1. The RE-LY Study: Randomized Evaluation of Long-term anticoagulant therapY
Dabigatran Compared to Warfarin in 18,113 Patients with Atrial Fibrillation at Risk of Stroke 1

2. Atrial Fibrillation and Stroke
AF responsible for 1/6 of all strokes
Warfarin reduces stroke in AF by 64%
significant increase in intracranial and other hemorrhage
Difficult to use
Only 50% of eligible patients receive warfarin
An alternative treatment is needed

3. Dabigatran
Dabigatran Etexilate, a pro-drug, is rapidly converted to dabigatran
6.5% bioavailability, 80% excreted by kidney
Half-life of hours
Phase 2 data identified 220 mg daily and 150 mg BID as viable doses

4. RE-LY: A Non-inferiority Trial
Atrial fibrillation
≥1 Risk Factor
Absence of contra-indications
951 centers in 44 countries
PROBE=Prospective Randomized
Open Trial with Blinded
Adjudication of Events. R
open
Blinded
Warfarin
(INR )
N=6000
Dabigatran Etexilate
110 mg b.i.d.
N=6000
Dabigatran Etexilate
150 mg b.i.d.
N=6000
10 efficacy outcome = stroke or systemic embolism
10 safety outcome = major bleeding
Non-inferiority margin 1.46

5. Trial Execution Performed December 2005-March 2009
Median Follow up 2.0 years
Follow up 99.9% complete
Mean TTR = 64% (patients on warfarin)

6. Baseline Characteristics
Dabigatran 110 mg
Dabigatran 150 mg
Warfarin
Randomized
6015
6076
6022
Mean age (years)
71.4
71.5
71.6
Male (%)
64.3
63.2
63.3
CHADS2 score (mean)
0-1 (%)
(%)
3+ (%)
2.1
32.6
34.7
32.7
2.2
32.2
35.2
30.9
37.0
32.1
Prior stroke/TIA (%)
19.9
20.3
19.8
Prior MI (%)
16.8
16.9
16.1
CHF (%)
31.8
31.9
Baseline ASA (%)
40.0
38.7
40.6
Warfarin Naïve (%)
49.9
49.8
51.4

7. Permanent Discontinuation
Years of Follow-up
Stopping Rates
0.0
0.1
0.2
0.3
0.4
0.5
1.0
1.5
2.0
2.5
Dabigatran110
Dabigatran150
Warfarin
D110
D150 W
# at Risk
Year 0.5
6015
5336
5026
3950
2491
1176
6076
5329
5015
3955
2528
1172
6022
5563
5269
4158
2561
1187

8. Stroke or Systemic Embolism
0.50
0.75
1.00
1.25
1.50
Dabigatran 110 vs. Warfarin
Dabigatran 150 vs. Warfarin
Non-inferiority
p-value
<0.001
Superiority
0.34
Margin = 1.46
HR (95% CI)

9. Primary Outcome
D 110mg
D 150mg
warfarin
D 110mg vs. Warfarin
D 150mg vs. Warfarin
Number
rate/yr RR
95% CI P*
Stroke or systemic Embolism
182
1.5 %/yr
134
1.1 %/yr
199
1.7 %/yr
0.91
0.34
0.66
<0.001
Stroke
171
1.4 %/yr
122
1.0 %/yr
185
1.6 %/yr
0.92
0.41
0.64
Systemic Embolism 14
0.1 %/yr 13 19
0.2 %/yr
0.73
0.38
0.67
0.27
* These, and all subsequent, p values, are for superiority

10. Stroke Classification
D 110mg
D 150mg
warfarin
D 110 mg vs. Warfarin
D 150 mg vs. Warfarin
Number
rate/yr RR
95% CI p
Ischemic/ Unspecified
159
1.3 %/yr
111
0.9 %/yr
142
1.2 %/yr
1.11
0.35
0.76
0.03
Hemorrhagic 14
0.1 %/yr 12 45
0.4 %/yr
0.31
<0.001
0.26

11. Stroke or Systemic Embolism
Cumulative Hazard Rates
0.0
0.01
0.02
0.03
0.04
0.05
0.5
1.0
1.5
2.0
2.5
Dabigatran110
Dabigatran 150
Warfarin
6022
5862
5718
4593
2890
1322
6015
5710
2945
1385
6076
5939
5779
4682
3044
1429
No. at Risk W
D110
D150
Years

12. All Intracranial Bleeding
Years
Cumulative Hazard Rates
0.0
0.01
0.02
0.03
0.04
0.5
1.0
1.5
2.0
2.5
Dabigatran110
Dabigatran150
Warfarin
# at Risk
Year 0.5
D110
D150 W
6015
5900
5771
4666
3006
1420
6076
5958
5817
4735
3080
1451
6022
5887
5759
4632
2933
1343

13. Cumulative Hazard Rates
Hemorrhagic Stroke
Years
Cumulative Hazard Rates
0.0
0.01
0.02
0.03
0.04
0.5
1.0
1.5
2.0
2.5
Dabigatran110
Dabigatran150
Warfarin
# at Risk
Year 0.5
D110
D150 W
6015
5901
5775
4669
3010
1423
6076
5963
5827
4743
3088
1457
6022
5899
5772
4652
2952
1351

