A comparison of the RE-LY and Rocket AF Trials: Difference between revisions

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*Both had non-inferiority to warfarin as primary endpoint
*Both had non-inferiority to warfarin as primary endpoint
*Rocket AF required 2 risk factors for entry, RE-LY 1 risk factor
*Rocket AF required 2 risk factors for entry, RE-LY 1 risk factor
*Rocket AF capped CHADS2 = 2 early in the trial unless a patient scored two points by having a prior stroke/TIA. This may account for the high rate of prior stroke in Rocket AF
*Both randomized trials
*Both randomized trials
*Rocket AF administered warfarin in a blinded fashion, RE-LY did not
*Rocket AF administered warfarin in a blinded fashion, RE-LY did not
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*INR target range 2-3 in both
*INR target range 2-3 in both


===Statistical Methods===
===Comparison of Study Designs in Other Trials===
{| class="wikitable" border="1"
|+ Comparison of Study Designs in Other Trials
! Trial !! Inclusion !! Design !! Start Date !! Duration (mo) !! Current / Goal Enrollment !! # sites
|-
| ROCKET AF || CHADS ≥ 3 or stroke/TIA (15% CHADS 2) || Sham INR || 12/2006 || 15 || 14,264 || ~1200
|-
| ARISTOTLE || CHADS ≥ 1 (50% VKA naïve) || Sham INR ||1/2007 || 15 || ~15,000 || ~937
|-
| RE-LY || CHADS ≥ 1 (30% VKA naïve) ||Open label || 12/2005 ||26 ||18,113 ||706
|-
| AMADEUS || CHADS ≥ 1 || Open label || 9/2003 || 23 || 4,576 || 165
|-
|SPORTIF V || CHADS ≥ 1 || Sham INR || 8/2000 || 17 || 3,922 || 409
|-
|ENGAGE || CHADS ≥ 2 || Sham INR || 10/2008 || 24 || 20,500 || ~1,400
|}
 
 
===Statistical Methods: Efficacy===
'''RELY:'''
'''RELY:'''
Primary Efficacy Evaluation: Stroke or non-CNS Embolism
Primary Efficacy Evaluation: Stroke or non-CNS Embolism
Line 29: Line 49:
''Non-Inferiority:''  Protocol Compliant  on treatment
''Non-Inferiority:''  Protocol Compliant  on treatment


''Superiority:''  On Treatment and then by Intention-to-Treat
''Superiority:''  On Treatment, then by Intention-to-Treat
 
RE-LY used ''Intention-to-Treat'' for both non-inferiority and superiority testing; Rocket AF used ''on treatment analysis'' for first tests of non-inferiority and superiority.
 
===Statistical Methods: Safety===
'''RELY:'''


===Trial Execution===
''Primary Safety Evaluation:'' Major Bleeding


{| class="wikitable" border="1"
'''Rocket AF:'''
|+ Trial Design
!  !! Re-LY !! Rocket AF
|-
| Countries || 44 || 45
|-
| Patients || 18,113 || 14,264
|-
| Median Duration of Follow-Up || 2 years (about 730 days) || 589 days of exposure, 707 days with follow-up
|-
| Time in Therapeutic Range (TTR) || 64% || 57.8%
|}


===Statistical Methods===
''Primary Safety Evaluation:'' Major or non-Major Clinically Relevant Bleeding
'''RELY:''' Primary Safety Evaluation: Major Bleeding


'''Rocket AF:''' Primary Safety Evaluation: Major or non-Major Clinically Relevant Bleeding
===RE-LY Definitions of Stroke===
*Stroke was defined as the sudden onset of a focal neurologic deficit in a location consistent with the territory of a major cerebral artery and categorized as ischemic, hemorrhagic, or unspecified.
*Hemorrhagic transformation of ischemic stroke was not considered to be hemorrhagic stroke.
*Intracranial hemorrhage consisted of hemorrhagic stroke and subdural or subarachnoid hemorrhage.
*Systemic embolism was defined as an acute vascular occlusion of an extremity or organ, documented by means of imaging, surgery, or autopsy.


