1. The document discusses Valentin Fuster's disclosure information and level of involvement as chair of BG Medicine. It then covers several topics related to atrial fibrillation (AF) and antithrombotic treatment including Virchow's triad, different disease compartments, bleeding risks, and new directions in treatment. 2. Several studies and trials are summarized related to anticoagulation therapy for AF, risks of bleeding, outcomes for different antithrombotic regimens, and prevalence and management of AF in clinical practice based on various surveys. 3. The document provides an overview of Valentin Fuster's disclosure statement and then reviews the literature on antithrombotic treatment and

1. Presenter Disclosure Information Valentin Fuster, M.D., Ph.D. Category Company Level Chair HRP BG Medicine Significant

2. ATHERO-THROMBOSIS- 2009 NOVEL ANTITHROMBOTIC RX - AF AS A MODEL 1. Basic Framework – Virchow’s Triad 2. Vascular Compartment – Platelets vs Fibrin 3. Antithrombotics – The Bleeding Problem 4. Antithrombotic Approaches – The Six Steps 5. New Directions – Non Pharmacological ACC/AHA/ESC (Fuster V et al) Circ 2006; 114:700 AHA Guidelines Handbook – Ed. V Fuster 2009

4. ATHERO-THROMBOSIS- 2009 NOVEL ANTITHROMBOTIC RX - AF AS A MODEL 1. Basic Framework – Virchow’s Triad 2. Vascular Compartment - Platelet vs Coagulation 3. Antithrombotics – The Bleeding Problem 4. Antithrombotic Approaches – The Six Steps 5. New Directions – Non Pharmacological ACC/AHA/ESC (Fuster V et al) Circ 2006; 114:700 AHA Guidelines Handbook – Ed. V Fuster 2009

6. ARTERIAL COMPARTEMENT Iba ñez B, et al. Eur Heart J 2006 ; 8 (suppl): G3-G9

7. CHAMBER & VENOUS COMPARTMENTS T Watson et. al. Lancet 2009 ;373:155. SPAF Investigators 1. JL Blackshear et. al. Stroke 1999 ;30:834. 2. Ann Intern Med. 1998 ;128:639.

8. WASHED RED BLOOD CELLS (HEMATOCRIT = 58%) AND FIBRINOGEN = 493MG/DL R A Merino et al JACC 1992 ;20:1661 R Rastegar et al., JACC 2003 ;41:603 STASIS – SEC – ACTIVATION OF THE COAGULATION SYSTEM

9. ATHERO-THROMBOSIS- 2009 NOVEL ANTITHROMBOTIC RX - AF AS A MODEL 1. Basic Framework – Virchow’s Triad 2. Vascular Compartment - Platelet vs Coagulation 3. Antithrombotics – The Bleeding Problem 4. Antithrombotic Approaches – The Six Steps 5. New Directions – Non Pharmacological ACC/AHA/ESC (Fuster V et al) Circ 2006; 114:700 AHA Guidelines Handbook – Ed. V Fuster 2009

10. 1) RISK FACTORS FOR MAJOR BLEEDING IN PATIENTS WITH ACUTE CORONARY SYNDROME Eikelboom et al. Kinnaird et al. Morcucci et al. Rao et al. Manoukian et al. Risk factor 2006 (N=34,126) 2003 (N=10,974) 2003 (N=24,045) 2005 (N=26,452) 2007 (N=13,819) Older age √ √ √ √ √ Diabetes mellitus √ √ √ √ √ Renal dysfunction √ √ √ √ √ Female sex √ √ √ √ History of hypert. √ √ √ √ SBP or MAP √ √ History of stroke √ √ M Cohen. Mayo Clin Proc 2009 ; 84:149

11. 1) RELATIONSHIP BETWEEN AGE AND FREQUENCY OF BLEEDING (95% CI) IN CHARISMA PATIENTS RECEIVING PLACEBO CHARISMA (PB Berger, DL Bhatt, V Fuster et al.,) 2009 (Subm) 0.15 0.14 0.13 0.12 0.11 0.10 0.09 0.08 0.07 0.06 0.05 0.04 0.03 0.02 0.01 0.00 39 41 43 45 47 49 51 53 55 57 59 61 63 65 67 69 71 73 75 77 79 81 83 85 87 89 91 93 95 600 550 500 450 350 250 150 50 400 300 200 100 0 Number of Patients Predicted Bleeding Probability Age

