The Long Term Multi-Center Extension of Dabigatran Treatment in Patients with Atrial Fibrillation (RELY-ABLE) study

To reviewers and moderators: These are preliminary slides. The figures are going to

be upgraded this week and I can send these to you if you email me at connostu@phri.ca

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RE-LY: Results with Dabigatran Etexilate

• Dabigatran (DE) 150 mg BID and 110 mg BID versus warfarin

• An 18,113 Patient Global Clinical Trial Mean follow up 2 years

• DE 150 reduced stroke/SEE by 35% versus warfarin• DE 110 non-inferior to warfarin, with 20% reduction in

major bleeding• Greater than 50% reduction in intracranial bleeding with

both doses compared to warfarin• Regulatory approval in 79 countries as of November

2012

Reference

RELY-ABLE Design

• Descriptive study to assess long-term efficacy and safety of two doses of DE

• 28 months of additional treatment with DE following RE-LY

• Patients eligible if completed RE-LY– Alive and on study medication

• DE blinded dose continued in RELY-ABLE• No event adjudication• Follow up stopped if study medication

discontinued

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Data Analysis

Primary analysis• RELY-ABLE patients during RELY-ABLE period

of follow up

Secondary Analyses• RELY-ABLE patients followed from beginning of

RE-LY to end of RELY-ABLE

• All dabigatran patients, from beginning of RE-LY to the end of RELY-ABLE

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Patient Flow: RE-LY and RELY-ABLE

  DE 110 DE 150

Randomized to dabigatran in RE-LY 6015 6076

Completed RE-LY alive, on Dabigatran 4492 (74.7%) 4519 (74.4%)

Followed at site participating in RELY-ABLE 3395 (75.6%) 3397 (75.2%)

Patient enrolled in RELY-ABLE 2914 (85.8%) 2937 (86.5%)

Completed RELY-ABLE still receiving study medication

2511 (86.2%) 2508 (85.4%)

Continued in RELY-ABLE beyond the 28 month visit

1082 (43.5%) 1104 (44.0%)

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RE-LY Baseline Characteristics: Patients in enrolling or not enrolling in RELY-ABLE

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RE-LY Patients Not Enrolled in RELY-ABLE

RE-LY Patients Enrolled in RELY-ABLE

p-values

110 mg(N=3101)

150 mg(N=3139)

110 mg(N=2914)

150 mg(N=2397)

Enrolled vs. not

enrolled

110 vs 150 mg

Age (years); mean, (SD) 72 (9) 72 (9) 71 (8) 71 (8) 0.001 0.55

Systolic BP-sitting (mmHg); mean, (SD)

131 (18) 131 (18) 131 (18) 131 (18) 0.20 0.46

Male; number (%) 1951 (63) 1929 (62) 1914 (66) 1911 (65) 0.03 0.64

AF diagnosed > 2yrs; number (%) 1463 (47) 1503 (48) 1380 (47) 1373 (47) 0.89 0.47

Permanent AF; number (%) 1177 (38) 1222 (39) 955 (33) 966 (33) <0.001 0.64

Prior stroke or TIA; number (%) 614 (20) 611 (20) 581 (20) 622 (21) 0.89 0.28

VKA Experienced; number (%) 1475 (48) 1524 (49) 1536 (53) 1525 (52) <0.001 0.33

History of Hypertension; number (%) 2417 (78) 2505 (80) 2321 (80) 2290 (78) 0.11 0.02

History of MI; number (%) 542 (18) 551 (18) 466 (16) 478 (16) 0.12 0.87

History of heart failure; number (%) 1147 (37) 1121 (36) 790 (27) 813 (28) <0.001 0.29

CHADS2 risk score; mean, (SD) 2 (1) 2 (1) 2 (1) 2 (1) <0.001 0.32

Baseline beta blocker; number (%) 1853 (60) 1892 (60) 1931 (66) 1980 (67) <0.001 0.68

Baseline ARB or ACE I; number (%) 2043 (66) 2118 (68) 1944 (67) 1935 (66) 0.52 0.16

Event Rates during RE-LY: Enrolled versus not enrolled patients

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RE-LY Patients Not in RELY-ABLE

RE-LY Patients in RELY-ABLE

p-values

110 mg(N=3101)

event number (rate/year)

150 mg(N=3139)

event number

(rate/year)

110 mg(N=2914)

event number

(rate/year)

150 mg(N=2397)

event number (rate/year)

Enrolled vs. not

enrolled

110 vs

150

Major bleed 251 (4) 309 (5) 91 (1) 91 (1) <0.001 0.21

Stroke 140 (2) 106 (2) 31 (1) 17(0) <0.001 0.33

Myocardial infarction

60 (1) 67 (1) 28 (0) 22 (0) <0.001 0.30

Ischemic Events: RELY-ABLE patients in RELY-ABLE follow up period

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 Event

150 mg

(%/yr)

110 mg

(%/yr)

HR 95% CI

Stroke or SEE 1.46 1.60 0.91 0.69-1.20

All Stroke 1.24 1.38 0.89 0.66-1.21

Ischemic 1.15 1.24 0.92 0.67-1.27

Hemorrhagic 0.13 0.14 0.89 0.34-2.30

Myocardial infarction 0.69) 0.72 0.96 0.63-1.45

Pulmonary embolism 0.13 0.11 1.14 0.41-3.15

Stroke or SEE

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RELY-ABLE Patients in RELY-ABLE Period

Ischemic Events: RE-LY + RELY-ABLE Periods

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 Event

Only RELY-ABLE Patients All Dabigatran patients

150 mg

(%/yr)

