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Stroke prevention in atrial fibrillation: current limitations and novel antithrombotic agents Module 5 Slide 2 Limitations of current antithrombotic agents Slide 3 3 Limitations of current treatment options for stroke prevention in AF Many patients with AF do not receive effective thromboprophylaxis due to limitations of currently available agents Aspirin is convenient to use but provides insufficient protection for stroke prevention in high-risk patients 1 Vitamin K antagonists have greater efficacy but a range of limitations make them challenging agents to use: 2,3 Narrow therapeutic window Variable and unpredictable pharmacokinetics and pharmacodynamics Wide variety of drugdrug and drugfood interactions Need for regular anticoagulation monitoring and dose adjustments Slow onset and offset of action 1. ACC/AHA/ESC guidelines: Fuster V et al. Circulation 2006;114:e257354 & Eur Heart J 2006;27:19792030; 2. Turpie AG. Eur Heart J 2008;29:15565; 3. Khoo CW et al. Int J Clin Pract 2009;63:63041 Slide 4 Intracerebral haemorrhage: the most feared complication of antithrombotic therapy >10% of intracerebral haemorrhages occur in patients on antithrombotic therapy Intracerebral haemorrhages during anticoagulation can be life-threatening Compared with placebo, antithrombotic therapy increases the risk of intracerebral haemorrhage: ~40% with Aspirin ~200% with warfarin (INR 2.03.0; increases to 0.30.6%/year) 4 Hart RG et al. Stroke 2005;36:158893 INR = international normalized ratio Slide 5 5 The VKA, warfarin, is used in only half of eligible patients with AF Warfarin use in eligible patients (%) Overall use = 55% Age (yrs) 100 8 The INR for VKAs is often outside the therapeutic range: international study of anticoagulation management Time in target range (%) 0 20 40 60 80 100 USACanadaFrance Italy Spain INR 3.0 Ansell J et al. J Thromb Thrombolysis 2007;23:8391 The predominant vitamin K antagonist (VKA) in use was warfarin in the US, Canada and Italy; acenocoumarol in Spain; and fluindione in France; INR = international normalized ratio Slide 9 9 Drug and food interactions associated with an increased potency of VKAs Holbrook AM et al. Arch Intern Med 2005;165:1095106; du Breuil AL & Umland EM. Am Fam Physician 2007;75:103142 Drug/foodExamples AnalgesicsAcetaminophen, propoyphene, salicylates Anti-arrhythmicsAmiodarone, propafenone, quinidine AntibioticsCiprofloxacin, erythromycin, metronidazole AntifungalsFluconazole, itraconazole, miconazole Beta-blockersPropranolol H 2 -receptor antagonists/PPIsCimetidine, omeprazole Lipid-lowering agentsLovastatin, atorvastatin Herbal products/dietary supplementsVitamin E, garlic, devils claw MiscellaneousAlcohol (if concomitant liver disease) PPIs = proton pump inhibitors; VKAs = vitamin K antagonists Slide 10 10 Drug and food interactions associated with a reduced potency of VKAs Holbrook AM et al. Arch Intern Med 2005;165:1095106; du Breuil AL & Umland EM. Am Fam Physician 2007;75:103142 Drug/foodExamples AntibioticsDicloxacillin, nafcillin, rifampicin AntifungalsGriseofulvin ImmunosupressantsAzathioprine, cyclosporine Lipid-lowering agentsCholestyramine Herbal products/dietary supplements Coenzyme Q10, ginseng, St Johns wort Foods Green tea, avocados (large amounts), food with high vitamin K content including broccoli and spinach MiscellaneousCarbamazepine, sucralfate, trazodone VKAs = vitamin K antagonists Slide 11 11 VKAs require regular anticoagulation monitoring Careful monitoring of patients being treated with VKAs is critical due to the: Narrow therapeutic window Unpredictable relationship between VKA dose and the anticoagulant response Influence of the quantity of vitamin K in the diet that can change over time Availability of small devices capable of measuring INR enables patients to self-monitor Reduces risk of thromboembolism and bleeding complications 1 Increases time in the therapeutic range 2 Improves patient compliance, treatment satisfaction and quality of life 2,3 Conflicting evidence