1. Stratifying stroke risk to guide antithrombotic therapy in patients with AF

2. No evidence that AF type significantly impacts stroke risk Scandinavian follow-up study of patients treated for paroxysmal (n=855) and permanent AF (n=1126) during 2002 (mean follow-up 3.6 years) Aim: to investigate differences in stroke risk in the two cohorts Paroxysmal AFPermanent AF p-value Multivariable-adjusted hazard ratio for ischaemic stroke (95% CI)* Events/ 1000 patient-yr 21250.451.07 (0.71–1.61) *In paroxysmal versus permanent AF in subjects without prior stroke Friberg et al, Eur Heart J 2010 Incidence of a first ischaemic stroke

3. Stroke Risk in AF Working Group: factors influencing stroke risk in patients with AF Risk factor Adjusted RR (95% CI) Prior stroke/TIA 2.5 (1.8–3.5) Increasing age 1.5/decade (1.3–1.7) History of hypertension 2.0 (1.6–2.5) Diabetes mellitus 1.7 (1.4–2.0) Female gender1.6–1.9* Heart failureInconclusive # Coronary artery diseaseInconclusive *Only a range of adjusted RRs reported for female gender # While studies show a clear risk of thromboembolism with moderate to severe systolic impairment, the risk of thromboembolism with heart failure and preserved ejection fraction is less defined 2 1. Stroke Risk in Atrial Fibrillation Working Group, Neurology 2007; 2. Camm et al, Eur Heart J 2010 Pooled analysis of seven randomized trials 1

4. Different schemes designed to stratify stroke risk in patients with AF Atrial Fibrillation Investigators (1994) 1 Stroke Prevention in Atrial Fibrillation (SPAF, 1999) 2 CHADS 2 (2001 and 2004) 3,4 American College of Chest Physicians (ACCP) guidelines (2001, 2004 and 2008) 5–7 Framingham (2003) 8 van Walraven (2003) 9 ACC/AHA/ESC guidelines (2006) 10 CHA 2 DS 2 -VASc (2010) 11 1. AFI, Arch Intern Med 1994; 2. Hart et al, Stroke 1999; 3. Gage et al, JAMA 2001; 4. Gage et al, Circulation 2004; 5. Albers et al, Chest 2001; 6. Singer et al, Chest 2004; 7. Singer et al, Chest 2008; 8. Wang et al, JAMA 2003; 9. van Walraven et al, Arch Intern Med 2003; 10. Fuster et al, Circulation 2006; 11. Lip et al, Chest 2010

5. Differences in risk stratification schemes yield varying degrees of stroke risk Percentage of patients with AF (enrolled in the SPORTIF III and V trials) classified as being at low, moderate and high risk of stroke, according to individual risk stratification schemes Baruch et al, Stroke 2007 100 80 60 40 20 0 AFISPAFACCP 2001 ACCP 2004 CHADS 2 Fram.van Walraven Low Moderate High Patients (%)

6. CHADS 2 is the most recognized risk stratification scheme 1 or 2 points are assigned as shown for each of the risk factors below Stroke risk is determined by the cumulative score Gage et al, JAMA 2001 *Per 100 patient-years without antithrombotic therapy ItemPoints Congestive heart failure 1 Hypertension 1 Age ≥75 years 1 Diabetes mellitus 1 Stroke/TIA 2 CHADS 2 6 5 4 3 2 1 0 Add points together Stroke rate (95% CI)* 18.2 (10.5–27.4) 12.5 (8.2–17.5) 8.5 (6.3–11.1) 5.9 (4.6–7.3) 4.0 (3.1–5.1) 2.8 (2.0–3.8) 1.9 (1.2–3.0)

