Oral Anticoagulation Which Drug for Which Patient in the era of New Oral Anti-coagulants Dr Scott McKenzie BSc MBBS FRACP FCSANZ Cardiologist, Vascular Physician, Telehealth Specialist, Advanced Heart Failure and Cardiac Transplant Unit, The Prince Charles Hospital Atrial Fibrillation The most common cardiac arrhythmia Global prevalence of 0.5 3.4% depending on definition and country Occurs in up to 5.5% of those over 65 Occurs in up to 15% of those over 80 Ball et al: International Journal of Cardiology 167 (2013) 1807 1824 Atrial Fibrillation Incidence is increasing AF as an embolic risk factor S. Chugh et al Circulation. 2014;129:837-847 ESC AF Guidelines 2010: European Heart Journal (2010) 31, 2369 2429 Atrial Fibrillation is bad for you 5 7 x increased risk of stroke 1 in 6 strokes occur in people with AF 3 x increased risk of heart failure 2 x risk of all cause mortality Bleeding Risk: 0-1: ~1% 2: 1.9% 3: 3.74% 4: 8.7% 5: 12.5% Chugh SS et al J Am Coll Cardiol 2001; 37: 371-378 Fuster V et al, Circ 2006; 114:e257-354 > 3 points = high bleeding risk ESC AF Guidelines 2010: European Heart Journal (2010) 31, 2369 2429 1
What are the current treatment options? Aspirin Warfarin adjusted to INR 2.0 3.0 NOAC: Apixaban Rivaroxaban Dabigatran Aspirin May reduce risk of stroke by ~22% But dose adjusted warfarin reduces risk of stroke by ~66% Risk of major intracranial haemorrhage or major bleeding On 75mg Aspirin risk = that of warfarin In 80+year olds 300mg Aspirin / day: Risk of SAE = 33% Vs 6% on warf arin Apixaban & AVERROES Trial Apixaban AVERROES: 5599 patients not suitable for Warfarin Due to inability to comply with INR, Unable to maintain INR in range, Patient refusal, or physician deemed insufficient risk ie CHADS 2 = 1 Mean CHADS 2 = 2 Randomised to aspirin or Apixaban 2.5 or 5mg bd (Apixaban 2.5mg bd if two of age > 80, weight < 60kg or creatinine > 133µmol/l) AVERROES Outcomes: Stroke in 1.1% on Apixaban and 3.3% on Aspirin No dif f erence in rate of major bleeds compared with aspirin (1.4% on Apixaban and 1.2% on aspirin (p = 0.57)) Lower rate of Composite end point of stroke, sy stemic embolism, my ocardial inf arction, death f rom v ascular causes, or major bleeding 5.3% on Apixaban and 7.2% on Aspirin (p = 0.03) Connolly et al N Engl J Med 2011;364:806-17 Conclusion on Aspirin No role for aspirin in AF Equivalent risk of major bleeding to oral anticoagulants At best 50% as effective as oral anticoagulants Aspirin & Clopidogrel Increases bleeding risk vs aspirin alone almost as much as lowers stroke risk If aspirin s bleeding risk vs oral anticoagulants is too high then with dual antiplatelets the risk is definitely too high ACTIVE Trial: N Engl J Med 2009;360 2
Warfarin The Gold standard Warfarin Meta-analysis including 28,044 patients at a mean 1.5 years of follow-up: Warfarin reduces risk of stroke by 64% Vs Aspirin reduces risk of stroke by 22% Hart RG et al Ann Intern Med 2007;146:857-67 Warfarin - Advantages Effect can be measured cheaply and rapidly Cheaper than chips Antidotes are readily available, relatively cheap Vitamin K FFP Prothrombinex Warfarin - Disadvantages Narrow therapeutic index Large inter-patient and intra-patient variability in dose requirements Numerous drug & f ood interactions Time to onset of stable