===Rates of Drug Discontinuation===
===Rocket AF Definitions of Stroke===
====The primary efficacy outcome is the composite of stroke====
*Stroke is defined as a new, sudden, focal neurological deficit resulting from a presumed cerebrovascular cause that is not reversible within 24 hours and not due to a readily identifiable cause such as a tumor or seizure
*All strokes will be classified as primary ischemic or primary hemorrhagic


{| class="wikitable" border="1"
====And non-CNS systemic embolism====
|+ Rates of Drug Discontinuation
*Non-CNS systemic embolism is defined as abrupt vascular insufficiency associated with clinical or radiological evidence of arterial occlusion in the absence of other likely mechanisms, (e.g., trauma, atherosclerosis, instrumentation)
!  RE-LY !!
|-
|1 Year:
|-
| Dabigatran 110 mg: || 14.5%
|-
| Dabigatran 150 mg: || 15.5%
|-
| Warfarin: || 10.2%
|-
|2 Years:
|-
| Dabigatran 110 mg: || 20.7%
|-
| Dabigatran 150 mg: || 21.2%
|-
| Warfarin: || 16.6%
|-
|-
| 
|             
|-
! Rocket AF !!
|-
| Rivaroxaban: || 23.9%
|-
| Warfarin: || 22.4%
|-
|}


===RE-LY: Baseline Characteristics===
===RE-LY: Baseline Characteristics===
Line 174: Line 165:
*About half of RE-LY patients were warfarin naïve, whereas 37.5% of Rocket AF patients were warfarin naïve
*About half of RE-LY patients were warfarin naïve, whereas 37.5% of Rocket AF patients were warfarin naïve


===Impact of Enrolling Higher CHADs Score Patients===
Higher CHADs Scores are associated with:
1. Higher rates of major bleeding
2. Lower TTRs
===Trial Execution===
{| class="wikitable" border="1"
|+ Comparison of Trial Metrics
!  !! RE-LY !! Rocket AF
|-
| Countries || 44 || 45
|-
| Patients || 18,113 || 14,264
|-
| Median Duration of Follow-Up || 2 years (about 730 days) || 589 days of exposure, 707 days including period off drug during follow-up
|-
| Time in Therapeutic Range (TTR) || 64% || 57.8%
|-
|    || 67% warfarin-experienced ||
|-
|    || 61% warfarin-naïve
|}
===Rates of Drug Discontinuation===
{| class="wikitable" border="1"
|+ Rates of Drug Discontinuation
!  RE-LY !!
|-
|1 Year:
|-
| Dabigatran 110 mg: || 14.5%
|-
| Dabigatran 150 mg: || 15.5%
|-
| Warfarin: || 10.2%
|-
|2 Years:
|-
| Dabigatran 110 mg: || 20.7%
|-
| Dabigatran 150 mg: || 21.2%
|-
| Warfarin: || 16.6%
|-
|-
| 
|             
|-
! Rocket AF !!
|-
| Rivaroxaban: || 23.9%
|-
| Warfarin: || 22.4%
|-
|}


===Primary Endpoint of Stroke or Systemic Embolism===
===Primary Endpoint of Stroke or Systemic Embolism===
{| class="wikitable" border="1"
{| class="wikitable" border="1"
|+ Primary Endpoint of Stroke or Systemic Embolism
|+ Primary Endpoint of Stroke or Systemic Embolism: Non-inferiority Analysis
! Rely !!  !!
!   !!  !! Non-Inferiority p vs warfarin
|-
|-
|Dabigatran 110 mg || 1.53% per year || p=0.34
|'''RE-LY''' ||    ||ITT Analysis
|-
|Dabigatran 110 mg || 1.53% per year || p<0.001
|-
|-
|Dabigatran 150 mg || 1.11% per year || p<0.001
|Dabigatran 150 mg || 1.11% per year || p<0.001
Line 190: Line 243:
|
|
|-
|-
! Rocket AF !!  !!
! '''Rocket AF''' !!  !! Per Protocol Analysis
|-
|-
|Rivaroxaban 20 mg || 2.12% per year || p=0.117
|Rivaroxaban 20 mg || 2.12% per year || p<0.001
|-
|-
|Warfarin ||2.42% ||   
|Warfarin ||2.42% ||   
|}
No ITT analysis is available for non-inferiority in Rocket AF.  An on treatment or per-protocol analysis is generally performed in the assessment of non-inferiority.  If numerous patients come off of study drug, this biases the trial towards a non-inferior result in an ITT analysis. This is the basis for performing a per-protocol analysis in a non-inferiority assessment.
===Primary Endpoint of Stroke or Systemic Embolism===
{| class="wikitable" border="1"
|+ Primary Endpoint of Stroke or Systemic Embolism: Superiority Analysis
!  !!  !! Superiority p vs warfarin, ITT Analysis
|-
|'''RE-LY''' ||    ||
|-
|Dabigatran 110 mg || 1.53% per year || p=0.34
|-
|Dabigatran 150 mg || 1.11% per year || p<0.001
|-
|Warfarin || 1.69% per year ||
|-
|
|
|
|-
! '''Rocket AF''' !!  !!
|-
|-
|Rivaroxaban 20 mg || 2.12% per year || p=0.117*
|-
|Warfarin ||2.42% per year || 
|}
|}


