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National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

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Presentation on theme: "National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in."— Presentation transcript:

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2 National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in Thrombosis Mitigation for the Cardiovascular SpecialistTranslating Evidence into Action New Dimensions and Landmark Practice Advances Program Moderator Samuel Z. Goldhaber, MD Cardiovascular Division Brigham and Womens Hospital Professor of Medicine Harvard Medical School

3 CME-accredited symposium jointly sponsored by the University of Massachusetts Medical School and CMEducation Resources, LLC Commercial Support: Sponsored by an independent educational grant from Boehringer-Ingelheim Mission statement: Improve patient care through evidence-based education, expert analysis, and case study-based management Processes: Strives for fair balance, clinical relevance, on-label indications for agents discussed, and emerging evidence and information from recent studies COI: Full faculty disclosures provided in syllabus and at the beginning of the program Welcome and Program Overview

4 Program Educational Objectives As a result of this educational activity, participants will learn about: Advances in oral anticoagulation based on new mechanisms involving inhibition of the coagulation cascade and possible implications for prophylaxis of arterial thromboembolism in the setting of atrial fibrillation. The mechanisms involved in thromboembolic prevention and the rationale for identifying agents with predictable anticoagulation, in the absence of clinical monitoring. Current ACCP, ACC, AHA, and AAN guidelines for stroke prevention in the setting of AF. Novel approaches for residual risk reduction and secondary prevention of adverse thromboembolic events (stroke) in the setting of atrial fibrillation, and related conditions. As a result of this educational activity, participants will learn about: Advances in oral anticoagulation based on new mechanisms involving inhibition of the coagulation cascade and possible implications for prophylaxis of arterial thromboembolism in the setting of atrial fibrillation. The mechanisms involved in thromboembolic prevention and the rationale for identifying agents with predictable anticoagulation, in the absence of clinical monitoring. Current ACCP, ACC, AHA, and AAN guidelines for stroke prevention in the setting of AF. Novel approaches for residual risk reduction and secondary prevention of adverse thromboembolic events (stroke) in the setting of atrial fibrillation, and related conditions.

5 Program Faculty Program Moderator Samuel Z. Goldhaber, MD Cardiovascular Division Brigham and Womens Hospital Professor of Medicine Harvard Medical School Jonathan L. Halperin, MD Professor of Medicine (Cardiology) Mount Sinai School of Medicine Director, Clinical Cardiology Services The Zena and Michael A. Wiener Cardiovascular Institute Cardiovascular Institute The Marie-Josée and Henry R. Kravis Center for Cardiovascular Health Center for Cardiovascular Health Elaine M. Hylek, MD, MPH Elaine M. Hylek, MD, MPH Associate Professor of Medicine Department of Medicine Director, Thrombosis Clinic and Anticoagulation Service Anticoagulation Service Boston University Medical Center Boston, Massachusetts Jeffrey I. Weitz, MD, FRCP, FACP Professor of Medicine and Biochemistry McMaster University Director, Henderson Research Center Canada Research Chair in Thrombosis Heart and Stroke Foundation J.F. Mustard Chair in Cardiovascular Research Research

6 Faculty COI Disclosures Samuel Z. Goldhaber, MD Research Support: BMS, Boehringer-Ingelheim, Eisai, Johnson and Johnson, sanofi- aventis Consultant: BMS, Boehringer-Ingelheim, Eisai, Medscape, Merck, sanofi-aventis, Vortex Jonathan L. Halperin, MD Consulting fees from the following companies involved in development of investigational drugs or devices: Astellas Pharma, U.S., Bayer HealthCare, Biotronik, Inc., Boehringer Ingelheim, Daiichi Sankyo Pharma, Johnson & Johnson, Portola Pharmaceuticals, and sanofi-aventis Elaine M. Hylek, MD, MPH Steering Committee: Bristol-Myers Squibb Advisory Board: Astellas, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, sanofi- aventis Jeffrey I. Weitz, MD, FRCP, FACP Grants/Research Support: CIHR, HSFO, CFI, ORF Speakers Bureau: Bristol-Myers Squibb, Boehringer Ingelheim, sanofi-aventis, Daiichi- Sankyo, Bayer, Pfizer, The Medicines Company, Eisai, Takeda

7 ATRIAL FIBRILLATION Current Challenges in Thrombosis Medicine for the Cardiovascular Specialist Samuel Z. Goldhaber, MD Cardiovascular Division Brigham and Womens Hospital Professor of Medicine Harvard Medical School New Frontiers in Atrial Fibrillation

8 Atrial Fibrillation: Twice as Common as Previously Suspected Incidence increased 13% over past 20 years Incidence increased 13% over past 20 years In USA, million will be affected by 2050 In USA, million will be affected by 2050 Increasing obesity and increasing age are risk factors that help explain rise in incidence Increasing obesity and increasing age are risk factors that help explain rise in incidence Incidence increased 13% over past 20 years Incidence increased 13% over past 20 years In USA, million will be affected by 2050 In USA, million will be affected by 2050 Increasing obesity and increasing age are risk factors that help explain rise in incidence Increasing obesity and increasing age are risk factors that help explain rise in incidence Miyasaka Y. Circulation 2006; 114:

9 AF Prevalence: Age and Gender JAMA 2001; 285: 2370 Prevalence of atrial fibrillation with age Prevalence of atrial fibrillation with age Age, years Prevalence, percent

10 Mortality Rates in AF Double the overall age and gender matched population Double the overall age and gender matched population No reduction in past two decades No reduction in past two decades Mortality 9-fold higher during 1 st 4 months after diagnosis Mortality 9-fold higher during 1 st 4 months after diagnosis Double the overall age and gender matched population Double the overall age and gender matched population No reduction in past two decades No reduction in past two decades Mortality 9-fold higher during 1 st 4 months after diagnosis Mortality 9-fold higher during 1 st 4 months after diagnosis Miyasaka Y, et al. JACC 2007; 49:

11 Risk Factors for Stroke Risk Factor Relative Risk Old Stroke/TIA 2.5 Hypertension1.6 CHF1.4 Increased age 1.4/10 years DM1.7 CAD1.5 Arch Intern Med 1994; 154: Arch Intern Med 1994; 154:

12 Atrial Fibrillation: A Risk Factor for Vascular Events Atherosclerosis/Atherothrombosis MIAF CHF Wolf PA et al. Arch Intern Med 1987; 147: Leckey R et al. Can J Cardiol 2000; 16: RISK FACTORS for THROMBOSIS RISK FACTORS for THROMBOSIS HypertensionHypertension Hyperlipidemia Hyperlipidemia Age Age Diabetes Mellitus Diabetes Mellitus Smoking Smoking Atherosclerosis/Atherothrombosis Stroke, MI, Vascular Death MI AF CHF

13 Thrombus in left atrial appendage is correlated with increased thromboembolic risk in AF Thrombus Left Atrial Appendage Chimowitz. Stroke 1993; 24: 1015 Zabalgoitia. J Am Coll Cardiol 1998; 31: 1622 Thrombus in Left Atrial Appendage Associated with Stroke

14 Wolf et al. Stroke 1991; 22: One Sixth of all Strokes Attributable to AF % AF prevalence Strokes attributable to AF Age Range (years) Framingham Study –5960–69 70–79 80–89

15 Problems with Established Therapy: Warfarin Delayed onset/offset Delayed onset/offset Unpredictable dose response Unpredictable dose response Narrow therapeutic range Narrow therapeutic range Drug–drug, drug–food interactions Drug–drug, drug–food interactions Problematic monitoring Problematic monitoring High bleeding rate High bleeding rate Slow reversibility Slow reversibility Delayed onset/offset Delayed onset/offset Unpredictable dose response Unpredictable dose response Narrow therapeutic range Narrow therapeutic range Drug–drug, drug–food interactions Drug–drug, drug–food interactions Problematic monitoring Problematic monitoring High bleeding rate High bleeding rate Slow reversibility Slow reversibility

16 First Month of Warfarin Therapy has High Bleeding Rate Bleeding Type Head Bleed Major Non- Head Bleed 1 st Month Warfarin 0.92% (annualized) 1.2% (annualized) Subsequent Warfarin 0.46% per year 0.61% per year Fang MC. J Am Geriatr Soc 2006; 54:

17 FDA Adds Black Box Warning/Precaution for Warfarin October 6, 2006 August 16, 2007 Precaution: Consider a lower initial warfarin dose for patients with certain genetic variations. Warning: Bleeding Risk

18 Warfarin dosing and genetics Warfarin dosing and genetics FDA warfarin labeling vs. NHLBI Randomized Clinical Trial FDA warfarin labeling vs. NHLBI Randomized Clinical Trial Warfarin dosing and genetics Warfarin dosing and genetics FDA warfarin labeling vs. NHLBI Randomized Clinical Trial FDA warfarin labeling vs. NHLBI Randomized Clinical Trial Learning Objectives

