ATRIAL FIBRILLATION AND STROKE

1
ATRIAL FIBRILLATIONAND STROKE

• WHY SHOULD WE CARE?

2
ATRIAL FIBRILLATION (AF)

• Uncoordinated electrical signals in the atria
  cause deterioration in atrial function and
  cardiac efficiency
• AF is the most common heart rhythm disturbance1
• It is estimated that 1 in 4 individuals aged 40
  years or older will develop AF1
• In 2007, 6.3 million people in the US, Japan,
  Germany, Italy, Spain, France and the UK were
  living with diagnosed AF2
• Due to the aging population, this number is
  expected to double within 30 years3

1. Lloyd-Jones DM, et al. Circulation
20041101042-1046. 2. Decision Resources. Atrial
Fibrillation Report. Dec 2008. 3. Go AS, et al.
JAMA 20012852370-2375.
3
AF PREVALENCE INCREASES WITH AGE
9
8
9.0
7
6
5
AF prevalence ()
4
3
3.8
2
1
0.95
0
General population
60 yrs
80 yrs
Age
1. Go AS, et al. JAMA 20012852370-2375..
4
AF SIGNIFICANTLY INCREASES THE RISK OF STROKE

• AF is associated with a pro-thrombotic state1
• 5-fold increase in stroke risk2
• Up to 3 million people worldwide suffer strokes
  related to AF each year2-4
• AF-related strokes tend to be especially severe
  and disabling with a 1-year mortality rate of
  504,5
• Cardioembolic stroke has a 30-day mortality rate
  of 254
• Risk of stroke is the same in AF patients
  regardless of whether they have paroxysmal or
  sustained AF6,7

1. Watson T, et al. Lancet 2009373155-166. 2.
Wolf PA, et al. Stroke 199122983-988. 3. Atlas
of Heart Disease and Stroke, World Health
Organization, September 2004. Viewed at
http//www.who.int/cardiovascular_diseases/en/cvd_
atlas_15_burden_stroke.pdf. 4. Lin HJ, et al.
Stroke 1996271760-1764. 5. Marini C, et al.
Stroke 2005361115-1119. 6. Rosamond W, et al.
Circulation 2008117e25-146. 7. Hart RG, et al.
J Am Coll Cardiol 200035183-187.
5
AF-RELATED STROKES ARE ASSOCIATED WITH GREATER
DISABILITY AND A HIGHER MORTALITY RATE
Disability at clinical presentation1
30-day post-stroke mortality2
60
30
Plt0.005
Plt0.0005
Plt0.048
50
25
40
20
Fatal strokes ()
Patients with clinical parameter ()
30
15
20
10
10
0
0
Severe limb weakness
Bedridden
Strokeswith AF(N103)
Strokeswithout AF(N398)
1. Dulli DA, et al. Neuroepidemiology
200322118-123. 2. Lin HJ, et al. Stroke
1996271760-1764.
6
ECONOMIC BURDEN OF STROKE
1. Rosamond W, et al. Circulation
2008117e25-146. 2. Kolominsky-Rabas PL, et al.
Stroke 2006371179-1183. 3. Stewart S, et al.
Heart. 200490286-292..
7
ATRIAL FIBRILLATIONAND STROKE

• CURRENT TREATMENTS

8
AF-RELATED STROKE IS PREVENTABLE

• Effective stroke prevention is a priority for
  patients with AF1
• Two-thirds of strokes due to AF are preventable
  with appropriate anticoagulant therapy2
• A meta-analysis of 29 trials in 28,044 patients
  showed that the vitamin K antagonist (VKA)
  warfarin reduces the risk of stroke and all-cause
  mortality2
• 64 reduction in stroke and 24 reduction in
  all-cause mortality compared with placebo
• Aspirin also reduced the risk of stroke, but less
  effectively than warfarin (19 reduction compared
  with placebo)
• However, VKAs are associated with complications,
  such as increased bleeding risk
• Guidelines for antithrombotic therapy in AF
  recommend Aspirin or VKA depending on the
  presence of risk factors for stroke1

1. Fuster V, et al. Circulation
2006114e257354. 2. Hart RG, et al. Ann Intern
Med 2007146857-867.
9
ACC/AHA/ESC GUIDELINES FOR ANTITHROMBOTIC THERAPY
IN AF
Risk category CHADS2 score Recommended therapy
No risk factors 0 Aspirin 81325 mg daily
One moderate-risk factor 1 Aspirin 81325 mg daily or warfarin (INR 2.03.0, target 2.5)
Any high-risk factor or ?2 moderate-risk factors ?2 Warfarin (INR 2.03.0, target 2.5)
Less validated/weaker-risk factors Moderate-risk factors High-risk factors
Female gender Age 6574 yrs Coronary artery disease Thyrotoxicosis Age ?75 yrs Hypertension Heart failure LVEF ?35 Diabetes mellitus Previous stroke, TIA or embolism Mitral stenosis Prosthetic heart valve
Choice of agent should be based on consideration
of bleeding risk, ability to sustain chronic
anticoagulation safely and patient preference
If mechanical valve, target INR gt2.5.
ACC American College of Cardiology AHA
American Heart Association ESC European
Society of Cardiology INR International
normalized ratio LVEF left ventricular
ejection fraction TIA transient ischaemic
attack. Fuster V, et al. Circulation
2006114e257354.
10
LIMITATIONS OF VKA THERAPY
INR International normalized ratio VKA
vitamin K antagonist. Ansell J, et al. Chest
2008133160S-198S. Umer Ushman MH, et al. J
Interv Card Electrophysiol 200822129-137.Nutesc
u EA, et al. Cardiol Clin 200826169-187.
11
NARROW THERAPEUTIC RANGE WITH VKAs
80
60
TargetINR (2.03.0)
Events / 1000 patient years
40
20
0
lt1.5
1.51.9
2.02.5
2.63.0
3.13.5
3.64.0
4.14.5
gt4.5
INR International normalized ratio VKA
vitamin K antagonist. Hylek EM, et al. N Eng J
Med 20033491019-1026.
12
INR CONTROL CLINICAL TRIALS VS. CLINICAL
PRACTICE (TTR)
66
44
Eligible patients receiving Warfarin()
38
25
18
9
lt2.0
2.03.0
gt3.0
INR
INR international normalized ratio TTR
time-in-therapeutic-range (INR 2.03.0). 1.
Kalra L, et al. BMJ 20003201236-1239 Pooled
data up to 8371 in individualized trials. 2.
Samsa GP, et al. Arch Intern Med
2000160967-973. 3. Matchar DB, et al. Am J Med
200211342-51.
13
TIME-IN-THERAPEUTIC-RANGE WITH WARFARIN USE IN
CLINICAL PRACTICE
100
80
60
63
Time in therapeutic range ()
56
55
52
51
51
40
49
47
42
36
20
0
Samsa 20002 N61
Samsa 20002 N125
McCormick 20013 N174
Matchar 20034 N363
Matchar 20034 N317
Matchar 20034 N317
Go 20035 N7,445
Shen 20076 N11,016
Nichol 20087 N756
Average1
Linear interpolation method not used.
Overall effect 0.55. 1. Baker WL, et al. J
Manag Care Pharm 200915244-252. 2. Samsa GP, et
al. Arch Intern Med 2000160967-973. 3.
McCormick D, et al. Arch Intern Med
20011612458-2463. 4. Matchar DB. Card
Electrophysiol Rev 20037379-381. 5. Go AS, et
al. JAMA 20032902685-2692. 6. Shen AY, et al. J
Am Coll Cardiol 200750309-315. 7. Nichol MB,
et al. Ann Pharmacother 20084262-70.
14
SIMILAR RATES OF MAJOR BLEEDING FOR ORAL
ANTICOAGULATION VS. ANTIPLATELET THERAPY
In BAFTA trial2 patients 75 yrs of age(N973)
In ACTIVE-W trial1
4
4
P0.53
P0.9
3
3
Rate of all major bleeding ()
Rate of major bleeding ( per year)
2
2
1
1
0
0
Oral anticoagulationN3,371
Clopidogrel Aspirin N3,335
Warfarin
Aspirin
42 ? risk of stroke with oral anticoagulation
vs. clopidogrel Aspirin
52 ? risk of stroke, intracranialhaemorrhage,
systemic embolismwith warfarin vs. Aspirin
Superior strokeprevention withanticoagulation
1. Connolly S for the ACTIVE Investigators.
Lancet 20063671903-1912. 2. Mant J, et al.
Lancet 2007370493-503.
15
MANAGEMENT OF AF IN CLINICAL PRACTICE
PRESCRIPTION OF VKAs
N11,409 ATRIA cohort(managed care
system,California, USA) Go AS, et al.JAMA
20032902685-2692
N5,333 EuroHeart survey Nieuwlaat R, et al.Eur
Heart J 2005262422-2434
N23,657 Medicare cohort, USA Birman-Deych E, et
al.Stroke 2006371070-1074
VKA vitamin K antagonist.
16
ATRIAL FIBRILLATIONAND STROKE