* In an on-treatment analysis in Rocket AF Stoke or SE rates were 1.70% / yr for rivaroxaban and 2.15% / yr for warfarin, p=0.015. No on-treatment analysis is available from RE-LY.


===Hemorrhagic Stroke===
===Hemorrhagic Stroke===
{| class="wikitable" border="1"
{| class="wikitable" border="1"
|+ Hemorrhagic Stroke
|+ Hemorrhagic Stroke
! Rely !!  !! HR !! p-value
! '''Rely''' !!  !! HR !! ITT p-value
|-
|-
|Dabigatran 110 mg || 0.12% / yr ||0.31 || <0.001
|Dabigatran 110 mg || 0.12% / yr ||0.31 || <0.001
Line 214: Line 293:
|
|
|-
|-
! Rocket AF !!  !!
! '''Rocket AF''' !!  !!
|-
|-
|Rivaroxaban 20 mg || 0.26 / year || 0.59 || 0.024
|Rivaroxaban 20 mg || 0.26% / year || 0.59 || 0.012*
|-
|-
|Warfarin || 0.44 / yr ||  ||  
|Warfarin || 0.44% / yr ||  ||  
|-
|-
|}
|}
* In an on-treatment analysis in Rocket AF Hemorrhagic Stoke rates were 0.26% / yr for rivaroxaban and 0.44% / yr for warfarin, p=0.024. No on-treatment analysis is available from RE-LY




===Ischemic Stroke===
===Ischemic Stroke===
{| class="wikitable" border="1"
{| class="wikitable" border="1"
|+ Hemorrhagic Stroke
|+ Ischemic Stroke
! Rely !!  !! HR !! p-value
! '''Rely''' !!  !! HR !! ITT p-value
|-
|-
|Dabigatran 110 mg || 1.34% / yr || 1.20 || 0.35
|Dabigatran 110 mg || 1.34% / yr || 1.20 || 0.35
Line 238: Line 319:
|
|
|-
|-
! Rocket AF !!  !!
! '''Rocket AF''' !!  !!
|-
|-
|Rivaroxaban 20 mg || 1.34 / year || 0.94 || 0.58
|Rivaroxaban 20 mg || 1.62% / year || 0.99 || 0.92*
|-
|-
|Warfarin || 1.42 / yr ||  ||  
|Warfarin || 1.64% / yr ||  ||  
|-
|-
|}
|}


* In an on-treatment analysis in Rocket AF Ischemic Stoke rates were 1.34% / yr for rivaroxaban and 1.42% / yr for warfarin, p=0.58. No-on treatment analysis is available from RE-LY.