on whether it may be more cost-effective 24 1. Heneghan C et al. Lancet 2006;367:40411; 2. Levi M. Expert Rev Cardiovasc Ther 2008;6:97985; 3. Braun S et al. Anal Bioanal Chem 2009;393:146371; 4. Connock M et al. Health Technol Assess 2007;11:iii66 INR = international normalized ratio; VKAs = vitamin K antagonists Slide 12 12 Contraindications to VKA treatment ACCP Guidelines, 2008: Signer DE et al. Chest 2008;133;546S92S; Coumadin: SmPC, 2009; Sudlow M et al. Lancet 1998;352:116771; Brass LM et al. Stroke 1997;28:23829; Kalra L et al. Stroke 1999;30:121822; Go AS et al. Ann Intern Med 1999;131:92734 PregnancyFrequent falls or seizures Coagulation factor abnormalitiesPoor drug or clinic compliance Thrombocytopenia (180/110 mmHg) Haemorrhagic strokeSevere hepatic or renal disease Excessive alcohol intake Threatened abortion (eclampsia, pre-eclampsia) DementiaNon-steroidal agents Recent or contemplated surgery of the CNS or the eye Gastrointestinal or urinary bleeding in the previous 6 months CNS = central nervous system; VKA = vitamin K antagonist Slide 13 13 Many patients with AF are unsuitable for treatment with VKAs 43% 38% 37% 17% 1. Sudlow M et al. Lancet 1998;352:116771; 2. Brass LM et al. Stroke 1997;28:23829; 3. Kalra L et al. Stroke 1999;30:121822; 4. Go AS et al. Ann Intern Med 1999;131:92734 The contraindications that make patients unsuitable for VKAs are found most frequently in elderly patients who are often at the greatest risk of stroke VKAs = vitamin K antagonists Patients unsuitable for VKAs (%) 50 >65 yrs 1 >65 yrs 2 >75 yrs 3 All ages 4 40 30 20 10 0 Slide 14 14 VKAs have a slow onset and offset of action VKAs inhibit the vitamin K-dependent synthesis of clotting factors Takes several days for functional clotting factors to be cleared from the circulation as well as new factors to be synthesized The initial effect of warfarin administration is to briefly promote clot formation Warfarin initially decreases the levels of protein S, which is a cofactor for the natural anticoagulant, protein C, resulting in a paradoxical increase in the tendency of the blood to clot The time lag between dosing and the anticoagulant response complicates dose titration to achieve a therapeutic INR Slow offset of action presents a problem if patients experience trauma or require emergency surgery Persistent anticoagulant activity may increase the risk of bleeding complications Connolly SJ et al. Circulation 2007;116:44955; Connock M et al. Health Technol Assess 2007;11:iii66 INR = international normalized ratio; VKAs = vitamin K antagonists Slide 15 15 Requirements of new antithrombotic agents At least as effective as warfarin Predictable response Wide therapeutic window Low incidence and severity of adverse effects Oral fixed dose No need for routine anticoagulation monitoring Low potential for food or drug interactions Fast onset and offset of action Cost-effective Adapted from Lip GY et al. EHJ Suppl 2005;7:E215 Slide 16 16 Summary: VKAs have many limitations Many AF patients (~50%) do not receive thromboprophylaxis due to the contraindications and limitations associated with current agents, particularly warfarin VKAs have a narrow therapeutic range, requiring regular anticoagulation monitoring for adequate stroke protection, while minimizing the risk of bleeding complications New antithrombotic therapies are needed, which do not share the limitations of warfarin, to deliver reliable stroke protection to a greater proportion of patients with AF VKAs = vitamin K antagonists Slide 17 Mechanism of action of new antithrombotic agents Slide 18 18 Targets for novel antithrombotic agents in the coagulation cascade 1 1. Adapted from Turpie AG. Eur Heart J 2008;29:15565; 2. Ellis DJ et al. Circulation 2009;22:120:102935; 3. Bousser MG et al. Lancet 2008;371:31521; 4. NCT00580216; available at www.ClinicalTrials.gov; accessed Sept 09; 5. Lopes RD et al. Am Heart J 2010;159:3319; 6. Eikelboom JW et al. Am Heart J 2010;159:34853; 7. ROCKET-AF Study Investigators. Am Heart J 2010;159:34047; 