1. Management of AF­related stroke

2. Strategies for prevention of stroke in AF
Management of risk factors for stroke other than AF
e.g. hypertension, diabetes mellitus
Antithrombotic therapy to prevent thrombus formation in the heart
Anticoagulation: vitamin K antagonist (VKA)
Antiplatelet therapy: ASA, clopidogrel
Other strategies
Cardioversion?
Ablation?
Left atrial appendage occlusion (e.g. PROTECT AF1)?
These strategies do not present an alternative to antithrombotic therapy
Reference: Holmes et al. Lancet 2009; 374:534–42
1. Holmes et al, Lancet 2009 2

3. Key studies of VKA and antiplatelet therapy for stroke prevention in AF
Study
Outcomes*
Meta-analysis1
VKA therapy:
64% reduction in risk of stroke and 26% reduction in risk of all-cause mortality vs placebo or no treatment
38% reduction in risk of stroke vs ASA
BAFTA2
VKA vs ASA (elderly)
54% reduction in risk of stroke vs ASA (p=0.003)
No increase in risk of major bleeding vs ASA (p=0.90)
ACTIVE-W3
VKA vs clopidogrel + ASA
72% reduction in risk of stroke vs dual antiplatelet therapy (p=0.001)
No increase in risk of major bleeding vs dual antiplatelet therapy (p=0.53)
ACTIVE-A4
Clopidogrel + ASA vs ASA
Clopidogrel + ASA:
28% reduction in risk of stroke vs ASA (p<0.001)
57% increase in major bleeding risk vs ASA (p<0.001)
References: Hart et al. Ann Intern Med 2007;146:857–867, Mant et al. Lancet 2007;370:493–503, Connolly et al. Lancet 2006;367:1903–1912, Connolly et al. N Engl J Med 2009;360:2066–2078
*The percentage differences shown are relative as opposed to absolute
1. Hart et al, Ann Intern Med 2007; 2. Mant et al, Lancet 2007; 3. Connolly et al, Lancet 2006; 4. Connolly et al, N Engl J Med 2009 3

4. 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 4

5. ESC 2010 guidelines: based on CHADS2 and CHA2DS2-VASc
Initial evaluation: CHADS2
If CHADS2 ≥2  oral anticoagulation
If CHADS2 <2  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
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 5

6. VKA limitations
Significant inter- and intra-patient variability in dose response1 due to:
Co-morbidities
Genetic polymorphisms
Interactions with food and concomitant drugs
Unpredictable pharmacology
Narrow therapeutic window1
Regular coagulation monitoring and dose adjustments required
Increased risk of stroke or bleeding outside the INR range2
References: Ansell et al. Chest 2008;133:160S–198S, Nieuwlaat et al. Am Heart J 2007;153:1006–1012
1. Ansell et al, Chest 2008; 2. Nieuwlaat et al, Am Heart J 2007 6

7. VKAs have a narrow therapeutic window
Adjusted odds ratios for ischaemic stroke and intracranial bleeding in relation to intensity of anticoagulation 20
Data on bleeding and stroke risk support recommendation for narrow INR target range 15
Ischaemic
stroke
Intracranial bleeding
Odds ratio for event 10 5
Reference: Fuster V et al. Circulation 2011;123:e269–e367 1
1.0
2.0
3.0
4.0
5.0
6.0
7.0
8.0
International normalized ratio
Fuster et al, Circulation 2011 7

8. CV death, any TE or major bleeding
Non-adherence to guidelines is associated with poorer outcomes: Euro Heart Survey
Non-adherence = undertreatment or overtreatment with antithrombotic therapy according to the 2001 ACC/AHA/ESC guidelines in use at the time
Undertreatment n=964
Guideline adherence n=2093
Overtreatment n=386
Patients (%)
Stroke
Major bleeding
Any TE
CV death, any TE or major bleeding 3 6 9 12 15
Reference: Nieuwlaat et al. Am Heart J 2007;153:1006–1012
Absolute numbers of events
Undertreatment 21 43 14 78
Guideline adherence 34 52 33
115
Overtreatment 5 18 17 49
Nieuwlaat et al, Am Heart J 2007 8

