The Challenge and Opportunities for Stroke Prevention in AF

20th International Symposium on Thromboembolism October 2013 in London, United Kingdom Plenary Session I: Thromboembolic Stroke The Challenge and Opportunities for Stroke Prevention in AF John Camm St. George s University of London, United Kingdom

Declaration of Interest Chairman: ESC Guidelines on Atrial Fibrillation 2012 and Update 2012, ACC/AHA/ESC Guidelines on VAs and SCD, ESC Guidelines on SVT, NICE Guidelines on ACS and NSTEMI Steering Committees: multiple trial of novel anticoagulants DSMBs: multiple trials of novel oral anticoagulants in AF Events Committees: one trial of novel oral anticoagulants Consultant/Advisor/Speaker: Astra Zeneca, ChanRX, Gilead, Merck, Menarini, Otsuka, Sanofi, Servier, Xention, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi, Pfizer, Boston Scientific, Biotronik, Medtronic, St. Jude Medical, Actelion, GlaxoSmithKline, InfoBionic, Incarda, Johnson and Johnson, Mitsubishi, Novartis, Takeda

Projected Number of Patients With AF by 2050 MarketScan & Thomson Reuters Medicare databases, 2009 Patients with atrial fibrillation (millions) 16 14 Olmsted County data, 2006 (assuming a continued increase in the AF incidence) Olmsted County data, 2006 (assuming no further increase in the AF incidence) 13.1 14.3 15.2 15.9 11.7 12 ATRIA study data, 2000 10.2 12.1 11.7 10 8.9 11.1 7.7 10.3 9.4 7.56 8 6.7 5.9 8.4 7.5 6 5.1 6.8 6.1 5.6 4.78 5.16 5.42 5.61 4 5.1 3.03 4.34 3.8 2 3.33 2.08 2.26 2.44 2.66 2.94 0 1990 1995 2000 2005 2010 2015 2020 2025 2030 2035 2040 2045 2050 Year

Opportunities and Challenges Atrial Fibrillation 5-fold stroke rate 3-fold dementia prevalence 2- fold CV mortality risk 2-fold sudden death risk 2-fold hospitalisation rate Identification of patients with AF Risk stratification for thromboembolic risk Elimination of inappropriate therapies Selection of new anticoagulants Adoption of best practice Development of comprehensive therapy Reduction of stroke/dementia/hospitalisation/mortality Following Guidelines

ESC AF Guideline Update - 2012

1,500,000 United Kingdom AF Prevalence 2005 0.75% of the general population 2007 GP QoF payments introduced for AF detection and anti-thrombotic treatment 2011 1.75% of the general population 2012 1.91% of the general population 1,000,000 500,000 0 + 700 K 2005 2011 2012 AF is often asymptomatic, intermittent and symptoms are attributed to age

Action in the Community Take the pulse Record ECG

CRYSTAL-AF CRYptogenic STroke And underlying AF Trial Inclusion Criteria: Recent cryptogenic symptomatic transient ischemic attack (TIA) or cryptogenic ischemic stroke. Primary Outcome Measures: Time to first documented episode of AF Estimated Enrollment: 450 Study Start Date: June 2009 Estimated Study Completion Date: December 2012 Sensitivity 98.1% Specificity 98.5% PPV 91.9% NPV 99.7% Sinha A-M, et al. Am Heart J 2010;160:36-41

REVEAL-AF 420 patients? AF or High-risk for development of AF (CHADS 2 score 3 or 2+ ) Need for continuous monitoring Purpose Determine incidence of AF lasting >6 min Identify predictors of AF Identify timing/nature of clinical actions following the detection of previously unknown AF In-Office follow-ups (6, 12, 18, 24, 30 mo) Enrollment Baseline Successful Reveal XT Implant CareLink transmission every month Clinical Trials.gov Sponsor Medtronic Inc P.I.: J. Reiffel NCT01727297 See also ASSERT II

Varieties of Atrial Fibrillation Electrical AF Anatomical AF Fibrosis Muscle Mahnkopf et al. Heart Rhythm 2010

Anticoagulation General Recommendations for prevention of thromboembolism in NVAF general Recommendations Class Level Antithrombotic therapy to prevent thromboembolism is recommended for all patients with AF, except in those patients (both male and female) who are at low risk (aged <65 years and lone AF), or with contraindications. The choice of antithrombotic therapy should be based upon the absolute risks of stroke/thromboembolism and bleeding and the net clinical benefit for a given patient. The CHA 2 DS 2 -VASc score is recommended as a means of assessing stroke risk in NVAF. I A I I A A NVAF, non-valvular atrial fibrillation Camm AJ, et al. Europace 2012;14(10):1385 1413; Camm AJ, et al. Eur Heart J 2012;33(21):2719 2747.