===Stroke Conclusions===
===Myocardial Infarction===
*Both Dabigatran and Rivaroxaban reduced hemorrhagic stroke
{| class="wikitable" border="1"
|+ Myocardial Infarction
! '''Rely''' !!  !! HR !! ITT p-value
|-
|Dabigatran 110 mg || 0.72% / yr || 1.35 || 0.07
|-
|Dabigatran 150 mg || 0.74% / yr || 1.38 || 0.048
|-
|Warfarin || 0.53% / yr ||  ||
|-
|
|
|
|-
! '''Rocket AF''' !!  !!
|-
|Rivaroxaban 20 mg || 1.02% / year || 0.91 || 0.46*
|-
|Warfarin || 1.11% / yr ||  ||
|-
|}


*The reduction in hemorrhagic stroke was relatively greater (numerically) for Dabigatran
===Major Bleeding===
{| class="wikitable" border="1"
|+ Major Bleeding
! '''Rely''' !!  !! HR !! ITT p-value
|-
|Dabigatran 110 mg || 2.71% / yr || 0.8 || 0.0003
|-
|Dabigatran 150 mg || 3.11% / yr || 0.93 || 0.31
|-
|Warfarin || 3.36% / year ||  ||
|-
|
|
|
|-
! '''Rocket AF''' !!  !!
|-
|Rivaroxaban 20 mg || 3.60% / year || 0.92 || 0.58*
|-
|Warfarin || 3.45% / yr ||  ||
|-
|}


*Both drugs were therefore safer
* There is no ITT analysis of safety in Rocket AF. There is no on treatment analysis of safety from RE-LY.


*Only Dabigatran, however, was associated with a reduction in ischemic stroke. Rivaroxaban was not.
===All Cause Mortality===
{| class="wikitable" border="1"
|+ All Cause Mortality
! '''Rely''' !!  !! HR !! ITT p-value
|-
|Dabigatran 110 mg || 3.75% / yr || 0.88 || 0.35
|-
|Dabigatran 150 mg || 3.64% / yr || 0.91 || 0.051
|-
|Warfarin || 4.13% / year ||  ||
|-
|
|
|
|-
! '''Rocket AF''' !!  !!
|-
|Rivaroxaban 20 mg || 4.52% / year || 0.92 || 0.152*
|-
|Warfarin || 4.91% / yr ||  ||
|-
|}
 
* In an on treatment analysis in Rocket AF mortality rates were 1.87% / yr for rivaroxaban and 2.21% / yr for warfarin, p=0.073. No on treatment analysis is available from RE-LY.
 
===Conclusions: RE-LY vs Rocket AF Regarding Primary Endpoint of Stroke and/or Systemic Embolization
 
====Primary Analysis of Non-Inferiority:====
Both drugs were non-inferior to warfarin in reducing the primary endpoint of stroke and systemic embolism
 
====Secondary Analysis of Superiority:====
In a pre-specified secondary on-treatment analysis, rivaroxaban was superior to warfarin. No on-treatment analysis is available for dabigatran versus warfarin.


In an intent-to-treat analysis, 150 mg of dabigatran was superior to warfarin while rivaroxaban was not.


===Conclusions: RE-LY vs Rocket AF===
===Conclusions: RE-LY vs Rocket AF===
*Both drugs were non-inferior to Warfarin in reducing stroke and systemic embolism


*In an Intent-to-Treat analysis, 150 mg of dabigatran was superior to warfarin while rivaroxaban was not
====Regarding Stroke====
*Dabigatran 150 mg reduced the risk of hemorrhagic stroke (HR 0.26, p<0.001) as did rivaroxaban (HR 0.59, p=0.024).
 
*Both drugs were therefore safer.
 
*Dabigatran 150 mg also reduced the risk of ischemic stroke (HR=0.76, p=0.03) while rivaroxaban did not (p=0.58)(dabigatran was associated with thrombotic efficacy)
 
====Regarding Bleeding====
*There was no difference in major bleeding associated with 150 mg of dabigatran therapy versus warfarin.
 
*There was statistically less major bleeding associated with 110 mg of dabigatran than warfarin.


*Dabigatran 150 mg reduced the risk of hemorrhagic stroke (HR 0.26, p<0.001) as did rivaroxaban (HR 0.59, p=0.024) (both were safe).  There was less fatal bleeding with rivaroxaban, but numerically more major bleeding with rivaroxaban.
*While there was numerically more major bleeding with rivaroxaban, there was less fatal bleeding with rivaroxaban compared with warfarin.


