RELY Slide Kit version 1.0 - Boehringer Ingelheim

Preventing stroke in Atrial Fibrillation: 

a year after the landmark RE-LY trial 

Jonas Oldgren MD, PhD 

Uppsala Clinical Research Centre 

Uppsala, Sweden 

Dabigatran etexilate is in clinical development and not licensed for 

clinical use in stroke prevention for patients with atrial fibrillation

Dabigatran etexilate: 

a novel direct thrombin inhibitor 

Oral pro-drug, converted to dabigatran, a potent 

reversible direct thrombin inhibitor (DTI) 

Half life of 12-17 h, 

~ 80% renally excreted 

6.5% bioavailability 

Rapid onset of action 

Predictable and consistent anticoagulant effects 

Low potential for drug-drug interactions, 

no drug-food interactions 

No requirement for routine coagulation monitoring 

Potent antithrombotic effects are achieved by specifically blocking 

the activity of thrombin (both free and clot-bound), the central 

enzyme in the process responsible for clot (thrombus) formation 

Stangier J et al British Journal of Clinical Pharmacology 2007 

Sorbera LA et al Dabigatran/Dabigatran Etexilate Drugs of the Future 

2005; 30 (9): 877-885. 

Belch S et al. DMB 2007 



RE-LY ® – largest AF outcomes trial 

RE-LY ® : Randomised Evaluation of Long term 

anticoagulant therapy 

18,113 patients randomised during 2 years 1,2 

50% of enrolled patients are naïve to previous oral AC 

Median treatment duration: 2 years 

951 centres in 44 countries 

Dec 2005 to March 2009 

Results first presented at ESC congress 2009 and 

published online in New England Journal of Medicine 

on Aug. 30th 2009 

1. Ezekowitz MD, et al. Am Heart J 2009;157:805-10. 

2. Connolly SJ., et al. N Engl J Med 2009; 361:1139-1151. 



RE-LY ® – study design 

Warfarin 

1 mg, 3 mg, 5 mg 

(INR 2.0-3.0) 

N=6022 

Atrial fibrillation with ≥ 1 risk factor 

Absence of contraindications 

R 

Dabigatran etexilate 

110 mg bid 

N=6015 

Dabigatran etexilate 

150 mg bid 

N=6076 

� Primary objective: To establish the non-inferiority of dabigatran etexilate to warfarin 

� Minimum 1 year follow-up, maximum of 3 years and mean of 2 years of follow-up 

Ezekowitz MD, et al. Am Heart J 2009;157:805-10. 

Connolly SJ., et al. N Engl J Med 2009; 361:1139-1151. 



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 

32.6 

34.7 

32.7 

2.2 

32.2 

35.2 

32.6 

2.1 

30.9 

37.0 

32.1 

CHF (%) 32.3 31.8 31.9 

Hypertension (%) 78.8 78.9 78.9 

Diabetes (%) 23.4 23.1 23.4 

Prior stroke/TIA (%) 19.9 20.3 19.8 

VKA naïve (%) 50.1 50.2 48.6 




% per year 

Stroke / SSE 

1.8 

1.5 

1.2 

0.9 

0.6 

0.3 

0 

RR 0.90 (95% CI: 0.74–1.10) 

1.54 

p

Cumulative hazard rates 

Time to first stroke / SSE 

0.05 

0.04 

0.03 

0.02 

0.01 

0.0 

Warfarin 

Dabigatran etexilate 110 mg 

Dabigatran etexilate 150 mg 

RR 0.90 

(95% CI: 0.74–1.10) 

p

% per year 

Vascular mortality 

3.00 

2.00 

1.00 

0.00 

RR 0.90 (95% CI: 0.77–1.06) 

p=0.21 (sup) 

2.43 2.28 

RR 0.85 (95% CI: 0.72–0.99) 

p=0.04 (sup) 

D110 mg BID D150 mg BID Warfarin 

289/ 6,015 


RRR 

15% 

2.69 

274 / 6,076 317 / 6,022 



% per year 

Major bleeding rates 

4.00 

3.50 

3.00 

2.50 

2.00 

1.50 


0.50 

0.00 

RR 0.80 (95% CI: 0.70–0.93) 

2.87 

p=0.003 (sup) 


RRR 

20% 

RR 0.93 (95% CI: 0.81–1.07) 

3.32 

p=0.31 (sup) 