CHA 2 DS 2 VASc refines Stroke Risk Stratification in AF Patients with CHADS 2 =0 A nationwide Danish cohort study in 47,576 non-warfarin treated NVAF patients with a CHADS 2 score = 0-1 at baseline (1997-2008) 100% Proportion of patients free of stroke / thromboembolism 98% 96% 94% CHADS 2 =0: n=17,327 person-years CHA 2 DS 2 VASc=0: n=6,919 person-years CHA 2 DS 2 VASc=1: n=6,811 person-years CHA 2 DS 2 VASc=2: n=3,347 person-years 0.84% 1.59% 1.75% 2.69% 3.20% Stroke / thromboembolism rate (% personyears) 92% CHA 2 DS 2 VASc=3: n=250 person-years 0% 0 100 200 300 Days from discharge Adapted from Olesen et al. Thromb Haemost 2012;107:1172-9.

Recommendations Relating to Stroke Risk Recommendations Class Level In patients with a CHA 2 DS 2 -VASc score of 0 (i.e., aged <65 years with lone AF) who are at low risk, with none of the risk factors, no antithrombotic therapy is recommended. In patients with a CHA 2 DS 2 -VASc score 2, OAC therapy with: adjusted-dose VKA (INR 2 3); or a direct thrombin inhibitor (dabigatran); or an oral factor Xa inhibitor (e.g., rivaroxaban, apixaban). is recommended, unless contraindicated. In patients with a CHA 2 DS 2 -VASc score of 1, OAC therapy with: adjusted-dose VKA (INR 2 3); or a direct thrombin inhibitor (dabigatran); or an oral factor Xa inhibitor (e.g., rivaroxaban, apixaban). should be considered, based upon an assessment of the risk of bleeding complications and patient preferences. I I IIa B A A Camm AJ, et al. Europace 2012;14(10):1385 1413; Camm AJ, et al. Eur Heart J 2012;33(21):2719 2747.

% GP-coded AF Patients Prior to Stroke Anticoagulant v Antiplatelet Therapy Percentage of paaents 0.8 0.6 0.4 0.2 Antiplatelet Anticoagulant 32151 patients with first stroke GPRD database 0 0 1 2 3 4 5 CHADS 2 score Lee S et al. BMJ Open 2011;1:e000269

Birmingham Atrial Fibrillation Treatment of the Aged (BAFTA) and AVERROES Trials Event free survival 100 Primary endpoint fatal or disabling stroke*, other intracranial haemorrhage or clinically significant arterial embolism 1 75 50 25 Aspirin Warfarin RR = 0.48 (0.28 0.80) p = 0.0027 48 (3.8%) 24 (1.8%) Stroke: 0.8% vs 1.8% RR = 0.30 (0.13 0.63) p = 0.0004 0 0 1 2 3 4 5 6 Years after randomisation Intracerebral haemorrhage, warfarin vs aspirin: 0.5% vs 0.4% (RR 1.15, 0.29 4.77, n.s.) Extracranial haemorrhage, warfarin vs aspirin: 1.4% vs 1.6% (RR 0.87, 043 1.73, n.s.) Cumulative Hazard 0.05 0.04 0.03 0.02 0.01 Stroke or systemic embolism 2 HR = 0.45 95%CI= 0.32 0.62 ARR = 2.1% P<0.001 for superiority Aspirin 81 324 mg/d Apixaban 5 mg bd (in 94% of patients)** 0 0 3 6 9 12 18 Months Major bleeding, apixaban vs aspirin: 1.4% / year vs 1.2% / year (HR 1.13, 0.74 1.75, n.s.) n.s., not significant. *Ischaemic or haemorrhagic. **Patients with 2 of the following received a reduced dose of 2.5 mg bd [6.4% of patients]: age 80 years, weight 60 kg, serum creatinine 1.5 mg/dl (133 µmol/l). Note: Per the SmPC, patients with the exclusive criterion of severe renal impairment (CrCl 15 29 ml/min) should also receive the lower dose of apixaban 2.5 mg bd. This new criterion differs from the trial conduct. 1. Adapted from Mant J, et al. Lancet 2007;370:493 503; 2. Adapted from Connolly SJ, et al. N Engl J Med 2011;364:806 17. EUAPI355cUK