*Dabigatran 150 mg also reduced the risk of ischemic stroke (HR=0.76, p=0.03) while rivaroxaban did not (p=0.58)(dabigatran was associated with efficacy)
====Regarding Mortality====
*In the intent-to-treat analysis, there was a strong trend for a mortality reduction with dabigatran 150 mg (p=0.051) while there was a modest trend for mortality reduction with rivaroxaban (4.52 / yr vs 4.91 / yr, p=0.152)


*In the intent-to-treat analysis, there was a strong trend for a mortality reduction with dabigatran 150 mg (p=0.051) while there was a modest trend for mortality improvement for rivaroxaban (4.52 / yr vs 4.91 / yr, p=0.152)
[[Category:Cardiology]]
[[Category:Cardiology]]


Revision as of 17:28, 19 November 2010

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

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Download the Powerpoint slides here:

Media:ROCKET_vs_RELY_comparison.ppt

Comparison of RE-LY and Rocket AF Trials

Trial Design

  • Both had non-inferiority to warfarin as primary endpoint
  • Rocket AF required 2 risk factors for entry, RE-LY 1 risk factor
  • Rocket AF capped CHADS2 = 2 early in the trial unless a patient scored two points by having a prior stroke/TIA. This may account for the high rate of prior stroke in Rocket AF
  • Both randomized trials
  • Rocket AF administered warfarin in a blinded fashion, RE-LY did not
  • There was a dose adjustment for impaired CrCl in Rocket AF
  • INR target range 2-3 in both

Comparison of Study Designs in Other Trials

Comparison of Study Designs in Other Trials
Trial Inclusion Design Start Date Duration (mo) Current / Goal Enrollment # sites
ROCKET AF CHADS ≥ 3 or stroke/TIA (15% CHADS 2) Sham INR 12/2006 15 14,264 ~1200
ARISTOTLE CHADS ≥ 1 (50% VKA naïve) Sham INR 1/2007 15 ~15,000 ~937
RE-LY CHADS ≥ 1 (30% VKA naïve) Open label 12/2005 26 18,113 706
AMADEUS CHADS ≥ 1 Open label 9/2003 23 4,576 165
SPORTIF V CHADS ≥ 1 Sham INR 8/2000 17 3,922 409
ENGAGE CHADS ≥ 2 Sham INR 10/2008 24 20,500 ~1,400


Statistical Methods: Efficacy

RELY: Primary Efficacy Evaluation: Stroke or non-CNS Embolism

Non-Inferiority: Intention-to-treat

Superiority: Intention-to-treat

Rocket AF: Primary Efficacy Evaluation: Stroke or non-CNS Embolism

Non-Inferiority: Protocol Compliant on treatment

Superiority: On Treatment, then by Intention-to-Treat

RE-LY used Intention-to-Treat for both non-inferiority and superiority testing; Rocket AF used on treatment analysis for first tests of non-inferiority and superiority.

Statistical Methods: Safety

RELY:

Primary Safety Evaluation: Major Bleeding

Rocket AF:

Primary Safety Evaluation: Major or non-Major Clinically Relevant Bleeding

RE-LY Definitions of Stroke

  • Stroke was defined as the sudden onset of a focal neurologic deficit in a location consistent with the territory of a major cerebral artery and categorized as ischemic, hemorrhagic, or unspecified.
  • Hemorrhagic transformation of ischemic stroke was not considered to be hemorrhagic stroke.
  • Intracranial hemorrhage consisted of hemorrhagic stroke and subdural or subarachnoid hemorrhage.
  • Systemic embolism was defined as an acute vascular occlusion of an extremity or organ, documented by means of imaging, surgery, or autopsy.

Rocket AF Definitions of Stroke

The primary efficacy outcome is the composite of stroke

  • Stroke is defined as a new, sudden, focal neurological deficit resulting from a presumed cerebrovascular cause that is not reversible within 24 hours and not due to a readily identifiable cause such as a tumor or seizure
  • All strokes will be classified as primary ischemic or primary hemorrhagic

And non-CNS systemic embolism

  • Non-CNS systemic embolism is defined as abrupt vascular insufficiency associated with clinical or radiological evidence of arterial occlusion in the absence of other likely mechanisms, (e.g., trauma, atherosclerosis, instrumentation)

