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Stroke Prevention in Atrial Fibrillation

New Frontiers and Treatment Paradigms for. Stroke Prevention in Atrial Fibrillation Evidence- and Guideline-Based Strategies for Optimizing Clinical Outcomes and Anticoagulation-Based Management for SPAF. Program Chairman Samuel Z. Goldhaber, MD Cardiovascular Division

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Stroke Prevention in Atrial Fibrillation

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  1. New Frontiers and Treatment Paradigms for Stroke Prevention in Atrial Fibrillation Evidence- and Guideline-Based Strategies for Optimizing Clinical Outcomes and Anticoagulation-Based Management for SPAF Program Chairman Samuel Z. Goldhaber, MD Cardiovascular Division Brigham and Women’s Hospital Professor of Medicine Harvard Medical School

  2. Welcome and Program Overview CME-certified symposium jointly sponsored by the University of Massachusetts Medical School and CMEducation Resources, LLCCommercial Support: This National Initiative is Sponsored by an Independent Educational Grant from the Bristol-Myers Squibb/Pfizer Cardiovascular Partnership.

  3. Program Faculty PROGRAM CHAIRMAN SAMUEL Z. GOLDHABER, MD Cardiovascular Division Brigham and Women’s Hospital Professor of Medicine Harvard Medical School CHRISTIAN T. RUFF, MD, MPH TIMI Study Group Brigham and Women’s Hospital Harvard Medical School Boston, MA ELAINE M. HYLEK, MD, MPHProfessor of Medicine Department of MedicineBoston University Medical CenterBoston, Massachusetts

  4. Conflict of Interest Disclosures Program Chairman SAMUEL Z. GOLDHABER, MD Research Support: Eisai, EKOS, Johnson & Johnson, sanofi-aventis Consultant: Baxter, Boehringer-Ingelheim, Bristol-Myers Squibb, Daiichi, Eisai, Janssen, Merck, Pfizer, Portola, sanofi-aventis CHRISTIAN T. RUFF, MD, MPH Research Support: Daiichi Sankyo, AstraZeneca, Bristol-Meyers Squibb, sanofi-aventis Consultant: Alere and Beckman Coulter ELAINE M. HYLEK, MD, MPHResearch Support: Bristol-Myers Squibb, Ortho-McNeil Consultant: Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Johnson & Johnson, Pfizer

  5. New Paradigms in the Science and Medicine of Stroke Prevention for Atrial Fibrillation Epidemiology and OverviewRisk, Disease Burden, and Deciphering the Maze of Risk-Specific Interventions for AFFocus on Non-Monitored Oral Anticoagulation and the Unmet Need for Safer and More Effective Stroke Prevention in NVAF Samuel Z. Goldhaber, MD Program Chairman Director, VTE Research Group Cardiovascular Division Brigham and Women’s Hospital Professor of Medicine Harvard Medical School

  6. Faculty COI Disclosures Research Support Eisai, EKOS, Johnson & Johnson, sanofi-aventis Consultant Baxter, Boehringer-Ingelheim, Bristol-Myers Squibb, Daiichi, Eisai, Janssen, Merck, Pfizer, Portola, sanofi-aventis

  7. Formal Definition: Atrial Fibrillation AF is an arrhythmia characterized by uncoordinated atrial activation, with consequent deterioration of atrial mechanical function Circulation 2011; 121: e269-e367

  8. The ECG of Atrial Fibrillation Normal sinus rhythm Atrial fibrillation

  9. The “3 Ps” and Natural History of Atrial Fibrillation Paroxysmal Self-Terminating Persistent Lasts > 7 Days Permanent Cardioversion Failed or Not Attempted Paroxysmal AF is as likely to cause stroke as persistent or permanent AF Normal Sinus Rhythm Atrial Fibrillation

  10. Atrial Fibrillation: Epidemiology The No. 1 preventable cause of stroke In the United States, up to 16 million individuals will be affected by the year 2050 Increasing survival from heart attack and increasing age (“the ‘graying’ of America”) help explain rise in incidence of AF

  11. Atrial Fibrillation Risk Factors Magnani JW et al. Circulation 2011; 124: 1982-1993

  12. Atrial Fibrillation: An Epidemic 18 16 million US Prevalence 16 14 12 1 in 4 lifetime risk in men and women ≥ 40 years old 10 Projected Number of People with AF (millions) 8 6 4 2 0 2000 2005 2010 2015 2020 2025 2030 2035 2040 2045 2050 Year Miyakasa Y, et al. Circulation. 2006; 114:119-125.