8. NCT00781391; available at www.ClinicalTrials.gov; accessed Sept 09; 9. NCT00742859; available at www.ClinicalTrials.gov; accessed Sept 09; 10. Connolly SJ et al. N Engl J Med 2009;361:113951; 11. Olsson SB et al. Lancet 2003;362:16918; 12. Albers GW et al. JAMA 2005;293:6908; 13. Lip GY et al. Eur Heart J 2009;30:2897907 AT= antithrombin; Ph = Phase Fibrin IX IXa X VIIIa Thrombin Fibrinogen Direct factor Xa inhibitors: Apixaban (Ph III ongoing) 5,6 Rivaroxaban (Ph III ongoing) 7 Edoxaban (Ph III ongoing) 8 Betrixaban (Ph II ongoing) 9 Va Xa II AT Direct thrombin inhibitors: Dabigatran etexilate (Ph III completed) 10 Ximelagatran (withdrawn 2006) 11,12 AZD0837 (Ph II completed) 13 Indirect factor Xa inhibitors: Idraparinux (Ph III terminated) 3 SSR 126517 (withdrawn 2009) 4 Vitamin K antagonist: Tecarfarin (Ph II completed) 2 Tissue factor/VIIa Slide 19 19 Thrombin is the central player in the coagulation cascade Thrombin has several properties that make it an excellent target for anticoagulation 1 Thrombin: Converts soluble fibrinogen to fibrin the essential step in thrombus (clot) formation Activates factor XIII to favour the formation of cross-linked bonds among fibrin molecules Triggers additional thrombin generation by activating factors V and VIII Stimulates thrombus-activated fibrinolysis inhibitor (TAFI) resulting in inhibition of fibrinolysis Is the single most potent stimulus for platelet activation 1. Di Nisio M et al. N Engl J Med 2005;353:102840 Slide 20 20 Direct thrombin inhibitors (DTIs) block both circulating and clot-bound thrombin Thrombin generation Clot-bound thrombin Heparin Conversion of fibrinogen to fibrin DTIs: dabigatran etexilate ximelagatran* AZD0837 Amplification Anti- thrombin Adapted from Eikelboom J et al. J Am Coll Cardiol 2003;41:70S8S DTIs: dabigatran etexilate ximelagatran* AZD0837 *Withdrawn from the market in 2006 Slide 21 21 ThrombinII Fibrinogen Fibrin clot Direct and indirect factor Xa (FXa) inhibition Adapted from Turpie AG et al. N Engl J Med 2001;344:61925 AT Indirect FXa inhibitor AT FXa Direct FXa inhibitor INDIRECT Binds to antithrombin (AT) and potentiates the activity of AT against FXa (e.g. idraparinux, SSR 126517) DIRECT Binds directly to the active site of FXa, blocking substrate interactions (e.g. apixaban, rivaroxaban, edoxaban, betrixaban) Slide 22 22 Summary: targets of novel antithrombotic agents Thrombin is the central player in the blood-clotting process and has several key properties that make it an excellent target for inhibition Direct thrombin inhibitors (e.g. dabigatran, ximelagatran and AZD0837) act directly on free and clot-bound thrombin, blocking its substrate interactions and thereby preventing fibrin formation Factor Xa (FXa) can be inhibited by antithrombotics either: Indirectly, through binding to antithrombin (e.g. idraparinux and SSR 126517) Directly, by interacting with the active site of FXa and blocking its substrate interactions (e.g. apixaban, rivaroxaban and edoxaban) Slide 23 Direct thrombin inhibitors Slide 24 24 Direct thrombin inhibitors (DTIs): past and present A well-established approach to antithrombotic therapy 1 CharacteristicHirudinBivalirudinArgatroban Ximelagatran* and melagatran Dabigatran etexilate AZD0837 Route of administration IV, SCIV IV, SC, oralOral Half-life60120 min 25 min45 min25 hrs1217 hrs914 hrs ClearanceKidney (100%) 2 Kidney (50%), endogenous peptidases (50%) 3 Liver (65%), kidney (20%) 4 Kidney (70%) 5 Kidney (80%) 6 Kidney, intestine 7 *Withdrawn in 2006 IV = intravenous; SC = subcutaneous 1. Data from Di Nisio M et al. N Engl J Med 2005;353:102840; 2. Markwardt F et al. Thromb Haemost 1984;52:1603; 3. Markwardt F et al. Biomed Biochim Acta 1987;46:23744; 4. Novastan: SmPC, 2009; 5. Erikkson UG et al. Drug Metab Dispos 2003;31:294305; 6. Pradaxa: SmPC, 2009; 7. Lip GY et al. Eur Heart J 2009;30:2897907 Slide 25 25 Dabigatran etexilate Oral prodrug, converted to dabigatran, which is a potent and reversible direct thrombin inhibitor (DTI) Inhibits both clot-bound and free thrombin 