12. Cardiovascular Events Hazard Ratio No Bleed Bleed HR (95% CI) p-value n (%) n (%) CV death/MI/stroke 949 (6.3) 59 (15.2) 2.518 (1.936, 3.276) <0.001 CV death 384 (2.5) 74 (15.5) 6.588 (5.136, 8.449) <0.001 Non-fatal MI 271 (1.8) 15 (3.9) 2.259 (1.343, 3.800) 0.002 Non-fatal stroke 294 (1.9) 3 (0.8) 0.412 (0.132, 1.286) 0.115 All-cause death 630 (4.2) 106 (22.2) 5.791 (4.714, 7.115) <0.001 CV death/MI/stroke/hosp 2464 (16.3) 61 (19.3) 1.183 (0.918, 1.525) 0.194 Hospitalization 1707 (11.3) 21 (6.6) 0.592 (0.385, 0.910) 0.016 2) CHRONIC EVENT RATES OF PATIENTS WHO SUFFERED A MODERATE OR SEVERE BLEED vs THOSE WHO DID NOT 0 1 2 3 4 5 6 7 8 9 CHARISMA (PB Berger, DL Bhatt, V Fuster et al.,) 2009 (Subm)

13. Linking Post-PCI Bleeding With Increased Mortality BJ Doyle et. al., J Am Coll Cardiol . 2009 ;53:2019 .

14. Impact of Storage on RBCs & Tissue Oxygen Delivery BJ Doyle et. al., J Am Coll Cardiol . 2009 ;53:2019

15. Kaplan-Meier Estimates of Survival and Death After Transfusion of Older or Newer Blood DH Adams et. al. JACC 2009 ;53:2389. CG Koch et. al. N Engl J Med . 2008 ;358:1229 .

16. 3) MAJOR BLEEDING IN MATCHED COHORT TRIALS OF STENTING Study Warf+Asp+Clop Asp+Clop RR (fixed) n/N n/N 95% CI De Eugenio et al . 14/97 3/97 Kanaiginen et al. 18/239 4/239 Khurram et al. 7/107 9/107 Total 95% CI 443 443 0.01 0.1 1 10 100 Favours Triple Therapy Favours DoubleTherapy A Sourgounis et al., Circ 2009 ; 119:1682

17. 3a) Efficacy and Safety of Drug-Eluting Stent Use in Patients With Atrial Fibrillation We reviewed 604 patients with AF who had undergone percutaneous coronary intervention with stent over a period of 7 years (January 2001 - January 2008). On the basis of this study, the routine use of DES in patients with AF does not seem to be justified. A higher risk of major bleeding with DES in comparison with BMS raises the possibility that DES should be limited to lesions or patients with a high risk of restenosis. JM Ruiz-Nodar et al., Eur Heart J 2009 ; 30:932

18. 3b) TRIPLE THERAPY WITHIN TARGETED INR VALUES 2.0 TO 2.5 AND THOSE WHO WERE NOT (>2.5) CUMULATIVE EVENT-FREE SURVIVAL FROM OVERALL BLEEDING 0 200 300 450 600 Days 100 90 90 90 90 90 Bleeding event free survival (%) Dual therapy (n=102) Triple therapy (INR: 2.0-2.5) (n=81) Triple therapy (INR > 2.5) (n=21) 66.7% 95.1% 95.1% R Rossini, DJ Angiolillo et al., AJC 2008; 102:1618 (non-randomized)

19. 3c) DES-T (N=6816): CHANGE IN THE RISK OF STENT THROMBOSIS IN RELATION TO CLOPIDOGREL TREATMENT DURATION S Schultz et al., EHJ 2009 (In Press) (Munich) 0 6 12 18 24 30 36 42 48 Clopidogrel treatment duration (months) 0 0.1 0.2 0.3 0.4 Risk of ST within 4 years (%) 0 50 100 150 200 days 0.0 0.025 0.05 0.075 0.10

20. ATHERO-THROMBOSIS- 2009 NOVEL ANTITHROMBOTIC RX - AF AS A MODEL 1. Basic Framework – Virchow’s Triad 2. Vascular Compartment - Platelet vs Coagulation 3. Antithrombotics – The Bleeding Problem 4. Antithrombotic Approaches – The Six Steps 5. New Directions – Non Pharmacological ACC/AHA/ESC (Fuster V et al) Circ 2006; 114:700 AHA Guidelines Handbook – Ed. V Fuster 2009

