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New Paradigms and Landscape Changes in Atrial Fibrillation

National Experts in Cardiovascular Medicine Illuminate and Debate. New Paradigms and Landscape Changes in Atrial Fibrillation Emerging Perspectives in Thrombosis Mitigation for the Cardiovascular Specialist—Applying Landmark Trials to the Front Lines of Cardiology Practice.

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New Paradigms and Landscape Changes in Atrial Fibrillation

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  1. National Experts in Cardiovascular Medicine Illuminate and Debate New Paradigms and Landscape Changes in Atrial Fibrillation Emerging Perspectives in Thrombosis Mitigation for the Cardiovascular Specialist—Applying Landmark Trials to the Front Lines of Cardiology Practice Program Chairman and Moderator Peter Libby, MD, FACC Chief, Cardiovascular Medicine Brigham and Women’s Hospital Mallinckrodt Professor of Medicine Harvard Medical School Boston, Massachusetts

  2. Welcome and Program Overview CME-certified symposium jointly sponsored by the University of Massachusetts Medical School and CMEducation Resources, LLCCommercial Support: Sponsored by an independent educational grant from Boehringer-IngelheimFaculty disclosures: Listed in program syllabus

  3. Program Faculty Peter Libby, MD, FACC Program Chairman and Moderator Chief, Cardiovascular Medicine Brigham and Women’s Hospital Mallinckrodt Professor of Medicine Harvard Medical School Boston, Massachusetts Jonathan L. Halperin, MD Mount Sinai School of Medicine Director, Clinical Cardiology Service The Zena and Michael A. Wiener Cardiovascular Institute The Marie-Josée and Henry R. Kravis Center for Cardiovascular Health New York, New York Elaine M. Hylek, MD, MPH Associate Professor of Medicine Department of Medicine 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 Ontario, Canada

  4. New Frontiers in Atrial Fibrillation Challenges in Stroke Prevention for Patients with Atrial Fibrillation Achieving Balance Between Prevention of Thromboembolism and Risk of Bleeding Risk Stratification, Current Guidelines and Therapeutic Choices 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

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

  6. Natural History of “Lone” Atrial Fibrillation No Cardiopulmonary Disease; <60 Years Old 97 Patients Mean Age = 44 14.8 years Follow-up 0.35%/yr Stroke 0.40%/yr Mortality Kopecky S, et al. N Engl J Med 1987; 317:669.

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

  8. Anticoagulation in Atrial FibrillationStroke Risk Reductions Warfarin Better Control Better AFASAK SPAF BAATAF CAFA SPINAF EAFT Aggregate -100% 50% -50% 100% 0 Hart R, et al. Ann Intern Med 2007;146:857.

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

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

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

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

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

  14. High-Risk Factors Mitral stenosis Prosthetic heart valve History of stroke or TIA Risk Stratification in AFStroke Risk Factors Moderate-Risk Factors • Age >75 years • Hypertension • Diabetes mellitus • Heart failure or ↓ LV function Singer DE, et al. Chest 2004;126:429S. Fang MC, et al. Circulation 2005; 112: 1687.

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

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

  17. The CHADS2 Index Stroke Risk Score for Atrial Fibrillation Score (points) Prevalence (%)* 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 >2 50-60 Low risk 0-1 40-50 VanWalraven C, et al. Arch Intern Med 2003; 163:936. * Nieuwlaat R, et al. (EuroHeart survey) Eur Heart J 2006 (E-published).

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

  19. The CHADS2 Index Stroke Risk Score for Atrial Fibrillation Score (points) Risk of Stroke (%/year) 0 1.9 1 2.8 2 4.0 3 5.9 4 8.5 5 12.5 6 18.2 Approximate Risk threshold for Anticoagulation 3%/year Van Walraven C, et al. Arch Intern Med 2003; 163:936. Go A, et al. JAMA 2003; 290: 2685. Gage BF, et al. Circulation 2004; 110: 2287.

  20. Risk Stratification and Anticoagulation Stroke Reduction with Warfarin Instead of Aspirin CHADS2 Score ~ 3 2 1 0 Number of patients Needed-to-treat to prevent 1 stroke/year 42 13 83 250 EAFT Study Group. Lancet 1993; 324:1255. Zabalgoitia M, et al. J Am Coll Cardiol 1998; 31:1622.

  21. Antithrombotic Therapy for Atrial FibrillationACC/AHA/ESC Guidelines 2006

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

  23. Patient Selection for AnticoagulationAdditional Considerations • Risk of bleeding • Newly anticoagulated vs. established therapy • Availability of high-quality anticoagulation management program • Patient preferences

  24. Aspirin + Placebo VKA (INR 2-3) Clopidogrel + Aspirin Clopidogrel + Aspirin The ACTIVE TrialClopidogrel + Aspirin Atrial Fibrillation + Risk Factors ACTIVE - W ACTIVE - A OAC Contraindications or Unwilling Anticoagulation-eligible Open-label Non-inferiority n = 6,706 Double-blind Superiority n = 7,554 Irbesartan, 300 mg/d vs. Placebo n = 9,016 ACTIVE - I Risk Factors: Age 75, hypertension, prior stroke/TIA, LVEF<45%, PAD, age 55-74 + CAD or diabetes Primary outcome: Stroke, systemic embolism, MI or cardiovascular death

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

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

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

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

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

  30. The ACTIVE TrialReasons for Exclusion from Anticoagulation • 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.

  31. ACTIVE-ATotal Stroke Rates 28% RRR HR 0.72 (95% CI, 0.62–0.83) p <0.001 0.15 408 (3.3%/year) Aspirin 0.10 296 (2.4%/year) Cumulative Incidence Clopidogrel + Aspirin 0.05 0.0 0 1 2 3 4 Years Connolly SJ, et al. N Engl J Med 2009; 360:2066.