  13. Relationship Between Atrial Fibrillation and Age Prevalence, percent Age, years Go AS, et al. JAMA. 2001; 285:2370-2375.

  14. Atrial Fibrillation Causes Stroke Left Atrial Appendage Thrombus Chimowitz. Stroke 1993; 24: 1015 Zabalgoitia. J Am Coll Cardiol 1998; 31: 1622

  15. Stroke and Atrial Fibrillation Burden • Approximately 5-fold increased risk of stroke • Quantify stroke risk: CHADS2/ CHA2DS2-VASc • AF strokes have worse outcomes • Costly health care ~ $16 billion/year 30 Framingham 20 AF prevalence % Strokes attributable to AF 10 0 50–59 60–69 70–79 80–89 Age Range (years) Wolf PA, et al. Stroke 1991; 22: 983-988

  16. Ischemic Strokes in Atrial Fibrillation More Likely to be Severely Disabling Framingham Heart Study 73 58 36 33 30 16 16 11 Lin HJ, et al. Stroke. 1996;27:1760-1764.

  17. AF PIE: FUTURE AF PIE: PAST Fuster V. Circulation 2012; epubl April 18

  18. ESC 2012 AF Update Guidelines Important New Developments • Assess stroke risk exclusively with CHA2DS2-VASc and no longer use CHADS2 • ESC Guidelines recommend anticoagulation for stroke prevention with CHA2DS2-VASc score of 1 or greater • Preference given to novel, non-monitored anticoagulants: apixaban, rivaroxaban, and dabigatran

  19. Anticoagulation in Atrial Fibrillation Effects on Stroke Risk Reduction Warfarin better Control better AFASAK RRR of stroke: 62% SPAF BAATAF CAFA SPINAF RRR All-cause mortality: 26% EAFT Aggregate -100% 50% -50% 100% 0 RRR, relative risk reduction. Hart RG, et al. Ann Intern Med. 1999;131:492-501.

  20. ESC 2012 Update Guidelines HAS-BLED for Evaluation of Bleeding Risk Pisters R, et al. Chest. 2010;138:1093-1100.

  21. Swedish AF Cohort; Circulation 2011; 125: 2298-2307

  22. Known Problems With Warfarin • Delayed onset/offset • Unpredictable dose response • Narrow therapeutic index • Drug-drug, drug-food interactions • Problematic monitoring • High bleeding rate • Slow reversibility

  23. Warfarin Will Likely Survive: Why? Established efficacy Low cost ($4/month; $10/3 mos) Long track record (1954) Centralized anticoagulation clinics that maintain TTRs > 60% Rapid, turnaround genetic testing Point-of-care self-testing INR testing q 12 weeks if stable CoumaGen-II. Circ 2012; March 19 ACCP Chest Guidelines 2012

  24. COUMAGEN-II Pharmacogenetic Dosing Achieves TTR of 71% Circulation 2012; epub March 19

  25. Comparison Overview of New Anticoagulants with Warfarin

  26. Sites of Action in Coagulation SystemNovel Factor Xa and DT Inhibitors Steps in Coagulation Pathway Drugs TF/VIIa Initiation X IX IXa VIIIa Va Rivaroxaban Apixaban Edoxaban Betrixaban Xa Propagation II Fibrin formation Dabigatran IIa Fibrinogen Fibrin Hankey GJ and Eikelboom JW. Circulation 2011;123:1436-1450

  27. Novel Oral AnticoagulantsImportant Comparative Features Circulation 2010;121:1523

  28. Comparison of Phase 3 SPAF Trials for NOACs: A Robust Trial Base Novel Anticoagulants Fxa Inhibitor FIIa Inhibitor Rivaroxaban Apixaban Edoxaban Dabigatran

  29. “Best Options” for Anticoagulation The Consensus is Shifting Despite continued use of warfarin, NOACs are considered by many professional medical organizations to be the “best option”for anticoagulation of SPAF patients: • ESC 2012 AF Update Guidelines • ACCP 2012 Guidelines • Canadian AF Guidelines

  30. ESC 2012 UPDATE GUIDELINES For ATRIAL FIBRILLATION

  31. The Rationale for AF Registries • Registries provide a “real life” perspective on patient populations, management “in the field,” and outcomes in settings that do not have the special resources and monitoring capabilities of pivotal randomized clinical trials. • Information from registries complements clinical trial data. • Registries can highlight the disconnect between evidence/guidelines and clinical practice.