21. 1) PREVALENCE / INCIDENCE OF ADULTS WITH AF IN THE US 1995 AND 2050 1990 1995 2000 2005 2050 2010 2045 2015 2020 2025 2030 2035 2040 Year Adults with Atrial Fibrillation in millions 0 1 2 3 4 5 6 7 2.08 2.26 2.44 2.68 2.94 3.33 3.50 4.34 4.78 5.16 5.42 6.07 ATRIA (AS Go et al.) JAMA 2001 ; 285: 2370 (Kaiser Permanente, North Ca) Age -1% at 60 y….+ 5% decade- , Cardiac Failure (1-25%) etc

22. 40-49 5 0-59 6 0-69 7 0-79 8 0-89 0 1 2 3 4 5 6 7 8 Stroke rate (%/year) 1) STROKE RATES IN RELATION TO AGE AMONG PATIENTS WITH ATRIAL FIBRILLATION Framingham - PA Wolf et al., Ann Int Med 1987;147:1561 – 10% Age Unrelated to Left Atrium (CVD, other Cardiac, aorta) 25% Bogousslavsky J et al & Miller VT et al Neurol 1990 ;40:1046 & 1993;43:32

23. 2) Meta-analysis - Antithrombotic Therapy in Atrial Fibrillation (AF) Thirteen new trials are available since a 1999 meta-analysis of antithrombotic agents for stroke prevention in patients with AF. This updated meta-analysis shows that adjusted-dose warfarin reduces stroke risk by 64% (6 trials) and antiplatelet agents reduce stroke risk by 22% (8 trials). Meta-analysis of 12 trials shows that adjusted-dose warfarin is more effective than antiplatelet therapy, but it doubles the risk for major extracranial and intracranial hemorrhage. But, these adverse events were only 0.2% per year. Additional trials are unlikely to change current estimates of the effectiveness of vitamin K antagonists and antiplatelet agents RG Hart et al., Ann Int Med 2007; 146:857 (San Antonio, Tx)

24. 3) ATRIAL FIBRILLATION - RISK OF STROKE BY CHAD * SCORE CHAD Index Antithrombotics High Risk: TE, MS, PHV Warfarin INR 2.0-3.5 2 RF Warfarin INR 2-3 Moderate Risk: 1 RF ASA 81-325mg Warfarin INR 2-3 (<EF) Low Risk: 0 RF ASA 81-325 mg * RF: C.Fail./ EF <35% 1 , Hypert. 1 , Age >75 1 , Diabetes 1 , ACC/AHA/ESC (Fuster V et al) Circ 2006; 114:700

25. 4a) USE OF ORAL ANTICOAGULANT THERAPY TO PREVENT STROKE ATRIAL FIBRILLATION - RESULTS OF RECENT SURVEYS ATRIA: Anticoagulation and Risk Factors in Atrial Fibrillation; NABOR: National Anticoagulation Benchmark and Outcomes Report. SJ Connolly, S Yusuf et al.Circ 2007 ; 116:450 Year Treated w/ Warfarin, % Published Survey Population (Patient Status) 1999 ATRIA Study 11,082 US patients large HMO - No 60 2005 NAROR Study 945 US patients from teaching, 55 community, and VA hospital 2006 Euro Heart Survey 2706 outpatients in 35 European 64 countries 2006 Hylek et al. 402 US patients,  55 years old, 51 learning hospital 2006 Birman-Deych et al. 16,007 US Medicare patients 49

26. 4a) Management of AF in Clinical Practice Prescription of vitamin K antagonists n = 11,379 ATRIA cohort (managed care system, California, U.S.A.) Go AS, et al. JAMA 2003; 290: 2685 n = 5,333 EuroHeart survey Nieuwlaat R, et al. Eur Heart J 2005; 29: 1181 n = 23,657 Medicare cohort, U.S.A. Birman-Deych E, et al. Stroke 2006; 37: 1070 vitamin K antagonists no anticoagulation

27. 4b) EURO HEART SURVEY ON AF ANTITHROMBOTIC Rx AT DISCHARGE 1 (2003-2004) 0 20 40 60 80 100 % Patients OAC OAC + antiplatelet Antiplatelet Other antithrombotic No antithrombotic 1 35 Countries,182 Hosp, 5333 pts - R Nieuwlaat et al.EHJ 2007 ; 26:2422 US - SB Rowan et al., JACC 2007 ; 49:1561 Ineligible (n=517) Eligible (n=517)