6.5% bioavailability Peak plasma levels of dabigatran achieved within 2 hours after administration in healthy volunteers Half-life of 1217 hours ~80% renal excretion Most advanced DTI in Phase III development for stroke prevention in patients with AF Recently demonstrated superiority to warfarin in the Phase III RE-LY study Pradaxa: SmPC, 2009; Connolly SJ et al. N Engl J Med 2009;361:113951 Disclaimer: Dabigatran etexilate is not approved for clinical use in stroke prevention in atrial fibrillation outside the US and Canada. This information is provided for medical education purposes only. Please be aware that there may be national differences between countries regarding specific medical information, including licensed uses, so please check local prescribing information for further details. Slide 26 26 Dabigatran etexilate has key features that make it an effective antithrombotic for stroke prevention Twice-daily dosing 1 Predictable and consistent pharmacokinetic profile 2,3 Rapid onset/offset of action 2 No requirement for anticoagulation monitoring 4 Low potential for drugdrug interactions 1,5 Not metabolized by CYP450 enzymes, and does not affect the metabolism of other drugs that utilize this system 1,5 No fooddrug interactions, with dosing independent of meals or dietary restrictions 6 1. Pradaxa: SmPC, 2009; 2. Stangier J et al. Clin Pharmacokinet 2008;28:4759; 3. Stangier J Clin Pharmacokinet 2008;47:28595; 4. Stangier J et al. Br J Pharmacol 2007;64:292303; 5. Blech S et al. Drug Metab Dispos 2008;36:38699; 6. Stangier J et al. J Clin Pharmacol 2005;45:55563 Disclaimer: Dabigatran etexilate is not approved for clinical use in stroke prevention in atrial fibrillation outside the US and Canada. This information is provided for medical education purposes only. Please be aware that there may be national differences between countries regarding specific medical information, including licensed uses, so please check local prescribing information for further details. Slide 27 27 Phase III RE-LY : largest AF outcomes trial 18 113 patients randomized during 2 years 1,2 50% of enrolled patients are nave to previous oral anticoagulant Median treatment duration: 2 years 951 centres in 44 countries December 2005 to March 2009 Results first presented at ESC congress 2009 and published online in New England Journal of Medicine on 30 Aug 2009 RE-LY : Randomized Evaluation of Long-term anticoagulant therapy 1. Ezekowitz MD et al. Am Heart J 2009;157:80510; 2. Connolly SJ et al. N Engl J Med 2009;361:113951 ESC = European Society of Cardiology Disclaimer: Dabigatran etexilate is not approved for clinical use in stroke prevention in atrial fibrillation outside the US and Canada. This information is provided for medical education purposes only. Please be aware that there may be national differences between countries regarding specific medical information, including licensed uses, so please check local prescribing information for further details. Slide 28 28 Phase III RE-LY : study design Ezekowitz MD et al. Am Heart J 2009;157:80510; Connolly SJ et al. N Engl J Med 2009;361:113951 Primary objective: to establish the non-inferiority of dabigatran to warfarin Minimum 1 year follow-up, maximum of 3 years and median of 2 years of follow-up AF with 1 risk factor Absence of contraindications* R Dabigatran 110 mg BID n=6000 Warfarin 1 mg, 3 mg, 5 mg (INR 2.03.0) n=6000 Dabigatran 150 mg BID n=6000 *Severe heart-valve disorder, stroke 14 days or severe stroke 6 months before screening, increased haemorrhage risk, creatinine clearanceSlide 29 Phase III RE-LY : study inclusion and exclusion criteria Ezekowitz MD et al. Am Heart J 2009;157:80510; Connolly SJ et al. N Engl J Med 2009;361:113951 Exclusion criteria 1.Severe heart-valve disorder 2.Stroke within 14 days or severe stroke within 6 months before screening 3.Any condition that increases the risk of haemorrhage 4.Creatinine clearance 45 Time-dependent elevation of liver enzymes (ALT >3xULN): pooled analysis of SPORTIF III and V trials Albers GW. Am J Manag