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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 Boehringer-Ingelheim

  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 CHRISTOPHER B. GRANGER, MD Professor of MedicineDuke University Medical Center Directory, Cardiac Care UnitDuke University Medical CenterDurham, NC

  4. Conflict of Interest Disclosures Program Chairman SAMUEL Z. GOLDHABER, MD Research Support: Eisai; EKOS; Johnson and Johnson; sanofi-aventis Consultant: Baxter, Boehringer-Ingelheim; BMS; 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 CHRISTOPHER GRANGER, MD Research Support: Boehring Ingelheim, Bristol Myers Squibb, GSK, Medtronic Foundation, Merck & Co., Pfizer, Sanofi-aventis, Takeda, The Medicines Company Consultant: Boehringer Ingelheim, Bristol Myers Squibb, GSK, Hoffmann-LaRoche, Lilly, Pfizer, Sanofi-aventis, Takeda, The Medicines Company, Astra Zeneca, Daiichi Sankyo, Ross Medical Corporation

  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, Thrombosis Research Group Cardiovascular Division Brigham and Women’s Hospital Professor of Medicine Harvard Medical School

  6. Faculty COI Disclosures Research Support Bristol-Myers Squibb, Daiichi, EKOS, NHLBI, Thrombosis Research Institute Consultant Boehringer-Ingelheim, Bristol-Myers Squibb, Daiichi, 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 atrial fibrillation

  11. 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.

  12. Atrial Fibrillation: An Epidemic Obesity CVD Diabetes Hypertension OSA Atrial Fibrillation Magnani J W et al. Circulation 2013;128:401-405

  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. More Patients are Vulnerable to Stroke than Previously Realized Fuster V, Chinitz JS. Circulation 2012; 125:2285-2287

  18. 2012 Focused Update: ESC Guidelines Camm AJ, et al. European Heart Journal 2012; 33: 2719

  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. 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

  21. 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

  22. 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

  23. Comparison Overview of New Anticoagulants with Warfarin

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

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

  26. A “Failure to Prophylax” Syndrome • Over the past decade, about 40% of patients with atrial fibrillation are unprotected from the risk of 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.

  27. Only 60% Use of Anticoagulation for SPAF: Euro Heart Survey 5,333 AF Patients; 35 Countries: 2003–2004 64 58 59 61 % Receiving Anticoagulation CHADS2 Score Nieuwlaat R, et al. Eur Heart J 2006; 27: 3018

  28. Only 60% Use of Anticoagulation: Minimal Variation by CHA2DS2-VASc Score Patients, N (%) (n=2,903) (n=2,180) (n=1,311) (n=2,471) (n=10,607) (n=305) (n=1,345) (n=902) Kakkar AK, et al. PLoS One. 2013 May 21;8(5):e63479

  29. Reasons Why VKAs Were Not Given: Patients with CHADS2 Score ≥ 2 Kakkar AK, et al. PLoS One. 2013 May 21;8(5):e63479

  30. Changing MD Behavior • Guidelines alone do not suffice. • Physician champions • Individual hospital protocols • Registries (GARFIELD) • Coalitions (“Stop AF”) • Public awareness/ advocacy • (North American Thrombosis Forum) • Litigation • Electronic alerts

  31. Computerized Support:Tricks of the Trade • Integrate support into quality improvement. • Link to an incentive system. • Foster acceptance of computer guidance. • Couple support with order entry software. • Limit to key decisions to avoid alert fatigue. • Use automatic, not user-initiated, systems. • Measure outcomes and provider behavior. Piazza G, Goldhaber SZ. Circulation 2009;120:113

  32. 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.

  33. 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 CHRISTOPHER B. GRANGER, MD Professor of MedicineDuke University Medical Center Directory, Cardiac Care UnitDuke University Medical CenterDurham, NC

  34. Complications of AF Hemodynamic Embolic Fatigue Shortness of Breath Palpitations CHF Stroke Systemic Embolism

  35. Treatment of AF

  36. AFFIRM: Rate vs. Rhythm Control 30 Rate p=0.078 unadjusted Rhythm 25 p=0.068 adjusted 20 15 Mortality, % Nearly ¾ of all strokes were related to discontinuation or inadequate anticoagulation Only 42% of strokes during documented AF 10 5 0 3 2 5 0 1 4 Time (years) Rhythm N: 2033 1932 1807 1316 780 255 Rate N: 2027 1925 1825 1328 774 236 The AFFIRM Investigators. N Engl J Med. 2002;347:1825-1833.

