A Randomized Trial of Dabigatran, a Oral Direct Thrombin Inhibitor, Compared to Warfarin in 18,113...
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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%– 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 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 TrialAtrial fibrillation
≥1 Risk FactorAbsence of contra-
indications951 centers in 44 countries
R
Warfarin (INR 2.0-3.0)
N=6000
Dabigatran Etexilate
110 mg b.i.d.N=6000
Dabigatran Etexilate
150 mg b.i.d.N=6000
PROBE=Prospective Randomized Open Trial with Blinded Adjudication of Events.
10 efficacy outcome = stroke or systemic embolism10 safety outcome = major bleedingNon-inferiority margin 1.46
open Blinded
Trial Execution
Performed December 2005-March 2009
Median Follow up 2.0 years
Follow up 99.9% complete
Mean TTR = 64% (patients on warfarin)
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
32.634.732.7
2.2
32.235.232.6
2.1
30.937.032.1
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
Permanent Discontinuation
Years of Follow-up
Sto
pp
ing
Ra
tes
0.0
0.1
0.2
0.3
0.4
0 0.5 1.0 1.5 2.0 2.5
Dabigatran110
Dabigatran150
Warfarin
D110D150W
# at Risk Year 0.5 1.0 1.5 2.0 2.56015 5336 5026 3950 2491 11766076 5329 5015 3955 2528 11726022 5563 5269 4158 2561 1187
Stroke or Systemic Embolism
0.50 0.75 1.00 1.25 1.50
Dabigatran 110 vs. Warfarin
Dabigatran 150 vs. Warfarin
Non-inferiorityp-value
<0.001
<0.001
Superiorityp-value
0.34
<0.001
Margin = 1.46
HR (95% CI)
Primary Outcome
D 110mg D 150mg warfarinD 110mg vs.
WarfarinD 150mg vs.
Warfarin
Number Number
rate/yrrate/yr
Number Number
rate/yrrate/yr
Number Number
rate/yrrate/yr
RRRR
95% CI95% CIP*P*
RRRR
95% CI95% CIP*P*
Stroke or systemic Embolism
182
1.5 %/yr
134
1.1 %/yr
199
1.7 %/yr
0.91
0.74-1.110.34
0.66
0.53-0.82<0.001
Stroke171
1.4 %/yr
122
1.0 %/yr
185
1.6 %/yr
0.92
0.74-1.130.41
0.64
0.51-0.81<0.001
Systemic Embolism
14
0.1 %/yr
13
0.1 %/yr
19
0.2 %/yr
0.73
0.37-1.460.38
0.67
0.33-1.360.27
* These, and all subsequent, p values, are for superiority
Stroke Classification
D 110mg D 150mg warfarinD 110 mg vs.
WarfarinD 150 mg vs.
Warfarin
Number Number
rate/yrrate/yr
Number Number
rate/yrrate/yr
Number Number
rate/yrrate/yr
RRRR
95% CI95% CIpp
RRRR
95% CI95% CIpp
Ischemic/ Unspecified
159
1.3 %/yr
111
0.9 %/yr
142
1.2 %/yr
1.11
0.89-1.400.35
0.76
0.60-0.980.03
Hemorrhagic14
0.1 %/yr
12
0.1 %/yr
45
0.4 %/yr
0.31
0.17-0.56<0.001
0.26
0.14-0.49<0.001
Stroke or Systemic Embolism
Cu
mu
lati
ve H
azar
d R
ates
0.0
0.01
0.02
0.03
0.04
0.05
0 0.5 1.0 1.5 2.0 2.5
Dabigatran110
Dabigatran 150
Warfarin
6022 5862 5718 4593 2890 1322
6015 5862 5710 4593 2945 1385
6076 5939 5779 4682 3044 1429
No. at Risk
W
D110
D150
Years
MI, Hospitalization and Death
D 110mg D 150mg warfarinD 110mg vs.
WarfarinD 150mg vs.