Care 2004;10(14 Suppl):S4629; discussion S46973 0.8% ALT >3xULN Event rate (%) 10 8 6 4 2 0 6.1% 50 40 30 20 10 0 Month 27211816151312111091345678 Incidence of ALT >3xULN (n) ALT = alanine transaminase; ULN = upper limit of normal WarfarinXimelagatran Figures reproduced with permission: 2004, Managed Care & Healthcare Communications, LLC Slide 46 46 AZD0837 Prodrug converted to the selective and reversible direct thrombin inhibitor, AR-H067637 Half-life of AR-H067637 is 914 hours in healthy subjects Excreted in the urine and faeces Phase II, randomized, double-blind, dose-guiding study completed in patients with AF to assess safety, tolerability, pharmacokinetics and pharmacodynamics AF patients (n=955) with 1 additional risk factors for stroke were randomized to receive AZD0837 (150, 300 or 450 mg OD or 200 mg BID) or a VKA for 39 months ~30% of patients were nave to VKA treatment Lip GY et al. Eur Heart J 2009;30:2897 907 BID = twice daily; OD = once daily; VKA = vitamin K antagonist Slide 47 47 Lower doses of AZD0837 are associated with less bleeding than VKA VKAAZD0837 BID = twice daily; INR = international normalized ratio; OD = once daily; VKA = vitamin K antagonist Lip GY et al. Eur Heart J 2009;30:2897907 10.6% 14.5% 11.0% 5.3% 14.1% Any bleeding (% patients) 20 15 10 5 0 150 mg OD 300 mg OD 450 mg OD 200 mg BID INR 2.03.0 Slide 48 48 Preliminary clinical results with AZD0837 AZD0837 was generally well tolerated at all doses Most commonly reported adverse events were gastrointestinal disorders (e.g. diarrhoea, flatulence or nausea) While the study was not powered to compare stroke and systemic embolic events associated with AZD0837 and VKAs, few events were reported in either treatment arm: Ischaemic stroke (two on AZD0837 150 mg OD, one on VKA) Transient ischaemic attack (one on AZD0837 200 mg BID, one on VKA) Systemic embolus (one on AZD0837 150 mg OD) Frequency of serum ALT >3xULN was similar for AZD0837 and VKA treatment AZD0837 300 mg OD provides similar suppression of thrombogenesis (based on levels of D-dimer) to dose-adjusted VKA, with a lower risk of bleeding Lip GY et al. Eur Heart J 2009;30:2897907 BID = twice daily; OD = once daily; ULN = upper limit of normal; VKA = vitamin K antagonist Slide 49 49 Summary: direct thrombin inhibitors (DTIs) Proof-of-concept for direct thrombin inhibition has been provided with ximelagatran Withdrawn from clinical development and all markets in 2006 due to liver toxicity Landmark studies have shown clinical effectiveness for DTIs in large Phase III trials The pivotal Phase III trial (RE-LY ) recently demonstrated superiority of dabigatran to warfarin in the prevention of stroke in patients with AF Disclaimer: Dabigatran etexilate is not approved for clinical use in stroke prevention in atrial fibrillation outside the US and Canada. This information is provided for medical education purposes only. Please be aware that there may be national differences between countries regarding specific medical information, including licensed uses, so please check local prescribing information for further details. Slide 50 Direct factor Xa inhibitors Slide 51 51 Ongoing Phase III trials with direct factor Xa inhibitors for the prevention of stroke in patients with AF Trial acronym DrugDoseComparatorN CHADS 2 score Expected completion date ARISTOTLE 1,2 Apixaban 5 mg BID Warfarin (INR 2.03.0) 18 0001Apr 2011 AVERROES 3,4 Apixaban 5 mg BID Aspirin (81324 mg OD) 60001Aug 2010 ROCKET-AF 5,6 Rivaroxaban 20 mg* OD Warfarin (INR 2.03.0) 14 0002May 2010 ENGAGE-AF TIMI 48 7 Edoxaban 30 mg OD 60 mg OD Warfarin (INR 2.03.0) 16 5002Mar 2011 *Adjusted based on renal function; BID = twice daily; INR = international normalized ratio; OD = once daily 1. NCT00412984 at www.clinicalTrials.gov, accessed Sept 09; 2. Lopes RD et al. Am Heart J 2010;159:3319; 3. NCT00496769 at www.clinicalTrials.gov, accessed Sept 09; 4. Eikelboom JW et al. Am Heart J 2010;159:34853; 5. NCT00403767 at www.clinicalTrials.gov, accessed Sept 09; 6. ROCKET-AF Study Investigators. Am Heart J 