19 Warfarin: Advantages 1.INR assesses anticoagulant level 2.Multiple antidotes available 3.Omitting one or two doses usually is not clinically problematic 4.Introduced in Has stood the test of time. No liver toxicity 5.Ability to maintain target INR is improving (Now > 60% in top facilities) 6.No anticoagulant has demonstrated superior efficacy or safety 7.Inexpensive 1.INR assesses anticoagulant level 2.Multiple antidotes available 3.Omitting one or two doses usually is not clinically problematic 4.Introduced in Has stood the test of time. No liver toxicity 5.Ability to maintain target INR is improving (Now > 60% in top facilities) 6.No anticoagulant has demonstrated superior efficacy or safety 7.Inexpensive

20 Excessive dose precipitates hemorrhage Excessive dose precipitates hemorrhage Inadequate dose predisposes to stroke and pulmonary embolism Inadequate dose predisposes to stroke and pulmonary embolism Dosing nomograms are awkward, cumbersome Dosing nomograms are awkward, cumbersome Dosing by trial and error predominates Dosing by trial and error predominates Excessive dose precipitates hemorrhage Excessive dose precipitates hemorrhage Inadequate dose predisposes to stroke and pulmonary embolism Inadequate dose predisposes to stroke and pulmonary embolism Dosing nomograms are awkward, cumbersome Dosing nomograms are awkward, cumbersome Dosing by trial and error predominates Dosing by trial and error predominates Warfarin: Walking a Tightrope

21 Therapeutic Range for Warfarin INR Values at Stroke or ICH Odds Ratio INR Stroke 1.0 Fuster et al. J Am Coll Cardiol. 2001;38: Intracranial Hemorrhage

22 Hylek, EM et al. N Engl J Med. 2003;349:

23 Fang MC et al. Ann Intern Med. 2004;141: Most intracranial hemorrhages (62%) occur at INRs < 3.0

24 Reduction of Stroke in AF – Warfarin Compared with Placebo Hart et al. Ann Intern Med 1999; 131: Hart et al. Ann Intern Med 1999; 131: Adjusted-dose warfarin compared with placebo AFASAK I SPAF BAATAF CAFA SPINAF EAFT All trials (n=6) Relative risk reduction (95% CI) Warfarin better Warfarin worse 62% (48% to 72%)

25 ACTIVE W Trial OAC Standard Care (INR 2.0 – 3.0) Standard Care (INR 2.0 – 3.0) INR at least monthly INR at least monthly Clopidogrel plus ASA Clopidogrel 75 mg once daily Clopidogrel 75 mg once daily ASA mg once daily ASA mg once daily

26 ACTIVE W: Outcome Events Primary Outcome Stroke, Non-CNS Systemic Embolism, MI, Vascular DeathStroke, Non-CNS Systemic Embolism, MI, Vascular Death Safety Outcome Major Bleeding Major Bleeding

27 ACTIVE W: Stroke, Non-CNS Embolism, MI and Vascular Death Cumulative Hazard Rates Years # at Risk C+A OAC %/year 5.64 %/year RR = 1.45 P =

28 ACTIVE W: Major Bleeding Cumulative Hazard Rates Years # at Risk C+A OAC %/year 2.2 %/year Lancet. 2006;367: , RR = 1.06 P = 0.67

29 New oral anticoagulants, given in fixed dose without laboratory coagulation monitoring, may improve and expand on existing anticoagulation options. We will hear about these exciting development tonight. The Frontiers of Thrombosis: Mitigation (Stroke Reduction) in Atrial Fibrillation

30 Challenges in Stroke Prevention for Patients with Atrial Fibrillation Achieving Balance Between Prevention of Thromboembolism and Risk of Bleeding New Frontiers in Atrial Fibrillation Jonathan L. Halperin, MD Professor of Medicine (Cardiology) Mount Sinai School of Medicine Director, Clinical Cardiology Services The Zena and Michael A. Wiener Cardiovascular Institute The Marie-Josée and Henry R. Kravis Center for Cardiovascular Health

31 Projected U.S. Prevalence of AF An Expanding Epidemic Miyakasa Y, et al. Circulation 2006; 114: Year Projected Number of People with AF (millions) Based on Projected Incidence Based on Current Incidence

32 Atrial Fibrillation A Substantial Threat to the Brain Affects Affects ~4% of people aged >60 years ~9% of those aged >80 years ~9% of those aged >80 years 5%/year stroke rate 5%/year stroke rate 12%/year for those with prior stroke 12%/year for those with prior stroke $ billions annual cost for stroke care $ billions annual cost for stroke care AF-related strokes have worse outcomes AF-related strokes have worse outcomes Affects Affects ~4% of people aged >60 years ~9% of those aged >80 years ~9% of those aged >80 years 5%/year stroke rate 5%/year stroke rate 12%/year for those with prior stroke 12%/year for those with prior stroke $ billions annual cost for stroke care $ billions annual cost for stroke care AF-related strokes have worse outcomes AF-related strokes have worse outcomes AF identifies millions of people with a five-fold increased risk of stroke

33 Priorities in the Management of AF The Patient Care Pathway Rhythm Control Prevention of Thromboembolism Rate Control

34 Natural History of Lone Atrial Fibrillation No Cardiopulmonary Disease: <60 Years Old Kopecky S, et al. N Engl J Med 1987; 317: Patients Mean Age = years Follow-up 0.35%/yr Stroke 0.40%/yr Mortality

35 Stroke Risk in Atrial Fibrillation Untreated Control Groups of Randomized Trials Atrial Fibrillation Investigators. Arch Intern Med 1994;154:1449. Stroke Rate (% per year) Age (years)

36 Anticoagulation in Atrial Fibrillation Stroke Risk Reductions Hart R, et al. Ann Intern Med 2007;146:857. WarfarinBetterControlBetter AFASAK SPAF BAATAF CAFA SPINAF EAFT 100% 50% 0 -50% -100% Aggregate

37 Anticoagulation in Atrial Fibrillation The Standard of Care for Stroke Prevention WarfarinBetterControlBetter AFASAK SPAF BAATAF CAFA SPINAF EAFT 100% 50% 0 -50% -100% Aggregate Terminated early Double-blind; Men only Unblinded 2 o prevention; Unblinded Hart R, et al. Ann Intern Med 2007;146:857.

38 Antithrombotic Therapy for Atrial Fibrillation Stroke Risk Reduction Antiplatelet drugs vs. Placebo Warfarin vs. Placebo/Control 100% 50% 0 -50% 6 Trials n = 2,900 8 Trials n = 4,876 TreatmentBetterTreatmentWorse Hart R, et al. Ann Intern Med 2007;146:857.

39 Efficacy of Warfarin in Trials vs. Practice Stroke Risk Reductions Warfarin vs. No anticoagulation Warfarin vs. Placebo/Control 100% 50% 0 -50% 6 Trials n = 2,900 Medicare cohort n = 23,657 TreatmentBetterTreatmentWorse Hart R, et al. Ann Intern Med 2007;146:857 Birman-Deych E. Stroke 2006; 37: 1070–1074

40 Intracerebral Hemorrhage >10% of intracerebral hemorrhages (ICH) occur in patients on antithrombotic therapy >10% of intracerebral hemorrhages (ICH) occur in patients on antithrombotic therapy Aspirin increases the by ~ 40% Aspirin increases the by ~ 40% Warfarin (INR 2–3) doubles the risk to 0.3– 0.6%/year Warfarin (INR 2–3) doubles the risk to 0.3– 0.6%/year ICH during anticoagulation is catastrophic ICH during anticoagulation is catastrophic Hart RG, et al. Stroke 2005;36:1588 The Most Feared Complication of Antithrombotic Therapy

41 Risk Stratification in AF Stroke Risk Factors High-Risk Factors Mitral stenosis Mitral stenosis Prosthetic heart valve Prosthetic heart valve History of stroke or TIA History of stroke or TIA High-Risk Factors Mitral stenosis Mitral stenosis Prosthetic heart valve Prosthetic heart valve History of stroke or TIA History of stroke or TIA Singer DE, et al. Chest 2004;126:429S. Fang MC, et al. Circulation 2005; 112: 1687.

42 High-Risk Factors Mitral stenosis Mitral stenosis Prosthetic heart valve Prosthetic heart valve History of stroke or TIA History of stroke or TIA High-Risk Factors Mitral stenosis Mitral stenosis Prosthetic heart valve Prosthetic heart valve History of stroke or TIA History of stroke or TIA Moderate-Risk Factors Age >75 yearsAge >75 years HypertensionHypertension Diabetes mellitusDiabetes mellitus Heart failure or LV functionHeart failure or LV function Risk Stratification in AF Stroke Risk Factors Singer DE, et al. Chest 2004;126:429S. Fang MC, et al. Circulation 2005; 112: 1687.