14. MI, Hospitalization and Death
D 110mg
D 150mg
warfarin
D 110mg vs. Warfarin
D 150mg vs. Warfarin
Annual
rate RR
95% CI p
Myocardial Infarction
0.7%
0.7 %
0.5 %
1.35
0.07
1.38
0.048
Hospitalization
19.4 %
20.2%
20.8 %
0.92
0.003
0.97
0.34
Vascular Death
2.4 %
2.3 %
2.7 %
0.90
0.21
0.85
0.04
Death
3.8 %
3.6 %
4.1 %
0.91
0.13
0.88
0.05

15. Bleeding and Net Clinical Benefit
110mg
150mg
warfarin
D 110mg vs. Warfarin
D 150mg vs. Warfarin
Annual
rate RR
95% CI p
Major Bleeding
2.7 %
3.1 %
3.4 %
0.80
0.003
0.93
0.31
Life-Threatening major
1.2 %
1.5 %
1.8 %
0.68
<0.001
0.81
0.04
Minor Bleeding
13.2 %
14.8 %
16.4%
0.79
0.91
0.005
Total Bleeding
(Major+Minor)
14.6
16.4
18.2
0.78
0.002
Net Clinical Benefit*
7.1 %
6.9 %
7.6 %
0.92
0.10
* stroke, systemic embolism, myocardial infarction, pulmonary embolism, death and major bleed

16. Important Sites of Major Bleeding
D 110mg
D 150mg
warfarin
D 110mg vs. Warfarin
D 150mg vs. Warfarin
Annual
rate RR
95% CI p
Gastro-intestinal
(GI)
1.1 %
1.5 %
1.0 %
1.10
0.43
1.50
<0.001
Intracranial
(ICH)
0.2 %
0.3 %
0.7 %
0.31
0.40
Major Bleed (non-GI,
non-ICH)
1.8 %
0.85
0.11
0.87
0.16

17. Cumulative Hazard Rates
Major Bleeding
Years
Cumulative Hazard Rates
0.0
0.02
0.04
0.06
0.08
0.10
0.12
0.5
1.0
1.5
2.0
2.5
Dabigatran110
Dabigatran150
Warfarin
# at Risk
Year 0.5
D110
D150 W
6015
5835
5640
4510
2872
1349
6076
5839
5638
4557
2928
1366
6022
5801
5600
4474
2797
1269

18. Dabigatran 150 mg vs. 110 mg Dabigatran 110mg Dabigatran 150mg
D 150mg vs. D 110 mg
Number
rate/yr
Relative Risk
95% CI p
Stroke and systemic embolism
1.5%
1.1 %
0.73
0.005
Ischemic/unspecified stroke
1.3 %
0.9 %
0.69
0.002
Hemorrhagic stroke
0.1%
0.1 %
0.85
0.67
Major Hemorrhage
2.7 %
3.1 %
1.16
0.05
GI Major Hemorrhage
1.5 %
1.36
0.007
Net Clinical Benefit
7.1 %
6.9 %
0.98
0.66

19. ALT or AST >3x ULN Years Warfarin Dabigatran150 Cumulative Risk 0.0
0.01
0.02
0.03
0.04
0.5
1.0
1.5
2.0
2.5
Dabigatran110
Dabigatran150
Warfarin
# at Risk
Year 0.5
D110
D150 W
6015
5860
5692
4601
2950
1394
6076
5925
5759
4675
3034
1427
6022
5858
5708
4592
2906
1331

20. Common Adverse Events Adverse events occurring in >5% of any group
Dabigatran 110 mg %
Dabigatran 150 mg
Warfarin
Dyspepsia *
11.8
11.3
5.8
Dyspnea
9.3
9.5
9.7
Dizziness
8.1
8.3
9.4
Peripheral edema
7.9
7.8
Fatigue
6.6
6.2
Cough
5.7
6.0
Chest pain
5.2
5.9
Arthralgia
4.5
5.5
Back pain
5.3
5.6
Nasopharyngitis
5.4
Diarrhea
6.3
6.5
Atrial fibrillation
Urinary tract infection
4.8
Upper respiratory tract infection
4.7
*Occurred more commonly on dabigatran p<0.001

21. Conclusions
Dabigatran 150 mg significantly reduced stoke compared to warfarin with similar risk of major bleeding
Dabigatran 110 mg had a similar rate of stroke as warfarin with significantly reduced major bleeding
Both doses markedly reduced intra-cranial and life-threatening hemorrhage
Both doses are free of liver and other major toxicity, although they increase dyspepsia and GI bleeding

22. Conclusions Both Dabigatran doses offer advantages over warfarin
Dabigatran 150 is more effective and dabigatran 110 has a better safety profile
The availability of two effective doses, with different benefit risk profiles, creates the potential to tailor therapy to individual patient characteristics