Warfarin
AnnualAnnual
raterate
AnnualAnnual
raterate
AnnualAnnual
raterate
RRRR
95% CI95% CIpp
RRRR
95% CI95% CIpp
Myocardial Infarction
0.7% 0.7 % 0.5 %1.35
0.98-1.870.07
1.38
1.00-1.910.048
Hospitalization 19.4 % 20.2% 20.8 %0.92
0.87-0.970.003
0.97
0.92-1.030.34
Vascular Death
2.4 % 2.3 % 2.7 %0.90
0.77-1.060.21
0.85
0.72-0.990.04
Death 3.8 % 3.6 % 4.1 %0.91
0.80-1.030.13
0.88
0.77-1.000.05
Bleeding and Net Clinical Benefit
D
110mg
D
150mgwarfarin
D 110mg vs. Warfarin
D 150mg vs. Warfarin
AnnualAnnual
raterate
AnnualAnnual
raterate
AnnualAnnual
raterate
RRRR
95% CI95% CIpp
RRRR
95% CI95% CIpp
Major Bleeding 2.7 % 3.1 % 3.4 %0.80
0.69-0.930.003
0.93
0.81-1.070.31
Life-Threatening major
1.2 % 1.5 % 1.8 %0.68
0.55-0.83<0.001
0.81
0.66-0.990.04
Minor Bleeding 13.2 % 14.8 % 16.4%0.79
0.74-0.84<0.001
0.91
0.85-0.970.005
Total Bleeding
(Major+Minor)14.6 16.4 18.2
0.78
0.74-0.83<0.001
0.91
0.86-0.970.002
Net Clinical Benefit*
7.1 % 6.9 % 7.6 %0.92
0.84-1.020.10
0.91
0.82-1.000.04
* stroke, systemic embolism, myocardial infarction, pulmonary embolism, death and major bleed
Important Sites of Major Bleeding
D 110mg D 150mg warfarinD 110mg vs.
WarfarinD 150mg vs.
Warfarin
AnnualAnnual
raterate
AnnualAnnual
raterate
AnnualAnnual
raterate
RRRR
95% CI95% CIpp
RRRR
95% CI95% CIpp
Gastro-intestinal
(GI)1.1 % 1.5 % 1.0 %
1.10
0.86-1.410.43
1.50
1.19-1.89<0.001
Intracranial
(ICH) 0.2 % 0.3 % 0.7 %
0.31
0.20-0.47<0.001
0.40
0.27-0.60<0.001
Major Bleed (non-GI,
non-ICH)1.5 % 1.5 % 1.8 %
0.85
0.70-1.040.11
0.87
0.71-1.060.16
Major Bleeding
Years
Cum
ula
tive
Haz
ard
Ra
tes
0.0
0.02
0.04
0.06
0.08
0.10
0.12
0 0.5 1.0 1.5 2.0 2.5
Dabigatran110
Dabigatran150
Warfarin
# at Risk Year 0.5 1.0 1.5 2.0 2.5
D110
D150
W
6015 5835 5640 4510 2872 1349
6076 5839 5638 4557 2928 1366
6022 5801 5600 4474 2797 1269
Dabigatran 150 mg vs. 110 mg
Dabigatran 110mg
Dabigatran 150mg
D 150mg vs. D 110 mg
Number Number
rate/yrrate/yr
Number Number
rate/yrrate/yr
Relative RiskRelative Risk
95% CI95% CIpp
Stroke and systemic embolism
1.5% 1.1 %0.73
0.58-0.910.005
Ischemic/unspecified stroke
1.3 % 0.9 %0.69
0.54-0.880.002
Hemorrhagic stroke 0.1% 0.1 %0.85
0.39-1.830.67
Major Hemorrhage 2.7 % 3.1 %1.16
1.00-1.340.05
GI Major Hemorrhage 1.1 % 1.5 %1.36
1.09-1.700.007
Net Clinical Benefit 7.1 % 6.9 %0.98
0.89-1.080.66
ALT or AST >3x ULN
Years
Cum
ula
tive
Ris
k
0.0
0.01
0.02
0.03
0.04
0 0.5 1.0 1.5 2.0 2.5
Dabigatran110
Dabigatran150
Warfarin
# at RiskYear 0.5 1.0 1.5 2.0 2.5
D110D150W
6015 5860 5692 4601 2950 13946076 5925 5759 4675 3034 14276022 5858 5708 4592 2906 1331
Adverse events occurring in >5% of any group
Dabigatran 110 mg
%%
Dabigatran 150 mg
%%
Warfarin
%%
Dyspepsia * 11.8 11.3 5.8Dyspnea 9.3 9.5 9.7Dizziness 8.1 8.3 9.4Peripheral edema 7.9 7.9 7.8Fatigue 6.6 6.6 6.2Cough 5.7 5.7 6.0Chest pain 5.2 6.2 5.9Arthralgia 4.5 5.5 5.7Back pain 5.3 5.2 5.6Nasopharyngitis 5.6 5.4 5.6Diarrhea 6.3 6.5 5.7Atrial fibrillation 5.5 5.9 5.8Urinary tract infection 4.5 4.8 5.6Upper respiratory tract infection
4.8 4.7 5.2
Common Adverse Events
*Occurred more commonly on dabigatran p<0.001
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
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