43 High-Risk Factors Mitral stenosis Mitral stenosis Prosthetic heart valve Prosthetic heart valve History of stroke or TIA History of stroke or TIA High-Risk Factors Mitral stenosis Mitral stenosis Prosthetic heart valve Prosthetic heart valve History of stroke or TIA History of stroke or TIA Moderate-Risk Factors Age >75 years Age >75 years Hypertension Hypertension Diabetes mellitus Diabetes mellitus Heart failure or LV function Heart failure or LV function Less Validated Risk Factors Age 65–75 years Coronary artery disease Coronary artery disease Female gender Female gender Thyrotoxicosis Thyrotoxicosis Risk Stratification in AF Stroke Risk Factors Singer DE, et al. Chest 2004;126:429S. Fang MC, et al. Circulation 2005; 112: 1687.

44 High-Risk Factors Mitral stenosis Mitral stenosis Prosthetic heart valve Prosthetic heart valve History of stroke or TIA History of stroke or TIA High-Risk Factors Mitral stenosis Mitral stenosis Prosthetic heart valve Prosthetic heart valve History of stroke or TIA History of stroke or TIA Moderate-Risk Factors Age >75 years Age >75 years Hypertension Hypertension Diabetes mellitus Diabetes mellitus Heart failure or LV function Heart failure or LV function Less Validated Risk Factors Age 65–75 years Coronary artery disease Coronary artery disease Female gender Female gender Thyrotoxicosis Thyrotoxicosis Dubious Factors Duration of AF Pattern of AF Pattern of AF (persistent vs. paroxysmal) Left atrial diameter Left atrial diameter Risk Stratification in AF Stroke Risk Factors Singer DE, et al. Chest 2004;126:429S. Fang MC, et al. Circulation 2005; 112: 1687.

45 The CHADS 2 Index Stroke Risk Score for Atrial Fibrillation Congestive Heart failure 1 32 Hypertension 1 65 Age >75 years 1 28 Diabetes mellitus 1 18 Stroke or TIA 2 10 Moderate-High risk> Low risk VanWalraven C, et al. Arch Intern Med 2003; 163:936. VanWalraven C, et al. Arch Intern Med 2003; 163:936. * Nieuwlaat R, et al. (EuroHeart survey) Eur Heart J 2006 (E-published). Prevalence (%)* Score (points)

46 Nonvalvular Atrial Fibrillation PriorStroke/TIA Age > 75 years Hypertension FemaleDiabetes Heart Failure LVEF LVEF Stroke Rate (%/year) Hart RG et al. Neurology 2007; 69: 546. Stroke Rates Without Anticoagulation According to Isolated Risk Factors

47 Van Walraven C, et al. Arch Intern Med 2003; 163:936. Go A, et al. JAMA 2003; 290: Gage BF, et al. Circulation 2004; 110: Risk of Stroke (%/year) Score(points) 3%/year Approximate Risk threshold for Anticoagulation The CHADS 2 Index Stroke Risk Score for Atrial Fibrillation

48 Risk Stratification and Anticoagulation Stroke Reduction with Warfarin Instead of Aspirin Number of patients Needed-to-treat to prevent 1 stroke/year EAFT Study Group. Lancet 1993; 324:1255. Zabalgoitia M, et al. J Am Coll Cardiol 1998; 31: CHADS 2 Score ~

49 Antithrombotic Therapy for Atrial Fibrillation ACC/AHA/ESC Guidelines 2006 Risk Factor Recommended Therapy No risk factors CHADS 2 = 0 Aspirin, mg qd One moderate risk factor CHADS 2 = 1 Aspirin, mg/d or Warfarin (INR , target 2.5) Any high risk factor or >1 moderate risk factor CHADS 2 >2 or Mitral stenosis Warfarin (INR , target 2.5) Prosthetic valve Warfarin (INR , target 3.0)

50 "Actually, it's more of a guideline than a rule. Bill Murray in Ghostbusters (1984), Bill Murray in Ghostbusters (1984), relaxing his rule "never to get involved with possessed people" in response to Sigourney Weaver's seductive advances. "Actually, it's more of a guideline than a rule. Bill Murray in Ghostbusters (1984), Bill Murray in Ghostbusters (1984), relaxing his rule "never to get involved with possessed people" in response to Sigourney Weaver's seductive advances.

51 Patient Selection for Anticoagulation Additional Considerations Risk of bleedingRisk of bleeding Newly anticoagulated vs. established therapyNewly anticoagulated vs. established therapy Availability of high-quality anticoagulation management programAvailability of high-quality anticoagulation management program Patient preferencesPatient preferences

52 INR at the Time of Stroke or Bleeding Efficacy and Safety of Warfarin Ischemic Stroke Intracranial bleeding 1 20 Odds Ratio International Normalized Ratio Fang MC, et al. Ann Intern Med 2004; 141:745. Hylek EM, et al. N Engl J Med 1996; 335:540.

53 Warfarin for Atrial Fibrillation Limitations Lead to Inadequate Treatment Samsa GP, et al. Arch Intern Med 2000;160:967. INR above target 6% Subtherapeutic INR 13% INR in target range 15% No warfarin 65% Adequacy of Anticoagulation in Patients with AF in Primary Care Practice

54 The ACTIVE Trial Clopidogrel + Aspirin Atrial Fibrillation + Risk Factors VKA (INR 2-3) Clopidogrel + Aspirin Aspirin + Placebo Clopidogrel + Aspirin Double-blind Superiority n = 7,554 Open-label Non-inferiority n = 6,706 Anticoagulation-eligible OAC Contraindications or Unwilling Irbesartan, 300 mg/d vs. Placebo n = 9,016 Primary outcome: Stroke, systemic embolism, MI or cardiovascular death ACTIVE - W ACTIVE - A ACTIVE - I Risk Factors: Age 75, hypertension, prior stroke/TIA, LVEF<45%, PAD, age CAD or diabetes

55 The ACTIVE Trial Clopidogrel + Aspirin Atrial Fibrillation + Risk Factors ACTIVE – W ACTIVE – W VKA (INR 2-3) Clopidogrel + Aspirin Aspirin + Placebo Clopidogrel + Aspirin Double-blind Superiority n = 7,554 Open-label Non-inferiority n = 6,706 Anticoagulation-eligible OAC Contraindications or Unwilling Irbesartan, 300 mg/d vs. Placebo n = 9,016 ACTIVE - A ACTIVE - I

56 Antithrombotic Therapy for Atrial Fibrillation Stroke Risk Reductions 100% 50% 0 -50% ACTIVE-W Anticoagulation vs. Aspirin + Clopidogrel Anticoagulation vs. Antiplatelet drugs 7 Trials n = 4,232 n = 6,706 WarfarinBetter Antiplatelet Rx Better Connolly S, et al. Lancet 2006; 367:1903. Hart R, et al. Ann Intern Med 2007;146:857.

57 Antithrombotic Therapy for Atrial Fibrillation Stroke Risk Reductions 100% 50% 0 -50% Warfarin vs. Aspirin + Clopidogrel WarfarinBetter Antiplatelet Rx Better Prior OAC VKA-naïve Connolly S, et al. Lancet 2006; 367:1903. All patients

58 Major Hemorrhage in Relation to Prior Anticoagulant Therapy: ACTIVE-W Interaction p=0.028 Yes Yes Anticoagulant Therapy at Entry No No Connolly S, et al. Lancet 2006; 367:1903. Event Rate (%/year) Starters Switchers

59 The ACTIVE Trial Clopidogrel + Aspirin Atrial Fibrillation + Risk Factors ACTIVE – W ACTIVE – W VKA (INR 2-3) Clopidogrel + Aspirin Aspirin + Placebo Clopidogrel + Aspirin Double-blind Superiority n = 7,554 Open-label Non-inferiority n = 6,706 Anticoagulation-eligible OAC Contraindications or Unwilling Irbesartan, 300 mg/d vs. Placebo n = 9,016 ACTIVE - A ACTIVE - I Connolly SJ, et al. N Engl J Med 2009; 360:2066.

60 ACTIVE-A Reasons for Exclusion from Anticoagulation Risk factor for bleeding* 23% Physician judgment against anticoagulation for patient 50% Patient preference only 26% * Inability to comply with INR monitoring * Predisposition to falling or head trauma * Persistent hypertension >160/100 mmHg * Previous serious bleeding on VKA * Severe alcohol abuse within 2 years * Peptic ulcer disease * Thrombocytopenia * Chronic need for NSAID Connolly SJ, et al. N Engl J Med 2009; 360:2066.

61 ACTIVE-A Total Stroke Rates 296 (2.4%/year) 408 (3.3%/year) Cumulative Incidence 28% RRR HR 0.72 (95% CI, 0.62–0.83) p < Aspirin Clopidogrel + Aspirin Years Connolly SJ, et al. N Engl J Med 2009; 360:2066.