RE-LY: Baseline Characteristics

RE-LY: Baseline Characteristics
Characteristics 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 2.1 2.2 2.1
(mean)
0-1 (%) 32.6 32.2 30.9
2 (%) 34.7 35.2 37.0
3+ (%) 32.7 32.6 32.1
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

Rocket AF: Baseline Demographics

Rocket AF: Baseline Demographics
Rivaroxaban (N=7081) Warfarin (N=7090)
CHADS2 Score (mean) 3.48 3.46
2 (%) 13 13
3 (%) 43 44
4 (%) 29 28
5 (%) 13 12
6 (%) 2 2
Prior VKA Use (%) 62 63
Congestive Heart Failure (%) 63 62
Hypertension (%) 90 91
Diabetes Mellitus (%) 40 39
Prior Stroke/TIA/Embollism (%) 55 55
Prior Myocardial Infarction (%) 17 18

Rocket AF was a Higher Risk Patient Population

  • Whereas 32.4% of patients in RE-LY were low risk CHADS 0-1, there were none of these patients in Rocket AF
  • Whereas just over 32% of patients in RE-LY were high risk CHADS score of 3 or more, over 85% of Rocket AF patients had a CHADS score of 3 or more
  • RE-LY patients were about 71.5 years old, and Rocket AF patients were 73 years old
  • Prior stroke TIA embolism was about 20% in RE-LY and was 55% in Rocket AF
  • About half of RE-LY patients were warfarin naïve, whereas 37.5% of Rocket AF patients were warfarin naïve

Impact of Enrolling Higher CHADs Score Patients

Higher CHADs Scores are associated with:

1. Higher rates of major bleeding

2. Lower TTRs

Trial Execution

Comparison of Trial Metrics
RE-LY Rocket AF
Countries 44 45
Patients 18,113 14,264
Median Duration of Follow-Up 2 years (about 730 days) 589 days of exposure, 707 days including period off drug during follow-up
Time in Therapeutic Range (TTR) 64% 57.8%
67% warfarin-experienced
61% warfarin-naïve

Rates of Drug Discontinuation

Rates of Drug Discontinuation
RE-LY
1 Year:
Dabigatran 110 mg: 14.5%
Dabigatran 150 mg: 15.5%
Warfarin: 10.2%
2 Years:
Dabigatran 110 mg: 20.7%
Dabigatran 150 mg: 21.2%
Warfarin: 16.6%
Rocket AF
Rivaroxaban: 23.9%
Warfarin: 22.4%

Primary Endpoint of Stroke or Systemic Embolism

Primary Endpoint of Stroke or Systemic Embolism: Non-inferiority Analysis
Non-Inferiority p vs warfarin
RE-LY ITT Analysis
Dabigatran 110 mg 1.53% per year p<0.001
Dabigatran 150 mg 1.11% per year p<0.001
Warfarin 1.69% per year
Rocket AF Per Protocol Analysis
Rivaroxaban 20 mg 2.12% per year p<0.001
Warfarin 2.42%

No ITT analysis is available for non-inferiority in Rocket AF. An on treatment or per-protocol analysis is generally performed in the assessment of non-inferiority. If numerous patients come off of study drug, this biases the trial towards a non-inferior result in an ITT analysis. This is the basis for performing a per-protocol analysis in a non-inferiority assessment.

Primary Endpoint of Stroke or Systemic Embolism

Primary Endpoint of Stroke or Systemic Embolism: Superiority Analysis
Superiority p vs warfarin, ITT Analysis
RE-LY
Dabigatran 110 mg 1.53% per year p=0.34
Dabigatran 150 mg 1.11% per year p<0.001
Warfarin 1.69% per year
Rocket AF
Rivaroxaban 20 mg 2.12% per year p=0.117*
Warfarin 2.42% per year
  • In an on-treatment analysis in Rocket AF Stoke or SE rates were 1.70% / yr for rivaroxaban and 2.15% / yr for warfarin, p=0.015. No on-treatment analysis is available from RE-LY.