28. 4c) PROPORTION OF PATIENTS PERSISTING WITH WARFARIN TREATMENT OVER TIME STRATIFIED BY AGE AND CHADS 2 SCORE 100 80 60 40 20 0 % Warfarin by age 0 2 4 6 Time (years after diagnosis) 100 80 60 40 20 0 % Warfarin by CHADS2 score 0 2 4 6 Time (years after diagnosis) Age 40-64 Age 65-69 Age 70-74 Age 75-79 Age 80-84 Age 85+ CHADS2=0 CHADS2=3 CHADS2=6 CHADS2=1 CHADS2=4 CHADS2=2 CHADS2=5 UK-GPs: n=41910 pts with chronic AF AM Gallagher et al., J Thromb Hemost 2008 ; 6:1500

29. 4d) Anticoagulation with Warfarin Intensity Often Outside the Target Range Ansell J, et al . J Thromb Thrombolysis 2007; 23: 83 International Study of Anticoagulation Management % Time in Target Range 0 20 40 60 80 100 U.S. Canada France Italy Spain INR <2 INR 2–3 INR >3

30. 4d) AF - RELATIONSHIP BETWEEN THE OR (RELATIVE TO C+A) OF STROKE, MI, SYSTEMIC EMBOLISM, VASCULAR DEATH, OR MAJOR HEMORRHAGE AND TTR ACTIVE W (SJ Connolly et al.) Circ 2008 ; 118:2029 – Dot = Country 4.0 3.5 2.0 2.5 2.0 1.5 1.0 0.5 0.0 40 50 60 70 80 Not TTR (%) OR for Primary + Major Bleed OAC

31. Thrombin SCH 530348 AZD0837 ADP ATP P2X 1 P2Y 1 Aspirin P2Y 12 Abciximab Eptifibatide Tirofiban Stable/sustained platelet aggregation Initiation of transient platelet aggregation Stable/sustained platelet aggregation Cross-linking of adjacent platelets TXA 2 and prothrombotic (ADP) molecules Shape change PAR-1 Gq Gr shape change granule release fibrinogen “ GPIIb/IIIa receptor activation” PLC [Ca++] PKC augmented granule release and TXA 2 production Adenyl cyclase downregulation /↓ camp Gi-coupled signaling pathways Gi-coupled signaling pathway Gq and Gi-coupled signaling pathways Ca++ flux COX-1 TXA 2 Shape change Gq G 12 ← Ticlopidine ← Clopidogrel ← Prasugrel Active metabolite Ticagrelor Cangrelor IV hepatic biotransformation Gi 5)

32. The ACTIVE Trial Clopidogrel + Aspirin Atrial Fibrillation + Risk Factors X Double-blind Superiority n~7,500 Open-label Non-inferiority n=6,500 Anticoagulation-eligible OAC Contraindications or Unwilling Irbesartan, 300 mg/d vs. Placebo n ~9,000 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 55-74 + CAD or diabetes VKA (INR 2-3) Clopidogrel + Aspirin Aspirin + Placebo Clopidogrel + Aspirin

33. Effect of Clopidogrel Added to Aspirin in Patients with Atrial Fibrillation 0 1 2 3 4 0.0 0.1 0.2 0.3 0.4 Aspirin Clopidogrel + aspirin Years Cumulative incidence 0 1 2 3 4 0.0 0.1 0.2 0.3 0.4 Aspirin Clopidogrel + aspirin Years Cumulative incidence Primary Outcome Stroke The Active A Invest . N Engl J Med 2009 ; 360 (In Press) P<0.001 P<0.0001 Major bleeding : 2.0% per year clopidogrel and 1.3% per year placebo (p<0.001).

34. 0 2 4 6 8 10 12 0 2 4 6 8 10 12 0 2 4 6 8 10 12 0 5 10 15 Ticagrelor Clopidogrel Clopidogrel Ticagrelor Months Months Cumulative Incidence of Primary End Point (%) Cumulative Incidence of Major Bleeding (%) Cumulative Kaplan–Meier Estimates of the Time to the First Major Bleeding End Point, According to Study Criteria Cumulative Kaplan–Meier Estimates of the Time to the First Adjudicated Occurrence of Primary Efficacy End Point PLATO (Lars Wallentin et al.,) N Engl J Med 2009 ; 361:1 ACS (N=18624) - TICAGRELOR (180LD-90mgx2d ) VS CLOPIDOGREL (300/600LD-75mgx2d ) End Point: Death (Vascular), MI, Stroke – Ticagrelor: Early reversibility (CABG etc)