62 The ACTIVE Trials Stroke Rates and Risk Reductions Connolly SJ, et al. Lancet 2006; 367:1903. Connolly SJ, et al. N Engl J Med 2009; 360:2066. TreatmentVKAC+AAspirin ACTIVE W (Annual Rate) ~ ACTIVE A (Annual Rate) ~ RRR versus Aspirin -58%-28%~ RRR versus C+A -42%~~ VKA = oral anticoagulant C+A = clopidogrel + aspirin

63 Warfarin Dosing and Genomics CYP2C9 – Gene encoding cytochrome P450 hepatic enzyme responsible for primary clearance of S-warfarin, the active enantiomer; variant alleles are associated with sensitivity to warfarin. VKORC1 – Gene encoding vitamin K epoxide reductase complex 1; variant alleles are associated with warfarin resistance. CYP2C9 – Gene encoding cytochrome P450 hepatic enzyme responsible for primary clearance of S-warfarin, the active enantiomer; variant alleles are associated with sensitivity to warfarin. VKORC1 – Gene encoding vitamin K epoxide reductase complex 1; variant alleles are associated with warfarin resistance.

64 Warfarin Dosing and Genomics Keeping Ahead of the Data

65 Dose Initiation Dose Titration 123 4, … Intervention Period: Informed by genetic/clinical information Objective: To compare the effect of pharmacogenetic & clinical warfarin dosing algorithms on initial proportion of time in therapeutic range of anticoagulation intensity

66 Dose, Concentration, or Intensity of Anticoagulation Thrombosis Bleeding Safe Therapeutic Range Thrombosis Bleeding The Ideal Anticoagulant Wide Therapeutic Margin

67 DVT/VTEProphylaxis Orthopaedic Surgery DVT/VTETreatment AFib/StrokeProphylaxis ArterialDisease OtherPotentialIndications New Anticoagulant Development The Clinical Trial Pathway

68 Investigational Anticoagulant Targets TFPI (tifacogin) Idraparinux Rivaroxaban Apixaban LY YM150 DU-176b Betrixaban TAK 42 Dabigatran ORALPARENTERAL DX-9065a Otamixaban XaXa IIaIIa TF/VIIaTF/VIIa XIX IXa VIIIa Va II (thrombin) FibrinFibrinogen AT APC (drotrecogin alfa) sTM (ART-123) Adapted from Weitz JI. Thromb Haemost 2007; 5 Suppl 1:65-7. TTP889 APC activated protein C AT antithrombin sTM soluble thrombomodulin TF tissue factor FPI tissue factor pathway inhibitor

69 SPORTIF III and V Stroke and Systemic Embolism Difference in Absolute Event Rates (Ximelagatran – Warfarin) Ximelagatran Better Warfarin Better 012 SPORTIF III SPORTIF V p=0.10 p=0.13 PooledPooled-0.03 p= SPORTIF-V Investigators. JAMA 2005; 293:

70 SPORTIF III and V Secondary Stroke Prevention Event Rate (%/year) p=NS Δ = –0.44%/year 95% CI –1.86, 0.98; p=0.625 Diener H-C, et al. Cerebrovasc Dis 2006; 21: 279

71 Major Bleeding Complications SPORTIF III and V Event Rate (%/year) SPORTIF V Pooled SPORTIF III p=0.054 Diener H-C, et al. Cerebrovasc Dis 2006; 21: 279 On-treatment Analysis

72 SPORTIF III and V Liver Enzyme Elevations XimelagatranWarfarin Months Number of patients Incidence (%) ALT >3x ULN Diener H-C, et al. Cerebrovasc Dis 2006; 21: 279 ALT >3 x ULN

73 Emerging Anticoagulants Potential Alternatives to Warfarin Thrombin inhibitors Direct, oral Ximelagatran Dabigatran Dabigatran (RE-LY Trial) (RE-LY Trial) Thrombin inhibitors Direct, oral Ximelagatran Dabigatran Dabigatran (RE-LY Trial) (RE-LY Trial) Factor Xa inhibitors Indirect, parenteral Indirect, parenteral Idraparinux Idraparinux Direct, oral Direct, oral Rivaroxaban Rivaroxaban Apixaban Apixaban Edoxaban Edoxaban others others

74 Oral Factor Xa Inhibitors Trial Acronym DrugDoseComparatorN Risk factors ROCKET-AFRivaroxaban 20 mg* qdWarfarin (INR 2-3) 14,000 2 ARISTOTLEApixaban 5 mg bidWarfarin (INR 2-3) 15,000 1 ENGAGE-AFEdoxaban 30 mg bid 60 mg* qd Warfarin (INR 2-3) 16,500 2 * Adjusted based on renal function Ongoing Phase III Trials for Prevention of Stroke and Systemic Embolism in Patients with AF

75 Emerging Anticoagulants Regulatory Issues Open-label vs. blinded trial design Open-label vs. blinded trial design Issues related to active-control trial design Issues related to active-control trial design How many trials are needed? How many trials are needed? Preventing use for unapproved indications Preventing use for unapproved indications Assessing patient-oriented outcomes Assessing patient-oriented outcomes

76 Alternatives to Anticoagulation Atrial Fibrillation Restoration and maintenance of sinus rhythm Antiarrhythmic drug therapyAntiarrhythmic drug therapy Catheter ablationCatheter ablation Maze operationMaze operation Restoration and maintenance of sinus rhythm Antiarrhythmic drug therapyAntiarrhythmic drug therapy Catheter ablationCatheter ablation Maze operationMaze operation Current approaches Emerging (investigational) approaches Obliteration of the left atrial appendage Trans-catheter occluding devicesTrans-catheter occluding devices Thoracoscopic epicardial plicationThoracoscopic epicardial plication AmputationAmputation

77 Strokes after Conversion to NSR Rate vs. Rhythm Control Trials n Rate control Rhythm control RR (95% CI) p AFFIRM4,9175.7%7.3% 1.28 ( ) 0.12 RACE5225.5%7.9% 1.44 ( ) 0.44 STAF2661.0%3.0% 3.01 ( ) 0.52 PIAF2520.8%0.8% 1.02 ( ) 0.49 Total5,9575.0%6.5% 1.28 ( ) 0.08 Verheugt F, et al. J Am Coll Cardiol 2003;41(suppl):130A.

78 AFFIRM Trial Stroke Rates 74% of all strokes were proven ischemic 74% of all strokes were proven ischemic 44% occurred after stopping warfarin 44% occurred after stopping warfarin 28% in patients taking warfarin with INR <2.0 28% in patients taking warfarin with INR <2.0 42% occurred during documented AF 42% occurred during documented AF 74% of all strokes were proven ischemic 74% of all strokes were proven ischemic 44% occurred after stopping warfarin 44% occurred after stopping warfarin 28% in patients taking warfarin with INR <2.0 28% in patients taking warfarin with INR <2.0 42% occurred during documented AF 42% occurred during documented AF Wyse AG, et al. N Engl J Med 2002; 347: 1825 Wyse AG, et al. N Engl J Med 2002; 347: 1825.

79 ATHENA Trial Dronedarone vs. Placebo in Patients with AF Stroke Rates (Secondary Analysis ) Event Placebo (%/y) Dronedarone (%/y) HR (95% CI) p Stroke Stroke or TIA Fatal stroke Hohnloser SH, et al. N Engl J Med 2009; 360:

80 Percutaneous LAA Occlusion The WATCHMAN ® Device Syed T, Halperin JL. Nature Clin Prac Cardiovasc Med 2007; 4:428 Holmes DR, et al. Lancet 2009; 374: 534

81 Alternatives to Anticoagulation Atrial Fibrillation Restoration and maintenance of sinus rhythm Antiarrhythmic drug therapyAntiarrhythmic drug therapy Catheter ablationCatheter ablation Maze operationMaze operation Restoration and maintenance of sinus rhythm Antiarrhythmic drug therapyAntiarrhythmic drug therapy Catheter ablationCatheter ablation Maze operationMaze operation Current approaches Emerging (investigational) approaches Obliteration of the left atrial appendage Trans-catheter occluding devicesTrans-catheter occluding devices Thoracoscopic epicardial plicationThoracoscopic epicardial plication AmputationAmputation Is atrial fibrillation the cause of stroke or a marker of a population at risk?