VKA Therapy in AF 6 trials, 2,900 patients with AF Highly selected patients, uncertain INR control RRR (95 % CI) Target INR Range AFASAK I, 1989; 1990 SPAF I, 1991 BAATAF, 1990 CAFA, 1991 SPINAF, 1992 EAFT, 1993 2.8 4.2 2.0 4.5 1.5 2.7 2.0 3.0 1.4 2.8 2.5 4.0 All trials (n = 6) RRR: 64% 100 % 50 % 0-50 % - 100 % RRR all-cause mortality 26% (3% to 43%) Absolute increase in risk of major ECH 0.3%/year Adapted from Hart et al. Ann Intern Med 2007;146:857-67. Favours Warfarin Favours Placebo or Control ECH, extracranial haemorrhage RRR, relative risk reduction

Warfarin Treatment Better Outcome Irrespective of Risks Swedish atrial fibrillation cohort study 182 678 AF subjects - average FU: 1.5 years All-cause mortality, ischemic stroke, and intracranial bleeds Risk for intracranial bleeding HAS-BLED 0 2 HAS-BLED 3 Proportion surviving Proportion surviving 1.0 0.8 0.6 0.4 0.2 0.0 1.0 0.8 0.6 0.4 0.2 0.0 CHA 2 DS 2 -VASc 0 2 OAC no OAC OAC no OAC Years Proportion surviving Proportion surviving 1.0 0.8 0.6 0.4 1.0 0.8 0.6 0.4 0.2 0.0 CHA 2 DS 2 -VASc 3 OAC no OAC p <0.00001 0.2 p <0.00001 (n=1,787) (n=59,817) 0.0 0 1 2 3 4 Years 0 1 2 3 4 p <0.00001 (n=43,395) 0 1 2 3 4 p <0.00001 (n=53,797) OAC no OAC 0 1 2 3 4 Years Years HRs range from 0.26 0.72 Friberg L et al. Circulation 2012;125:2298 307 Risk for embolic stroke

VKA-related Intracranial Haemorrhage 1512 patients with ICH 68 during VKA Rx, 42 intracerebral 1324 AF patients 170 VKA-associated ICHs 14 INR Values on Admission With Intracerebral Haemorrhage 3 Age-related VKA-Associated ICH No. of Patients With Intracerebral haemorrhage 12 10 8 6 4 2 Relative Odds 2 1 0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 9.0 10.0 11.0 INR at Admission 0 <60 60-64 65-69 70-74 75-79 80-84 85 Age, years Berwaerts J et al. Stroke. 2000;31:2558-2562 Fang MC et al. Ann Intern Med. 2004;141:745-752

Warfarin Modern Role Standard of Care for the Following PaAent Groups Warfarin with monitoring should be the standard of care if: There is a risk of non-compliance Renal impairment is present The patient has ACS ± angioplasty ± stent (DES) A mechanical heart valve is in situ The patient has hypertrophic cardiomyopathy The patients are children or adolescents A drug that has an antidote is preferred The patient is intolerant to the new drugs Cost is an issue Wann et al (2011). J Am Coll Cardiol 57:1330-1337, Fuster et al (2011). Circulation 123:269-367 Connolly et al (2009). N Engl J Med 361:1139-1151

Efficacy and Safety of NOACs vs. Warfarin Systematic reviews and meta-analyses Stroke or SE in trials of warfarin vs comparators RR (95% CI) NOACs vs warfarin in modern phase II/III trials (n = 54,875) RR (95% CI) W vs Placebo W vs W low dose W vs Aspirin W vs Aspirin + Clop W vs Ximelagatran ACM CVM Stroke/SE Ischemic stroke Major bleeding ICH 23% 54% 14% 11% 11% 8% 0 0.3 0.6 0.9 1.2 1.5 1.8 2.0 Favours Favours warfarin comparator MI 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 1.1 1.2 Favours NOACs Favours warfarin ACM, all-cause mortality; CVM, cardiovascular mortality; ICH, intracranial haemorrhage; MI, myocardial infarction; RR, relative risk; SE, systemic embolism; W, warfarin Modified from: Lip GY, et al. Thromb Res 2006;118:321 33. EUAPI355cUK 1% Dentali F, et al. Circulation 2012;126:2381-91.