110 mg

(%/yr)

HR 95% CI

150 mg

(%/yr)

110 mg

(%/yr)

HR 95% CI

Stroke or SEE 0.89 1.05 0.84 0.65-1.09 1.25 1.54 0.81 0.68-0.96

All Stroke 0.76 0.93 0.81 0.62-1.08 1.11 1.40 0.79 0.65-0.95

Ischemic 0.71 0.86 0.82 0.62-1.09 1.01 1.29 0.78 0.65-0.95

Hemorrhagic 0.06 0.07 0.88 0.34-2.29 0.11 0.13 0.91 0.50-1.64

Myocardial infarction

0.51 0.57 0.90 0.64-1.26 0.71 0.72 0.98 0.77-1.25

Pulmonary embolism

0.07 0.06 1.12 0.43-2.89 0.14 0.11 1.23 0.69-2.18

Stroke or Systemic Embolism: RE-LY + RELY-ABLE periods

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RELY-ABLE Only All Dabigatran

Bleeding: RELY-ABLE patients in RELY-ABLE follow up period

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Event

RELY-ABLE Only150 mg

(%/yr)110 mg

(%/yr)HR 95% CI

Major Bleeding 3.74 2.99 1.26 1.04-1.53

Life-threatening 1.79 1.57 1.14 0.87-1.49

GI 1.54 1.56 0.99 0.75-1.31

Intra-cranial 0.33 0.25 1.31 0.68-2.51

Extra-cranial 3.43 2.82 1.23 1.01-1.49

Fatal 0.24 0.25 0.94 0.46-1.89

Minor Bleeding 9.70 8.19 1.21 1.07-1.36

RELY-ABLE Period Only

Major Bleeding

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RELY-ABLE Patients in RELY-ABLE Period

Bleeding: RE-LY + RELY-ABLE Periods

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Event

RELY-ABLE Only patients All Dabigatran patients

110 mg (%/yr)

150 mg (%/y

r)

HR 95% CI110 mg

(%/yr)

150 mg

(%/yr)HR 95% CI

Major Bleeding 2.13 2.50 1.18 1.00-1.38 2.83 3.38 1.20 1.07-1.35

Life-threatening

1.01 1.10 1.08 0.85-1.36 1.36 1.58 1.16 0.98-1.38

GI 0.99 0.98 1.00 0.78-1.28 1.29 1.52 1.18 1.00-1.41

Intra-cranial 0.16 0.18 1.09 0.60-2.00 0.22 0.33 1.45 0.98-2.16

Extra-cranial 2.02 2.33 1.16 0.0.98-1.37 2.65 3.08 1.17 1.04-1.32

Fatal 0.25 0.24 0.94 0.46-1.89 0.13 0.16 1.25 0.72-2.16

Major Bleeding:

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RELY-ABLE Only All Dabigatran

Net Benefit: RELY-ABLE

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EventRELY-ABLE

110 mg (%/yr)

150 mg (%/yr)

HR 95% CI

Total mortality3.10 3.02 0.97 0.80-1.19

Vascular mortality1.62 1.67 1.03 0.78-1.35

Disabling stroke, life-threatening bleed or death

4.45 4.53 1.02 0.86-1.20

Stroke, systemic embolism, myocardial infarction, pulmonary embolism, major bleed or death

6.89 7.36 1.07 0.94-1.22

Total Mortality

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Net Benefit: RE-LY + RELY-ABLE Periods

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Event

RELY-ABLE patients only All dabigatran patients

110 mg

(%/yr)

150 mg

(%/yr)HR 95% CI

110 mg

(%/yr)

150 mg

(%/yr)HR 95% CI

Total mortality1.58 1.54 0.97 0.80-1.18 3.54 3.46 0.98 0.88-1.09

Vascular mortalityo.83 0.85 1.03 0.78-1.35 2.14 2.09 0.97 0.85-1.12

Disabling stroke, life-threatening bleed or death

4.45 4.53 1.02 0.86-1.20 4.83 4.69 0.97 0.88-1.07

Stroke, systemic embolism, myocardial infarction, pulmonary embolism, major bleed or death

6.89 7.36 1.07 0.94-1.22 1.54 0. 1.01 0.94-1.10

Total Mortality: RE-LY + RELY-ABLE Periods

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All Dabigatran patients

0.0 0.5 1.00 1.5 2.0

OVERALL

AGE <65

AGE 65-74

AGE 75+

MALE

FEMALE

STROKE/SEE/TIANONE

CHADS 0-1

CHADS 2

CHADS 3+

CCLEAR <50

CCLEAR 50-79

CCLEAR 80

# PTS

12091

2028

5248

4815

7705

4385

2666

9424

3921

4224

3945

49

2379

5655

P(INTER)

0.60

0.14

0.86

0.36

0.64

Stoke or Systemic embolism150mg better 110mg better

0.0 0.5 1.00 1.5 2.0

P(INTER)

0.95

0.76

0.02

0.44

0.42

Major Bleeding150mg better 110mg better

Hazard Ratio Hazard Ratio

0.0 0.5 1.00 1.5 2.0

P(INTER)

0.31

0.39

0.04

0.03

0.63

Total Mortality150mg better 110mg better

Hazard Ratio

Sub-groups: RE-LY + RELY-ABLE

Conclusions

• During 2.3 years of treatment on dabigatran, after RE-LY, rates of stroke and major bleeding remain low on dabigatran

• Including all dabigatran follow up, there is a dose response effect– With dabigatran 150 mg compared to 110 mg

• 22% reduction in ischemic stroke• 20% increase in major bleeding• Very similar mortality

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