82 Atrial Fibrillation and Thromboembolism The Next Challenges Better tools to stratify bleeding risk Better tools to stratify bleeding risk Noninvasive imaging and biomarkers of inflammation and thrombosis to predict clinical events and guide therapy Noninvasive imaging and biomarkers of inflammation and thrombosis to predict clinical events and guide therapy Confirming successful rhythm control over time Confirming successful rhythm control over time Targeted therapy to prevent AF in patients at risk Targeted therapy to prevent AF in patients at risk Better tools to stratify bleeding risk Better tools to stratify bleeding risk Noninvasive imaging and biomarkers of inflammation and thrombosis to predict clinical events and guide therapy Noninvasive imaging and biomarkers of inflammation and thrombosis to predict clinical events and guide therapy Confirming successful rhythm control over time Confirming successful rhythm control over time Targeted therapy to prevent AF in patients at risk Targeted therapy to prevent AF in patients at risk

83 From Fermented Sweet Clover to Molecular Targeting of Coagulation The Promise of New Approaches The Goal: To bring effective therapy to many more patients and prevent thousands of strokes.

84 Stroke Prevention in High Risk Populations The Journey from Warfarin to New Options and Strategies New Frontiers in Atrial Fibrillation Elaine M. Hylek, MD, MPH Associate Professor of Medicine Department of Medicine Director, Thrombosis Clinic and Anticoagulation Service Boston University Medical Center Boston, Massachusetts

85 Miyasaka, Y. et al. Circulation 2006;114: Projected Number of Persons with AF in the U.S. Between 2000 and 2050 Assumes no further increase in age-adjusted AF incidence (blue curve) and assumes a continued increase in incidence rate as evident in 1980 to 2000 (yellow curve) Year Projected Number of Persons with AF (Millions)

86 Atrial Fibrillation Morbidity and Mortality 4- to 5-fold increased risk of stroke4- to 5-fold increased risk of stroke Doubling of the risk for dementiaDoubling of the risk for dementia Tripling of risk for heart failureTripling of risk for heart failure 40 to 90% increased risk for overall mortality40 to 90% increased risk for overall mortality Risk of stroke in AF patients by age groupRisk of stroke in AF patients by age group –1.5% in 50 to 59 year age group –23.5% in 80 to 89 year age group Benjamin EJ, et al. Circulation 2009;119:

87 Prevalence of AF by Age Feinberg WM. Arch Intern Med. 1995;155(5):469–473 Framingham Study Cardiovascular Health Study Mayo Clinic Study Western Australia Study Prevalence (%) Age (years)

88 * Coronary heart disease, heart failure, stroke and hypertension Prevalence of CVD* in Adults by Age and Sex (NHANES: ) Source: NCHS and NHLBI Age

89 * MD review of medical records using strict diagnostic criteria Incidence of Heart Failure* by Age and Sex (Framingham Heart Study: ) Source: NHLBI

90 Source: NCHS and NHLBI Prevalence of Heart Failure by Age and Sex (NHANES: ) Age

91 Prevalence of Dementia North America: 6.9% prevalence; 63% increase ; 151% increase

92 The graying population will slowly, radically transform society. Richard Suzman, NIAThe graying population will slowly, radically transform society. Richard Suzman, NIA More than 37 million people are age 65. More than 37 million people are age 65. By 2030, this number will exceed 70 million. By 2030, this number will exceed 70 million. By 2040, those aged 75 years will exceed the By 2040, those aged 75 years will exceed the population 65 to 74 years old. By 2050, 12%, or 1 in 8 Americans, will be By 2050, 12%, or 1 in 8 Americans, will be age 75 or older. More than 37 million people are age 65. More than 37 million people are age 65. By 2030, this number will exceed 70 million. By 2030, this number will exceed 70 million. By 2040, those aged 75 years will exceed the By 2040, those aged 75 years will exceed the population 65 to 74 years old. By 2050, 12%, or 1 in 8 Americans, will be By 2050, 12%, or 1 in 8 Americans, will be age 75 or older.

93 Polypharmacy in the Elderly Elderly = 12% of population; Elderly = 12% of population; 32% of prescriptions 32% of prescriptions Average of 6 prescription medications; Average of 6 prescription medications; 1 to 3.5 over-the-counter drugs Average nursing home patient Average nursing home patient takes 7 medications Average American senior spends Average American senior spends $670/year for pharmaceuticals Elderly = 12% of population; Elderly = 12% of population; 32% of prescriptions 32% of prescriptions Average of 6 prescription medications; Average of 6 prescription medications; 1 to 3.5 over-the-counter drugs Average nursing home patient Average nursing home patient takes 7 medications Average American senior spends Average American senior spends $670/year for pharmaceuticals

94 Pharmacokinetic and Pharmacodynamic Changes with Aging Metabolism Metabolism Generally, lower drug doses are required to achieve the same effect Generally, lower drug doses are required to achieve the same effect Receptor numbers, affinity, or post-receptor cellular effects may change Receptor numbers, affinity, or post-receptor cellular effects may change Overall decline in metabolic capacity Overall decline in metabolic capacity Decreased liver mass Decreased liver mass Decreased oxidative metabolism through P450 system decreased clearance of drugs Decreased oxidative metabolism through P450 system decreased clearance of drugs Metabolism Metabolism Generally, lower drug doses are required to achieve the same effect Generally, lower drug doses are required to achieve the same effect Receptor numbers, affinity, or post-receptor cellular effects may change Receptor numbers, affinity, or post-receptor cellular effects may change Overall decline in metabolic capacity Overall decline in metabolic capacity Decreased liver mass Decreased liver mass Decreased oxidative metabolism through P450 system decreased clearance of drugs Decreased oxidative metabolism through P450 system decreased clearance of drugs

95 Kidney Function and Age Andres and Tobin, 1976 Age (years) Standard Creatine Clearance ml/min/

96 Adverse Drug Reactions Adverse Drug Reactions About 15% of hospitalizations in the elderly are related to adverse drug reactions About 15% of hospitalizations in the elderly are related to adverse drug reactions The risk of adverse drug reactions increases with the number of prescription medications The risk of adverse drug reactions increases with the number of prescription medications About 15% of hospitalizations in the elderly are related to adverse drug reactions About 15% of hospitalizations in the elderly are related to adverse drug reactions The risk of adverse drug reactions increases with the number of prescription medications The risk of adverse drug reactions increases with the number of prescription medications

97 Odds Ratio INR Stroke Intracranial Bleed 1.0 Fuster et al. J Am Coll Cardiol. 2001;38: Adjusted Odds Ratios for Ischemic Stroke and Intracranial Bleeding in Relation to Intensity of Anticoagulation

98 Polypharmacy and Non-adherence Strongest predictor of non-adherence is Strongest predictor of non-adherence is the number of medications Non-adherence rates estimated 25-50% Non-adherence rates estimated 25-50% Intentional about 75% of the time Intentional about 75% of the time Changes in regimen made by patients to: - Increase convenience - Reduce adverse effects or - Decrease refill expense Strongest predictor of non-adherence is Strongest predictor of non-adherence is the number of medications Non-adherence rates estimated 25-50% Non-adherence rates estimated 25-50% Intentional about 75% of the time Intentional about 75% of the time Changes in regimen made by patients to: - Increase convenience - Reduce adverse effects or - Decrease refill expense

99 ACTIVE W Trial VKA vs dual antiplatelet Rx Circulation 2008;118. Connolly SJ for Active W Investigators Minimum threshold TTR necessary to realize benefit of warfarin: 58% 58%

100 Comparison of Outcomes Among Patients Randomized to Warfarin According to Anticoagulant Control Results From SPORTIF III and V TTR 75% TTR 75%Outcome TTR < 60% TTR 60-75% TTR>75% Mortality, % Major Bleed, % Stroke/SEE,% Arch Intern Med White HD, Gruber M, Feyzi J, Kaatz S, Tse H, Husted S, Albers G

101 Hazards of Anticoagulant Medications #1 in 2003 and 2004 in the number of mentions of deaths for drugs causing adverse effects in therapeutic use 1#1 in 2003 and 2004 in the number of mentions of deaths for drugs causing adverse effects in therapeutic use 1 Warfarin-6% of 702,000 ADEs treated in ED per year; 17% require hospitalization 1Warfarin-6% of 702,000 ADEs treated in ED per year; 17% require hospitalization 1 21 million warfarin prescriptions in 1998>>>31 million in million warfarin prescriptions in 1998>>>31 million in The incidence AC-related intracranial hemorrhage quintupled during this time period 3The incidence AC-related intracranial hemorrhage quintupled during this time period 3 1 Wysowski DK, et al. Arch Intern Med. 2007;167: Budnitz DS, et al. JAMA. 2006;296: Flaherty ML, et al. Neurology. 2007;68:

102 Major Hemorrhage Rates Randomized Trials INR Target ICHMajorAge AFI SPAF II AFFIRM RE-LY Observational INR Target ICHMajorAge Van der Meer, et al. (1993) Palareti, et al (1996) Go, et al (2003)

103 Caveats Relating to Published Data on Hemorrhage Randomized trials - Enrolled few patients 80 years - Highly selected, closely monitored - Vitamin K antagonist at entry Prospective cohort studies - Predominantly non-inception cohort studies of prevalent warfarin use (survivor bias) prevalent warfarin use (survivor bias) - Enrolled few patients 80 years - Varying definitions of bleeding - Most conducted within anticoagulation clinic setting