• NEW TREATMENTS

17
NOVEL ANTICOAGULANTS IN PHASE III DEVELOPMENT FOR
STROKE PREVENTION IN AF
Trial acronym Drug Dose Comparator Estimate completion date
Direct thrombin inhibitors Direct thrombin inhibitors Direct thrombin inhibitors Direct thrombin inhibitors Direct thrombin inhibitors
RE-LY 1 Dabigatran etexilate 150 mg BID110 mg BID Warfarin (INR 23) Completed
Direct factor Xa inhibitors Direct factor Xa inhibitors Direct factor Xa inhibitors Direct factor Xa inhibitors Direct factor Xa inhibitors
ARISTOTLE 2 Apixaban 5 mg BID Warfarin (INR 23) April 2011
AVERROES 3 Apixaban 5 mg BID Aspirin (81324 mg OD) Completed
ROCKET-AF 4 Rivaroxaban 20 mg OD Warfarin (INR 23) Completed
ENGAGE-AF TIMI 48 5 Edoxaban 30 mg OD 60 mg OD Warfarin (INR 23) March 2011
Indirect factor Xa inhibitors Indirect factor Xa inhibitors Indirect factor Xa inhibitors Indirect factor Xa inhibitors Indirect factor Xa inhibitors
AMADEUS 6 Idraparinux 2.5 mg once weekly Warfarin (INR 23) Terminated
BOREALIS- AF 7 SSR 126517 2.5 mg once weekly Warfarin (INR 23) Withdrawn from development
Adjusted based on renal function 1. Connolly
SJ, et al. N Engl J Med 20093611139-1151 2.
www.clinicaltrials.gov, clinical trial
identifier NCT00781391 3. Eikelboom JW, et al.
Am Heart J 2010159348-353 4. ROCKET-AF
Investigators. Am Heart J 2010159340-347 5.
Lopes RD, et al. Am Heart J 2010159331-339 6.
AMADEUS Investigators et al. Lancet
2008371315-321 7. Sanofi-aventis press
release http//en.sanofi-aventis.com/binaries/200
91221_rdupdate_en_tcm28-26977.pdf Accessed March
2010.
18
DABIGATRAN ETEXILATE

• Dabigatran etexilate is a novel, small molecule,
  reversible, direct thrombin inhibitor (DTI)
• The prodrug dabigatran etexilate was developed
  for oral administration

Dabigatran etexilate is not approved for clinical
use in stroke prevention in atrial fibrillation
outside the US and Canada. Stangier J, et al. Br
J Clin Pharmacol 200764292-303. Sorbera LA, et
al. Drugs Future 200530877-885. Blech S, et
al. Drug Metab Dispos 200836386-399.
19
DABIGATRAN ETEXILATE A NOVEL DTI

• Oral prodrug, converted to dabigatran, a potent
  reversible DTI
• Half life of 1217 hours
• 80 renally excreted
• 6.5 bioavailability
• Rapid onset of action
• Predictable and consistent anticoagulant effects
• Low potential for drugdrug interactions, no
  drugfood interactions
• No requirement for routine coagulation monitoring
  
• Potent antithrombotic effects are achieved with
  DTIs by specifically blocking the activity of
  thrombin (both free and clot-bound), the central
  enzyme in the process responsible for clot
  (thrombus) formation

DTI direct thrombin inhibitor. Dabigatran
etexilate is not approved for clinical use in
stroke prevention in atrial fibrillation outside
the US and Canada. Stangier J, et al. Br J Clin
Pharmacol 200764292-303. Sorbera LA, et al.
Drugs Future 200530877-885. Blech S, et al.
Drug Metab Dispos 200836386-399.
20
THE RE-LY STUDYRANDOMIZED EVALUATION OF
LONG-TERM ANTICOAGULANT THERAPY

• Dabigatran compared with warfarin in 18,113
  patients with atrial fibrillation at risk of
  stroke
• Dabigatran etexilate is not approved for clinical
  use in stroke prevention in atrial fibrillation
  outside the US and Canada

Connolly SJ, et al. N Engl J Med
20093611139-1151.
21
RE-LY ACADEMIC LEADERSHIP

• Principal Investigators and Chairmen of
  Operations Committee
• Stuart Connolly Co-PI PHRI, McMaster University,
  Canada
• Michael Ezekowitz Co-PI Lankenau Institute for
  Medical Research, USA
• Lars Wallentin Co-Chair Uppsala Clinical
  Research Centre, Sweden
• Salim Yusuf Co-Chair PHRI, McMaster University,
  Canada

PHRI Population Health Research Institute PI
Principal Investigator. Dabigatran etexilate is
not approved for clinical use in stroke
prevention in atrial fibrillation outside the US
and Canada. Connolly SJ, et al. N Engl J Med
20093611139-1151.
22
RE-LY LARGEST AF OUTCOMES TRIALEVER COMPLETED

• RE-LY Randomized Evaluation of Long-term
  anticoagulant therapY
• 18,113 patients randomized during 2 years1,2,3
• 50 of enrolled patients were naïve to previous
  oral anticoagulants
• Median treatment duration 2 years
• 951 centres in 44 countries
• December 2005 to March 2009
• Results first presented at ESC 2009 and published
  online in the New England Journal of Medicine on
  30 August 2009update to the data analysis
  published 4 November 2010

ESC European Society of Cardiology. Dabigatran
etexilate is not approved for clinical use in
stroke prevention in atrial fibrillation outside
the US and Canada. 1. Connolly SJ, et al. N Engl
J Med 2009 3611139-1151. 2. Ezekowitz MD, et
al. Am Heart J 2009157805-810. 3. Connolly SJ,
et al. N Engl J Med 20103631875-1876.
23
RE-LY PARTICIPATING COUNTRIES
RE-LY was an international, multicentre study
and enrolled patients from Europe, North and
South America, Asia, Africa and Australasia
(N17,600)
Additional recruitmentin 10 other countries
(N513)
Dabigatran etexilate is not approved for clinical
use in stroke prevention in atrial fibrillation
outside the US and Canada. Connolly SJ, et al. N
Engl J Med 2009 3611139-1151.
24
RE-LY STUDY DESIGN
AF with 1 risk factor Absence of
contraindications
Dabigatran etexilate 150 mg BID N6,000
(planned)
Warfarin 1 mg, 3 mg, 5 mg (INR 2.0?3.0) N6,000
(planned)
Dabigatran etexilate 110 mg BID N6,000
(planned)
Primary objective To establish the
non-inferiority of dabigatran etexilate to
warfarin Planned mean follow-up 2 years
(minimum 1 year maximum 3 years)
INR International normalized ratio. Dabigatran
etexilate is not approved for clinical use in
stroke prevention in atrial fibrillation outside
the US and Canada. Connolly SJ, et al. N Engl J
Med 2009 3611139-1151. Ezekowitz MD, et al. Am
Heart J 2009157805-810.
25
RE-LY INCLUSION CRITERIA