3.57 

D110 mg BID D150 mg BID Warfarin 

342 / 6,015 399 / 6,076 421 / 6,022 



Major bleeding and components 

Characteristic 

D 

110 mg 

D 

150 mg Warfarin 

Number of patients (n) 6015 6076 6022 

P-value 

110 vs. W 

P-value 

150 vs. W 

Major bleeding 2.87 3.32 3.57 0.003 0.31 

- Life threatening 

- Non-life threatening 

- Gastrointestinal 

Data represents %/year 


1.24 

1.83 

1.15 

1.49 

2.06 

1.56 

1.85 

1.92 


Intracranial bleeding rates 

Number of events 

90 

80 

70 

60 

50 

40 

30 

20 

10 

0 

RR 0.30 (95% CI: 0.19–0.45) 

27 

0.23% 

p

CHADS 2 subgroup analysis 

� CHADS 2 is a simple, widely accepted risk score 

Congestive heart failure 1 point 

Hypertension 1 point 

Age ≥75 years 1 point 

Diabetes mellitus 1 point 

Stroke and TIA 2 points 

� CHADS 2 >1; oral anticoagulation recommended 

� CHADS 2 = 1; choice between oral anticoagulation 

and aspirin, as bleeding risk with oral 

anticoagulation may outweigh the benefit 

ACC/AHA/ESC 2006 guidelines for atrial fibrillation 



CHADS 2 score – overall event rates 

6 

5 

4 

3 

2 

1 

0 

CHADS 2 

%/year 

No of pts 

6 

5 

4 

3 

2 

1 

0 

CHADS 2 

Stroke and systemic embolism 

5 102 153 139 69 39 8 

0 1 2 3 4 5 6 

452 5323 6455 3654 1619 524 85 

Major bleeding 

15 235 364 263 149 60 8 

0 1 2 3 4 5 6 

Oldgren et al. ACC, Atlanta, March 2010 



Stroke and systemic embolism (SE) 

CHADS2 

0-1 

2 

3-6 

D110 


1.45 

2.12 

Annual rate, % 

D150 

0.65 

0.84 

1.88 

WARFARIN 


1.38 

2.73 


D110 BID vs. warfarin 

P = 0.37 

0.50 1.00 1.50 

Dabigatran 

better 

Warfarin 

better 

D150 BID vs. warfarin 

P = 0.84 

0.50 1.00 1.50 

Dabigatran 

better 

Warfarin 

better 




CHADS2 

0-1 

2 

3-6 

1.86 

2.98 

3.8 


D110 D150 WARFARIN 

2.11 

3.03 

4.85 

2.84 

3.3 

4.6 


D110 BID vs. warfarin D150 BID vs. warfarin 

0.50 1.00 1.50 

Dabigatran 

better 

P = 0.26 P = 0.14 

Warfarin 

better 

0.50 1.00 1.50 

Dabigatran 

better 

Warfarin 

better 



Intracranial bleeding 

CHADS2 

0-1 

2 

3-6 

0.20 

0.22 

0.26 


D110 D150 WARFARIN 

0.20 

0.26 

0.52 

0.54 

0.69 



D110 BID vs. warfarin D150 BID vs. warfarin 

0.50 1.00 1.50 

Dabigatran 

better 

P = 0.7 P = 0.82 

Warfarin 

better 

0.50 1.00 1.50 

Dabigatran 

better 

Warfarin 

better 



Mean Time in Treatment Range (TTR) 

during warfarin treatment by country 



% per year 

Stroke / SSE 

According to center based time in therapeutic range (cTTR) 

2,4 

1,8 

1,2 

0,6 

0 

W D* D † 

110 150 

W D* D † 

110 150 

* Interaction p-value (D 110mg BID vs W.) = 0.90 

† Interaction p-value (D 150mg BID vs W.) = 0.20 

*Interaction p evaluated by a multivariable approach 

with center based TTR as a continuous variable. 