104 Baseline Characteristics AF Trials Historical trials SPORTIF III/V ACTIVE W RE-LY Year published N3,763 7,327 6,706 18,113 Age, yrs Female29% 31% 33% 37% Prior stroke5% 21% 15% 20% Hypertension45% 77% 83% 79% CHF26% 18% 21% 32% Diabetes13% 18% 21% 23% CHADS 2 scoreNA NA

105 Cumulative Incidence of Major Bleeding in the First Year Among Patients Newly Starting Warfarin by Age Hylek EM et al, Circulation 2007;115(21): Days of Warfarin Age =80 Cumulative Proportion with Major Hemorrhage

106 Risk of Stopping Therapy in the First Year Among Patients Newly Starting Warfarin by Age Hylek EM et al, Circulation 2007;115(21): Days of Warfarin Risk of Stopping Warfarin Age =80

107 CHADS 2 Score N Major Bleed (N) Bleeding Rates % Taken Off Therapy (N) Taken Off Rates % Total Major Hemorrhagic Events and Warfarin Terminations by CHADS 2 Score Hylek EM et al, Circulation 2007;115(21):

108 How Do We Reconcile These Disparate Rates? Inception versus prevalent? Inception versus prevalent? Burden of hemorrhagic risk factors? Burden of hemorrhagic risk factors? Post-discharge versus outpatient? Post-discharge versus outpatient? Prevalence of combination therapy? Prevalence of combination therapy? Degree of initial selection bias? Degree of initial selection bias? Observation period? Observation period?

109 Hemorrhage Thrombosis Optimizing Benefit and Reducing Risk

110 Bleeding Risk Scores for Warfarin Therapy LowModerateHigh Kuijer et al. Arch Intern Med 1999;159: >3 1.6 x age x sex +2.2 x cancer with 1 point for 60, female or malignancy and 0 if none Beyth et al. Am J Med 1998;105: years old; GI bleed in last 2 weeks; previous stroke; comorbidities (recent MI, Hct 1.5) with 1 point for presence of each condition and 0 if absent Gage et al. Am Heart J 2006;151: HEMORR2HAGES score: liver/renal disease, ETOH abuse, malignancy, >75 years old, low platelet count or function, rebleeding risk, uncontrolled HTN, anemia, genetic factors (CYP2C9) risk of fall or stroke, with 1 point for each risk factor present with 2 points for previous bleed Shireman et al. Chest 2006;130: > <2.19>2.19 (0.49 x age >70) + (0.32 x female) + (0.58 x remote bleed) x recent bleed) x ETOH/drug abuse) + (0.27 x diabetes) + (0.86 x anemia) + (0.32 x antiplatelet drug use) with 1 point for presence of each and 0 if absent

111 Maintenance Warfarin Dose by Age INR Target 2-3 Derived from two independent ambulatory populations Garcia D, et al. Chest ;127: Female Male AgeAge Warfarin Weekly Dose, mg =90 =

112 Hylek et al, Ann Intern Med. 2001;135:

113 Risk Factors for INR > 4.0 After Holding Two Doses of Warfarin Adjusted Odds Ratio Warfarin dose, weekly per 10 mg 0.87 ( ) Age, per decade 1.18 (1.01 – 1.38) Decompensated heart failure 2.79 (1.30 – 5.98) Active malignancy 2.48 (1.11 – 5.57) Index INR, per unit 1.25 (1.14 – 1.37)

114 Initiation Initiation Decreased vitamin K intake Decreased vitamin K intake Potentiating Medications Potentiating Medications Decompensated heart failure Decompensated heart failure Chemotherapy Chemotherapy Warfarin dosing error Warfarin dosing error Binge alcohol consumption Binge alcohol consumption Causes of Elevated INRs

115 Risk of UGIB with Different Combinations of Antithrombotic Agents Hallas J, et al. BMJ doi: /bmj AE Mean age=72 years

116 Strategies To Minimize Risk Of Hemorrhage Incidence of UGIB and LGIB increases with age. 70% of acute UGIB occur > 60 years of age. Differential mucosal effect of ASA by age Incidence of LGIB increases 200-fold from the 3 rd to 9 th decade of life: d iverticulosis, angiodysplasias, ischemic colitis, malignancy THE FACTS: THE FACTS:

117 Strategies to Improve Quality of VKA-Based Anticoagulant Therapy Vigilant monitoring around all transitions in care Vigilant monitoring around all transitions in care Initiate lower doses in most susceptible patient subsets Initiate lower doses in most susceptible patient subsets Increase monitoring with medication changes Increase monitoring with medication changes Reinforce safety points with patients and caregivers Reinforce safety points with patients and caregivers Justify use of concomitant antiplatelet therapy Justify use of concomitant antiplatelet therapy Promise of novel anticoagulants Promise of novel anticoagulants

118 Incidence of Intracranial Hemorrhage Dabigatran vs Warfarin (RE-LY) Anticoagulant/DoseICHRRP Dabigatran 110 mg BID 0.23%0.29<0.001 Dabigatran 150 mg BID 0.30%0.41<0.001 Warfarin (open label) 0.74%REFREF Connolly et al., NEJM, 2009

119 Risk Factors for Intracranial Hemorrhage INR intensity INR intensity Age Age Aspirin therapy Aspirin therapy Ischemic cerebrovascular disease Ischemic cerebrovascular disease Hypertension Hypertension Trauma Trauma Vasculopathy-Leukoaraiosis, amyloid angiopathy Vasculopathy-Leukoaraiosis, amyloid angiopathy

120 Summary Points and Conclusions Elderly patients with AF are at the highest risk of stroke and the highest risk of hemorrhage. Elderly patients with AF are at the highest risk of stroke and the highest risk of hemorrhage. Rates of ischemic stroke significantly exceed rates of ICH and major extracranial hemorrhage on OAC. Rates of ischemic stroke significantly exceed rates of ICH and major extracranial hemorrhage on OAC. Intensive efforts to optimize OAC will help to decrease major bleeding. Intensive efforts to optimize OAC will help to decrease major bleeding. Novel anticoagulants may be safer in the elderly population due to their wider therapeutic index, shorter t 1/2, lack of dietary interference, and fewer drug interactions. Novel anticoagulants may be safer in the elderly population due to their wider therapeutic index, shorter t 1/2, lack of dietary interference, and fewer drug interactions.

121 The Emerging Role of New Oral Anticoagulants Landmark Trials That May Alter the Landscape of Stroke Prevention in AF New Frontiers in Atrial Fibrillation Jeffrey I. Weitz, MD, FRCP, FACP Professor of Medicine and Biochemistry McMaster University Director, Henderson Research Center Canada Research Chair in Thrombosis Heart and Stroke Foundation J.F. Mustard Chair in Cardiovascular Research

122 Overview of Presentation Limitations of warfarin Limitations of warfarin New oral anticoagulants New oral anticoagulants Role of new agents in AF Role of new agents in AF Limitations of warfarin Limitations of warfarin New oral anticoagulants New oral anticoagulants Role of new agents in AF Role of new agents in AF

123 Limitations of Warfarin LimitationConsequence Slow onset of action Overlap with a parenteral anticoagulant Genetic variation in metabolism Variable dose requirements Multiple food and drug interactions Frequent coagulation monitoring Narrow therapeutic index Frequent coagulation monitoring

124 New Oral Anticoagulants for Stroke Prevention in AF Direct Inhibitors of Factor Xa or Thrombin Direct Inhibitors of Factor Xa or Thrombin

125 Comparison of Features of New Oral Anticoagulants in Advanced Stages of Development FeaturesRivaroxabanApixaban Dabigatran Etexilate TargetXaXaIIa Molecular Weight ProdrugNoNoYes Bioavailability (%) Time to peak (h) 332 Half-life (h) Renal excretion (%) AntidoteNoneNoneNone

126 Comparison of Features of New Anticoagulants With Those of Warfarin FeaturesWarfarin New Agents OnsetSlowRapid DosingVariableFixed Food effect YesNo Drug interactions ManyFew MonitoringYesNo Half-lifeLongShort AntidoteYesNo

127 RE-LY: A Non-inferiority Trial R Open Atrial Fibrillation with 1 Risk Factor Absence of Contraindications Conducted in 951 centers in 44 countries Warfarin Adjusted INR 2.0 – 3.0 N=6000 Dabigatran etexilate 110 mg BID N=6000 Dabigatran etexilate 150 mg BID N=6000 Blinded Event Adjudication OpenBlinded R