anticoagulation ~ 1 w eek after commencement of therapy Warrants regular testing to ensure dosing achieves appropriate therapeutic effect Wien Med Wochenschr (2011) 161/3 4: 54 57 Xa Antagonists Rivaroxaban Approved for prevention of thromboembolic events in non-valvular AF Available Oral Xa Antagonists: Apixaban Rivaroxaban Soon: Edoxaban ENGAGE-AF-TIMI 48 (Giugliano et al: N Engl Jn Med 369(22) :2093-104) Metabolised by CYP3A4 & CYP2J2 Potent inhibitors will produce a 2.5 x increase in levels Itraconazole & Ketoconazole Ritonavir Pheny toin & Carbemazepine Potent inducers will reduce levels Rif ampicin (50% reduction) Giorgi et al Expert Opin. Pharmacother. (2011) 12(4):567-577 3
Apixaban Direct Thrombin Inhibitors Metabolised by CYP3A4 & CYP1A1/2 Potent inhibitors will produce a 2.5 x increase in levels Itraconazole Ketoconazole Ritonavir Grape Fruit juice Potent inducers will reduce levels Rifampicin Oral Agents: Dabigatran Giorgi et al Expert Opin. Pharmacother. (2011) 12(4):567-577 Dabigatran Is excreted by p-glycoprotein Verapamil & Amiodarone will down regulate this But not of sufficient impact to change outcomes in RELY Rif ampacin will upregulate this A LOT Pantoprazole will upregulate this a bit Choosing an oral anticoagulant Dosing Adherence Medication Adherence Previous Stroke Comparative Efficacy Renal impairment Previous GI upset Triple Therapy In addition to dual antiplatelet therapy Overall Mortality Patients are 39 61% more likely to adhere to therapy with once daily than twice daily regimens Patients are more likely to take their drugs in the day s bef ore and af ter an appointment Laliberte et al; Patient (2013) 6:213 224 4
Warfarin time in therapeutic Range & Outcomes Improving Patient Adherence If adherence likely to be poor perhaps rivaroxaban with once daily dosing is advantageous See your patient often and enquire about adherence especially to a NOAC Morgan et al: Thrombosis Research 124 (2009) 37 41 Caution in comparing drugs RELY: Dabigatran ROCKET-AF: Rivaroxaban ARISTOTLE: Apixaban Follow Up Period 24 months 40 months 40 months Mean Age 71.5 +/- 8.7 73 [65 78] 70 [63 76] Female % 36.4 39.7 35.2 CHADS2 (mean) 2.2 3.5 2.1 CHADS2 3 6 % 32.5 87 30.2 Prior Stroke / TIA 20.0 54.8 19.4 Paroxysmal AF % 32.8 17.3 15.3 Heart Failure % 32 62.5 35.4 Diabetes % 23.3 40.0 25.0 TTR % in warfarin 64 55 62 Previous warfarin % 49.6 62.4 57.2 Previous Stroke RELY minimum 14 days post minor stroke or 6 months post major stroke ROCKET-AF minimum 14 days post minor stroke or 3 months post major stroke ARISTOTLE minimum 7 days post stroke Comparative Efficacy Stroke Prevention Dabigatran 150mg bd RR 0.66 vs warfarin Apixaban 5mg bd RR 0.79 vs warfarin Rivaroxaban 20mg daily RR NS vs warfarin Or RR 0.79 vs warfarin in on treatment analysis Contentious issues in Comparing studies Significant geographic variation in apparent relative efficacy Different definitions for analysis of outcomes in the intention to treat population Different CHADS 2 scores between studies Different rates of previous warfarin use 5
Renal Impairment Dabigatran 80% renal clearance Contraindicated if GFR < 30ml/min Rivaroxaban 30% renal clearance of active metabolites Contraindicated if GFR < 30ml/min Apixaban 30% renal clearance of active metabolites Contraindicated if GFR < 25ml/min Gastrointestinal Bleeding Dabigatran has poor GI tolerance RR of GI Bleeding 1.5 (p < 0.001) vs warfarin RR of dyspepsia 11.8% vs 5.8% on warfarin Rivaroxaban RR of GI Bleeding 1.45 (p < 0.001) vs warfarin Apixaban RR of GI Bleeding 0.89 (p = 0.37) vs warfarin Overall Bleeding Overall Bleeding Dabigatran: Major Bleeding RR = 0.93 vs warfarin (p < 0.34) Non-major Bleeding RR = 0.91 vs warfarin (p < 0.001) Intracranial Bleed RR = 0.40 vs warfarin (p < 0.001) Rivaroxaban Major Bleeding RR = 1.04 vs warfarin (p = 0.58) Non-Major Bleeding RR = 1.04 vs warfarin (p = 0.34) Intracranial Bleed RR = 0.67 vs warfarin (p = 0.02) Epistaxis RR = 1.18 vs warfarin (p < 0.05) Overall Bleeding Apixaban Major Bleeding RR = 0.69 vs warfarin (p < 0.01) Minor Bleeding RR = Not reported Intracranial Bleed RR = 0.42 vs warfarin (p < 0.01) Ischaemic Heart Disease Dabigatran 150mg bd vs warfarin Risk of MI of 0.74% / year vs 0.53% / year (p = 0.048) Rivaroxaban vs warfarin Risk of MI 0.91% / year vs 1.12% / year (p = 0.121) Apixaban vs warfarin Risk of MI 0.53% / year vs 0.61% / year (p = 0.37) 6
Anticoagulation post MI / PCI Apixaban 5mg + dual antiplatelet therapy: HR 2.59 vs placebo (p < 0.001) (APPRAISE-2) Rivaroxaban 20mg + dual antiplatelet therapy: HR 5.06 vs placebo (p < 0.001) (ATLAS) Rivaroxaban 15mg + dual antiplatelet therapy: HR 3.06 vs placebo (p < 0.001) (ATLAS) Dabigatran 150mg bd HR 2.31 v s placebo (RELY) or 0.94 v s warf arin (NS) All Cause Mortality Dabigatran vs warfarin HR = 0.88 (p = 0.051) Rivaroxaban vs warfarin HR = 0.85 (p = 0.073) Apixaban vs warfarin HR = 0.89 (p = 0.047) Cardioversion Mechanical Valves Safety with Dabigatran Confirmed Pre-specified analysis of RELY of 1983 patients Dabigatran evidence of increased risk of mechanical valve thrombosis Safety with Rivaroxaban Confirmed X-VeRT 1 trial of 1504 cardioversions Rivaroxaban and Apixaban contraindicated but no data yet Safety with Apixaban Confirmed Analysis of ARISTOTLE of 743 cardioversions (540 patients) 1: Cappato et al: European Heart Journal doi:10.1093/eurheartj/ehu367 Non-Valvular AF?? Non-Valvular AF?? It refers to moderate to severe mitral valve stenosis OR Any mechanical valve requiring w arfarin Dabigatran evidence of increased risk of mechanical valve thrombosis Rivaroxaban and Apixaban contraindicated but no data yet Eikelboom et al N Engl J Med 2013;369:1206-14 7
The End Summary Dabigatran Possibly most effective at stroke prevention * Requires willingness to take BD drugs Least drug interactions Most renal clearance High rate of dyspepsia discontinuation Highest rate of GI bleeding? Increases risk of MI (HR ~ 1.5) Summary Rivaroxaban Superiority to warfarin in stroke prevention only in on treatment analysis Summary Apixaban Second most effective at stroke prevention * Only once daily dosing NOAC Drug interaction with phenytoin, carbamazepine and others Moderate renal clearance Higher than warfarin rate of GI bleeding Requires willingness to take BD drugs Some drug interactions & grape fruit juice Moderate renal clearance No increased rate of GI bleeding Only drug to show mortality advantage Summary NOACs are ideally suited to general practice initiation Adherence to therapy is crucial Investigate causes of AF after commencing treatment 8