W D* D † 

110 150 

W D* D † 

Q1 Q2 Q3 Q4 

Wallentin L., et al. Lancet Published on-line 29 Aug 2010 

Q1: cTTR < 57.1% Q2: cTTR 57.1-65.5% 

Q3: cTTR 65.5 – 72.6% Q4: cTTR > 72.6% 

110 150 



% per year 

Major Bleeding 


Q1: cTTR < 57.1% Q2: cTTR 57.1-65.5% 

Q3: cTTR 65.5 – 72.6% Q4: cTTR > 72.6% 

4 

3 

2 

1 

0 

W D* D † 

110 150 

W D* D † 

110 150 



W D* D † 

110 150 

W D* D † 

Q1 Q2 Q3 Q4 




110 150 



% per year 

Intracranial bleeding 


1 

0,75 

0,5 

0,25 

0 

W D* D † 

110 150 

W D* D † 

110 150 



W D* D † 

110 150 

W D* D † 

Q1 Q2 Q3 Q4 


Q1: cTTR < 57.1% Q2: cTTR 57.1-65.5% 

Q3: cTTR 65.5 – 72.6% Q4: cTTR > 72.6% 



110 150 



% per year 

Total death 


Q1: cTTR < 57.1% Q2: cTTR 57.1-65.5% 

Q3: cTTR 65.5 – 72.6% Q4: cTTR > 72.6% 

6 

5 

4 

3 

2 

1 

0 

W D* D † 

110 150 

W D* D † 

110 150 



W D* D † 

110 150 

W D* D † 

Q1 Q2 Q3 Q4 




110 150 



Prior stroke subgroup analysis 

Characteristic 

Dabigatran 

110 mg bid 

N=6015 

Prior 

stroke 

n=1195 

No prior 

stroke 

n=4819 

Dabigatran 

150 mg bid 

N=6015 

Prior 

stroke 

n=1233 

No prior 

stroke 

n=4843 

Prior 

stroke 

n=1195 

Warfarin 

n=6022 

No prior 

stroke 

n=4827 

Mean age (years) 70.2 71.7* 70.8 71.7* 70.4 71.9* 

Male (%) 64.1 64.3 62.2 63.5 62.4 63.5 

CHADS2 score 

(mean) 

0-1 (%) 

2 (%) 

3+ (%) 

0 

10.0 

90.0 

40.6* 

40.8* 

18.5* 

0 

9.8 

90.2 

40.4* 

41.6* 

17.9* 

0 

11.4 

88.6 

38.5* 

43.4* 

18.1* 

Diabetes (%) 22.4 23.7 23.7 22.9 21.4 23.9 

Hypertension (%) 77.0 79.2 77.3 79.3 76.2 79.6* 

VKA naïve (%) 43.9 51.4* 44.0 51.3* 45.8 52.7* 

* = P

% per year 

Stroke/SSE in patients with prior stroke or TIA 

3 

2,5 

2 

1,5 

1 

0,5 

0 

RR 0.85 (95% CI: 0.59–1.22) 

2,32 

P=0.37 

RRR 15% 

RR 0.76 (95% CI: 0.53–1.10) 

2,07 

P=0.14 

RRR 24% 

2,74 

D110 mg bid D150 mg bid Warfarin 

55 / 1195 51 / 1233 64 / 1195 

Diener HC et al. ASA International Stroke Conference; February 

2010; San Antonio, TX 



All death 

Prior Stroke/TIA 

Rate(% per year) 

Dabigatran110 vs. Warfarin 

D110 D150 WAR P(INTER) 

3.24 4.39 4.58 

No Prior Stroke/TIA 3.87 3.45 4.02 

0.06 0.5 

Haemorrhagic Stroke 


0.08 0.2 0.77 


0.09 0.97 



2.74 4.14 4.15 


0.15 0.51 

0.50 1.00 1.50 

Dabigatran better Warfarin better 

Diener HC et al. ASA International Stroke Conference; February 

2010; San Antonio, TX 

Dabigatran150 vs. Warfarin 

0.50 1.00 1.50 

Dabigatran better Warfarin better 

P(INTER) 



Conclusions 

For stroke and major bleeding both doses of dabigatran provide 

advantages over warfarin at average TTR of 64 % 

150 mg BID is superior in efficacy with similar major bleeding 

110 mg BID is noninferior in efficacy with less major bleeding 

Both doses provide less intracranial bleeding 

These results were consistent irrespective of CHADS 2 scores, 

centres’ quality of INR control and in patients with prior stroke/TIA 

For secondary outcomes advantages of dabigatran were greater at 

centres with poor INR control than at those with good INR control 

Connolly SJ. et al. N Engl J Med 2009; 361:1139-1151 


Oldgren et al. ACC2010, Diener et al. ASA-ISC2010

RELY Slide Kit version 1.0 - Boehringer Ingelheim

You also want an ePaper? Increase the reach of your titles

Delete template?

Save as template?