The RE­LY Study:

Randomized Evaluation of Long­
term anticoagulant therapY
Dabigatran Compared to Warfarin in 18,113 Patients 
with Atrial Fibrillation at Risk of Stroke
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
Dabigatran

 Dabigatran Etexilate, a pro­drug, is rapidly 
converted to dabigatran

 6.5% bioavailability, 80% excreted by kidney

 Half­life of 12­17 hours

 Phase 2 data identified 220 mg daily and 150 mg 
BID as viable doses
 RE­LY: A Non­inferiority Trial
Atrial fibrillation
≥1 Risk Factor
Absence of contra-
indications
951 centers in 44 countries
ROBE=Prospective Randomized
pen Trial with Blinded R
djudication of Events.
open Blinded

Warfarin Dabigatran Dabigatran

(INR 2.0-3.0) Etexilate Etexilate
110 mg b.i.d. 150 mg b.i.d.
N=6000 N=6000 N=6000

10 efficacy outcome = stroke or systemic embolism

10 safety outcome = major bleeding
Non-inferiority margin 1.46
Trial Execution

Performed December 2005­March 2009

Median Follow up 2.0 years

Follow up 99.9% complete

Mean TTR = 64% (patients on warfarin)
Baseline Characteristics
Characteristic Dabigatran 110  Dabigatran 150 
Warfarin
mg mg
Randomized 6015 6076 6022
Mean age (years) 71.4 71.5 71.6
Male (%) 64.3 63.2 63.3
CHADS2 score  2.1 2.2 2.1
(mean)
     0­1   (%) 32.6 32.2 30.9
     2      (%) 34.7 35.2 37.0
     3+    (%) 32.7 32.6 32.1
Prior stroke/TIA (%) 19.9 20.3 19.8
Prior MI (%) 16.8 16.9 16.1
CHF (%) 32.2 31.8 31.9
Baseline ASA (%) 40.0 38.7 40.6
Warfarin Naïve (%) 49.9 49.8 51.4
 Permanent Discontinuation
# at Risk Year 0.5 1.0 1.5 2.0 2.5
D110 6015 5336 5026 3950 2491 1176
D150 6076 5329 5015 3955 2528 1172
0.4

W 6022 5563 5269 4158 2561 1187

0.3
Stopping Rates

Dabigatran150

Dabigatran110
0.2

Warfarin
0.1
0.0

0 0.5 1.0 1.5 2.0 2.5

Years of Follow-up
 Stroke or Systemic Embolism

Non-inferiority Superiority
p-value p-value

Dabigatran 110 vs. Warfarin <0.001 0.34

Dabigatran 150 vs. Warfarin <0.001 <0.001

Margin = 1.46

0.50 0.75 1.00 1.25 1.50

HR (95% CI)
Primary Outcome

D 110mg vs.  D 150mg vs. 
D 110mg D 150mg warfarin
Warfarin Warfarin

Number  Number  Number  RR RR

P* P*
rate/yr rate/yr rate/yr 95% CI 95% CI

Stroke or  182 134 199 0.91 0.66

systemic  0.34 <0.001
Embolism 1.5 %/yr 1.1 %/yr 1.7 %/yr 0.74­1.11 0.53­0.82

171 122 185 0.92 0.64

Stroke 0.41 <0.001
1.4 %/yr 1.0 %/yr 1.6 %/yr 0.74­1.13 0.51­0.81

Systemic  14 13 19 0.73 0.67

0.38 0.27
Embolism 0.1 %/yr 0.1 %/yr 0.2 %/yr 0.37­1.46 0.33­1.36

* These, and all subsequent, p values, are for superiority

Stroke Classification

D 110 mg vs.  D 150 mg vs. 
D 110mg D 150mg warfarin
Warfarin Warfarin

Number  Number  Number  RR RR

p p
rate/yr rate/yr rate/yr 95% CI 95% CI

Ischemic/  159 111 142 1.11 0.76

0.35 0.03
Unspecified 1.3 %/yr 0.9 %/yr 1.2 %/yr 0.89­1.40 0.60­0.98

14 12 45 0.31 0.26
Hemorrhagic <0.001 <0.001
0.1 %/yr 0.1 %/yr 0.4 %/yr 0.17­0.56 0.14­0.49
 Stroke or Systemic Embolism
No. at Risk
0.05