• Documented AF and
• At least one additional risk factor for stroke
• History of previous stroke, transient ischaemic
  attack, or systemic embolism
• Left ventricular ejection fraction lt40
• Symptomatic heart failure, NYHA Class II or
  greater
• Aged 75 years
• Aged 65 years and one of the following
  additional risk factors diabetes mellitus,
  coronary artery disease, or hypertension

NYHA New York Heart Association. Dabigatran
etexilate is not approved for clinical use in
stroke prevention in atrial fibrillation outside
the US and Canada. Connolly SJ, et al. N Engl J
Med 2009 3611139-1151. Ezekowitz MD, et al. Am
Heart J 2009157805-810.
26
RE-LY OUTCOME MEASURES
PRIMARY EFFICACY ENDPOINTALL STROKE (ISCHAEMIC HAEMORRHAGIC) AND SYSTEMIC EMBOLISM PRIMARY EFFICACY ENDPOINTALL STROKE (ISCHAEMIC HAEMORRHAGIC) AND SYSTEMIC EMBOLISM
Secondary efficacy endpoints All stroke(ischaemic haemorrhagic) Systemic embolism All death Pulmonary embolism Acute myocardial infarction Vascular death (including deaths from bleeding) Safety criteria included Bleeding events (major and minor) Intracranial haemorrhage Cerebral haemorrhage Subdural haematoma Subarachnoid haemorrhage Elevations in liver enzymes or hepatic dysfunction
Dabigatran etexilate is not approved for clinical
use in stroke prevention in atrial fibrillation
outside the US and Canada. Connolly SJ, et al. N
Engl J Med 20093611139-1151.
27
BASELINE CHARACTERISTICS
Characteristic Dabigatran 150 mg Dabigatran 110 mg Warfarin
Randomized 6,076 6,015 6,022
Mean age (yrs) 71.5 71.4 71.6
Male () 63.2 64.3 63.3
CHADS2 score (mean) 0?1 () 2 () 3 () 2.2 32.2 35.2 32.6 2.1 32.6 34.7 32.7 2.1 30.9 37.0 32.1
Prior stroke/TIA () 20.3 19.9 19.8
Prior MI () 16.9 16.8 16.1
CHF () 31.8 32.2 31.9
Baseline Aspirin () 38.7 40.0 40.6
VKA naïve () 50.2 50.1 48.6
CHF congestive heart failure MI myocardial
infarction TIA transient ischaemic attack VKA
vitamin K antagonist. Dabigatran etexilate is
not approved for clinical use in stroke
prevention in atrial fibrillation outside the US
and Canada. Connolly SJ, et al. N Engl J Med
20093611139-1151.
28
RE-LY TRIAL CONDUCT
99.9 of patients completed follow-up 20 patients
of 18,113 lost to follow-up
Time in Therapeutic Range (TTR) 67 of
warfarin-experienced patients 61 of
warfarin-naïve patients 64 of patients overall
Dabigatran etexilate is not approved for clinical
use in stroke prevention in atrial fibrillation
outside the US and Canada. Connolly SJ, et al. N
Engl J Med 20093611139-1151.
29
STROKE OR SYSTEMIC EMBOLISM (SSE)
Superiority
Non-inferiority
P value
P value
Dabigatran110 mg BID vs. warfarin
lt0.001
0.30
Margin1.46
Dabigatran150 mg BID vs. warfarin
lt0.001
lt0.001
0.50
0.75
1.00
1.25
1.50
Hazard ratio
Error bars 95 CI BID twice
daily. Dabigatran etexilate is not approved for
clinical use in stroke prevention in atrial
fibrillation outside the US and Canada. Connolly
SJ, et al. N Engl J Med 20103631875-1876.
30
TIME TO FIRST STROKE OR SSE
0.05
0.04
RRR35
0.03
Cumulative hazard rates
0.02
0.01
0.0
0
0.5
1.0
1.5
2.0
2.5
3.0
Years
RR relative risk RRR relative risk
reduction SSE systemic embolism. Dabigatran
etexilate is not approved for clinical use in
stroke prevention in atrial fibrillation outside
the US and Canada. Connolly SJ, et al. N Engl J
Med 20103631875-1876.
31
RATE OF STROKE OR SSE
RR 0.65 (95 CI 0.520.81) Plt0.001 (superiority)
RRR 35
RR 0.90 (95 CI 0.741.10) Plt0.001
(non-inferiority)
1.8
1.5
1.2
Rate per year ()
0.9
0.6
0.3
0
D110 mg BID
D150 mg BID
Warfarin
Events/n
183 / 6,015
134 / 6,076
202 / 6,022
D dabigatran RR relative risk RRR
relative risk reduction SSE systemic
embolism. Dabigatran etexilate is not approved
for clinical use in stroke prevention in atrial
fibrillation outside the US and Canada. Connolly
SJ, et al. N Engl J Med 20103631875-1876.
32
HAEMORRHAGIC STROKE
RR 0.26 (95 CI 0.140.49) Plt0.001 (superiority)
RRR 74
RR 0.31 (95 CI 0.170.56) Plt0.001 (superiority)
RRR 69
Number of pateitns with event
D110 mg BID
D150 mg BID
Warfarin
6,015
6,076
6,022
D dabigatran RR relative risk RRR
relative risk reduction. Dabigatran etexilate is
not approved for clinical use in stroke
prevention in atrial fibrillation outside the US
and Canada. Connolly SJ, et al. N Engl J Med
20093611139-1151.
33
VASCULAR MORTALITY
RR 0.85 (95 CI 0.720.99) P0.04 (superiority)
RRR 15
RR 0.90 (95 CI 0.771.06) P0.21 (superiority)
3.0
2.0
Rate per year ()
1.0
0
D110 mg BID
D150 mg BID
Warfarin
289 / 6,015
274 / 6,076
317 / 6,022
D dabigatran RR relative risk RRR
relative risk reduction. Dabigatran etexilate is
not approved for clinical use in stroke
prevention in atrial fibrillation outside the US
and Canada. Connolly SJ, et al. N Engl J Med
20093611139-1151.
34
ALL-CAUSE MORTALITY
RR 0.88 (95 CI 0.771.00) P0.051 (superiority)
RR 0.91 (95 CI 0.801.03) P0.13 (superiority)
Rate per year ()
D110 mg BID
D150 mg BID
Warfarin
446 / 6,015
438 / 6,076
487 / 6,022
D dabigatran RR relative risk RRR
relative risk reduction. Dabigatran etexilate is
not approved for clinical use in stroke
prevention in atrial fibrillation outside the US
and Canada. Connolly SJ, et al. N Engl J Med
20093611139-1151.
35
RE-LY IN PERSPECTIVE
Meta-analysis of ischaemic stroke or systemic
embolism
0
0.3
0.6
0.9
1.2
1.5
1.8
2.1
Favours warfarin
Favours other treatment
ASA acetylsalicylic acid. Dabigatran etexilate
is not approved for clinical use in stroke
prevention in atrial fibrillation outside the US
and Canada. Camm J. Oral presentation at ESC on
30 Aug 2009 http//www.escardio.org/congresses/e
sc-2009/webcasts/pages/sunday.aspx
36
MAJOR BLEEDING RATES
RR 0.93 (95 CI 0.811.07) P0.32 (superiority)
RR 0.80 (95 CI 0.700.93) P0.003 (superiority)
RRR 20
Rate per year ()
D110 mg BID
D150 mg BID
Warfarin
Events/n
342 / 6,015
399 / 6,076
421 / 6,022
D dabigatran RR relative risk RRR
relative risk reduction. Dabigatran etexilate is
not approved for clinical use in stroke
prevention in atrial fibrillation outside the US
and Canada. Connolly SJ, et al. N Engl J Med
20093611139-1151.
37
MAJOR BLEEDING AND COMPONENTS
Characteristic Dabigatran 150 mg Dabigatran 110 mg Warfarin P value D150 vs. W P value D110vs. W
Number of patients 6,076 6,015 6,022
Major bleeding rate ( per year) 3.32 2.87 3.57 0.32 0.003
Life threatening Non-life threatening Gastro-intestinal 1.49 2.06 1.56 1.24 1.83 1.15 1.85 1.92 1.07 0.03 0.39 0.001 lt0.001 0.65 0.52
D dabigatran W warfarin. Data represent
/year. Dabigatran etexilate is not approved for
clinical use in stroke prevention in atrial
fibrillation outside the US and Canada. Connolly
SJ, et al. N Engl J Med 20103631875-1876.
38
TOTAL BLEEDING RATES
RR 0.91 (95 CI 0.850.96) P0.002 (superiority)
RRR 9
RR 0.78 (95 CI 0.730.83) Plt0.001 (superiority)
RRR 22
Rate ( per year)
D110 mg BID
D150 mg BID
Warfarin
Events/n
1,754 / 6,015
1,993 / 6,076
2,166 / 6,022
D dabigatran RR relative risk RRR
relative risk reduction. Dabigatran etexilate is
not approved for clinical use in stroke
prevention in atrial fibrillation outside the US
and Canada. Connolly SJ, et al. N Engl J Med
20103631875-1876.
39
LIFE-THREATENING BLEEDING RATES
RR 0.80 (95 CI 0.660.98) P0.03 (superiority)
RRR 20
RR 0.67 (95 CI 0.540.82) Plt0.001 (superiority)
RRR 33
Rate ( per year)
D110 mg BID
D150 mg BID
Warfarin
Events/n
147 / 6,015
179 / 6,076
218 / 6,022
D dabigatran RR relative risk RRR
relative risk reduction. Dabigatran etexilate is
not approved for clinical use in stroke
prevention in atrial fibrillation outside the US
and Canada. Connolly SJ, et al. N Engl J Med
20103631875-1876.
40
INTRACRANIAL BLEEDING
RR 0.41 (95 CI 0.280.60) Plt0.001 (superiority)
RRR 59
RR 0.30 (95 CI 0.190.45) Plt0.001 (superiority)
RRR 70
80
60
Number of events
40
20
0
D110 mg BID
D150 mg BID
Warfarin
Events/n
27 / 6,015
38 / 6,076
90 / 6,022
D dabigatran RR relative risk RRR
relative risk reduction. Percentages on bars show
rate ( per year). Dabigatran etexilate is not
approved for clinical use in stroke prevention in
atrial fibrillation outside the US and
Canada. Connolly SJ, et al. N Engl J Med
20103631875-1876.
41
TIME TO FIRST INTRACRANIAL BLEED
0.02
RRR59
RRR70
Cumulative hazard rates
0.01
0.0
0
0.5
1.0
1.5
2.0
2.5
3.0
Years
RR relative risk RRR relative risk
reduction. Dabigatran etexilate is not approved
for clinical use in stroke prevention in atrial
fibrillation outside the US and Canada. Connolly
SJ, et al. N Engl J Med 20103631875-1876.
42
NET CLINICAL BENEFIT AND COMPONENTS
Characteristic Dabigatran 150 mg Dabigatran 110 mg Warfarin P value D150vs. W P value D110vs. W
Number of patients 6,076 6,015 6,022
Net clinical benefit 7.11 7.34 7.91 0.02 0.09
Stroke or SSE 1.11 1.54 1.71 lt0.001(NI) lt0.001(NI)
lt0.001(sup) 0.30(sup)
Death 3.64 3.75 4.13 0.051 0.13
Major bleeding 3.32 2.87 3.57 0.32 0.003
Pulmonary embolism 0.15 0.12 0.10 0.30 0.71
Myocardial infarction 0.81 0.82 0.64 0.12 0.09
Data represent /year. D dabigatran W
warfarin. NI non-inferiority Sup
superiority SSE systemic embolism. Dabigatran
etexilate is not approved for clinical use in
stroke prevention in atrial fibrillation outside
the US and Canada. Connolly SJ, et al. N Engl J
Med 20103631875-1876.
43
STOKE OR SSE VKA-NAÏVE VS.VKA-EXPERIENCED
PATIENTS
All patients
VKA-naïve
VKA-experienced
0.05
0.04
0.03
Cumulative hazard rates
0.02
0.01
0
0
0.5
1.0
1.5
2.0
2.5
0
0.5
1.0
1.5
2.0
2.5
0
0.5
1.0
1.5
2.0
2.5
Years of follow-up
SSE systemic embolism VKA vitamin K
antagonist. Dabigatran etexilate is not approved
for clinical use in stroke prevention in atrial
fibrillation outside the US and Canada. Connolly
SJ, et al. N Engl J Med 20093611139-1151.
Ezekowitz M, et al. Oral presentation at ESC on
Sept 2, 2009.
44
ADDITIONAL SAFETY OUTCOMESLIVER ENZYME
ELEVATIONS
Dabigatran 150 mg Dabigatran 110 mg Warfarin
Number of patients 6,076 6,015 6,022
ALT or AST gt3xULN 117 124 132
1.9 2.1 2.2

