1. Antithrombotic Therapy for Stroke Prevention in Atrial Fibrillation

2. “ To this variety of apoplexy those are most liable who lead an idle life, who are obese, whose face and hands are constantly livid and whose pulse constantly unequal.” Wepfer, 1658

3. Left Atrial Appendage (LAA)

4. Thromboembolic Events Control Patients in AF Trials Cerebral 49 (91%) Systemic 5 (9%)

5. Severity of Ischemic Strokes in Atrial Fibrillation Fatal: 5 (10%) Moderate to severe: 23 (45%) Mild: 23 (45%) Number of events in 1,092 control patients

6. Age Distribution of People With AF Compared With U.S. General Population 30,000 20,000 10,000 0 Arch Int Med. 1995;155:471. 5–9 Population with Atrial Fibrillation U.S. Population 500 400 300 200 100 0 Age, years U.S. Population (x 1000) <5 10–14 15–19 20–24 25–29 30–34 35–39 40–44 50–54 60–64 70–74 80–84 90–94 45–49 55–59 65–69 75–79 85–89 >95 AF Population (x 10)

7. Efficacy of Warfarin Compared with Control in Five Studies AFASAK 27 811 BAATAF 15 922 CAFA 14 478 SPAF 23 508 SPINAF 29 972 Combined* 108 3691 No. of Events Patient- years 100 50 0 -50 -100 Warfarin Better Warfarin Worse Risk Reduction, % *Total risk reduction for all 5 studies combined is 68%

8. Patients Assigned to Warfarin in AF Trials Intensity of Anticoagulation When Stroke Occurred AFASAK SPAF I BAATAF SPINAF CAFA 1.0 2.0 3.0 4.0 1.7 1.6 1.5 1.4 1.3 1.2 1.1 1.0 INR Ratio PT Ratio (ISI 2.4) ACCP recommendation: INR: 2.0–3.0 1.8 Target range for individual study

9. Efficacy of Aspirin Compared with Control AFASAK 35 807 SPAF 65 1457 EAFT 130 838 Combined * 230 3102 No. of Events Patient- years 100 50 0 -50 -100 Aspirin Better Aspirin Worse Risk Reduction (%) *Total risk reduction for all 3 studies combined is 21%

10. SPAF III Study Atrial Fibrillation Clinical Assessment Echocardiography (TTE) Female > 75 years Systolic hypertension Impaired LV function Prior thromboembolism Low Risk Cohort Aspirin 325 mg/day High Risk Cohort Warfarin Combination INR 2–3 1–3 mg Warfarin + Monthly INR to 325 mg Aspirin adjust dose fixed dose – +

11. SPAF III Results High Risk Cohort Lancet 1996; 348; 633-638. 0 1 2 3 4 5 6 7 8 Stroke or Systemic Embolism Major Bleeding Intracranial Hemorrhage Aspirin Plus Fixed-Dose Warfarin Adjusted-Dose Warfarin (INR 2-3) Event Rate, % per Patient-year

12. SPAF III Study Atrial Fibrillation Clinical Assessment Echocardiography (TTE) Female > 75 years Systolic hypertension Impaired LV function Prior thromboembolism Low Risk Cohort Aspirin 325 mg/day High Risk Cohort Warfarin Combination INR 2–3 1–3 mg Warfarin + Monthly INR to 325 mg Aspirin adjust dose fixed dose – +

13. SPAF III Non-Randomized Aspirin-Only Arm Low Stroke Risk Cohort * % per year 95% CI % per year 95% CI Stroke or syst. 1.1% (0.6%–2.0%) 3.6% (2.5%–5.2%) embolism No History of Hypertension History of Hypertension *Patients enrolled had none of these high risk features: female >75 years, impaired LV function, current SBP >160 mm Hg, prior thromboembolism

14. Risk Factors for Stroke and Efficacy of Antithrombotic Therapy in Atrial Fibrillation Archives of Internal Medicine July 11, 1994

15. Predicting Stroke Risk in AF—Who Benefits Most? Multivariate Analysis of Pooled Data Clinical risk factors Relative risk Previous stroke or TIA 2.5 x History of hypertension 1.6 x Diabetes 1.7 x Increasing age (per decade) 1.4 x Adapted from Arch Intern Med 1994; 154:1454

18. AFFIRM Stroke Events 5.5 7.1 1.1 1.3 0.8 0.8 7.4 8.9 P =.79 P =.73 P =.68 P =.93 The AFFIRM Investigators. N Engl J Med . 2002;347:1825-1833. Percent

19. 7th ACCP Consensus Conference on Antithrombotic Therapy CHEST Supplement: 2004

21. ACCP 2004 Recommendations for Stroke Prevention in Atrial Fibrillation* Risk Factors Recommended Therapy Any High Risk Factor Warfarin (target INR 2.5, range 2.0-3.0)** Age 65-75 years and Aspirin 325 mg qd No high risk factors or Warfarin (target INR 2.5, range 2.0-3.0)** No Risk Factors and age < 65 Aspirin 325 mg qd *Applies to persistent (sustained or permanent) and paroxysmal (intermittent) AF **target INR > 2.5 for patients with mechanical heart valves

23. Warfarin for Atrial Fibrillation Limitations Lead to Under-treatment <55 55-64 65-74 75-84  85 44% 58% 61% 57% 35% Age (years) Warfarin Use in Eligible Patients (%) 55% Overall Use Go A et al. Ann Intern Med 1999;131:927.

24. 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

26. S troke P revention Using an OR al Direct T hrombin I nhibitor in A trial F ibrillation The SPORTIF III and V Trials Patients with Nonvalvular AF and Risk Factors for Stroke n=7,320 SPORTIF III 23 nations open-label ( n =3,407) SPORTIF V US, Canada double-blind ( n =3,913) Fixed-dose Ximelagatran (36 mg bid) Adjusted-dose Warfarin (INR 2-3)

27. SPORTIF Program Primary Analyses Intention-to-treat Analysis Difference in Absolute Event Rates (Ximelagatran – Warfarin) Ximelagatran Better Warfarin Better -1 0 1 2 3 4 -2 -3 -4 SPORTIF III SPORTIF V -0.66 +0.45 p =0.10 p =0.13 Pooled -0.03 p =0.94

28. SPORTIF V Hemorrhage Event Rate (% /year) p <0.0001 p= 0.16 p= NS

29. SPORTIF V Liver Enzyme Elevation ALT >3 x ULN Months Number of Patients Ximelagatran Warfarin Incidence (%) ALT >3x ULN p <0.001