W 6022 5862 4593 2890 1322

5718
D110 6015 5862 5710 4593 2945 1385
D150 6076 5939 5779 4682 3044 1429
0.04
Cumulative Hazard Rates

0.03
0.02

Warfarin Dabigatran110

Dabigatran 150
0.01
0.0

0 0.5 1.0 1.5 2.0 2.5

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

0.02

Warfarin
0.01

Dabigatran150

Dabigatran110
0.0

0 0.5 1.0 1.5 2.0 2.5

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

Warfarin
0.01

Dabigatran110
0.0

Dabigatran150

0 0.5 1.0 1.5 2.0 2.5

Years
 MI, Hospitalization and Death

D 110mg vs.  D 150mg vs. 
D 110mg D 150mg warfarin
Warfarin Warfarin

Annual Annual  Annual RR RR

p p
rate rate rate 95% CI 95% CI

Myocardial  1.35 1.38

0.7% 0.7 % 0.5 % 0.07 0.048
Infarction 0.98­1.87 1.00­1.91

0.92 0.97
Hospitalization 19.4 % 20.2% 20.8 % 0.003 0.34
0.87­0.97 0.92­1.03

Vascular  0.90 0.85

2.4 % 2.3 % 2.7 % 0.21 0.04
Death 0.77­1.06 0.72­0.99

0.91 0.88
Death 3.8 % 3.6 % 4.1 % 0.13 0.05
0.80­1.03 0.77­1.00
 Bleeding and Net Clinical Benefit
D  D  D 110mg vs.  D 150mg vs. 
warfarin
110mg 150mg Warfarin Warfarin

Annual Annual Annual RR RR

p p
rate rate rate 95% CI 95% CI

0.80 0.93
Major Bleeding 2.7 % 3.1 % 3.4 % 0.003 0.31
0.69­0.93 0.81­1.07
Life­ 0.68 0.81
Threatening  1.2 % 1.5 % 1.8 % <0.001 0.04
major 0.55­0.83 0.66­0.99

0.79 0.91
Minor Bleeding 13.2 % 14.8 % 16.4% <0.001 0.005
0.74­0.84 0.85­0.97

Total  Bleeding 0.78 0.91

14.6 16.4 18.2 <0.001 0.002
(Major+Minor) 0.74­0.83 0.86­0.97

Net Clinical  0.92 0.91

7.1 % 6.9 % 7.6 % 0.10 0.04
Benefit* 0.84­1.02 0.82­1.00

* stroke, systemic embolism, myocardial infarction, pulmonary embolism, death and major bleed
 Important Sites of Major Bleeding

D 110mg vs.  D 150mg vs. 
D 110mg D 150mg warfarin
Warfarin Warfarin

RR RR
Annual Annual Annual p p
95% CI 95% CI
rate rate rate

Gastro­
1.10 1.50
intestinal 1.1 % 1.5 % 1.0 % 0.43 <0.001
0.86­1.41 1.19­1.89
(GI)

Intracranial  0.31 0.40

0.2 % 0.3 % 0.7 % <0.001 <0.001
(ICH)  0.20­0.47 0.27­0.60

Major Bleed     
0.85 0.87
 (non­GI,  1.5 % 1.5 % 1.8 % 0.11 0.16
0.70­1.04 0.71­1.06
non­ICH)
 Major Bleeding
# at Risk Year 0.5 1.0 1.5 2.0 2.5
0.12

D110 6015 5835 5640 4510 2872 1349

D150 6076 5839 5638 4557 2928 1366
W 6022 5801 5600 4474 2797 1269
0.10
Cumulative Hazard Rates

Warfarin
0.08

Dabigatran150
0.06

Dabigatran110
0.04
0.02
0.0

0 0.5 1.0 1.5 2.0 2.5

Years
Dabigatran 150 mg vs. 110 mg

Dabigatran  Dabigatran 
D 150mg vs. D 110 mg
110mg 150mg
Number  Number  Relative Risk
p
rate/yr rate/yr 95% CI
Stroke and systemic  0.73
1.5% 1.1 % 0.005
embolism 0.58­0.91
Ischemic/unspecified  0.69
1.3 % 0.9 % 0.002
stroke 0.54­0.88
0.85
Hemorrhagic stroke 0.1% 0.1 % 0.67
0.39­1.83
1.16
Major Hemorrhage 2.7 % 3.1 % 0.05
1.00­1.34
1.36
GI Major Hemorrhage 1.1 % 1.5 % 0.007
1.09­1.70
0.98
Net Clinical Benefit 7.1 % 6.9 % 0.66
0.89­1.08
 ALT or AST >3x ULN
0.04

# at Risk
Year 0.5 1.0 1.5 2.0 2.5
D110 6015 5860 5692 4601 2950 1394
D150 6076 5925 5759 4675 3034 1427
W 6022 5858 5708 4592 2906 1331
0.03
Cumulative Risk

Warfarin
0.02

Dabigatran110

Dabigatran150
0.01
0.0

0 0.5 1.0 1.5 2.0 2.5

Years
Common Adverse Events
Dabigatran  Dabigatran 
Adverse events occurring in  110 mg 150 mg Warfarin
>5% of any group
% % %
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 7.9 7.8
Fatigue  6.6 6.6 6.2
Cough  5.7 5.7 6.0
Chest pain  5.2 6.2 5.9
Arthralgia  4.5 5.5 5.7
Back pain  5.3 5.2 5.6
Nasopharyngitis  5.6 5.4 5.6
Diarrhea  6.3 6.5 5.7
Atrial fibrillation  5.5 5.9 5.8
Urinary tract infection  4.5 4.8 5.6
Upper respiratory tract 
4.8 4.7 5.2
infection
*Occurred more commonly on dabigatran p<0.001
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 intra­cranial and life­
threatening hemorrhage
 Both doses are free of liver and other major toxicity, 
although they increase dyspepsia and GI bleeding
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