35. 6) Investigational Anticoagulant Targets TFPI (tifacogin) Idraparinux Rivaroxaban Apixaban LY517717 YM150 DU-176b Betrixaban TAK 42 Dabigatran ORAL PARENTERAL DX-9065a Otamixaban Xa IIa TF/VIIa X IX IXa VIIIa Va II (thrombin) Fibrin Fibrinogen 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

36. 5B)ANTITHROMBOTIC REGIMENS UNDER INVESTIGATION FOR CHRONIC TREATMENT OF PATIENTS WITH ATRIAL FIBRILLATION Phase 3 trial in AF Drug Class Phase 2 trial in AF Non-inf trial vs OAC Sup trial vs aspirin Dabigatran Dir thromb. inhib Done NCT00262600 (RE-LV) Not done Results 2009 AZD0837 Plat.-thromb. inhib Not done Planned Rivaroxaban Oral Xa inhib Not done NCT00403767 Not done Results 2010 Apixaban Oral Xa inhib Not done NCT00412984 NCT00496769 (AVERROES) (ARISTOTLE) Results 2010 Results 2010 Betrixoban Oral Xa inhib Plan 10/2008 ‒ Not done Du-176b Oral Xa inhib Done NCT00504556 Not done Biotimyl. Idrap. Parent Xa inhib Not done NCT00580216 ( BOREALIS) Not done Results 2010? R Nicuwlaat, SJ Connolly, Heart 2009; 95:95

37. RE-LY ® Trial R andomized E valuation of L ong-term Anticoagulant Therap y with Dabigatran Etexilate Primary objective: noninferiority vs. warfarin Observation period: minimum 1, mean 2, maximum 3 years Primary endpoint: all stroke + systemic embolism Safety measure: bleeding during treatment Connolly SJ, Ezekowitz MD et al. N Engl J Med 2009; 361, August 30, Open-label n = 18,113 Non-valvular AF + > 1 stroke risk factor Warfarin (INR 2.0-3.0) n = 6,022 Dabigatran 110 mg bid n = 6,015 Dabigatran 150 mg bid n = 6,076 Blinded

38. RE-LY ® Trial Primary Events Event Rate (%/year) p <0.001 (Noninferiority) p <0.001 (Superiority) All Strokes and Systemic Embolic Events Connolly SJ, Ezekowitz MD et al. N Engl J Med 2009; 361, August 30,

39. RE-LY ® Trial All-Cause Mortality Event Rate (%/year) p = NS p = 0.051 Connolly SJ, Ezekowitz MD et al. N Engl J Med 2009; 361, August 30, 2009

40. RE-LY ® Trial Hemorrhagic Stroke Events Event Rate (%/year) p <0.001 p <0.001 Connolly SJ, Ezekowitz MD et al. N Engl J Med 2009 ; 361, August 30

41. RE-LY ® Trial All Major Bleeding Event Rate (%/year ) p = 0.003 p = NS Hgb  > 2 g/dl or Transfusion > 2 units or Critical Site Connolly SJ, Ezekowitz MD et al. N Engl J Med 2009 ; 361, August 30 p = 0.04

43. 5B)ANTITHROMBOTIC REGIMENS UNDER INVESTIGATION FOR CHRONIC TREATMENT OF PATIENTS WITH ATRIAL FIBRILLATION Phase 3 trial in AF Drug Class Phase 2 trial in AF Non-inf trial vs OAC Sup trial vs aspirin Dabigatran Dir thromb. inhib Done NCT00262600 (RE-LV) Not done Results 2009- AZD0837 Plat.-thromb. inhib Not done Planned Rivaroxaban Oral Xa inhib Not done NCT00403767 Not done Results 2010 Apixaban Oral Xa inhib Not done NCT00412984 NCT00496769 (AVERROES) (ARISTOTLE) Results 2010 Results 2010 Betrixoban Oral Xa inhib Plan 10/2008 ‒ Not done Du-176b Oral Xa inhib Done NCT00504556 Not done Biotimyl. Idrap. Parent Xa inhib Not done NCT00580216 ( BOREALIS) Not done Results 2010? R Nicuwlaat, SJ Connolly, Heart 2009; 95:95