9. Rationale for novel oral anticoagulants
Novel oral anticoagulants should fulfill the following unmet needs:
Predictable pharmacology
Target a single coagulation factor
Fewer interactions with food or concomitant drugs
Can be used at a fixed dose
No requirement for routine coagulation monitoring
Improved benefit–risk profile compared with VKAs in patients with suboptimal INR control
References: Bauer. Rev Neurol Dis 2010;7:1–8, Turpie. Eur Heart J 2007;29:155–165, Weitz. Thromb Haemost 2010;103:62–70
Bauer, Rev Neurol Dis 2010; Turpie, Eur Heart J 2007; Weitz, Thromb Haemost 2010 9

10. Phase II safety (Japan)7
Clinical data
Newer oral anticoagulants for stroke prevention in AF: clinical trial overview
Oral anticoagulant
Phase II studies
Phase III studies
Direct thrombin inhibitors
Dabigatran
PETRO1
RE-LY2,3
RELY-ABLE4
Direct Factor Xa inhibitors
Rivaroxaban
ROCKET AF5
J-ROCKET AF6
Apixaban
Phase II safety (Japan)7
ARISTOTLE8
AVERROES9
AVERROES-LTOLE10
Edoxaban
Phase II dose-finding11
Phase II safety (Asia)12
ENGAGE AF-TIMI 4813
References: Ezekowitz et al. Am J Cardiol 2007;100:1419–1426 , Connolly et al. N Engl J Med 2009;361:1139−1151, Connolly et al. N Engl J Med 2010;363:1875–1876 , Boehringer Ingelheim GmbH. Available at: Patel et al. N Engl J Med 2011;365:883–891, Hori et al. J Thromb Haemost 2011;9 (Suppl. 2):20 [abstract O-MO-032], Ogawa et al. Circ J 2011;75:1852–1859, Granger et al. N Engl J Med 2011; 365:981–992, Connolly et al. N Engl J Med 2011;364:806–817 , Bristol-Myers Squibb. Available at: Weitz et al. Thromb Haemost 2010;104:633–641 , Chung et al. Thromb Haemost 2011;105:535–544, Ruff et al. Am Heart J 2010;160:635–641
Studies in yellow are complete, the others are ongoing
1. Ezekowitz et al, Am J Cardiol 2007; 2. Connolly et al, N Engl J Med 2009; 3. Connolly et al, N Engl J Med 2010; 4. clinicaltrials.gov, NCT ; 5. Patel et al, N Engl J Med 2011; 6. Hori et al, J Thromb Haemost 2011; 7. Ogawa et al, Circ J 2011; 8. Granger et al, N Engl J Med 2011; 9. Connolly et al, N Engl J Med 2011; 10. clinicaltrials.gov, NCT ; 11. Weitz et al, Thromb Haemost 2010; 12. Chung et al, Thromb Haemost 2011; 13. Ruff et al, Am Heart J 2010

11. Phase III trials: study design and baseline data
RE-LY1
ROCKET AF2
ARISTOTLE3,4
AVERROES5
ENGAGE AF-TIMI 486*
No. of patients
18,113
14,264
18,201
5599
~20,500
Statistical objective
Non-inferiority
Superiority
No. of study arms 3 2
Study drug
Two doses of double-blind dabigatran
Double-blind rivaroxaban
Double-blind apixaban
Two doses of double-blind edoxaban
Control
Open-label warfarin (INR 2–3)
Double-blind warfarin (INR 2–3)
Double-blind warfarin (INR 2–3)
Double-blind ASA
AF type of patients included
Non-valvular
All except mechanical valves
Mean baseline CHADS2 score
2.1
3.5
2.0 (apixaban) 2.1 (ASA)
N/A
Patients with prior stroke/SE/TIA
20%
55%
19%
14%
References: Connolly et al. N Engl J Med 2009;361:1139–1151, Patel et al. N Engl J Med 2011;365:883–891 , Lopes et al. Am Heart J 2010;159:331–339, Granger et al. N Engl J Med 2011;365:981–992, Connolly et al. N Engl J Med 2011;364:806–817, Ruff et al. Am Heart J 2010;160:635–641
1. Connolly et al, N Engl J Med 2009; 2. Patel et al, N Engl J Med 2011; 3. Lopes et al, Am Heart J 2010; 4. Granger et al, N Engl J Med 2011; 5. Connolly et al, N Engl J Med 2011; 6. Ruff et al, Am Heart J 2010 11