  32. The GARFIELD Registry • Novel approach to outcomes research • Planned to be conducted in 50 countries • 50,000 prospective and 5000 retrospective patients • Patients newly diagnosed with non-valvular AF • Five sequential cohorts • Random site selection • Sites representative of national AF care settings • Consecutive patients • Minimum follow-up period of 2 years

  33. Summary of Garfield Data Cohort One: ESC 2012 • 10,537 were available for this analysis • 5075 retrospective and 5462 prospective • Newly diagnosed patients carry high risk for stroke • 57% with CHADS2 score >2 • 83% with CHA2DS2-VASc score >2 • VKAs not prescribed in: • 38% of patients with CHADS2 score >2 • 40% of patients with CHA2DS2-VASc score >2

  34. Modest Use of Vitamin K Antagonists Even in High-Risk Patients European Heart Survey 100 5333 AF patients in 35 countries: 2003–2004 80 64 61 59 58 60 OAC therapy (%) 40 20 0 1 2 3 4 CHADS2 score OAC, oral anticoagulant Nieuwlaat et al. Eur Heart J 2006; Gage et al. JAMA 2001

  35. A “Failure to Prophylax” Syndrome • Over the past decade, about 40% of patients with atrial fibrillation are unprotected from stroke because of failure to prescribe anticoagulation. • Because criteria for anticoagulation have expanded in 2012, the problem has intensified. • Heightened awareness of the disconnect between guidelines/evidence and suboptimal intervention for SPAF. Anticoagulation is necessary as a first step.

  36. The SPAF Landscape 2012: Conclusions The frequency of atrial fibrillation is increasing, so risk of devastating stroke is increasing as well. Anticoagulants can effectively reduce stroke risk, but they are underutilized. NOACs have less ICH bleeding risk than warfarin and are superior—or at least noninferior—for stroke prevention. We must overcome the failure-to-prophylax syndrome.

  37. New Paradigms in the Science and Medicine of Heart Disease State-of-the-Art Risk Stratification of Patients with Atrial Fibrillation Anticoagulation Strategies Based on Established and Evolving Atrial Fibrillation Scoring Systems for Thrombosis and Hemorrhagic Risk Elaine M. Hylek, MD, MPHProfessor of Medicine Department of MedicineBoston University Medical CenterBoston, Massachusetts

  38. Independent Predictors of Stroke in AF Systematic Review *Significant in a subgroup of participants undergoing echocardiography in trials included AFI pooled analysis Hart RG et al. Neurology 2007; 69: 546.

  39. 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.

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

  41. The CHADS2 Score Stroke Risk Threshold Favoring Anticoagulation 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.

  42. The CHADS2 Score 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).

  43. CV Event Rates in Patients with Atrial Fibrillation Related to CHADS2 Score REACH Registry Goto S, et al. Am Heart J 2008; 156: 855.

  44. The CHA2DS2-VASc Score Stroke Risk Score for Atrial Fibrillation Weight (points) Congestive heart failure or LVEF < 35% 1 Hypertension 1 Age > 75 years 2 Diabetes mellitus 1 Stroke/TIA/systemic embolism 2 VascularDisease (MI/PAD/Aortic plaque) 1 Age 65-74 years 1 Sex category (female) 1 Moderate-High risk > 2 Low risk 0-1 Lip GYH, Halperin JL. Am J Med 2010; 123: 484.

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

  46. Published Bleeding Risk ScoresPatients on Oral Vitamin K Antagonist Anticoagulant Therapy Tay, Lane & Lip. Thromb Haemost 2008; 100: 955.

  47. Advances in the Science and Medicine of SPAF

  48. Importance of the HAS-BLED Score Risk Score for Predicting Bleeding in Anticoagulated Patients with Atrial Fibrillation Weight (points) Hypertension (> 160 mm Hg systolic) 1 Abnormal renal or hepatic function 1-2 Stroke 1 Bleeding history or anemia 1 Labile INR (TTR < 60%) 1 Elderly (age > 75 years) 1 Drugs (antiplatelet, NSAID) or alcohol 1-2 High risk (> 4%/year) > 4 Moderate risk (2-4%/year) 2-3 Low risk (< 2%.year) 0-1 Pisters R, et al. Chest 2010; 138: 1093. Lip GYH, et al. J Am Coll Cardiol 2010; 57: 173.

  49. Canadian Cardiovascular SocietyAF Guidelines 2012 Update Assess Thromboembolic Risk (CHADS2) CHADS2 = 1 CHADS2 = 0 CHADS2 > 2 Increasing stroke risk OAC OAC* OAC* ASA No anti-thrombotic No additional risk factors of stroke Either female sex or vascular disease Age > 65 y or combination of female sex and vascular disease *Aspirin is a reasonable alternative in some as indicated by risk/benefit

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