7. ACCF/AHA/HRS 2011 and ACCP 2008 guidelines: based on CHADS 2 CHADS 2 scoring 1 CHF+1 Hypertension+1 Age ≥75 years+1 Diabetes mellitus+1 Prior Stroke or TIA+2 1. Gage et al, JAMA 2001; 2. Singer et al, Chest 2008; 3. Fuster et al, Circulation 2011 Recommended therapy CHADS 2 score ACCP 2008 2 ACCF/AHA/HRS 2011 3 0ASA 75–325 mg/day ASA 81–325 mg/day 1VKA (INR 2–3) or ASA 75–325 mg/day VKA (INR 2–3) or ASA 81–325 mg/day ≥2VKA (INR 2–3)

8. CHA 2 DS 2 -VASc: a further refinement of CHADS 2 *Left ventricular ejection fraction ≤40%; # Including prior revascularization, amputation due to peripheral artery disease or angiographic evidence of peripheral artery disease Camm et al, Eur Heart J 2010; Lip et al, Chest 2010 Risk factorPoints Congestive heart failure/LV dysfunction*+1 Hypertension+1 Age ≥75 years+2 Diabetes mellitus+1 Previous stroke/TIA/thromboembolism+2 Vascular disease (MI, aortic plaque, peripheral artery disease) # +1 Age 65–74 years+1 Sex category (female)+1 Maximum score9

9. ESC 2010 guidelines: based on CHADS 2 and CHA 2 DS 2 -VASc CHF/LV dysfunction+1 Hypertension+1 Age ≥75 years+2 Diabetes mellitus+1 Prior Stroke/TIA/TE+2 Vascular disease +1 Age 65–74 years+1 Sex category (female)+1 Initial evaluation: CHADS 2 If CHADS 2 ≥2  oral anticoagulation If CHADS 2 <2  CHA 2 DS 2 -VASc Camm et al, Eur Heart J 2010 Risk categoryCHA 2 DS 2 -VASc scoreAntithrombotic therapy No risk factors0 ASA 75–325 mg/day or nothing (preferably nothing) One ‘clinically relevant non-major’ risk factor 1 Oral anticoagulation (INR 2–3) or ASA 75–325 mg/day (preferably oral anticoagulant) One ‘major’ risk factor or ≥2 ‘clinically relevant non-major’ risk factors ≥2Oral anticoagulation (INR 2–3)

10. Many stroke risk factors are also risk factors for bleeding Higher stroke risk = higher bleeding risk 1. Lip et al, Chest 2010; 2. Hylek et al, Ann Intern Med 1994; 3. Hughes et al, QJM 2007; 4. Pisters et al, Chest 2010 The relationship between stroke risk and bleeding risk complicates the evaluation of benefit–risk Risk factor for stroke* Risk factor for anticoagulant-related bleeding* Advanced age 1  4 History of hypertension 1,3,4 History of MI or ischaemic heart disease 1,3 Cerebrovascular disease 1–4 Anaemia 3,4 Previous history of bleeding 3,4 Kidney or liver dysfunction 4 Concomitant use of antiplatelets 3,4 *Not exhaustive

11. 1-year risk of major bleeding increases with HAS-BLED score Pisters et al, Chest 2010 AF cohort of the Euro Heart Survey HAS-BLED score Number of patients 79812867441874682000 Number of bleeding events 913147410000 Clinical characteristicPoints Hypertension (SBP >160 mm Hg) 1 Abnormal renal or liver function 1 + 1 Stroke1 Bleeding1 Labile INRs1 Elderly (age >65 years) 1 Drugs or alcohol1 + 1 Cumulative scoreRange 0−9 P value for trend = 0.007

12. ATRIA: a risk scheme to predict warfarin-associated haemorrhage Fang et al, J Am Coll Cardiol 2011 Clinical characteristicPoints Anaemia3 Severe renal disease*3 Age ≥75 years2 Any prior haemorrhage diagnosis1 Diagnosed hypertension1 *Defined as estimated glomerular filtration rate <30 ml/min or dialysis-dependent Low risk0–3 Intermediate risk4 High risk5–10