /inducers CYP3A4 CYP3A4 P-glycoprotein pump inhibitors /inducers Antidote No specific antidote No specific antidote No specific antidote No specific antidote Current Indications Dabigatran Thromboprophylaxis post hip / knee NV AF DVT treatment and secondary prevention Rivaroxaban Apixaban Current Indications Dabigatran Rivaroxaban Apixaban Thromboprophylaxis post hip / knee NV AF DVT treatment and secondary prevention Anticipated Indications Dabigatran NV AF DVT treatment and secondary prevention PE treatment and secondary prevention ACS Rivaroxaban Apixaban Anticipated Indications Dabigatran NV AF DVT treatment and secondary prevention Licensed Q3 2013, NICE guidance not in schedule yet PE treatment and secondary prevention ACS Rivaroxaban Apixaban Licensed Q4 2012 with NICE guidance due Feb 2013 licensed Q2 2013, NICE guidance not in schedule yet licence expected Q4 2012 and NICE guidance currently scheduled for Sept 2013 Unfavourable risk / benefit profile Q2 2013, NICE guidance not yet scheduled Unfavourable risk / benefit profile Comparing AF Trials Characteristic Dabigatran: RE-LY Rivaroxaban: ROCKET – AF Apixaban: ARISTOTLE Randomised to NOAC (total in trial) 12 000 (~18 000) 7000 (~14 000) 9000 (~18 000) Mean age 71 73 70 Male 64 60 65 CHADS2 (mean) 2.1 3.5 2.1 Prior stroke % 20 55 19 Prior MI % 17 17 - Prior CHF % 32 62 35 Baseline aspirin % 40 20 - Warfarin naïve % 50 40 43 Comparing AF Trials Characteristic Dabigatran: RE-LY Rivaroxaban: ROCKET – AF Apixaban: ARISTOTLE Mean duration of follow up ~730 days 589 days of exposure, 707 days including period off drug during follow up ~660 days TTR % 64 58 62 Efficacy outcome 110mg bd – non-inferior 150mg bd – superior Non-inferior - (20mg / 15mg od) Superior – 5mg bd / 2.5 mg bd for a subset of patients Efficacy outcome (ischaemic) 110mg bd – non-inferior 150mg bd – superior Non-inferior Non-inferior Efficacy outcome (haemorrhagic) 110mg bd - superior 150mg bd – superior Superior Superior Safety (major bleeds) 110mg – superior (less bleeds) 150mg – non-inferior Non-inferior - (NOTE: >2 g/dL Hgb dropTransfusion (> 2 units) favour warfarin) Superior (less bleeds) Note: equivalent GI Bleeds Safety other Trend to more MI, More GI bleeds (150mg) More GI bleeds Features Comparison Feature Warfarin NOAC Onset / offset of action Slow Rapid (dabigatran twice daily dosing) Predictability of patient response Low (narrow therapeutic window), variable dosing required High, therefore fixed daily dosing Food and drink interactions Vitamin K containing foods, alcohol, cranberry juice(?) No dietary interactions reported Drug interactions Numerous drugs affect INR Less drug interactions compared with warfarin; Pgp inhibitors and inducers additionally for Xa inhibitors CYP 3A4 inhibitors, inducers, substrates) Coagulation monitoring requirements Routine monitoring required Routine monitoring not required. Routine monitoring not widely available, potential cause for concern particularly in emergency circumstances where quick decision required (e.g. thrombolysis) Bleeding profile Overall rate of intracranial haemorrhages low Lower rates of intracranial haemorrhages than warfarin, higher rate of gastrointestinal bleed Reversal agents Vitamin K, prothrombin concentrate complex No specific agent available for reversal, cause for concern, particularly in profuse bleeding and emergency surgery Non-bleed Side effects Rash, alopecia, GI disturbances GI disturbances,anaemia Renal function More frequent monitoring may be required in renal impairment Requires dose adjustment. Caution required in renal impairment Experience Real-world experience is extensive Experience growing, still lots to learn Renal impairment Dabigatran Rivaroxaban Mild renal impairment (CrCL 50- 80 ml/min no dose adjustment no dose adjustment Moderate renal impairment (CrCL 30-50 ml/min) no dose adjustment however, for patients with high risk of bleeding, consider dose reduction Reduced dose – 15mg (↑age, ↓weight) severe renal impairment (CrCL < 30 ml/min) contraindicated CrCl 15-29ml/min – 15mg CrCl<15 - contraindicated Warfarin and Novel Oral Anticoagulants Frances Akinwunmi PhD Consultant Pharmacist – Anticoagulation Imperial College Healthcare NHS Trust