Stratifying stroke risk to guide antithrombotic therapy in patients with AF

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 Incidence of a first ischaemic stroke Paroxysmal AF Permanent AF p-value Multivariable-adjusted hazard ratio for ischaemic stroke (95% CI)* Events/ 1000 patient-yr Events/ 1000 patient-yr 21 25 0.45 1.07 (0.71–1.61) Reference: Friberg et al. Eur Heart J 2010;31:967–975 *In paroxysmal versus permanent AF in subjects without prior stroke Friberg et al, Eur Heart J 2010

Stroke Risk in AF Working Group: factors influencing stroke risk in patients with AF Pooled analysis of seven randomized trials1 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 gender 1.6–1.9* Heart failure Inconclusive# Coronary artery disease Inconclusive References; Stroke Risk in Atrial Fibrillation Working Group. Neurology 2007;69:546−554, Camm et al. Eur Heart J 2010;31:2369–2429 *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 defined2 1. Stroke Risk in Atrial Fibrillation Working Group, Neurology 2007; 2. Camm et al, Eur Heart J 2010 3

Different schemes designed to stratify stroke risk in patients with AF Atrial Fibrillation Investigators (1994)1 Stroke Prevention in Atrial Fibrillation (SPAF, 1999)2 CHADS2 (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 CHA2DS2-VASc (2010)11 References: Atrial Fibrillation Investigators. Arch Intern Med 1994;154:1449–1457, Hart et al. Stroke 1999;30:1223–1229, Gage et al. JAMA 2001;285:2864–2870, Gage et al. Circulation 2004;110:2287–2292, Albers et al.Chest 2001;119:194S–206S, Singer et al. Chest 2004;126:429S–456S, Singer et al. Chest 2008;133:546S–592S, Wang et al. JAMA 2003;290:1049–1056, van Walraven et al. Arch Intern Med 2003;163:936–943, Fuster et al. Circulation 2006;114:e257– e354, Lip et al. Chest 2010;137:263–272 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

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 100 Low Moderate 80 High 60 Patients (%) 40 Reference: Baruch et al. Stroke 2007;38:2459–2463 20 AFI SPAF ACCP 2001 ACCP 2004 CHADS2 Fram. van Walraven Baruch et al, Stroke 2007

CHADS2 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 Item Points Congestive heart failure 1 Hypertension Age ≥75 years Diabetes mellitus Stroke/TIA 2 CHADS2 6 5 4 3 2 1 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) Add points together Reference; Gage et al. JAMA 2001;285:2864–2870 *Per 100 patient-years without antithrombotic therapy Gage et al, JAMA 2001 6

ACCF/AHA/HRS 2011 and ACCP 2008 guidelines: based on CHADS2 CHADS2 scoring1 CHF +1 Hypertension +1 Age ≥75 years +1 Diabetes mellitus +1 Prior Stroke or TIA +2 Recommended therapy CHADS2 score ACCP 20082 ACCF/AHA/HRS 20113 ASA 75–325 mg/day ASA 81–325 mg/day 1 VKA (INR 2–3) or ASA 75–325 mg/day VKA (INR 2–3) or ASA 81–325 mg/day ≥2 VKA (INR 2–3) References; Gage et al. JAMA 2001;285:2864–2870, Singer et al. Chest 2008;133:546S–592S, Fuster et al. Circulation 2011;123:e269–e367 1. Gage et al, JAMA 2001; 2. Singer et al, Chest 2008; 3. Fuster et al, Circulation 2011

CHA2DS2-VASc: a further refinement of CHADS2 Risk factor Points Congestive heart failure/LV dysfunction* +1 Hypertension Age ≥75 years +2 Diabetes mellitus Previous stroke/TIA/thromboembolism Vascular disease (MI, aortic plaque, peripheral artery disease)# Age 65–74 years Sex category (female) Maximum score 9 References: Camm et al. Eur Heart J 2010;31:2369–2429, Lip et al. Chest 2010;137:263–272 *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

ESC 2010 guidelines: based on CHADS2 and CHA2DS2-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: CHADS2 If CHADS2 ≥2  oral anticoagulation If CHADS2 <2  CHA2DS2-VASc Risk category CHA2DS2-VASc score Antithrombotic therapy No risk factors 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 ≥2 Oral anticoagulation (INR 2–3) Reference: Camm et al. Eur Heart J 2010;31:2369–429 Camm et al, Eur Heart J 2010 9

Many stroke risk factors are also risk factors for bleeding Higher stroke risk = higher bleeding risk Risk factor for stroke* Risk factor for anticoagulant-related bleeding* Advanced age14  History of hypertension1,3,4 History of MI or ischaemic heart disease1,3 Cerebrovascular disease1–4 Anaemia3,4 Previous history of bleeding3,4 Kidney or liver dysfunction4 Concomitant use of antiplatelets3,4 References: Lip et al. Chest 2010;137:263–272, Hylek et al. Ann Intern Med 1994;120:897–902, Hughes et al. QJM 2007;100:599−607, Pisters et al. Chest 2010;138:1093–1100 *Not exhaustive The relationship between stroke risk and bleeding risk complicates the evaluation of benefit–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 10

1-year risk of major bleeding increases with HAS-BLED score AF cohort of the Euro Heart Survey Clinical characteristic Points Hypertension (SBP >160 mm Hg) 1 Abnormal renal or liver function 1 + 1 Stroke Bleeding Labile INRs Elderly (age >65 years) Drugs or alcohol Cumulative score Range 0−9 P value for trend = 0.007 Reference: Pisters et al. Chest 2010;138:1093–110 HAS-BLED score Pisters et al, Chest 2010 11

ATRIA: a risk scheme to predict warfarin-associated haemorrhage Clinical characteristic Points Anaemia 3 Severe renal disease* Age ≥75 years 2 Any prior haemorrhage diagnosis 1 Diagnosed hypertension *Defined as estimated glomerular filtration rate <30 ml/min or dialysis-dependent Low risk 0–3 Intermediate risk 4 High risk 5–10 ATRIA, Anticoagulation and Risk Factors in Atrial Fibrillation, Reference: Fang et al. J Am Coll Cardiol 2011;58:395–401 Fang et al, J Am Coll Cardiol 2011