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

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 pro-drug, is rapidly converted to dabigatran

6.5% bioavailability, 80% excreted by kidney

Half-life of 12-17 hours

Phase 2 data identified 220 mg daily and 150 mg BID as viable doses

RE-LY: A Non-inferiority TrialAtrial fibrillation

≥1 Risk FactorAbsence of contra-

indications951 centers in 44 countries

R

Warfarin (INR 2.0-3.0)

N=6000

Dabigatran Etexilate

110 mg b.i.d.N=6000

Dabigatran Etexilate

150 mg b.i.d.N=6000

PROBE=Prospective Randomized Open Trial with Blinded Adjudication of Events.

10 efficacy outcome = stroke or systemic embolism10 safety outcome = major bleedingNon-inferiority margin 1.46

open Blinded

Trial Execution

Performed December 2005-March 2009

Median Follow up 2.0 years

Follow up 99.9% complete

Mean TTR = 64% (patients on warfarin)

Baseline Characteristics

Characteristic 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 (%) 2 (%) 3+ (%)

2.1

32.634.732.7

2.2

32.235.232.6

2.1

30.937.032.1

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

Years of Follow-up

Sto

pp

ing

Ra

tes

0.0

0.1

0.2

0.3

0.4

0 0.5 1.0 1.5 2.0 2.5

Dabigatran110

Dabigatran150

Warfarin

D110D150W

# at Risk Year 0.5 1.0 1.5 2.0 2.56015 5336 5026 3950 2491 11766076 5329 5015 3955 2528 11726022 5563 5269 4158 2561 1187

Stroke or Systemic Embolism

0.50 0.75 1.00 1.25 1.50

Dabigatran 110 vs. Warfarin

Dabigatran 150 vs. Warfarin

Non-inferiorityp-value

<0.001

<0.001

Superiorityp-value

0.34

<0.001

Margin = 1.46

HR (95% CI)

Primary Outcome

D 110mg D 150mg warfarinD 110mg vs.

WarfarinD 150mg vs.

Warfarin

Number Number

rate/yrrate/yr

Number Number

rate/yrrate/yr

Number Number

rate/yrrate/yr

RRRR

95% CI95% CIP*P*

RRRR

95% CI95% CIP*P*

Stroke or systemic Embolism

182

1.5 %/yr

134

1.1 %/yr

199

1.7 %/yr

0.91

0.74-1.110.34

0.66

0.53-0.82<0.001

Stroke171

1.4 %/yr

122

1.0 %/yr

185

1.6 %/yr

0.92

0.74-1.130.41

0.64

0.51-0.81<0.001

Systemic Embolism

14

0.1 %/yr

13

0.1 %/yr

19

0.2 %/yr

0.73

0.37-1.460.38

0.67

0.33-1.360.27

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

Stroke Classification

D 110mg D 150mg warfarinD 110 mg vs.

WarfarinD 150 mg vs.

Warfarin

Number Number

rate/yrrate/yr

Number Number

rate/yrrate/yr

Number Number

rate/yrrate/yr

RRRR

95% CI95% CIpp

RRRR

95% CI95% CIpp

Ischemic/ Unspecified

159

1.3 %/yr

111

0.9 %/yr

142

1.2 %/yr

1.11

0.89-1.400.35

0.76

0.60-0.980.03

Hemorrhagic14

0.1 %/yr

12

0.1 %/yr

45

0.4 %/yr

0.31

0.17-0.56<0.001

0.26

0.14-0.49<0.001

Stroke or Systemic Embolism

Cu

mu

lati

ve H

azar

d R

ates

0.0

0.01

0.02

0.03

0.04

0.05

0 0.5 1.0 1.5 2.0 2.5

Dabigatran110

Dabigatran 150

Warfarin

6022 5862 5718 4593 2890 1322

6015 5862 5710 4593 2945 1385

6076 5939 5779 4682 3044 1429

No. at Risk

W

D110

D150

Years

MI, Hospitalization and Death

D 110mg D 150mg warfarinD 110mg vs.

WarfarinD 150mg vs.