2010;159:340477; 7. NCT00781391; available at www.ClinicalTrials.gov; accessed Sept 09 Slide 52 52 Apixaban Highly selective and potent inhibitor of factor Xa Bioavailability of >50% Half-life of between 9 and 14 hours Metabolized in the liver via CYP3A4 Eliminated through renal (~25%) and intestinal routes (~70%) Two Phase III studies are currently underway to investigate stroke prevention in AF ARISTOTLE (vs. warfarin) AVERROES (vs. Aspirin) Khoo CW et al. Int J Clin Pract 2009;63:63041 Slide 53 53 Apixaban and stroke prevention in AF: Phase III ARISTOTLE Randomized, double-blind, non-inferiority trial 1 Investigating the safety and efficacy of apixaban 5 mg BID compared with dose-adjusted warfarin Approximately 18 000 patients with non-valvular AF Primary outcome: Stroke or systemic embolism Secondary outcomes: Ischaemic stroke, haemorrhagic stroke, systemic embolism and all causes of death 1. Lopes RD et al. Am Heart J 2010;159:3319 Slide 54 54 Phase III ARISTOTLE: study inclusion criteria LVEF = left ventricular ejection fraction Inclusion criteria 1.Males and females aged 18 yrs with documented AF 2.Presence of at least one of the following risk factors for stroke (CHADS 2 1): Age 75 yrs Previous stroke, transient ischaemic attack or systemic embolism Symptomatic congestive heart failure or left ventricular dysfunction with LVEF 40% Diabetes mellitus or hypertension requiring pharmacological treatment Lopes RD et al. Am Heart J 2010;159:3319 Slide 55 55 Phase III ARISTOTLE: study exclusion criteria Exclusion criteria 1.AF or flutter due to reversible causes (e.g. thyrotoxicosis, pericarditis) 2.Clinically significant (moderate or severe) mitral stenosis 3.Increased bleeding risk 4.Conditions other than AF that require chronic anticoagulation 5.Persistent, uncontrolled hypertension 6.Active infective endocarditis 7.Planned major surgery (e.g. AF or flutter ablation procedure) 8.Use of an unapproved, investigational drug or device within the past 30 days 9.Required treatment with Aspirin >165 mg/day 10.Simultaneous treatment with both Aspirin and a thienopyridine (e.g. clopidogrel, ticlopidine) 11.Severe comorbid condition with life expectancy of 59 Phase III AVERROES: study exclusion criteria Exclusion criteria 1.AF due to reversible causes (e.g. thyrotoxicosis, pericarditis) 2.Valvular disease requiring surgery 3.Planned AF ablation procedure within 3 months 4.Conditions other than AF that require chronic anticoagulation 5.Patients with serious bleeding in the past 6 months or at high risk of bleeding: Active peptic ulcer disease Platelet count 2.5 mg/dL or a calculated creatinine clearance 2xULN or a total bilirubin 1.5xULN (unless an alternative causative factor [e.g. Gilbert's syndrome] is identified) 10.Women who are pregnant or breastfeeding ALT = alanine transferase; AST = aspartate transferase; ULN = upper limit of normal Eikelboom JW et al. Am Heart J 2010;159:34853 Slide 60 60 Phase III AVERROES: baseline characteristics CharacteristicApixabanAspirin Randomized28092791 Age (meanSD)7010 yrs Male59%58% CHADS 2 score (meanSD)2.11.1 0136%37% 2 34% 3+27%29% Prior stroke/TIA14%13% Diabetes19%20% Hypertension86%87% CHF40%38% Baseline ASA76%74% Unsuitable for VKA VKA used and discontinued39%40% VKA expected unsuitable61%60% TIA = transient ischaemic attack; CHF = congestive heart failure; VKA = vitamin K antagonist Connolly SJ et al. Presented at ESC 2010; session number 708005-708006. Available at: http://www.escardio.org/congresses/esc-2010/congress- reports/Pages/708-3-AVERROES.aspx [Accessed September 2010] Slide 61 61 Phase III AVERROES: stroke or systemic embolic event Connolly SJ et al. Presented at ESC 2010; session number 708005-708006. Available at: http://www.escardio.org/congresses/esc-2010/congress- reports/Pages/708-3-AVERROES.aspx [Accessed September 2010] RR = relative risk; CI = confidence interval Cumulative risk 0.02 0.04 0.05 0.06 0.07 0 0.01 0.03 0 Months 369121821 27912720254121241541626329 28092761258721271523617352 Aspirin Apixaban RR 0.46 95% CI: 0.330.64 P