12. RE-LY: dabigatran vs warfarin
Randomized, phase III, single-blind, non-inferiority study
Non-valvular
AF plus
at least 1 additional risk factor*
Dabigatran 110 mg bid
Dabigatran 150 mg bid
Open-label warfarin
(target INR range 2–3) R
N=18,113
Follow-up
End of treatment
Primary efficacy: composite of all-cause stroke or systemic embolism
Major safety: major bleeding
Excludes patients with severe renal impairment (CrCl ≤30 ml/min)
Reference: Connolly et al. N Engl J Med 2009;361:1139−1151
*Previous stroke or TIA, NYHA ≥Class II HF, LVEF <40%, age ≥75 years, age ≥65 years with either a history of coronary artery disease, hypertension or diabetes mellitus
Connolly et al, N Engl J Med 2009

13. RE-LY: primary efficacy endpoints
Dabigatran 110 mg bid %/year (n=6015)
Dabigatran 150 mg bid %/year (n=6076)
Warfarin %/year (n=6022)
Dabigatran 110 mg bid vs warfarin RR, p-value*
Dabigatran 150 mg bid vs warfarin RR, p-value*
Stroke/systemic embolism#
1.54
1.11
1.71
0.90 (0.74–1.10) p=0.30 [p<0.001 non-inf.]
0.65 (0.52–0.81) p<0.001
All-cause stroke#
1.44
1.01
1.58
0.91 (0.74–1.12) p=0.38
0.64 (0.51–0.81) p<0.001
Ischaemic or unspecified stroke#
1.34
0.92
1.21
1.11 (0.88–1.39) p=0.35
0.76 (0.59–0.97) p=0.03
Haemorrhagic stroke
0.12
0.10
0.38
0.31 (0.17–0.56) p<0.001
0.26 (0.14–0.49) p<0.001
Reference: Connolly et al. N Engl J Med 2010;363:1875–1876 (supplementary appendix)
*p-values are for superiority, unless otherwise indicated #Post-hoc analysis including additional events that were not reported at the time of the original analysis
Connolly et al, N Engl J Med 2010

14. RE-LY: bleeding outcomes
Dabigatran 110 mg bid %/year (n=6015)
Dabigatran 150 mg bid %/year (n=6076)
Warfarin %/year (n=6022)
Dabigatran 110 mg bid vs warfarin RR, p-value*
Dabigatran 150 mg bid vs warfarin RR, p-value*
Major bleeding (principal safety outcome)#
2.87
3.32
3.57
0.80 (0.70–0.93) p=0.003
0.93 (0.81–1.07) p=0.31
Major gastrointestinal bleeding#
1.15
1.56
1.07
1.08 (0.85–1.38) p=0.52
1.48 (1.18–1.85) p=0.001
Intracranial haemorrhage#
0.23
0.32
0.76
0.30 (0.19–0.45) p<0.001
0.41 (0.28–0.60) p<0.001
Reference: Connolly et al. N Engl J Med 2010;363:1875–1876 (supplementary appendix)
*Post-hoc analysis including additional events that were not reported at the time of the original analysis
Connolly et al, N Engl J Med 2010