  32. Treatment VKA C+A Aspirin ACTIVE W (Annual Rate) 1.4 2.4 ~ ACTIVE A (Annual Rate) ~ 2.4 3.3 RRR versus Aspirin -58% -28% ~ RRR versus C+A -42% ~ ~ The ACTIVE TrialsStroke Rates and Risk Reductions VKA = oral anticoagulant C+A = clopidogrel + aspirin Connolly SJ, et al. Lancet 2006; 367:1903. Connolly SJ, et al. N Engl J Med 2009; 360:2066.

  33. Investigational Anticoagulant Targets ORAL PARENTERAL TF/VIIa TFPI (tifacogin) TTP889 X IX APC (drotrecogin alfa) sTM (ART-123) IXa VIIIa RivaroxabanApixabanEdoxaban LY517717YM150 Betrixaban TAK 42 Va AT Xa Idraparinux II (thrombin) DX-9065aOtamixaban IIa Dabigatran APC activated protein C AT antithrombin sTM soluble thrombomodulin TF tissue factor FPI tissue factor pathway inhibitor Fibrinogen Fibrin Adapted from Weitz JI.ThrombHaemost2007; 5 Suppl 1:65-7.

  34. The Ideal AnticoagulantWide Therapeutic Margin Safe TherapeuticRange Thrombosis Bleeding Bleeding Thrombosis Dose, Concentration, or Intensity of Anticoagulation

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

  36. Alternatives to AnticoagulationAtrial Fibrillation Restoration and maintenance of sinus rhythm • Antiarrhythmic drug therapy • Catheter ablation • Maze operation Current approaches Emerging (investigational) approaches • Obliteration of the left atrial appendage • Trans-catheter occluding devices • Thoracoscopicepicardialplication • Amputation

  37. Strokes after Conversion to NSRRate vs. Rhythm Control Trials Verheugt F, et al. J Am CollCardiol 2003;41(suppl):130A.

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

  39. ATHENA TrialDronedarone vs. Placebo in Patients with AF Stroke Rates(Secondary Analysis) Hohnloser SH, et al. N Engl J Med 2009; 360: 668-78.

  40. Percutaneous LAA OcclusionThe WATCHMAN®Device Syed T, Halperin JL. Nature ClinPracCardiovasc Med 2007; 4:428 Holmes DR, et al. Lancet 2009; 374: 534

  41. Alternatives to AnticoagulationAtrial Fibrillation Current approaches Restoration and maintenance of sinus rhythm • Antiarrhythmic drug therapy • Catheter ablation • Maze operation Emerging (investigational) approaches • Obliteration of the left atrial appendage • Trans-catheter occluding devices • Thoracoscopicepicardialplication • Amputation Is atrial fibrillation the cause of stroke or a marker of a population at risk?

  42. Atrial Fibrillation and ThromboembolismThe Next Challenges • Better tools to stratify bleeding risk • Noninvasive imaging and biomarkers of inflammation and thrombosis to predict clinical events and guide therapy • Confirming successful rhythm control over time • Targeted therapy to prevent AF in patients at risk • Defining role and risk stratification strategies for non-monitored, oral anticoagulants

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

  44. Atrial Fibrillation Case Study

  45. Atrial Fibrillation Case Study • An 82-year-old man with hypertension and diabetes has permanent atrial fibrillation • He has a history of spinal stenosis and walks with a walker

  46. Atrial Fibrillation Case Study • Question 1: Which regimen would you prescribe for prophylaxis against thromboembolism? • Warfarin (INR 2.0-3.0) • Warfarin (INR 1.5-2.0) • Aspirin, 81 mg daily • Aspirin, 81 mg + clopidogrel, 75 mg daily • No antithrombotic therapy

  47. Atrial Fibrillation Case StudyAssessment of Thromboembolic Risk Score (points) Risk of Stroke (%/year) 0 1.9 1 2.8 2 4.0 3 5.9 4 8.5 5 12.5 6 18.2 Van Walraven C, et al. Arch Intern Med 2003; 163: 936. Go A, et al. JAMA 2003; 290: 2685. Gage BF, et al. Circulation 2004; 110: 2287.

  48. Atrial Fibrillation Case Study Question 2: What if you learn that he has tripped and fallen twice in the past two years? • Warfarin (INR 2.0-3.0) • Warfarin (INR 1.5-2.0) • Aspirin, 81 mg daily • Aspirin, 81 mg + clopidogrel, 75 mg daily • No antithrombotic therapy

  49. Atrial Fibrillation Case Study Question 3: If the oral direct thrombin inhibitor dabigatran were available and FDA-approved for stroke prevention in AF, in this patient with a history of tripping you would treat with: • Warfarin (INR 2.0-3.0) • Warfarin (INR 1.5-2.0) • Dabigatran 110 mg P.O. B.I.D • Dabigatran 150 mg P.O. B.I.D. • Aspirin, 81 mg + clopidogrel, 75 mg daily • No antithrombotic therapy

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