Anticoagulation - NOACs Recommendations for prevention of thromboembolism in nonvalvular AF - NOACs Recommendations Class Level When adjusted-dose VKA (INR 2 3) cannot be used in a patient with AF where an OAC is recommended, due to difficulties in keeping within therapeutic anticoagulation, experiencing side effects of VKAs, or inability to attend or undertake INR monitoring, one of the NOACs, either: a direct thrombin inhibitor (dabigatran); or an oral factor Xa inhibitor (e.g., rivaroxaban, apixaban) d is recommended. Where OAC is recommended, one of the NOACs, either: a direct thrombin inhibitor (dabigatran); or an oral factor Xa inhibitor (e.g., rivaroxaban, apixaban) d should be considered rather than adjusted-dose VKA (INR 2 3) for most patients with non-valvular AF, based on their net clinical benefit. I IIa B A European Heart Journal 2012 - doi:10.1093/eurheartj/ ehs253

AHA/ASA 2012 Update SPAF and OAC 1. Warfarin (Class I; Level of Evidence A), dabigatran (Class I; Level of Evidence B), apixaban (Class I; Level of Evidence B), and rivaroxaban (Class IIa; Level of Evidence B) are all indicated for the prevention of first and recurrent stroke in patients with nonvalvular AF The selection of an antithrombotic agent should be individualized on the basis of risk factors, cost, tolerability, patient preference, potential for drug interactions, and other clinical characteristics, including time in INR therapeutic range if the patient has been taking warfarin. Furie KL, et al. http://stroke.ahajournals.org/content/early/2012/08/02/str.0b013e318266722a.citation

Summary of Recommendations Proposed by ESC 2012 and APHRS 2013. ESC 2012 APHRS 2013 CHA2DS2-VASc score 2 1 0 NOAC NOAC No Tx W (alternative) CHA2DS2-VASC score 2 1 0 OAC (D/R/A/ W) NOAC (D/A) W/R (alternative) No Tx Abbreviations: NOAC, novel oral anticoagulants; OAC, oral anticoagulants; W, warfarin; D, dabigatran; R, rivaroxaban; A, apixaban; No Tx, no treatment Ogawa S, et al. Journal of Arrhythmia 29 (2013) 190 200

Study Design N=21,105 AF on electrical recording < 12 mo Intended oral anticoagulant CHADS 2 > 2 Exposure strategy: patients anticipated to have increased drug exposure received a 50% dose reduction R Randomization stratified by 1. CHADS2 2-3 vs 4-6 2. Increased Drug Exposure Low exposure strategy Edoxaban 30 mg QD High exposure strategy Edoxaban 60 mg QD Median duration of follow up 24-months Active control: warfarin (INR 2.0 3.0) Primary objective Edoxaban: therapeutically as good as warfarin 1º endpoint = stroke or SEE (non-inferiority boundary HR 1.38) 2º endpoint = stroke or SEE or all-cause mortality Safety endpoints = major bleeding, hepatic function AF, atrial fibrillation, mo, months; QD, once daily; HR, hazard ratio SEE, systemic embolic event; INR, International Normalised Ratio Ruff et al. Am Heart J 2010;160:635-641

National Warfarin and Dabigatran Treatment Visits 2007 to 2011 Treatment Visits (thousands) 2500 2000 1500 Warfarin 1000 Dabigatran 500 0 Quarter 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 Year 2007 2008 2009 2010 2011 Source: IMS Health National Disease and Therapeutic Index Kirley K et al. Circ Cardiovasc Qual Outcomes 2012;5:615-621 Copyright American Heart Association

Universal Xa Inhibitor Antidote PRT4445: a recombinant biologic designed to reverse the anticoagulant activity of oral and injectable Factor Xa inhibitors in patients suffering lifethreatening bleeds or requiring urgent surgery. PRT4445 is a modified version of human Factor Xa designed to sequester direct inhibitors (apixaban, betrixaban, rivaroxaban), thereby allowing native Factor Xa to restore haemostasis. Current strategies for mitigating serious bleeding in patients taking Factor Xa inhibitors include administration of coagulation factors such as recombinant Factor VIIa or blood-derived prothombin complex concentrates PRT4445: Phase 1 single ascending dose safety and tolerability study Clinical proof-of-concept study to demonstrate the safety of PRT4445 and its ability to reverse the anticoagulation activity of Factor Xa inhibitors Not approved