ALT or AST gt3xULN and bilirubin gt2xULN 13 13 21
0.2 0.2 0.3
ALT, alanine transaminase AST, aspartate
aminotransferase ULN, upper limit of
normal. Dabigatran etexilate is not approved for
clinical use in stroke prevention in atrial
fibrillation outside the US and Canada. Connolly
SJ, et al. N Engl J Med 20093611139-1151.
45
CUMULATIVE RISK OF ALT OR AST gt3X ULN AFTER
RANDOMIZATION
Cumulative hazard rates
0
0.5
1.0
1.5
2.0
2.5
Years of follow-up
ALT, alanine transaminase AST, aspartate
aminotransferase ULN, upper limit of
normal. Dabigatran etexilate is not approved for
clinical use in stroke prevention in atrial
fibrillation outside the US and Canada. Connolly
SJ, et al. N Engl J Med 20093611139-1151.
Connolly SJ. Oral presentation at ESC on Aug 30,
2009.http//www.escardio.org/congresses/esc-009/w
ebcasts/pages/sunday.aspx
46
MOST COMMON ADVERSE EVENTS
Dabigatran 150 mg Dabigatran 110 mg Warfarin
Dyspepsia 11.3 11.8 5.8
Dyspnoea 9.5 9.3 9.7
Dizziness 8.3 8.1 9.4
Peripheral oedema 7.9 7.9 7.8
Fatigue 6.6 6.6 6.2
Cough 5.7 5.7 6.0
Chest pain 6.2 5.2 5.9
Arthralgia 5.5 4.5 5.7
Back pain 5.2 5.3 5.6
Nasopharyngitis 5.4 5.6 5.6
Diarrhoea 6.5 6.3 5.7
Urinary tract infection 4.8 4.5 5.6
Upper respiratory tract infection 4.7 4.8 5.2
Occurred more commonly on dabigatran
Plt0.001. Dabigatran etexilate is not approved for
clinical use in stroke prevention in atrial
fibrillation outside the US and Canada. Connolly
SJ, et al. N Engl J Med 20093611139-1151.
47
RE-LY SUMMARY OF RESULTS