15. RE-LY: other outcomes
2-year discontinuation rates were higher with both dabigatran doses (21%) versus warfarin (17%, p<0.001)1
Dyspepsia was the most frequently recorded adverse event associated with dabigatran1
Rates of dyspepsia were higher with dabigatran(110 mg bid 12%; 150 mg bid 11%) compared with warfarin (6%, p<0.001 for both comparisons)
Compared with warfarin (0.64%), there was a non-significant trend towards higher annual MI rates with dabigatran (110 mg bid 0.82% [p=0.09]; 150 mg bid 0.81% [p=0.12])2
A recent meta-analysis of dabigatran trials subsequently reported an increased risk of MI or ACS with dabigatran compared with control agents3
References: Connolly et al. N Engl J Med 2009;361:1139−1151, Connolly et al. N Engl J Med 2010;363:1875–1876 ,Uchino and Hernandez. Arch Intern Med 2012; January 9 [Epub ahead of print]
1. Connolly et al, N Engl J Med 2009; 2. Connolly et al, N Engl J Med 2010; 3. Uchino & Hernandez, Arch Intern Med 2012

16. ROCKET AF: rivaroxaban vs warfarin
Randomized, double-blind, double-dummy, non-inferiority, event-driven trial
Non-valvular AF
History of stroke, TIA or non-CNS SE OR
≥2* of the following:
CHF or LVEF ≤35%
Hypertension
Age ≥75 years
Diabetes
Rivaroxaban 20 mg once daily**
N=14,264 R
End of study
30-day follow-up
References: Patel et al. Am Heart J 2010;159:340–347, Patel et al. N Engl J Med 2011;365:883–891
Warfarin target INR 2.5 (2–3 inclusive)
*Enrolment of patients with <3 risk factors or without prior stroke/TIA or non-CNS SE was limited to 10% **Patients with CrCl 30–49 ml/min: 15 mg rivaroxaban once daily
Patel et al, Am Heart J 2010; Patel et al, N Engl J Med 2011 16

17. ROCKET AF: primary efficacy endpoint
Stroke or systemic embolism
Population/ analysis*
No. of patients
Rivaroxaban (% per year)
Warfarin (% per year)
Hazard ratio (95% CI)
p-value
Non-inferiority
Superiority
Per-protocol, on-treatment
6958
1.7
2.2
0.79 (0.66–0.96)
<0.001
Safety, on-treatment
7061
0.79 (0.65–0.95)
0.02
Intention-to-treat
7081
2.1
2.4
0.88 (0.75–1.03)
0.12
Per-protocol population: all patients who received at least one dose of study drug and did not have a major protocol violation
Safety population: all patients who received at least one dose of study drug
Intention-to-treat population: all patients who were randomized in the study and were followed for events during treatment or after premature discontinuation
On-treatment analysis: period between the date of the first double-blind study medication and the date of the last double-blind study medication administration plus 2 days
*The order shown is as set out in the statistical analysis plan
Reference: Patel et al. N Engl J Med 2011;365:883–891
Patel et al, N Engl J Med 2011

18. ROCKET AF: bleeding outcomes
Clinical data
Parameter
Rivaroxaban (N=7111)
Warfarin (N=7125)
HR (95% CI)
n (% per year)
Principal safety endpoint
1475 (14.9)
1449 (14.5)
1.03 (0.96,1.11)
Major bleeding
395 (3.6)
386 (3.4)
1.04 (0.90,1.20)
Haemoglobin drop (≥2 g/dl)
305 (2.8)
254 (2.3)
1.22 (1.03,1.44)*
Transfusion
183 (1.6)
149 (1.3)
1.25 (1.01,1.55)*
Critical bleeding
91 (0.8)
133 (1.2)
0.69 (0.53,0.91)*
Intracranial haemorrhage
55 (0.5)
84 (0.7)
0.67 (0.47,0.93)*
Fatal bleeding
27 (0.2)
0.50 (0.31,0.79)*
Non-major clinically relevant bleeding
1185 (11.8)
1151 (11.4)
1.04 (0.96,1.13)
Reference: Patel et al. N Engl J Med 2011;365:883–891
Major bleeding from gastrointestinal site (upper, lower and rectal): rivaroxaban = 224 events (3.2%); warfarin = 154 events (2.2%); p<0.001* Safety population – on-treatment analysis. *Statistically significant
Patel et al, N Engl J Med 2011

