A Randomized Trial Of Dabigatran, A Oral Direct Thrombin Inhibitor, Compared To Warfarin In 18,113 Patients With Atrial Fibrillation At High Risk Of Stroke (re-ly) – Stuart J. Connolly

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 contraindications 951 centers in 44 countries

ROBE=Prospective Randomized pen Trial with Blinded djudication of Events. open Warfarin (INR 2.0-3.0) N=6000

R Blinded

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

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 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)      0­1   (%)      2      (%)      3+    (%)

2.1

2.2

2.1

32.6 34.7 32.7

32.2 35.2 32.6

30.9 37.0 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

Characteristic

Year 0.5 5336 5329 5563

1.0 5026 5015 5269

1.5 3950 3955 4158

2.0 2491 2528 2561

2.5 1176 1172 1187

0.3

# at Risk D110 6015 D150 6076 W 6022

Dabigatran150 0.2

Dabigatran110

0.1

Warfarin

0.0

Stopping Rates

0.4

Permanent Discontinuation

0

0.5

1.0

1.5

Years of Follow-up

2.0

2.5

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

HR (95% CI)

1.50

Primary Outcome D 110mg vs.  Warfarin

D 150mg vs.  Warfarin

D 110mg

D 150mg

warfarin

Number  rate/yr

Number  rate/yr

Number  rate/yr

RR 95% CI

P*

RR 95% CI

P*

Stroke or  systemic  Embolism

182 1.5 %/yr

134 1.1 %/yr

199 1.7 %/yr

0.91 0.74­1.11

0.34

0.66 0.53­0.82

<0.001

Stroke

171 1.4 %/yr

122 1.0 %/yr

185 1.6 %/yr

0.92 0.74­1.13

0.41

0.64 0.51­0.81

<0.001

Systemic  Embolism

14 0.1 %/yr

13 0.1 %/yr

19 0.2 %/yr

0.73 0.37­1.46

0.38

0.67 0.33­1.36

0.27

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

Stroke Classification D 110 mg vs.  Warfarin

D 150 mg vs.  Warfarin

D 110mg

D 150mg

warfarin

Number  rate/yr

Number  rate/yr

Number  rate/yr

RR 95% CI

p

RR 95% CI

p

Ischemic/  Unspecified

159 1.3 %/yr

111 0.9 %/yr

142 1.2 %/yr

1.11 0.89­1.40

0.35

0.76 0.60­0.98

0.03

Hemorrhagic

14 0.1 %/yr

12 0.1 %/yr

45 0.4 %/yr

0.31 0.17­0.56

<0.001

0.26 0.14­0.49

<0.001

No. at Risk W

6022

5862

2890

1322

5862

5718 5710

4593

D110 6015

4593

2945

1385

D150 6076

5939

5779

4682

3044

1429

2.0

2.5

0.03 0.02

Dabigatran110

Warfarin

0.01

Dabigatran 150

0.0

Cumulative Hazard Rates

0.04

0.05

Stroke or Systemic Embolism

0

0.5

1.0

Years

1.5

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

0.02

0.03

# at Risk

0.01

Warfarin

Dabigatran150

Dabigatran110

0.0

Cumulative Hazard Rates

0.04

All Intracranial Bleeding

0

0.5

1.0

Years

1.5

2.0

2.5

# at Risk

Year 0.5

1.0

1.5

2.0

2.5

6015

5901

5775

4669

3010

1423

D150

6076

5963

5827

4743

3088

1457

W

6022

5899

5772

4652

2952

1351

0.02

0.03

D110

0.01

Warfarin Dabigatran110

0.0

Cumulative Hazard Rates

0.04

Hemorrhagic Stroke

Dabigatran150 0

0.5

1.0

1.5

Years

2.0

2.5

MI, Hospitalization and Death D 110mg vs.  Warfarin

D 150mg vs.  Warfarin

D 110mg

D 150mg

warfarin

Annual rate

Annual rate

 Annual rate

RR 95% CI

p

RR 95% CI

p

0.7%

0.7 %

0.5 %

1.35 0.98­1.87

0.07

1.38 1.00­1.91

0.048