44. APIXABAN AND ACUTE CORONARY SYNDROME Composite of CV Death, MI, Severe Rec. Ischemia , and Ischemic Stroke Composite of Major and Clinically Relevant Nonmajor Bleeding APPRAISE Steering Committee and Invest. – Circ 2009; 119:2877 0 4 8 12 16 20 24 28 0 0.02 0.04 0.06 0.08 0.1 Weeks from Randomization Proportion with ISTH Major or CRNM Bleeding Apix 10 mg OD Apix 2.5 mg BID Placebo 0 4 8 12 16 20 24 28 0 0.02 0.04 0.06 0.08 0.1 Weeks from Randomization Proportion with CV Death, MI, SRI, or Stroke Apix 10 mg OD Apix 2.5 mg BID Placebo

45. APIXABAN AND CLOPIDOGREL CV Death, MI, Severe Ischemia And Ischemic Stroke Major or Clinically Relevant Nonmajor Bleeding APPRAISE Steering Committee and Invest. – Circ 2009 ; 119:2877 0.1 0.08 0.06 0.04 0.02 0 Clopidogrel No Clopidogrel 0.03 0.04 0.02 0.03 0.07 0.09 Placebo Apixaban 2.5 mg BID Apixaban 10 mg OD N 453 230 241 146 85 74 0.16 0.12 0.08 0.04 0 Clopidogrel No Clopidogrel 0.07 0.09 0.13 0.15 0.06 0.05 N 462 232 243 149 85 75

46. ATHERO-THROMBOSIS- 2009 NOVEL ANTITHROMBOTIC RX - AF AS A MODEL 1. Basic Framework – Virchow’s Triad 2. Vascular Compartment - Platelet vs Coagulation 3. Antithrombotics – The Bleeding Problem 4. Antithrombotic Approaches – The Six Steps 5. New Directions – Non Pharmacological ACC/AHA/ESC (Fuster V et al) Circ 2006; 114:700 AHA Guidelines Handbook – Ed. V Fuster 2009

47. 1) LAA Closure: Clinical Outcomes Holmes, Reddy, et al. Lancet 2009 ; 374:534. PROTECT-AF Trial LA LV Watchman Device Follow-Up Non-Valvular AF CHADs ≥ 1 Randomization (1:2) Warfarin Watchman Barbs Engage LAA Wall 160 µ PET fabric

49. PROTECT-AF: Primary Safety Results 900 patient-year Analysis - - - - Watchman _____ Control / Warfarin Primary Safety All-Cause Mortality DR Holmes, VY Reddy et al.) Lancet 2009 ; 374:534 Cohort 1050 Pt-Yrs WATCHMAN Control Relative Risk 95% CI Rate (Events/Pt-Yrs) Rate (Events/Pt-Yrs) Primary Endpoint 7.4 49/658.8 4.4 16/364.2 1.69 0.96, 2.97 All-Cause Mortality 3.0 20/658.8 4.8 /364.2 0.62 0.34, 1.24

50. LAA Closure: Pericardial Suture Ligation V Reddy et al 2009 Pre-Ligation LAA Mitral Valve Post-Ligation Mitral Valve Sternum Needle Liver RV LV Provided by: E Sosa, M Scanavacca, A d’Avila

51. 2) D Display and Integration of Scar Within the Electroanatomic Map FM Bogun et. al. J Am Coll Cardiol . 2009 ;53:1138.

52. AF - CORRELATION BETWEEN ENHANCEMENT ON DE-MRI AND LOW-VOLTAGE REGIONS ON ELECTROANATOMIC (EA) MAP 40 30 20 10 0 0 5 10 15 20 25 30 35 40 45 Extent of Delayed Enhancement (MRI) Low Voltage Tissue (EA Map) R 2 =0.67 P<0.05 95% CI (0.81-1.30) RS Oakes et al., Circulation 2009; 119:1758 (Utah)

53. AF - PATIENTS IN NSR AFTER LA ABLATION. COX REGRESSION CURVES FOR PATIENTS WITH DIFFERENT DEGREES OF DE-MRI RS Oakes et al., Circulation 2009 ; 119:1758 (Utah) 100 200 300 400 500 Time since ablation (days) Proportion of Patients in Sinus Rhythm 0.00 0.25 0.50 0.75 1.00 Mild Moderate Extensive Enhancement

54. ATHERO-THROMBOSIS- 2009 NOVEL ANTITHROMBOTIC RX - AF AS A MODEL 1. Basic Framework – Virchow’s Triad 2. Vascular Compartment - Platelet vs Coagulation 3. Antithrombotics – The Bleeding Problem 4. Antithrombotic Approaches – The Six Steps 5. New Directions – Non Pharmacological ACC/AHA/ESC (Fuster V et al) Circ 2006; 114:700 AHA Guidelines Handbook – Ed. V Fuster 2009