• 150 mg dose vs. warfarin
• Statistically significant reduction in
  stroke/systemic embolism
• Statistically significant reduction in
  haemorrhagic stroke
• Statistically significant reduction in vascular
  mortality
• Comparable rates of major bleeding
• Significant reduction in total bleeds,
  life-threatening bleeds and intracranial
  bleeds

• 110 mg dose vs. warfarin
• Comparable rates of stroke/systemic embolism
• Statistically significant reduction in
  haemorrhagic stroke
• Statistically significant reduction in major
  bleeding rates
• Significant reduction in total bleeds,
  life-threatening bleeds and intracranial
  bleeds

Dabigatran etexilate is not approved for clinical
use in stroke prevention in atrial fibrillation
outside the US and Canada. Connolly SJ, et al. N
Engl J Med 20093611139-1151.
48
TIME IN THERAPEUTIC RANGE (TTR)

• SUBGROUP ANALYSIS

49
TTR SUBGROUP ANALYSIS RATIONALE

• Lowest risk of stroke and bleeding is achieved by
  maximizing the TTR
• Centre-level INR control may influence effects of
  dabigatran vs. warfarin
• Average TTR was calculated for each centre
• Primary and secondary outcomes of the RE-LY
  trial were assessed in relation to each centres
  mean TTR (cTTR)in the warfarin population
• Centres were divided into quartiles according to
  mean TTR achieved

INR international normalized range TTR time
in therapeutic range. Dabigatran etexilate is not
approved for clinical use in stroke prevention in
atrial fibrillation outside the US and
Canada. Wallentin L, et al. Lancet
2010376975-983.
50
TTR SUBGROUP ANALYSISMEAN TTR BY COUNTRY
80
70
60
50
40
Mean TTR ()
30
20
10
0
TTR time in therapeutic range.
Dabigatran etexilate is not approved for clinical
use in stroke prevention in atrial fibrillation
outside the US and Canada. Wallentin L, et al.
Lancet 2010376975-983.
51
TTR SUBGROUP ANALYSISBASELINE CHARACTERISTICS
BY CTTR QUARTILE
cTTR lt57.1 (n4510) 57.165.5 (n4564) 65.572.6 (n4445) gt72.6 (n4505) P value
Mean age (yrs) 70.0 71.3 72.1 72.5 lt0.0001
Male gender () 60 65 65 64 0.0014
CHADS2 score (mean) 2.2 2.2 2.1 2.0 lt0.0001
01 () 28 32 32 35 lt0.0001
2 () 37 35 35 36 0.20
36 () 35 33 33 29 lt0.0001
Prior stroke () 15 13 12 10 lt0.0001
Prior myocardial infarction () 14 17 18 17 lt0.0001
Heart failure () 38 33 29 27 lt0.0001
Baseline Aspirin () 43 42 39 36 lt0.0001
TTR time in therapeutic range cTTR centre
mean TTR. Dabigatran etexilate is not approved
for clinical use in stroke prevention in atrial
fibrillation outside the US and Canada. Wallentin
L, et al. Lancet 2010376975-983.
52
STROKE OR SYSTEMIC EMBOLISM ACCORDING TO CTTR
Dabigatran 110 mg Dabigatran 150 mg Warfarin Dabigatran 110 mgvs. warfarin Dabigatran 110 mgvs. warfarin Dabigatran 150 mgvs. warfarin Dabigatran 150 mgvs. warfarin
cTTR Rate per 100-person yrs Rate per 100-person yrs Rate per 100-person yrs HR (95 CI) P value(interaction) HR (95 CI) P value(interaction)
lt57.1 1.91 1.10 1.92 1.00 (0.681.45) - 0.57 (0.370.88) -
57.165.5 1.67 1.04 2.06 0.81 (0.561.17) - 0.50 (0.33-0.77) -
65.572.6 1.34 1.04 1.51 0.89 (0.581.36) - 0.69 (0.441.09) -
gt72.6 1.23 1.27 1.34 0.92 (0.591.45) 0.89 0.95 (0.611.48) 0.20

• The primary outcomes of the RE-LY study are
  consistent irrespective of centre-based INR
  control

TTR time in therapeutic range cTTR centre
mean TTR HR hazard ratio CI confidence
interval.Interaction P evaluated by a
multivariate approach with centre based TTR as a
continuous variable. Dabigatran etexilate is not
approved for clinical use in stroke prevention in
atrial fibrillation outside the US and
Canada.Wallentin L, et al. Lancet
2010376975-983.
53
TTR SUBGROUP ANALYSISTIME TO PRIMARY OUTCOME
0.06
0.06
cTTR lt57.1
cTTR 57.165.5
0.05
0.05
0.04
0.04
Cumulative hazard ratio
0.03
0.03
0.02
0.02
0.01
0.01
0
0
0
0.5
1.0
1.5
2.0
2.5
0
0.5
1.0
1.5
2.0
2.5
Number at risk
1497
1450
1411
1144
649
274
Dabigatran 110 mg
1524
1477
1440
1169
783
379
1509
1469
1427
1164
699
283
Dabigatran 150 mg
1526
1493
1453
1192
801
394
1504
1445
1395
1094
640
242
Warfarin
1514
1476
1438
1175
752
351
0.06
0.06
cTTR 65.572.6
cTTR gt72.6
0.05
0.05
0.04
0.04
Cumulative hazard ratio
0.03
0.03
0.02
0.02
0.01
0.01
0
0
0
0.5
1.0
1.5
2.0
2.5
0
0.5
1.0
1.5
2.0
2.5
Follow-up (yrs)
Follow-up (yrs)
Number at risk
1474
1456
1420
1142
760
370
Dabigatran 110 mg
1482
1444
1405
1108
730
347
1484
1419
1419
1153
761
369
Dabigatran 150 mg
1514
1487
1437
1135
750
367
1487
1458
1436
1150
755
359
Warfarin
1509
1476
1440
1166
737
366
TTR time in therapeutic range cTTR centre
mean TTR. Dabigatran etexilate is not approved
for clinical use in stroke prevention in atrial
fibrillation outside the US and Canada. Wallentin
L, et al. Lancet 2010376975-983.
54
TTR SUBGROUP ANALYSISNON-HAEMORRHAGIC STROKE
AND SYSTEMIC EMBOLISM
Dabigatran 110 mg Dabigatran150 mg Warfarin Dabigatran 110 mgvs. warfarin Dabigatran 110 mgvs. warfarin Dabigatran 150 mgvs. warfarin Dabigatran 150 mgvs. warfarin
cTTR Rate per100-person yrs Rate per100-person yrs Rate per100-person yrs HR(95 CI) P value(interaction) HR (95 CI) P value(interaction)
lt57.1 1.77 0.89 1.63 1.09 (0.731.62) - 0.54 (0.340.88) -
57.165.5 1.51 0.98 1.63 0.92 (0.621.38) - 0.59 (0.380.94) -
65.572.6 1.31 1.01 1.11 1.19 (0.751.89) - 0.91 (0.561.50) -
gt72.6 1.10 1.17 0.97 1.13 (0.691.87) 0.86 1.21 (0.741.98) 0.076