  37. Outcomes by AF Type - ARISTOTLE Adjusted HR 0.70, 95% CI 0.51-0.93 P=0.015 Al-Khatib SM, et al. EHJ 2013; 34: 2464-2471

  38. Subclinical AF and Risk of Stroke Atrial Tachyarrhythmia > 6 min ≤ 3 Months After Pacemaker or Defibrillator Implantation Stroke or Systemic Embolism Years Healey JS, et al. NEJM 2012; 366:120-129

  39. RACE II: Lenient vs. Strict Rate Control Noninferior 20 15 10 5 0 14.9 Strict control 12.9 Cumulative Incidence of Primary Outcome (%) Lenient control 0 6 12 18 24 30 36 Months No. at Risk Strict control 303 282 273 262 246 212 131 Lenient control 311 298 290 285 255 218 138 Van Gelder IC et al. N Engl J Med. 2010;362:1363-1373.

  40. Balancing the Risks of Thrombosis and Bleeding High risk of Thrombotic events High risk ofbleeding events “Sweet spot” Risk of Any Event Risk of Any Event – + Potency of Antithrombotic Therapy Bleeding risk Thrombotic risk Adapted from Ferreiro JL et al. ThrombHaemost. 2010;103:1-8.

  41. CHADS2 Risk Score 3% / year Gage BF, et al. JAMA. 2001;285:2864-2870. VanWalraven C, et al. Arch Intern Med 2003; 163:936. Nieuwlaat R, et al. (EuroHeart survey) Eur Heart J 2006 (E-published). Go A, et al. JAMA 2003; 290: 2685. Gage BF, et al. Circulation 2004; 110: 2287.

  42. Prior ACC/AHA/ESC Guidelines

  43. Redefining Risk: CHA2DS2-VASc ESC Guidelines: Eur Heart J . 2010;31:2369-2429.

  44. CHA2DS2VASc Refines Stroke Risk Stratification in CHADS2=0 A nationwide Danish cohort study in 47,576 non-warfarin treated NVAF patients with a CHADS2 score = 0-1 at baseline (1997-2008) 100% 0.84% 1.59% 98% 1.75% 2.69% 3.20% Proportion of patients free of stroke / thromboembolism 96% Stroke / thromboembolism rate (% person-years) CHADS2=0: n=17,327 person-years 94% CHA2DS2VASc=0: n=6,919 person-years CHA2DS2VASc=1: n=6,811 person-years CHA2DS2VASc=2: n=3,347 person-years CHA2DS2VASc=3: n=250 person-years 92% 0% Days from discharge 0 100 200 300 Olesen et al. Thromb Haemost 2012; 107:1172-1179

  45. Danish Hospital Registry Data 1997-200614,572 patients CHADS-VASc 0 or 1 Olesen J. BMJ 2011;342:d124

  46. CHA2DS2VASc Refines Stroke Risk Stratification in CHADS2=1 A nationwideDanishcohortstudy in 47,576 non-warfarintreated NVAF patients with a CHADS2 score = 0-1 atbaseline (1997-2008) Stroke / thromboembolism rate (% person-years) 100% 1.93% 98% 4.05% 96% Proportion of patients free of stroke / thromboembolism 4.92% 5.81% CHADS2=1: n=22,945 person-years 94% CHA2DS2VASc=1: n=2,069 person-years CHA2DS2VASc=2: n=8,516 person-years 8.18% CHA2DS2VASc=3: n=11,223 person-years 92% CHA2DS2VASc=4: n=1,137 person-years 0% Days from discharge 0 100 200 300 Olesen et al. Thromb Haemost 2012; 107:1172-1179

  47. Redefining Risk: HAS-BLED Pisters R, et al. Chest 2010; 138(5): 1093-1100 ESC Guidelines: Eur Heart J . 2010;31:2369-2429

  48. The Problem with Risk Scores (ARISTOTLE) Stroke or SEE Major Bleeding Lopes RD, et al. Lancet 2012; 380:1749-1758 Apixaban Better Warfarin Better

  49. HAS-BLED Pisters R, et al. Chest 2010; 138(5): 1093-1100 ESC Guidelines: Eur Heart J . 2010;31:2369-2429

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