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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%

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the re ly study randomized evaluation of long term anticoagulant therapy

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
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
  • 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 trial
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

Dabigatran Etexilate

150 mg b.i.d.

N=6000

Warfarin

(INR 2.0-3.0)

N=6000

Dabigatran Etexilate

110 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
Trial Execution
  • Performed December 2005-March 2009
  • Median Follow up 2.0 years
  • Follow up 99.9% complete
  • Mean TTR = 64% (patients on warfarin)
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

Dabigatran150

Stopping Rates

Dabigatran110

0.2

Warfarin

0.1

0.0

0

0.5

1.0

1.5

2.0

2.5

Years of Follow-up

Permanent Discontinuation
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)

Stroke or Systemic Embolism
primary outcome
Primary Outcome

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

stroke or systemic embolism11

No. at Risk

0.05

W

6022

5862

4593

2890

1322

5718

D110

6015

5862

5710

4593

2945

1385

D150

5939

5779

4682

3044

1429

6076

0.04

0.03

Cumulative Hazard Rates

Dabigatran110

0.02

Warfarin

Dabigatran 150

0.01

0.0

0

0.5

1.0

1.5

2.0

2.5

Years

Stroke or Systemic Embolism
bleeding and net clinical benefit
Bleeding and Net Clinical Benefit

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

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

Warfarin

0.08

Dabigatran150

Cumulative Hazard Rates

0.06

Dabigatran110

0.04

0.02

0.0

0

0.5

1.0

1.5

2.0

2.5

Years

Major Bleeding
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

Warfarin

Cumulative Risk

0.02

Dabigatran110

Dabigatran150

0.01

0.0

0

0.5

1.0

1.5

2.0

2.5

Years

ALT or AST >3x ULN
common adverse events
Common Adverse Events

*Occurred more commonly on dabigatran p<0.001

conclusions
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
conclusions20
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