128 RE-LY: Baseline Characteristics Characteristic Dabigatran 110 mg Dabigatran 150 mg Warfarin Randomized Mean age (years) Male (%) CHADS2 score (mean) 0-1 (%) 0-1 (%) 2 (%) 2 (%) 3+ (%) 3+ (%) Prior stroke/TIA (%) Prior MI (%) CHF (%) Baseline ASA (%) Warfarin Naïve (%) Connolly et al., NEJM, 2009

129 RE-LY: Stroke or Systemic Embolism Dabigatran 110 vs. Warfarin Dabigatran 150 vs. Warfarin Non-inferiority p-value <0.001 <0.001 Superiority p-value <0.001 Margin = 1.46 HR (95% CI) Warfarin better Dabigatran better Connolly et al., NEJM, 2009

130 RE-LY: Annual Rates of Bleeding Dabigatran110mgDabigatran150mgWarfarin Dabigatran 110mg vs. Warfarin Dabigatran 150mg vs. Warfarin n RR 95% CI pRR p Total14.6%16.4%18.2% < Major 2.7 % 3.1 % 3.4 % Life- Life-Threatening 1.2 % 1.5 % 1.8 % < Gastro-intestinal 1.1 % 1.5 % 1.0 % <0.001 Connolly et al., NEJM, 2009

131 RR 0.40 (95% CI: 0.27–0.60) p<0.001 (sup) RE-LY: Intra-cranial Bleeding Rates RR 0.31 (95% CI: 0.20–0.47) p<0.001 (sup) Number of events 0,23 % 0,74 % 0,30 % RRR69% RRR60% Connolly et al., NEJM, 2009

132 Targeted inhibition of thrombin Targeted inhibition of thrombin Consistent and predictable anticoagulant effect Consistent and predictable anticoagulant effect Targeted inhibition of thrombin Targeted inhibition of thrombin Consistent and predictable anticoagulant effect Consistent and predictable anticoagulant effect How can dabigatran be more effective than warfarin yet cause less bleeding?

133 RE-LY: Secondary Efficacy Outcomes According to Treatment Group N Engl J Med Connolly, et al. N Engl J Med 2009;361: Event Dabigatran 110 mg Dabigatran 150 mg Warfarin Myocardial infarction 0.7%0.7%0.5% Vascular death 2.4%2.3%2.7% All-cause mortality 3.8%3.6%4.1%

134 RE-LY: Cumulative risk of ALT or AST >3x ULN after randomization Years of follow-up Dabigatran 110 mg Cumulative risk Dabigatran 150 mg Warfarin N Engl J Med Connolly, et al. N Engl J Med 2009;361:

135 Lower-dose regimen Elderly Elderly Renal insufficiency Renal insufficiency Lower stroke risk (CHADS 2 score of 1) Lower stroke risk (CHADS 2 score of 1) Higher-dose regimen Higher stroke risk (CHADS 2 score 2) Higher stroke risk (CHADS 2 score 2) Lower-dose regimen Elderly Elderly Renal insufficiency Renal insufficiency Lower stroke risk (CHADS 2 score of 1) Lower stroke risk (CHADS 2 score of 1) Higher-dose regimen Higher stroke risk (CHADS 2 score 2) Higher stroke risk (CHADS 2 score 2) Which Dose for Which Patient?

136 Camm J.: Oral presentation at ESC on Aug 30th Meta-analysis of Ischemic Stroke or Systemic Embolism W vs placebo W vs W low dose W vs ASA W vs ASA + clopidogrel W vs dabigatran Favours warfarin Favours other treatment

137 What About Trials with Other New Oral Anticoagulants? ROCKET – Rivaroxaban ROCKET – Rivaroxaban ARISTOTLE – Apixaban ARISTOTLE – Apixaban ENGAGE - Edoxaban ENGAGE - Edoxaban ROCKET – Rivaroxaban ROCKET – Rivaroxaban ARISTOTLE – Apixaban ARISTOTLE – Apixaban ENGAGE - Edoxaban ENGAGE - Edoxaban

138 Is Warfarin Obsolete? New oral anticoagulants are more convenient New oral anticoagulants are more convenient But, warfarin effective when time in therapeutic range is high But, warfarin effective when time in therapeutic range is high New oral anticoagulants are more convenient New oral anticoagulants are more convenient But, warfarin effective when time in therapeutic range is high But, warfarin effective when time in therapeutic range is high

139 Cumulative risk of stroke, myocardial infarction, systemic embolism, or vascular death for patients treated at centers with a TTR below or above the study median (65%) Connolly, S. J. et al. Circulation 2008;118: OAC OAC C+A C+A Years Years Event Rate (%) TTR < 65% TTR >= 65% RR=0.93 ( ) p=0.61 RR=2.14 ( ) P=

140 Time in Therapeutic Range (TTR) with Warfarin in the RE-LY Trial Group Relative Risk Overall64% VKA Experienced 61% VKA Nave VKA Naïve67%

141 All patients Long-term VKA therapy No Yes Region North America South America Western Europe Central Europe South Asia East Asia Other Dabigatran Better Warfarin Better , , , , , , , , , , Subgroup Patients total no. 110 mg 150 mg Warfarin Dabigatran Hazard Ratio with Dabigatran, 100 mg (95% CI) Hazard Ratio with Dabigatran, 150 mg (95% CI) P Value for Interaction P Value for Interaction Relative Risk of Stroke or Systemic Embolism with Dabigatran Versus Warfarin According to Geographical Region Connolly et al., NEJM 2009

142 Stable on warfarinStable on warfarin Renal impairmentRenal impairment Severe hepatic diseaseSevere hepatic disease Poor compliancePoor compliance Stable on warfarinStable on warfarin Renal impairmentRenal impairment Severe hepatic diseaseSevere hepatic disease Poor compliancePoor compliance Who is Not a Candidate for Dabigatran?

143 Management of patients with severe coronary artery disease or recent GI bleeding? Management of patients with severe coronary artery disease or recent GI bleeding? Will short half-life obviate need for antidotes? Will short half-life obviate need for antidotes? Will elimination of monitoring adversely impact patient care? Will elimination of monitoring adversely impact patient care? Management of patients with severe coronary artery disease or recent GI bleeding? Management of patients with severe coronary artery disease or recent GI bleeding? Will short half-life obviate need for antidotes? Will short half-life obviate need for antidotes? Will elimination of monitoring adversely impact patient care? Will elimination of monitoring adversely impact patient care? Unanswered Questions

144 Dabigatran etexilate is superior to warfarin for stroke prevention Dabigatran etexilate is superior to warfarin for stroke prevention Dosing of new oral anticoagulants is critical: are the doses of factor Xa inhibitors optimal? Dosing of new oral anticoagulants is critical: are the doses of factor Xa inhibitors optimal? New oral anticoagulants will replace warfarin, but transition may be slow New oral anticoagulants will replace warfarin, but transition may be slow Dabigatran etexilate is superior to warfarin for stroke prevention Dabigatran etexilate is superior to warfarin for stroke prevention Dosing of new oral anticoagulants is critical: are the doses of factor Xa inhibitors optimal? Dosing of new oral anticoagulants is critical: are the doses of factor Xa inhibitors optimal? New oral anticoagulants will replace warfarin, but transition may be slow New oral anticoagulants will replace warfarin, but transition may be slow Conclusions: RE-LY and New, Oral Non- Monitored Anticoagulation

145 Atrial Fibrillation Current Challenges in Thrombosis Medicine for the Cardiovascular Specialist Discussion, Comments, and The Way Forward Samuel Z. Goldhaber, MD Cardiovascular Division Brigham and Womens Hospital Professor of Medicine Harvard Medical School New Frontiers in Atrial Fibrillation

146 It is fighting back with: 1) Excellent efficacy (ACTIVE) 2) Pharmacogenetics analysis 3) Point-of-care testing 4) Low cost 5) Track Record (approved in 1954) Warfarin is Not Just Sitting Around

147 Can rapid turnaround genetic testing reduce the Educated Guessing Game and Play of Chance in warfarin dosing? The Red Line in the Sand

148 Warfarin Pharmacogenomics 1.Cytochrome P450 2C9 genotyping identifies mutations associated with impaired warfarin metabolism. 2.Vitamin K receptor polymorphism testing can identify whether patients require low, intermediate, or high doses of warfarin. 1.Cytochrome P450 2C9 genotyping identifies mutations associated with impaired warfarin metabolism. 2.Vitamin K receptor polymorphism testing can identify whether patients require low, intermediate, or high doses of warfarin. Schwartz UI. NEJM 2008; 358: 999

149 Warfarin Pharmacogenetics Consortium. NEJM 2009;360: Warfarin Pharmacogenetics Consortium. NEJM 2009;360: Percent with Dose Estimates within 20% of Actual Dose Pharmacogenetic Algorithm versus Clinical Algorithm versus Fixed-Dose Approach