Hemorrhagic Stroke

Hemorrhagic Stroke
Rely HR ITT p-value
Dabigatran 110 mg 0.12% / yr 0.31 <0.001
Dabigatran 150 mg 0.10% / yr 0.26 <0.001
Warfarin 0.38% / yr
Rocket AF
Rivaroxaban 20 mg 0.26% / year 0.59 0.012*
Warfarin 0.44% / yr
  • In an on-treatment analysis in Rocket AF Hemorrhagic Stoke rates were 0.26% / yr for rivaroxaban and 0.44% / yr for warfarin, p=0.024. No on-treatment analysis is available from RE-LY


Ischemic Stroke

Ischemic Stroke
Rely HR ITT p-value
Dabigatran 110 mg 1.34% / yr 1.20 0.35
Dabigatran 150 mg 0.92% / yr 0.76 0.03
Warfarin 1.20% / yr
Rocket AF
Rivaroxaban 20 mg 1.62% / year 0.99 0.92*
Warfarin 1.64% / yr
  • In an on-treatment analysis in Rocket AF Ischemic Stoke rates were 1.34% / yr for rivaroxaban and 1.42% / yr for warfarin, p=0.58. No-on treatment analysis is available from RE-LY.

Myocardial Infarction

Myocardial Infarction
Rely HR ITT p-value
Dabigatran 110 mg 0.72% / yr 1.35 0.07
Dabigatran 150 mg 0.74% / yr 1.38 0.048
Warfarin 0.53% / yr
Rocket AF
Rivaroxaban 20 mg 1.02% / year 0.91 0.46*
Warfarin 1.11% / yr

Major Bleeding

Major Bleeding
Rely HR ITT p-value
Dabigatran 110 mg 2.71% / yr 0.8 0.0003
Dabigatran 150 mg 3.11% / yr 0.93 0.31
Warfarin 3.36% / year
Rocket AF
Rivaroxaban 20 mg 3.60% / year 0.92 0.58*
Warfarin 3.45% / yr
  • There is no ITT analysis of safety in Rocket AF. There is no on treatment analysis of safety from RE-LY.

All Cause Mortality

All Cause Mortality
Rely HR ITT p-value
Dabigatran 110 mg 3.75% / yr 0.88 0.35
Dabigatran 150 mg 3.64% / yr 0.91 0.051
Warfarin 4.13% / year
Rocket AF
Rivaroxaban 20 mg 4.52% / year 0.92 0.152*
Warfarin 4.91% / yr
  • In an on treatment analysis in Rocket AF mortality rates were 1.87% / yr for rivaroxaban and 2.21% / yr for warfarin, p=0.073. No on treatment analysis is available from RE-LY.

===Conclusions: RE-LY vs Rocket AF Regarding Primary Endpoint of Stroke and/or Systemic Embolization

Primary Analysis of Non-Inferiority:

Both drugs were non-inferior to warfarin in reducing the primary endpoint of stroke and systemic embolism

Secondary Analysis of Superiority:

In a pre-specified secondary on-treatment analysis, rivaroxaban was superior to warfarin. No on-treatment analysis is available for dabigatran versus warfarin.

In an intent-to-treat analysis, 150 mg of dabigatran was superior to warfarin while rivaroxaban was not.

Conclusions: RE-LY vs Rocket AF

Regarding Stroke

  • Dabigatran 150 mg reduced the risk of hemorrhagic stroke (HR 0.26, p<0.001) as did rivaroxaban (HR 0.59, p=0.024).
  • Both drugs were therefore safer.
  • Dabigatran 150 mg also reduced the risk of ischemic stroke (HR=0.76, p=0.03) while rivaroxaban did not (p=0.58)(dabigatran was associated with thrombotic efficacy)

Regarding Bleeding

  • There was no difference in major bleeding associated with 150 mg of dabigatran therapy versus warfarin.
  • There was statistically less major bleeding associated with 110 mg of dabigatran than warfarin.
  • While there was numerically more major bleeding with rivaroxaban, there was less fatal bleeding with rivaroxaban compared with warfarin.

Regarding Mortality

  • In the intent-to-treat analysis, there was a strong trend for a mortality reduction with dabigatran 150 mg (p=0.051) while there was a modest trend for mortality reduction with rivaroxaban (4.52 / yr vs 4.91 / yr, p=0.152)

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