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 [email protected]
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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 150Randomized 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 0.55Systolic 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 <65AGE 65-74AGE 75+
MALEFEMALE
STROKE/SEE/TIANONE
CHADS 0-1CHADS 2CHADS 3+
CCLEAR <50CCLEAR 50-79CCLEAR 80
# PTS12091
202852484815
77054385
26669424
392142243945
4923795655
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 Ratio0.0 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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