150 Rapid turnaround CYP2C9 and VKORC1 testing vs. empiric Rapid turnaround CYP2C9 and VKORC1 testing vs. empiric Primary endpoint: TTR Primary endpoint: TTR Smaller and fewer dosing changes with genetic testing Smaller and fewer dosing changes with genetic testing No difference in TTR No difference in TTR Rapid turnaround CYP2C9 and VKORC1 testing vs. empiric Rapid turnaround CYP2C9 and VKORC1 testing vs. empiric Primary endpoint: TTR Primary endpoint: TTR Smaller and fewer dosing changes with genetic testing Smaller and fewer dosing changes with genetic testing No difference in TTR No difference in TTR Genotype vs Standard Warfarin Dosing (N=206) Couma-Gen Trial Circulation 2007; 116:

151 Warfarin Clinical Dosing Nomogram NEJM 2009; 360:

152 PHARMACO- GENETIC NOMOGRAM NEJM 2009; 360:

153 Warfarin Pharmacogenetics Routine use of CYP2C9 and VKORC1 genotyping in patients who begin warfarin therapy is not supported by evidence currently available. Pharmacotherapy 2008; 28:

154 Genetic Testing for Warfarin Remains Unproven: NHLBI Trial About 1,200 Patients will be randomized to: 1.Genetic plus clinical guided nomogram, versus 1.Clinically-guided nomogram Results will be available in 2012 Results will be available in 2012

155 NHLBI Trial: Primary Endpoint: % Time in Therapeutic Range (TTR) Hypothesis: 60% TTR in Clinical arm versus > 72% TTR in Genetics Plus Clinical Nomogram arm Primary Endpoint: % Time in Therapeutic Range (TTR) Hypothesis: 60% TTR in Clinical arm versus > 72% TTR in Genetics Plus Clinical Nomogram arm Clinical Trials # NCT

156 Self-Monitoring INR Meta-analysis of 14 RCTS Reduced TE events (55% fewer) Reduced TE events (55% fewer) Reduced all-cause mortality (39% less) Reduced all-cause mortality (39% less) Reduced major bleeds (35% fewer) Reduced major bleeds (35% fewer) Benefits increase further with self-dosing 73% fewer TE events 73% fewer TE events 63% lower all-cause mortality 63% lower all-cause mortality Reduced TE events (55% fewer) Reduced TE events (55% fewer) Reduced all-cause mortality (39% less) Reduced all-cause mortality (39% less) Reduced major bleeds (35% fewer) Reduced major bleeds (35% fewer) Benefits increase further with self-dosing 73% fewer TE events 73% fewer TE events 63% lower all-cause mortality 63% lower all-cause mortality Heneghan C. Lancet 2006; 367:

157 March 19, 2008: Medicare Expanded Reimbursement for Home INR Monitoring Medicare used to cover only mechanical heart valves Medicare used to cover only mechanical heart valves Now will reimburse VTE (after 3 months of warfarin) and permanent atrial fibrillation Now will reimburse VTE (after 3 months of warfarin) and permanent atrial fibrillation Aetna follows new Medicare guidelines (and surely others will, too) Aetna follows new Medicare guidelines (and surely others will, too) Medicare used to cover only mechanical heart valves Medicare used to cover only mechanical heart valves Now will reimburse VTE (after 3 months of warfarin) and permanent atrial fibrillation Now will reimburse VTE (after 3 months of warfarin) and permanent atrial fibrillation Aetna follows new Medicare guidelines (and surely others will, too) Aetna follows new Medicare guidelines (and surely others will, too)

158 Will Novel Anticoagulants Warrant Additional Costs? 1.Does this require deconstruction, demobilization, and/or reconstruction of anticoagulation management services? 2.Will patients require monitoring of renal/ hepatic function? 1.Does this require deconstruction, demobilization, and/or reconstruction of anticoagulation management services? 2.Will patients require monitoring of renal/ hepatic function?

159 Novel Oral Anticoagulants 1.Noninferiority may not suffice, but superiority findings (150 mg dose) in RE-LY are encouraging. 2.Superiority may be necessary to alter prescribing behavior. 3.More trials will be forthcoming. 4.Beware of off-label use. 1.Noninferiority may not suffice, but superiority findings (150 mg dose) in RE-LY are encouraging. 2.Superiority may be necessary to alter prescribing behavior. 3.More trials will be forthcoming. 4.Beware of off-label use.

160 RE-LY: Stroke or Systemic Embolism Dabigatran 110 vs. Warfarin Dabigatran 150 vs. Warfarin Non-inferiority p-value <0.001 <0.001 Superiority p-value <0.001 Margin = 1.46 Margin = 1.46 HR (95% CI) Warfarin better Dabigatran better Connolly et al., NEJM, 2009

161 RE-LY: Cumulative Hazard Rates for the Primary Outcome of Stroke or Systemic Embolism Connolly, et al. N Engl J Med 2009;361: Warfarin Dabigatran 110 mg Dabigatran 150 mg Warfarin Dabigatran 110 mg Dabigatran 150 mg

162 Relative Risk of Stroke or Systemic Embolism with Dabigatran versus Warfarin: RE-LY Connolly, et al. N Engl J Med 2009;361: Hazard Ratio with Dabigatran, 110 mg(95% CI) Hazard Ratio with Dabigatran, 150 mg(95% CI) Dabigatran Better Warfarin Better

163 N Engl J Med Connolly, et al. N Engl J Med 2009;361: Relative Risk of Stroke or Systemic Embolism with Dabigatran versus Warfarin: RE-LY Hazard Ratio with Dabigatran, 110 mg(95% CI) Hazard Ratio with Dabigatran, 150 mg(95% CI)

164 Gage, B N Engl J Med 361;12 nejm.org September 17, 2009 Connolly SJ, Pogue J, Eikelboom J, et al. Circulation 2008;118:2029­37. RE-LY participants who were randomly assigned to receive warfarin would have needed to have an INR time within the therapeutic range (TTR) approximately 79% of the time to have a stroke rate as low as that in the group receiving 150 mg of dabigatran.RE-LY participants who were randomly assigned to receive warfarin would have needed to have an INR time within the therapeutic range (TTR) approximately 79% of the time to have a stroke rate as low as that in the group receiving 150 mg of dabigatran. Even with diligent, patient self-monitoring or pharmacogenetic dosing, such tight control is unlikely in real world practice.Even with diligent, patient self-monitoring or pharmacogenetic dosing, such tight control is unlikely in real world practice. RE-LY: Analysis and Comments

165 Rose, AJ Thromb Haemost Oct;6(10): Baker WL et al, J Manag Care Pharm Apr;15(3): Community-Based Practices in 38 States (1) Mean TTR was 66.5%, but varies widely, with 37% having TTR above 75%, and 34% with TTR below 60% Mean TTR was 66.5%, but varies widely, with 37% having TTR above 75%, and 34% with TTR below 60% Mean TTR for new warfarin users (57.5%) lower than prevalent users for first six months Mean TTR for new warfarin users (57.5%) lower than prevalent users for first six months TTR of patients with warfarin interruptions had TTR of 61.6% TTR of patients with warfarin interruptions had TTR of 61.6% TTR rates vary widely and are affected by new warfarin use, procedural interruptions and INR target rangeTTR rates vary widely and are affected by new warfarin use, procedural interruptions and INR target range Meta-Analysis (2) Meta-Analysis (2) TTR was 55% TTR was 55% Time in Therapeutic Range (TTR) in Time in Therapeutic Range (TTR) in Community-Based Practice: Ranges

166 To prevent one nonhemorrhagic stroke, the number of patients who would need to be treated with dabigatran at a dose of 150 mg twice daily, rather than warfarin, is approximately 357.To prevent one nonhemorrhagic stroke, the number of patients who would need to be treated with dabigatran at a dose of 150 mg twice daily, rather than warfarin, is approximately 357. The number of patients who would need to be treated with dabigatran (rather than warfarin) to prevent one hemorrhagic stroke is approximately 370.The number of patients who would need to be treated with dabigatran (rather than warfarin) to prevent one hemorrhagic stroke is approximately 370. RE-LY: Analysis and Comments

167 Discussion: Novel Oral Anticoagulants 1. In summary although there are qualifications, we can rely on RE-LY. 1. In summary although there are qualifications, we can rely on RE-LY. Brian F. Gage, MD (NEJM, September 17, 2009, RE-LY Editorial) Brian F. Gage, MD (NEJM, September 17, 2009, RE-LY Editorial) 2. The RE-LY Trial represents the most compelling evidence to date for revising, reconsidering, and reshaping our current VKA-based paradigm for stroke prevention in AF. 2. The RE-LY Trial represents the most compelling evidence to date for revising, reconsidering, and reshaping our current VKA-based paradigm for stroke prevention in AF. Where Do We Stand, November 12, 2009?

168 Discussion: Novel Oral Anticoagulants Discussion, Questions, and Comments Discussion, Questions, and Comments


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