• There was no significant interaction between cTTR
  and the rate of non-haemorrhagic stroke

TTR time in therapeutic range cTTR centre
mean TTR HR hazard ratio CI confidence
interval.Interaction P value evaluated by a
multivariate approach with centre-based TTR as a
continuous variable. Dabigatran etexilate is not
approved for clinical use in stroke prevention in
atrial fibrillation outside the US and
Canada. Wallentin L, et al. Lancet
2010376975-983.
55
TTR SUBGROUP ANALYSISINTRACRANIAL BLEEDING
Dabigatran 110 mg Dabigatran150 mg Warfarin Dabigatran 110 mgvs. warfarin Dabigatran 110 mgvs. warfarin Dabigatran 150 mgvs. warfarin Dabigatran 150 mgvs. warfarin
cTTR Rate per100-person yrs Rate per100-person yrs Rate per100-person yrs HR(95 CI) P value(interaction) HR (95 CI) P value(interaction)
lt57.1 0.28 0.34 0.64 0.43 (0.191.00) - 0.53 (0.251.15) -
57.165.5 0.30 0.42 0.93 0.31 (0.150.66) - 0.45 (0.240.88) -
65.572.6 0.13 0.24 0.67 0.20 (0.070.58) - 0.35 (0.150.82) -
gt72.6 0.21 0.30 0.77 0.27 (0.110.66) 0.71 0.39 (0.180.84) 0.89

• Dabigatran 110 mg and 150 mg reduce the risk of
  intracranial bleeding compared with warfarin,
  irrespective of centre-based INR control

TTR time in therapeutic range cTTR centre
mean TTR HR hazard ratio CI confidence
interval.Interaction P value evaluated by a
multivariate approach with centre-based TTR as a
continuous variable. Dabigatran etexilate is not
approved for clinical use in stroke prevention in
atrial fibrillation outside the US and
Canada. Wallentin L, et al. Lancet
2010376975-983.
56
TTR SUBGROUP ANALYSISMAJOR BLEEDING
Dabigatran 110 mg Dabigatran150 mg Warfarin Dabigatran 110 mgvs. warfarin Dabigatran 110 mgvs. warfarin Dabigatran 150 mgvs. warfarin Dabigatran 150 mgvs. warfarin
cTTR Rate per100-person yrs Rate per100-person yrs Rate per100-person yrs HR(95 CI) P value(interaction) HR (95 CI) P value(interaction)
lt57.1 2.36 2.54 3.59 0.65(0.480.89) - 0.71(0.520.96) -
57.165.5 3.38 3.33 4.13 0.82(0.631.06) - 0.81(0.621.05) -
65.572.6 2.82 3.80 3.40 0.83(0.621.11) - 1.13(0.871.48) -
gt72.6 2.81 3.60 3.11 0.90(0.671.21) 0.50 1.16(0.881.54) 0.03

• Dabigatran 110 mg is superior to warfarin in
  terms of major bleeding, irrespective of
  centre-based INR control
• With dabigatran 150 mg there are less major
  bleedings compared with warfarin at lower cTTR,
  but similar events at higher cTTR

TTR time in therapeutic range cTTR centre
mean TTR HR hazard ratio CI confidence
interval.Interaction P value evaluated by a
multivariate approach with centre-based TTR as a
continuous variable. Dabigatran etexilate is not
approved for clinical use in stroke prevention in
atrial fibrillation outside the US and
Canada. Wallentin L, et al. Lancet
2010376975-983.
57
TTR SUBGROUP ANALYSISTIME TO MAJOR BLEEDING
TTR time in therapeutic range cTTR centre
mean TTR HR hazard ratio CI confidence
interval.Dabigatran etexilate is not approved
for clinical use in stroke prevention in atrial
fibrillation outside the US and Canada. Wallentin
L, et al. Lancet 2010376975-983.
58
TTR SUBGROUP ANALYSISTOTAL BLEEDING
Dabigatran 110 mg Dabigatran150 mg Warfarin Dabigatran 110 mgvs. warfarin Dabigatran 110 mgvs. warfarin Dabigatran 150 mgvs. warfarin Dabigatran 150 mgvs. warfarin
cTTR Rate per100-person yrs Rate per100-person yrs Rate per100-person yrs HR(95 CI) P value(interaction) HR (95 CI) P value(interaction)
lt57.1 12.20 14.42 16.56 0.71(0.620.82) 0.89(0.781.01)
57.165.5 14.04 15.88 18.96 0.71(0.630.80) 0.82(0.730.93)
65.572.6 16.07 17.24 18.74 0.85(0.750.96) 0.92(0.811.03)
gt72.6 16.03 18.08 18.55 0.84(0.740.95) 0.076 1.00(0.891.12) 0.15

• There was no significant interaction between cTTR
  and the rate of total bleeding the results are
  consistent with the overall data

TTR time in therapeutic range cTTR centre
mean TTR HR hazard ratio CI confidence
interval.Interaction P value evaluated by a
multivariate approach with centre-based TTR as a
continuous variable. Dabigatran etexilate is not
approved for clinical use in stroke prevention in
atrial fibrillation outside the US and
Canada. Wallentin L, et al. Lancet
2010376975-983.
59
TTR SUBGROUP ANALYSISTOTAL DEATH
Dabigatran 110 mg Dabigatran150 mg Warfarin Dabigatran 110 mgvs. warfarin Dabigatran 110 mgvs. warfarin Dabigatran 150 mgvs. warfarin Dabigatran 150 mgvs. warfarin
cTTR Rate per100-person yrs Rate per100-person yrs Rate per100-person yrs HR(95 CI) P value(interaction) HR (95 CI) P value(interaction)
lt57.1 4.17 3.85 5.72 0.73(0.580.92) - 0.67(0.530.85) -
57.165.5 3.97 3.75 4.09 0.97(0.751.24) - 0.92(0.711.18) -
65.572.6 3.19 3.64 3.70 0.86(0.651.13) - 0.98(0.751.28) -
gt72.6 3.60 3.30 3.04 1.18(0.891.57) 0.066 1.08(0.811.44) 0.052

• Dabigatran 110 mg and 150 mg are associated with
  fewer deaths compared with warfarin at sites with
  poor INR control and comparable rates at sites
  with good INR control

TTR time in therapeutic range cTTR centre
mean TTR HR hazard ratio CI confidence
interval.Interaction P value evaluated by a
multivariate approach with centre-based TTR as a
continuous variable. Dabigatran etexilate is not
approved for clinical use in stroke prevention in
atrial fibrillation outside the US and
Canada. Wallentin L, et al. Lancet
2010376975-983.
60
TTR SUBGROUP ANALYSISALL CARDIOVASCULAR EVENTS
Dabigatran 110 mg Dabigatran150 mg Warfarin Dabigatran 110 mgvs. warfarin Dabigatran 110 mgvs. warfarin Dabigatran 150 mgvs. warfarin Dabigatran 150 mgvs. warfarin
cTTR Rate per100-person yrs Rate per100-person yrs Rate per100-person yrs HR(95 CI) P value(interaction) HR (95 CI) P value(interaction)
lt57.1 7.65 6.83 10.13 0.74(0.620.89) - 0.67(0.560.80) -
57.165.5 7.84 7.09 8.03 0.97(0.811.16) - 0.87(0.731.05) -
65.572.6 6.88 7.41 7.13 0.97(0.801.17) - 1.05(0.871.27) -
gt72.6 6.85 7.07 6.42 1.07(0.871.30) 0.036 1.11(0.911.35) 0.0006