19. ROCKET AF: other outcomes
The proportion of patients who permanently discontinued therapy before an endpoint event and the termination date was 24% and 22% for rivaroxaban and warfarin, respectively
Epistaxis was the most frequently observed adverse event, occurring in 10% and 9% of patients in the rivaroxaban and warfarin groups, respectively (p<0.05)
There was no indication of an increased MI rate in the rivaroxaban group (0.9% per year) compared with warfarin (1.1% per year [p=0.12])
Reference: Patel et al. N Engl J Med 2011;365:883–891
Patel et al, N Engl J Med 2011

20. ARISTOTLE: apixaban vs warfarin
Randomized, phase III, double-blind, non-inferiority, event-driven trial
Apixaban 5 mg bid
Warfarin target INR range 2–3 R
N=18,201
Apixaban 2.5 mg bid*
End of treatment
Follow-up
AF AND at least
one additional
risk factor:
Prior stroke/ TIA or SE
Age ≥75 years
Symptomatic HF or LVEF ≤40%
Diabetes mellitus
Hypertension
Reference: Granger et al. N Engl J Med 2011;365:981–992
*Lower dose for patients with ≥2 of the following:
Age ≥80 years
Body weight ≤60 kg
Serum creatinine ≥1.5 mg/dl (133 µmol/l)
Granger et al, N Engl J Med 2011

21. ARISTOTLE: primary efficacy endpoint
Apixaban n (%/year)
Warfarin n (%/year) HR
95% CI
p-value
Primary efficacy: composite of stroke and systemic embolism
212 (1.27)
265 (1.60)
0.79
0.66–0.95
<0.001 (non-inferiority) 0.01 (sup)
Stroke
199 (1.19)
250 (1.51)
0.65–0.95
0.01
Ischaemic stroke (including uncertain type of stroke)
162 (0.97)
175 (1.05)
0.92
0.74–1.13
0.42
Haemorrhagic stroke
40 (0.24)
78 (0.47)
0.51
0.35–0.75
<0.001
Systemic embolism
15 (0.09)
17 (0.10)
0.87
0.44–1.75
0.70
All-cause mortality*
603 (3.52)
669 (3.94)
0.89
0.80–0.998
0.047
Reference: Granger et al. N Engl J Med 2011;365:981–992
ITT population *Key secondary efficacy endpoint
Granger et al, N Engl J Med 2011

22. ARISTOTLE: bleeding outcomes
Apixaban n (%/year)
Warfarin n (%/year) HR
95% CI
p-value
Major bleeding
327 (2.13)
462 (3.09)
0.69
0.60–0.80
<0.001
Intracranial haemorrhage
52 (0.33)
122 (0.80)
0.42
0.30–0.58
Other location
275 (1.79)
340 (2.27)
0.79
0.68–0.93
0.004
Gastrointestinal
105 (0.76)
119 (0.86)
0.89
0.70–1.15
0.37
Other bleeding outcomes
Major or non-major clinically relevant bleeding
613 (4.07)
877 (6.01)
0.68
0.61–0.75
Any bleeding
2356 (18.1)
3060 (25.8)
0.71
0.68–0.75
Reference: Granger et al. N Engl J Med 2011;365:981–992
Safety population. Major bleeding is defined as clinically overt bleeding accompanied by ≥1 of the following: a fall in haemoglobin of ≥2 g/dl; a transfusion of ≥2 units of packed red blood cells; and/or bleeding that is fatal or occurs in at least one critical site
Granger et al, N Engl J Med 2011

23. ARISTOTLE: other outcomes
The total number of patients with an adverse event with apixaban and warfarin was 82% and 83%, respectively
No breakdown of the most common types of adverse event is given
Serious adverse events were reported by 35% and 37% of patients in the apixaban and warfarin groups, respectively
Serious AEs reported in ≥1% of patients in either treatment group:
Worsening AF (apixaban 3.3%, warfarin 3.2%)
Pneumonia (apixaban 2.2%, warfarin 2.6%)
Discontinuation rates due to an adverse event were ~8% for apixaban and warfarin
There was no indication of an increased MI rate in the apixaban group (0.5% per year) compared with warfarin (0.6% per year [p=0.37])
Reference; Granger et al. N Engl J Med 2011;365:981–992
Granger et al, N Engl J Med 2011