Warfarin

AnnualAnnual

raterate

AnnualAnnual

raterate

AnnualAnnual

raterate

RRRR

95% CI95% CIpp

RRRR

95% CI95% CIpp

Myocardial Infarction

0.7% 0.7 % 0.5 %1.35

0.98-1.870.07

1.38

1.00-1.910.048

Hospitalization 19.4 % 20.2% 20.8 %0.92

0.87-0.970.003

0.97

0.92-1.030.34

Vascular Death

2.4 % 2.3 % 2.7 %0.90

0.77-1.060.21

0.85

0.72-0.990.04

Death 3.8 % 3.6 % 4.1 %0.91

0.80-1.030.13

0.88

0.77-1.000.05

Bleeding and Net Clinical Benefit

D

110mg

D

150mgwarfarin

D 110mg vs. Warfarin

D 150mg vs. Warfarin

AnnualAnnual

raterate

AnnualAnnual

raterate

AnnualAnnual

raterate

RRRR

95% CI95% CIpp

RRRR

95% CI95% CIpp

Major Bleeding 2.7 % 3.1 % 3.4 %0.80

0.69-0.930.003

0.93

0.81-1.070.31

Life-Threatening major

1.2 % 1.5 % 1.8 %0.68

0.55-0.83<0.001

0.81

0.66-0.990.04

Minor Bleeding 13.2 % 14.8 % 16.4%0.79

0.74-0.84<0.001

0.91

0.85-0.970.005

Total Bleeding

(Major+Minor)14.6 16.4 18.2

0.78

0.74-0.83<0.001

0.91

0.86-0.970.002

Net Clinical Benefit*

7.1 % 6.9 % 7.6 %0.92

0.84-1.020.10

0.91

0.82-1.000.04

* stroke, systemic embolism, myocardial infarction, pulmonary embolism, death and major bleed

Important Sites of Major Bleeding

D 110mg D 150mg warfarinD 110mg vs.

WarfarinD 150mg vs.

Warfarin

AnnualAnnual

raterate

AnnualAnnual

raterate

AnnualAnnual

raterate

RRRR

95% CI95% CIpp

RRRR

95% CI95% CIpp

Gastro-intestinal

(GI)1.1 % 1.5 % 1.0 %

1.10

0.86-1.410.43

1.50

1.19-1.89<0.001

Intracranial

(ICH) 0.2 % 0.3 % 0.7 %

0.31

0.20-0.47<0.001

0.40

0.27-0.60<0.001

Major Bleed (non-GI,

non-ICH)1.5 % 1.5 % 1.8 %

0.85

0.70-1.040.11

0.87

0.71-1.060.16

Major Bleeding

Years

Cum

ula

tive

Haz

ard

Ra

tes

0.0

0.02

0.04

0.06

0.08

0.10

0.12

0 0.5 1.0 1.5 2.0 2.5

Dabigatran110

Dabigatran150

Warfarin

# at Risk Year 0.5 1.0 1.5 2.0 2.5

D110

D150

W

6015 5835 5640 4510 2872 1349

6076 5839 5638 4557 2928 1366

6022 5801 5600 4474 2797 1269

Dabigatran 150 mg vs. 110 mg

Dabigatran 110mg

Dabigatran 150mg

D 150mg vs. D 110 mg

Number Number

rate/yrrate/yr

Number Number

rate/yrrate/yr

Relative RiskRelative Risk

95% CI95% CIpp

Stroke and systemic embolism

1.5% 1.1 %0.73

0.58-0.910.005

Ischemic/unspecified stroke

1.3 % 0.9 %0.69

0.54-0.880.002

Hemorrhagic stroke 0.1% 0.1 %0.85

0.39-1.830.67

Major Hemorrhage 2.7 % 3.1 %1.16

1.00-1.340.05

GI Major Hemorrhage 1.1 % 1.5 %1.36

1.09-1.700.007

Net Clinical Benefit 7.1 % 6.9 %0.98

0.89-1.080.66

ALT or AST >3x ULN

Years

Cum

ula

tive

Ris

k

0.0

0.01

0.02

0.03

0.04

0 0.5 1.0 1.5 2.0 2.5

Dabigatran110

Dabigatran150

Warfarin

# at RiskYear 0.5 1.0 1.5 2.0 2.5

D110D150W

6015 5860 5692 4601 2950 13946076 5925 5759 4675 3034 14276022 5858 5708 4592 2906 1331

Adverse events occurring in >5% of any group

Dabigatran 110 mg

%%

Dabigatran 150 mg

%%

Warfarin

%%

Dyspepsia * 11.8 11.3 5.8Dyspnea 9.3 9.5 9.7Dizziness 8.1 8.3 9.4Peripheral edema 7.9 7.9 7.8Fatigue 6.6 6.6 6.2Cough 5.7 5.7 6.0Chest pain 5.2 6.2 5.9Arthralgia 4.5 5.5 5.7Back pain 5.3 5.2 5.6Nasopharyngitis 5.6 5.4 5.6Diarrhea 6.3 6.5 5.7Atrial fibrillation 5.5 5.9 5.8Urinary tract infection 4.5 4.8 5.6Upper respiratory tract infection

4.8 4.7 5.2

Common Adverse Events

*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 intra-cranial 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