• Dabigatran 110 mg and 150 mg provide reduced
  event rates at sites with poor INR control and
  similar rates to warfarin at sites with good INR
  control

TTR time in therapeutic range cTTR centre
mean TTR HR hazard ratio CI confidence
interval.Interaction P value evaluated by a
multivariate approach with centre-based TTR as a
continuous variable. stroke, systemic embolism,
pulmonary embolism, myocardial infarction, death
and major bleeding. Dabigatran etexilate is not
approved for clinical use in stroke prevention in
atrial fibrillation outside the US and
Canada. Wallentin L, et al. Lancet
2010376975-983.
61
TTR SUBGROUP ANALYSISLIMITATIONS

• Analyses were pre-specified for primary outcome
  but not for secondary endpoints
• Centre-based INR control has limitations
• Might not represent INR control of individual
  patients
• Does not show the effect of good and poor
  treatment response
• Does not reflect treatment adherence or
  discontinuation
• Post-randomization variable, which might not be
  compensated for in the multivariate analysis

TTR time in therapeutic range INR
international normalized ratio. Dabigatran
etexilate is not approved for clinical use in
stroke prevention in atrial fibrillation outside
the US and Canada. Wallentin L, et al. Lancet
2010376975-983.
62
TTR SUBGROUP ANALYSISSUMMARY

• In patients with AF, dabigatran 110 mg BID is
  non-inferior and dabigatran 150 mg BID is
  superior to warfarin for prevention of stroke
  irrespective of centre-based INR control
• Dabigatran 110 mg BID and 150 mg BID are
  superior to warfarin in terms of intracranial
  haemorrhage irrespective of centre-based INR
  control
• Dabigatran 110 mg BID is superior to warfarin
  in terms of major bleeding irrespective of
  centre-based INR control
• Dabigatran 110 mg BID and 150 mg BID provide
  lower event rates compared with warfarin in
  terms of vascular events and mortality at sites
  with poor INR control (and similar rates at sites
  with averagegood INR control)

TTR time in therapeutic range INR
international normalized ratio BID twice
daily. Dabigatran etexilate is not approved for
clinical use in stroke prevention in atrial
fibrillation outside the US and Canada. Wallentin
L, et al. Lancet 2010376975-983.
63
TTR SUBGROUP ANALYSISCONCLUSIONS
The main efficacy and safety findings of the
RE-LY study, that dabigatran 150 mg reduces the
rate of stroke and SEE and that 110 mg reduces
major bleeding, are consistent irrespective of
INR control
For secondary outcomes, such as non-haemorrhagic
events and mortality, the advantages of
dabigatran may be greater at sites with poorer
INR control
TTR time in therapeutic range INR
international normalized ratio SEE systemic
embolic event. Dabigatran etexilate is not
approved for clinical use in stroke prevention in
atrial fibrillation outside the US and
Canada. Wallentin L, et al. Lancet
2010376975-983.
64
CHADS2

• SUBGROUPANALYSIS

65
CHADS2 SUBGROUP ANALYSIS BASELINE
CHARACTERISTICS
CHADS2 score 01 2 36
Number of patients 5775 6455 5882
Mean age (yrs) 69.5 71.9 73.0
Type of AF () Persistent Paroxysmal Permanent 31 36 33 33 32 35 32 30 38
Congestive heart failure () 12 35 48
Hypertension () 59 85 91
Age 75 yrs () 18 46 55
Diabetes mellitus () 3 22 45
Stroke/TIA () 0 6 55
Myocardial infarction () 13 15 22
Time in treatment range () (warfarin patients only) 66 65 62
TIA transient ischaemic attack. Dabigatran
etexilate is not approved for clinical use in
stroke prevention in atrial fibrillation outside
the US and Canada. Oldgren J, et al. ACC 2010
abstr 0903-04
66
CHADS2 SUBGROUP ANALYSIS STROKE AND SYSTEMIC
EMBOLISM
Annual rate () Annual rate () Annual rate ()
CHADS2 score D 110 mg BID D 150 mg BID Warfarin
01 1.06 0.65 1.05
2 1.43 0.84 1.38
36 2.12 1.88 2.68
D 110 mg BID vs. warfarin
D 150 mg BID vs. warfarin
P0.82
P0.44
0.5
1.0
1.5
0
2.0
0.5
1.0
1.5
0
2.0
Dabigatran better
Warfarin better
Dabigatran better
Warfarin better
BID twice daily D dabigatran P values for
interaction. Dabigatran etexilate is not approved
for clinical use in stroke prevention in atrial
fibrillation outside the US and Canada. Oldgren
J, et al. ACC 2010 abstr 0903-04.
67
CHADS2 SUBGROUP ANALYSIS MAJOR BLEEDING
Annual rate () Annual rate () Annual rate ()
CHADS2 score D 110 mg BID D 150 mg BID Warfarin
01 1.81 1.96 2.70
2 2.71 2.80 3.14
36 3.62 4.64 4.28
D 110 mg BID vs. warfarin
D 150 mg BID vs. warfarin
P0.08
P0.4
0.5
1.0
1.5
0
2.0
0.5
1.0
1.5
0
2.0
Dabigatran better
Warfarin better
Dabigatran better
Warfarin better
BID twice daily D dabigatran P values for
interaction. Dabigatran etexilate is not approved
for clinical use in stroke prevention in atrial
fibrillation outside the US and Canada. Oldgren
J, et al. ACC 2010 abstr 0903-04.
68
CHADS2 SUBGROUP ANALYSISINTRACRANIAL BLEEDING
Annual rate () Annual rate () Annual rate ()
CHADS2 score D 110 mg BID D 150 mg BID Warfarin
01 0.20 0.20 0.51
2 0.22 0.24 0.64
36 0.26 0.49 1.07
D 110 mg BID vs. warfarin
D 150 mg BID vs. warfarin
P0.089
P0.63
0.5
1.0
1.5
0
2.0
0.5
1.0
1.5
0
2.0
Dabigatran better
Warfarin better
Dabigatran better
Warfarin better
BID twice daily D dabigatran P values for
interaction. Dabigatran etexilate is not approved
for clinical use in stroke prevention in atrial
fibrillation outside the US and Canada. Oldgren
J, et al. ACC 2010 abstr 0903-04.
69
AGE AND RENAL FUNCTION