Hospitalization

19.4 %

20.2%

20.8 %

0.92 0.87­0.97

0.003

0.97 0.92­1.03

0.34

Vascular  Death

2.4 %

2.3 %

2.7 %

0.90 0.77­1.06

0.21

0.85 0.72­0.99

0.04

Death

3.8 %

3.6 %

4.1 %

0.91 0.80­1.03

0.13

0.88 0.77­1.00

0.05

Myocardial  Infarction

Bleeding and Net Clinical Benefit D  110mg

D  150mg

warfarin

Annual rate

Annual rate

Annual rate

RR 95% CI

p

RR 95% CI

p

Major Bleeding

2.7 %

3.1 %

3.4 %

0.80 0.69­0.93

0.003

0.93 0.81­1.07

0.31

Life­ Threatening  major

1.2 %

1.5 %

1.8 %

0.68 0.55­0.83

<0.001

0.81 0.66­0.99

0.04

Minor Bleeding

13.2 %

14.8 %

16.4%

0.79 0.74­0.84

<0.001

0.91 0.85­0.97

0.005

Total  Bleeding (Major+Minor)

14.6

16.4

18.2

0.78 0.74­0.83

<0.001

0.91 0.86­0.97

0.002

7.1 %

6.9 %

7.6 %

0.92 0.84­1.02

0.10

0.91 0.82­1.00

0.04

Net Clinical  Benefit*

D 110mg vs.  Warfarin

D 150mg vs.  Warfarin

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

Important Sites of Major Bleeding D 110mg

D 150mg

warfarin

Annual rate

Annual rate

Annual rate

Gastro­ intestinal (GI)

1.1 %

1.5 %

Intracranial  (ICH) 

0.2 %

Major Bleed       (non­GI,  non­ICH)

1.5 %

D 110mg vs.  Warfarin

D 150mg vs.  Warfarin

RR 95% CI

p

RR 95% CI

p

1.0 %

1.10 0.86­1.41

0.43

1.50 1.19­1.89

<0.001

0.3 %

0.7 %

0.31 0.20­0.47

<0.001

0.40 0.27­0.60

<0.001

1.5 %

1.8 %

0.85 0.70­1.04

0.11

0.87 0.71­1.06

0.16

Major Bleeding 1.0

1.5

2.0

2.5

D110

6015

5835

5640

4510

2872

1349

D150

6076

5839

5638

4557

2928

1366

W

6022

5801

5600

4474

2797

1269

Warfarin

0.08

0.10

Year 0.5

0.06

Dabigatran150

0.02

0.04

Dabigatran110

0.0

Cumulative Hazard Rates

0.12

# at Risk

0

0.5

1.0

Years

1.5

2.0

2.5

Dabigatran 150 mg vs. 110 mg Dabigatran  110mg

Dabigatran  150mg

Number  rate/yr

Number  rate/yr

Relative Risk 95% CI

p

Stroke and systemic  embolism

1.5%

1.1 %

0.73 0.58­0.91

0.005

Ischemic/unspecified  stroke

1.3 %

0.9 %

0.69 0.54­0.88

0.002

Hemorrhagic stroke

0.1%

0.1 %

0.85 0.39­1.83

0.67

Major Hemorrhage

2.7 %

3.1 %

1.16 1.00­1.34

0.05

GI Major Hemorrhage

1.1 %

1.5 %

1.36 1.09­1.70

0.007

Net Clinical Benefit

7.1 %

6.9 %

0.98 0.89­1.08

0.66

D 150mg vs. D 110 mg

# at Risk D110 6015 D150 6076 W 6022

Year 0.5 5860 5925 5858

1.0 5692 5759 5708

1.5 4601 4675 4592

2.0 2950 3034 2906

2.5 1394 1427 1331

0.02

Warfarin Dabigatran110

0.01

Dabigatran150

0.0

Cumulative Risk

0.03

0.04

ALT or AST >3x ULN

0

0.5

1.0

Years

1.5

2.0

2.5

Common Adverse Events Adverse events occurring in  >5% of any group Dyspepsia * Dyspnea  Dizziness  Peripheral edema  Fatigue  Cough  Chest pain  Arthralgia  Back pain  Nasopharyngitis  Diarrhea  Atrial fibrillation  Urinary tract infection  Upper respiratory tract  infection

Dabigatran  Dabigatran  110 mg 150 mg Warfarin % % % 11.8 11.3 5.8 9.3 9.5 9.7 8.1 8.3 9.4 7.9 7.9 7.8 6.6 6.6 6.2 5.7 5.7 6.0 5.2 6.2 5.9 4.5 5.5 5.7 5.3 5.2 5.6 5.6 5.4 5.6 6.3 6.5 5.7 5.5 5.9 5.8 4.5 4.8 5.6 4.8

*Occurred more commonly on dabigatran p<0.001

4.7

5.2

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