How to Choose a NOAC? Indirect comparison Adverse event profile Subgroup analyses Non- AF trials Experience Registries Local DTC decisions Single drug choice Cost- benefit analyses

Effect on NOAC Plasma Levels from D-D interactions, and Recommendations via Dabigatran Apixaban Edoxaban Rivaroxaban Atorvastatin P-gp weak CYP3A4 +18% no data no effect no effect Digoxin P-gp no effect no data no effect no effect Verapamil Diltiazem P-gp weak CYP3A4 P-gp weak CYP3A4 +12-180% reduce dose take together no data +53% (SR) reduce dose no effect +40% no data Quinidine P-gp +50% no data +80% reduce dose Amiodarone P-gp +12-60% no data no effect Dronedarone minor effect use with caution if CrCL: 15-50ml/min minor effect use with caution if CrCL: 15-50ml/min www.noacforaf.eu P-gp weak CYP3A4 +70-100% no data +88% reduce dose +50% minor effect use with caution if CrCL: 15-50ml/min No data yet Heidbuchel H, et al. Europace (2013) 15, 625 651 Not recommended/contraindicated Reduce dose Reduce dose if 2 factors or more No data yet

PROTECT-AF Latest Results 463 patients received the Watchman and 244 warfarin management Average CHADS 2 scores 2.2 and 2.3, respectively Mean follow-up: 45 months Rate Ratios (95% CI) for Primary Efficacy and Safety End Points and Secondary End Points in PROTECT-AF, by Intention to Treat End points (2621 pt/years) RR (95% CI) Primary efficacy end point: Stroke, systemic embolism, or cardiovascular or unexplained death 0.60 (0.41 1.05) All-cause mortality 0.66 (0.45 0.98) Cardiovascular mortality 0.40 (0.21 0.72) Hemorrhagic stroke 0.15 (0.03 0.49) Primary safety end point: serious pericardial effusion, major bleeding, procedure-related stroke, hemorrhagic stroke, and device embolization 1.17 (0.78 1.95) Reddy VY, et al. Abstract HRS Denver 2013

Stroke/Systemic Embolus/All Cause Mortality NOACs and LAAC Reduction of Relative and Absolute Risk of All Cause Mortality of Stroke/Systemic Embolus 40 35 30 25 20 15 10 5 0 S/SE RRR S/SE ARR ACM RRR ACM ARR Dabigatran 150 Rivaroxaban Apixaban LAAC

Left Atrial Appendage Occlusion Study III (LAAOS III) Surgical LAA excision vs. no LAA excision Randomised double blind study 4700 patients On-going until 2019 1 0 endpoint: stroke or systemic arterial embolism 2 0 endpoints: total mortality, major bleeding, hospitalisation with HF, etc. Inclusion Criteria: Greater than 18 years of age Undergoing a clinically indicated cardiac surgical procedure Have a documented history of AF or atrial flutter Have provided informed consent Exclusion Criteria: Patients undergoing off-pump cardiac surgery Patients undergoing any of the following procedures: heart transplant complex congenital heart surgery ventricular assist device insertion re-operation Patients who have had a previous placement of a percutaneous LAAO device NCT01561651: Richard Whitlock and Stuart Connolly

ESC 2012 Update AF Guidelines Non-valvular AF Paroxysmal, Persistent or Permanent Valvular* No antithrombotic therapy Dashed lines: less preferable or less validated < 65 years, no cardiovascular disease CHA 2 DS 2 -VASc Dose-adjusted VKA INR:2-3) * = mechanical or rheumatic = not female only = dual antiplatelet therapy preferred = see Summary of Product Characteristics for specific indications 1 2 OAC therapy Assess bleeding risk (HAS-BLED) Consider patient values and preferences Modified from the 2012 focused update of the ESC Guidelines for the management of AF Savelieva I and Camm AJ In press Clinical Cardiology 2013 CHA 2 DS 2 -VASc:1 and not suitable for, or refusing NOAC or VKA Suitable for OAC therapy CHA 2 DS 2 -VASc: 2 refusing OAC CHA 2 DS 2 -VASc: 2 unsuitable for OAC Consider aspirin + clopidogrel or aspirin only NOAC drugs Apixaban Dabigatran Rivaroxaban Dose-adjusted VKA (INR:2 3) Consider aspirin + clopidogrel or aspirin only Consider LAAO, or LAA excision ESC, European Society of Cardiology; LAA, left atrial appendage; LAAO, left atrial appendage occlusion

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