1. A Comparison of RE-LY and ROCKET AF Trial Designs and Outcomes
C. Michael Gibson, M.S., MD.

2. Absence of contra-indications
RE-LY: Study Design
Patients were eligible if they had atrial fibrillation documented on electrocardiography performed at screening or within 6 months beforehand and at least one of the following characteristics:
Previous stroke or transient ischemic attack
a left ventricular ejection fraction of less than 40%
New York Heart Association class II or higher heart-failure symptoms within 6 months before screening
An age of at least 75 years or an age of 65 to 74 years plus diabetes mellitus, hypertension, or coronary artery disease.
Atrial fibrillation
≥1 Risk Factor
Absence of contra-indications
951 centers in 44 countries
Blinded Event Adjudication. R
Open
Blinded
Warfarin
adjusted
(INR )
N=6000
Dabigatran Etexilate
110 mg BID
N=6000
Dabigatran Etexilate
150 mg BID
N=6000
Connolly SJ, et al. N Engl J Med. 2009;361:

3. Rocket AF Study Design Atrial Fibrillation Rivaroxaban Warfarin
G w_script.ppt
6/16/2018 2:03:08 AM
Risk Factors
CHF
Hypertension
Age  75
Diabetes OR
Stroke, TIA or Systemic embolus
Rocket AF Study Design
At least 2 or 3 required*
Atrial Fibrillation
Rivaroxaban
Randomize
Double Blind / Double Dummy
(n ~ 14,000)
Warfarin
20 mg daily
15 mg for Cr Cl ml/min
INR target - 2.5
( inclusive)
Monthly Monitoring
Adherence to standard of care guidelines
Primary Endpoint: Stroke or non-CNS Systemic Embolism
* Enrollment of patients without prior Stroke, TIA or systemic embolism and only 2 factors capped at 10%
Rocket AF Investigators, AHA 2010

4. Comparison of Study Designs
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
C. Michael Gibson, M.S., M.D.
Rocket AF Investigators, AHA 2010; Connolly SJ, et al. N Engl J Med. 2009;361:

5. Comparison of Study Designs in Other Trials
Inclusion
Design
Start date
Duration (mo)
Current / Goal Enrollment
# sites
ROCKET AF
CHADS ≥ 3 or stroke/TIA
(15% CHADS 2)
Sham INR
12/06 15
14,264
~1200
ARISTOTLE
CHADS ≥ 1
(50% VKA naïve)
1/07
~15,000
~937
RE-LY
(30% VKA naïve)
Open label
12/2005 26
18,113
706
AMADEUS
9/2003 23
4576
165
SPORTIF V
8/2000 17
3922
409
ENGAGE
CHADS > 2
10/2008 24
20,500
~1400
C. Michael Gibson, M.S., M.D.
Rocket AF Investigators, AHA 2010; Connolly SJ, et al. N Engl J Med. 2009;361:

6. 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 Intent-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
C. Michael Gibson, M.S., M.D.
Rocket AF Investigators, AHA 2010; Connolly SJ, et al. N Engl J Med. 2009;361:

7. Statistical Methods: Safety
RELY:
Primary Safety Evaluation: Major bleeding
Rocket AF:
Primary Safety Evaluation: Major or non-Major Clinically Relevant Bleeding
C. Michael Gibson, M.S., M.D.
Rocket AF Investigators, AHA 2010; Connolly SJ, et al. N Engl J Med. 2009;361:

8. 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.
C. Michael Gibson, M.S., M.D.
Rocket AF Investigators, AHA 2010; Connolly SJ, et al. N Engl J Med. 2009;361:

9. 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)
C. Michael Gibson, M.S., M.D.
Rocket AF Investigators, AHA 2010; Connolly SJ, et al. N Engl J Med. 2009;361:

10. RE-LY: Baseline 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 (mean)
0-1 (%)
(%)
3+ (%)
2.1
32.6
34.7
32.7
2.2
32.2
35.2
30.9
37.0
32.1
Prior stroke/TIA (%)
19.9
20.3
19.8
Prior MI (%)
16.8
16.9
16.1
CHF (%)
31.8
31.9
Baseline ASA (%)
40.0
38.7
40.6
Warfarin Naïve (%)
49.9
49.8
51.4
C. Michael Gibson, M.S., M.D.
Rocket AF Investigators, AHA 2010; Connolly SJ, et al. N Engl J Med. 2009;361:

11. Rocket AF: Baseline Demographics
Rivaroxaban (N=7081)
Warfarin (N=7090)
CHADS2 Score (mean)
2 (%)
3 (%)
4 (%)
5 (%)
6 (%)
3.48 13 43 29 2
3.46 44 28 12
Prior VKA Use (%) 62 63
Congestive Heart Failure (%)
Hypertension (%) 90 91
Diabetes Mellitus (%) 40 39
Prior Stroke/TIA/Embolism (%) 55
Prior Myocardial Infarction (%) 17 18
Based on Intention-to-Treat Population
C. Michael Gibson, M.S., M.D.
Rocket AF Investigators, AHA 2010; Connolly SJ, et al. N Engl J Med. 2009;361:

12. 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 on 37.5% of Rocket AF patients were warfarin naive
C. Michael Gibson, M.S., M.D.
Rocket AF Investigators, AHA 2010; Connolly SJ, et al. N Engl J Med. 2009;361:

13. Impact of Enrolling Higher CHADs Score Patients
Higher CHADs scores are associated with:
Higher rates of major bleeding
Lower TTRs
C. Michael Gibson, M.S., M.D.
Personal communication RE-LY Investigators. Connolly SJ, et al. N Engl J Med. 2009;361:

14. 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%
67% warfarin-experienced
61% warfarin-naïve
57.8%
C. Michael Gibson, M.S., M.D.
Rocket AF Investigators, AHA 2010; Connolly SJ, et al. N Engl J Med. 2009;361:

15. Rates of Drug Discontinuation
RE-LY
1 Year:
Dabigatran 110 mg: %
Dabigatran 150 mg: %
Warfarin: %
2 Years:
Dabigatran 110 mg: 20.7%
Dabigatran 150 mg: %,
Warfarin: %
Rocket AF
Rivaroxaban: %
Warfarin: %
C. Michael Gibson, M.S., M.D.
Rocket AF Investigators, AHA 2010; Connolly SJ, et al. N Engl J Med. 2009;361:

16. Dabigatran 110 mg 1.53% per year Dabigatran 150 mg 1.11% per year
Primary Endpoint of Stroke or Systemic Embolism: Non-inferiority Analysis
Non Inferiorirty
p vs warfarin
RE-LY
Dabigatran 110 mg 1.53% per year
Dabigatran 150 mg 1.11% per year
Warfarin % per year
Rocket AF
Rivaroxaban 20mg 2.12% per year
Warfarin % per year
ITT Analysis
p<0.001
p<0.001
Per Protocol
Analysis
p<0.001
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.
C. Michael Gibson, M.S., M.D.
Rocket AF Investigators, AHA 2010; Connolly SJ, et al. N Engl J Med. 2009;361:

17. Primary Endpoint of Stroke or Systemic Embolism: Superiority Analysis
p vs warfarin
ITT Analysis
RE-LY
Dabigatran 110 mg 1.53% per year
Dabigatran 150 mg 1.11% per year
Warfarin % per year
Rocket AF
Rivaroxaban 20mg 2.12% per year
Warfarin % per year
p=0.34
p<0.001
p=0.117*
*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= No on treatment analysis is available from RE-LY.
C. Michael Gibson, M.S., M.D.
Rocket AF Investigators, AHA 2010; Connolly SJ, et al. N Engl J Med. 2009;361:

18. Hemorrhagic Stroke ITT P-value HR RELY
Dabigatran 110 mg 0.12% / yr 0.31 <0.001
Dabigatran 150 mg 0.10% / yr 0.26 <0.001
Warfarin % / yr
Rocket AF
Rivaroxaban 20 mg 0.26% / yr *
Warfarin % / 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= No on treatment analysis is available from RE-LY.
C. Michael Gibson, M.S., M.D.
Rocket AF Investigators, AHA 2010; Connolly SJ, et al. N Engl J Med. 2009;361:

19. Ischemic Stroke ITT P-value HR RELY
Dabigatran 110 mg 1.34% / yr
Dabigatran 150 mg 0.92% / yr
Warfarin % / yr
Rocket AF
Rivaroxaban 20 mg 1.62% / yr *
Warfarin % / 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.
C. Michael Gibson, M.S., M.D.
Rocket AF Investigators, AHA 2010; Connolly SJ, et al. N Engl J Med. 2009;361:

20. Myocardial Infarction
ITT
P-value HR
RELY
Dabigatran 110 mg 0.72% / yr
Dabigatran 150 mg 0.74% / yr
Warfarin % / yr
Rocket AF
Rivaroxaban 20 mg 1.02% / yr *
Warfarin % / yr
*In an on treatment analysis in Rocket AF MI rates were 0.91% / yr for rivaroxaban and 1.12% / yr for warfarin, p= No on treatment analysis is available from RE-LY.
C. Michael Gibson, M.S., M.D.
Rocket AF Investigators, AHA 2010; Connolly SJ, et al. N Engl J Med. 2009;361:

21. Major Bleeding RE-LY HR Dabigatran 110 mg 2.71% / yr 0.8 0.003
ITT
P-value
RE-LY HR
Dabigatran 110 mg % / yr
Dabigatran 150 mg 3.11% / yr
Warfarin
150 mg Dabigatran vs 110 mg Dabigatran = HR of 1.16 (1.00–1.34) p = 0.052
On Treatment
P-value
Rocket AF
Rivaroxaban 20 mg 3.60% / yr *
Warfarin % / yr
*There is no ITT analysis of safety in Rocket AF. There is no on treatment analysis of safety from RE-LY.
C. Michael Gibson, M.S., M.D.
Rocket AF Investigators, AHA 2010; Connolly SJ, et al. N Engl J Med. 2009;361:

22. All Cause Mortality ITT P-value HR RELY
Dabigatran 110 mg 3.75% / yr
Dabigatran 150 mg 3.64% / yr
Warfarin % / yr
Rocket AF
Rivaroxaban 20 mg 4.52% / yr *
Warfarin % / yr
*In an on treatment analysis in Rocket AF mortality rates were 1.87% / yr for rivaroxaban and 2.21% / yr for warfarin, p= No on treatment analysis is available from RE-LY.
C. Michael Gibson, M.S., M.D.
Rocket AF Investigators, AHA 2010; Connolly SJ, et al. N Engl J Med. 2009;361:

23. 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.
C. Michael Gibson, M.S., M.D.
Rocket AF Investigators, AHA 2010; Connolly SJ, et al. N Engl J Med. 2009;361:

24. 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)
C. Michael Gibson, M.S., M.D.
Rocket AF Investigators, AHA 2010; Connolly SJ, et al. N Engl J Med. 2009;361:

25. Conclusions: RE-LY vs Rocket AF 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.
C. Michael Gibson, M.S., M.D.
Rocket AF Investigators, AHA 2010; Connolly SJ, et al. N Engl J Med. 2009;361:

26. Conclusions: RE-LY vs Rocket AF 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 a mortality reduction with rivaroxaban (4.52 / yr vs 4.91 / yr, p=0.152)
C. