The GARFIELD Registry is funded by an unrestricted research grant from Bayer Pharma AG The Role of Anticoagulants Keith A A Fox Edinburgh Centre for Cardiovascular Science

Disclosure Statement Keith A. A. Fox President of the British Cardiovascular Society European Society of Cardiology: ESC Programme Chair KAA Fox member of the ESC guidelines group: –ESC Guidelines: Non-ST elevation ACS EHJ (2007) 28, 1598–1660 –ESC Guidelines: ST Elevation MI EHJ (2008) 29: Co-Chair ROCKET-AF, Steering Committee Major funding: British Heart Foundation, Medical Research Council and the Wellcome Trust Additional funding: Bayer, Janssen, Sanofi, Lilly, Astra Zeneca No stock ownership

Untreated and Under-treated Patients Clear need to: –Identify patients with unsuspected AF and stroke risk –Anticoagulate those at stroke risk –Improve adherence to anticoagulation –Aspirin is not an adequate therapy for stroke prevention in AF

Hylek EM, et al. An analysis of the lowest effective intensity of prophylactic anticoagulation for patients with non-rheumatic atrial fibrillation. N Engl J Med. 1996;335: v INR below 2.0 results in a higher risk of stroke INROdds Ratio Odds Ratio INR Lowest Effective Intensity for Warfarin Therapy

Hylek EM, and Singer DE. Risk factors for intracranial hemorrhage in outpatients taking warfarin. Ann Intern Med. 1994;120: Prothrombin Time Ratio Odds Ratio Risk of Intracranial Haemorrhage (Outpatients) v PTR above 2.0 increases the risk of bleeding v The odds ratio of subdural hemorrhage increased 7.6 fold as the PTR increased from 2.0 to 2.5

Warfarin vs Antiplatelet Agents Systematic Overview Hart RG, et al. Ann Intern Med. 2007;146: million people with AF in the EU

Problems With Vitamin K-Based Oral Anticoagulation Risk of bleeding –Many contra-indications Narrow therapeutic window Frequent blood testing Many drug interactions Discontinuations for surgery/procedures Lifestyle restrictions

Bleeding Risk Stroke and ACS Risk Finding the right balance is key!

Dutch bypass OA vs ASA. Lancet. 2000;355: The Dutch Bypass Oral Anticoagulants Study: Distribution of Time in Each INR Range >6.5 RANGE 50% Time in INR Class (patient-years) INR

Tolerability of Warfarin During First Year of Therapy Elderly Patients in the US 58% time in therapeutic range Major haemorrhage 7.2%; ICH 2.5% – Rates were 2.75× higher in patients ≥80 years 28% of patients discontinued warfarin at 1 year Major bleeding eventTaken off therapy CHADS 2 scoreRate (per 100 person- years) ≥ Hylek EM, et al. Circulation. 2007;115:

Time in Therapeutic Range (UK) n=2,074,928 INRs in Primary Care

12 UFH Targets for Anticoagulants ORAL DIRECT PARENTERAL INDIRECT Xa IIa TF/VIIa XIX IXa VIIIa Va II FibrinFibrinogen Rivaroxaban Apixaban Edoxaban LMWH Fondaparinux Weitz JI, Bates SM. J Thromb Haemost. 2005;3: Weitz JI, et al. Chest. 2008;133: Dabigatran AZD 0837

NOACs vs Warfarin: Trial Summary Outcome RE-LY 1 Dabigatran 150 mg vs Warfarin RR (95% CI) ROCKET AF 2 Rivaroxaban vs Warfarin RR (95% CI) ARISTOTLE 3 Apixaban vs Warfarin RR (95% CI) ENGAGE AF 4 Edoxaban * 60 mg vs Warfarin HR (95% CI) Stroke or SE 0.65 ( ) P < ( ) P < ( ) P = (0.63–0.99) P <.001 Death from any cause 0.88 ( ) P = (0.70, 1.02) ( ) P = ( ) P =.08 Intracranial hemorrhage 0.40 ( ) P < ( ) P = ( ) P < ( ) P <.001 Trial group size Dabig 150: 6076 W: 6022 Riva: 7131 † W: 7133 Apix: 9120 W: 9081 Edox 60mg: 7035 W: 7036 Connolly SJ, et al. N Engl J Med. 2009;361: [1] Patel MR, et al. N Engl J Med. 2011;365: [2] Granger CB, et al. N Engl J Med. 2011;365: [3] Giugliano RP, et al. N Engl J Med. 2013;369: [4] * Edoxaban is not yet approved for stroke prevention in AF patients. † ITT population at baseline NB: trial populations differ in characteristics

ESC 2012 Guidelines: All Novel OACs Preferred Over VKAs Based on Net Clinical Benefit RecommendationsClass*Level # CHA 2 DS 2 -VASc ≥2 : VKA or novel OACsIA CHA 2 DS 2 -VASc = 1: VKA or novel OACs (except female patients <65 years with score = 1 based on gender) IIaA Novel OACs in patients with VKA issues, e.g. unstable INR, VKA-related adverse events IB Novel OAC over VKA based on net clinical benefit for most patients with non-valvular AF IIaA *Class of recommendation; # Level of evidence Camm AJ, et al. Eur Heart J. 2012;33:

So, based on the evidence, what is the future….? Systematic detection of AF and stroke risk Improved patient education for compliance Registry programmes and quality control Reduced stroke risk, ICH and major complications with “NOACs” No need to routinely monitor Do we need antidotes? Yes, rarely New indications – AF and ACS, post ACS The NOACs will become the norm for anticoagulation