• SUBGROUP ANALYSIS

70
AGE AND RENAL FUNCTION SUBGROUP ANALYSIS STROKE
AND NON-CNS EMBOLISM
Annual rate () Annual rate () Annual rate ()
D 110 mg BID D 150 mg BID Warfarin
Age (yrs) Age (yrs) Age (yrs) Age (yrs)
lt65 1.48 0.69 1.35
6574 1.26 0.98 1.43
75 1.87 1.43 2.1
Creatinine clearance (mL/min) Creatinine clearance (mL/min) Creatinine clearance (mL/min) Creatinine clearance (mL/min)
3050 2.26 1.33 2.65
5180 1.65 1.24 1.76
gt80 0.92 0.72 1
D 150 mg BID vs. warfarin
D 110 mg BID vs. warfarin
P0.072
P0.76
P0.036
P0.58
0.5
1.0
1.5
0
2.0
0.5
1.0
1.5
0
2.0
Dabigatran better
Warfarin better
Dabigatran better
Warfarin better
BID twice daily CNS central nervous system
D dabigatran P values for interaction. Dabigatr
an etexilate is not approved for clinical use in
stroke prevention in atrial fibrillation outside
the US and Canada. Healey JS, et al. ACC 2010
abstr 1078-120.
71
AGE AND RENAL FUNCTION SUBGROUP ANALYSIS MAJOR
BLEEDING
Annual rate () Annual rate () Annual rate ()
D 110 mg BID D 150 mg BID Warfarin
Age (yrs) Age (yrs) Age (yrs) Age (yrs)
lt65 0.76 0.79 2.32
6574 2.12 2.45 3.08
75 4.21 4.81 4.09
Creatinine clearance (mL/min) Creatinine clearance (mL/min) Creatinine clearance (mL/min) Creatinine clearance (mL/min)
3050 5.07 4.85 5.17
5180 2.62 3.04 3.44
gt80 1.36 1.88 2.18
D 150 mg BID vs. warfarin
D 110 mg BID vs. warfarin
P0.0001
P0.0003
P0.091
P0.1
0.5
1.0
1.5
0
2.0
0.5
1.0
1.5
0
2.0
Dabigatran better
Warfarin better
Dabigatran better
Warfarin better
BID twice daily D dabigatran P values for
interaction. Dabigatran etexilate is not approved
for clinical use in stroke prevention in atrial
fibrillation outside the US and Canada. Healey
JS, et al. ACC 2010 abstr 1078-120.
72
AGE AND RENAL FUNCTION SUBGROUP ANALYSIS
HAEMORRHAGIC STROKE
Annual rate () Annual rate () Annual rate ()
D 110 mg BID D 150 mg BID Warfarin
Age (yrs) Age (yrs) Age (yrs) Age (yrs)
lt65 0.05 0.05 0.38
6574 0.08 0.08 0.31
75 0.2 0.15 0.47
Creatinine clearance (mL/min) Creatinine clearance (mL/min) Creatinine clearance (mL/min) Creatinine clearance (mL/min)
3050 0.26 0.12 0.58
5180 0.12 0.09 0.47
gt80 0.03 0.08 0.13
D 150 mg BID vs. warfarin
D 110 mg BID vs. warfarin
P0.75
P0.51
P0.4
P0.67
0.5
1.0
1.5
0
2.0
0.5
1.0
1.5
0
2.0
Dabigatran better
Warfarin better
Dabigatran better
Warfarin better
BID twice daily D dabigatran P values for
interaction. Dabigatran etexilate is not approved
for clinical use in stroke prevention in atrial
fibrillation outside the US and Canada. Healey
JS, et al. ACC 2010 abstr 1078-120.
73
PRIORSTROKE

• SUBGROUPANALYSIS

74
PRIOR STROKE SUBGROUP ANALYSISSTROKE OR
SYSTEMIC EMBOLISM
Warfarin D 110 mg BID D 150 mg BID
Overall study population Overall study population Overall study population Overall study population
Annual rate () 1.71 1.54 1.11
RR vs. warfarin 0.90 0.65
P value 0.30 lt0.001
Prior stroke/TIA Prior stroke/TIA Prior stroke/TIA Prior stroke/TIA
Annual rate () 2.78 2.32 2.07
RR vs. warfarin 0.84 0.75
P value 0.37 0.14
BID twice daily D dabigatran RR relative
risk TIA transient ischaemic attack.P values
for superiority vs. warfarin Plt0.001 for
non-inferiority. Dabigatran etexilate is not
approved for clinical use in stroke prevention in
atrial fibrillation outside the US and
Canada. Diener HC, et al. Lancet Neurol.
20109115763 Connolly SJ, et al. N Engl J Med
20103631875-1876
75
PRIOR STROKE SUBGROUP ANALYSISHAEMORRHAGIC
STROKE
Warfarin D 110 mg BID D 150 mg BID
Overall study population Overall study population Overall study population Overall study population
Annual rate () 0.38 0.12 0.10
RR vs. warfarin 0.31 0.26
P value lt0.001 lt0.001
Prior stroke/TIA Prior stroke/TIA Prior stroke/TIA Prior stroke/TIA
Annual rate () 0.77 0.08 0.20
RR vs. warfarin 0.11 0.27
P value 0.003 0.009
BID twice daily D dabigatran RR relative
risk TIA transient ischaemic attack.P values
for superiority vs. warfarin Plt0.001 for
non-inferiority. Dabigatran etexilate is not
approved for clinical use in stroke prevention in
atrial fibrillation outside the US and
Canada. Diener HC, et al. Lancet Neurol.
20109115763 Connolly SJ, et al. N Engl J Med
20103631875-1876
76
CARDIOVERSION

• SUBGROUPANALYSIS

77
CARDIOVERSION SUBGROUP ANALYSISSTROKE OR
SYSTEMIC EMBOLISM
1.8
P0.71
1.5
1.2
P0.40
0.9
Stroke/systemic embolism ()
0.6
0.3
0
Dabigatran150 mg BID
Warfarin
Dabigatran110 mg BID
n
672
664
647
BID twice daily. Dabigatran etexilate is not
approved for clinical use in stroke prevention in
atrial fibrillation outside the US and
Canada. Koti MJ, et al. ACC 2010 abstr 1078-124.
78
CARDIOVERSION SUBGROUP ANALYSISSTROKE OR
SYSTEMIC EMBOLISM WITH/WITHOUT TEE
With TEE prior to cardioversion
Without TEE prior to cardioversion
1.8
1.5
1.2
Stroke/systemic embolism ()
0.9
0.62
0.6
0.45
0.30
0.3
0.15
0.15
0
0
Dabigatran110 mg BID
Dabigatran150 mg BID
Warfarin
Dabigatran110 mg BID
Dabigatran150 mg BID
Warfarin
BID twice daily. Dabigatran etexilate is not
approved for clinical use in stroke prevention in
atrial fibrillation outside the US and
Canada. Koti MJ, et al. ACC 2010 abstr 1078-124.
79
CONCLUSIONS (1)

• AF is the most common cardiac arrhythmia with
  prevalence expected to double within 30 years1
• Up to 3 million people worldwide suffer strokes
  related to AF each year2-4
• Effective stroke prevention should be the main
  priority for patients with AF5

1. Go AS, et al. JAMA 20012852370-2375. 2.
Atlas of Heart Disease and Stroke, World Health
Organization, September 2004. Viewed at
http//www.who.int/cardiovascular_diseases/en/cvd_
atlas_15_burden_stroke.pdf. 3. Wolf PA, et al.
Stroke 199122983-988. 4. Lin HJ, et al. Stroke
1996271760-1764. 5. Fuster V, et al. J Am Coll
Cardiol 200648854-906.
80
CONCLUSIONS (2)

• Both doses of dabigatran provide advantages over
  warfarin for specific patient groups with AF1,2
• With 150 mg BID, 3 out of 4 AF-related strokes
  can be prevented
• Warfarin prevents 64 of strokes and dabigatran
  prevents an additional 35 of strokes or systemic
  embolisms vs. warfarin
• Dabigatran 150 mg BID demonstrated a comparable
  major bleeding rate vs. warfarin and provides
  additional safety benefits
• 59reducedrisk of intracranial bleeding vs.
  warfarin
• Reduced risk of total bleeding
• 110 mg BID has significantly less bleedings with
  similar efficacy. This may be the more
  appropriate dose for patients with a potentially
  higher risk of major bleeding, or for elderly
  patients gt80 years of age
• The benefits of dabigatran were generally
  consistent across patient subgroups

Dabigatran etexilate is not approved for clinical
use in stroke prevention in atrial fibrillation
outside the US and Canada. 1. Connolly SJ, et
al. N Engl J Med 20093611139-1151. 2. Connolly
SJ, et al. N Engl J Med 20103631875-1876.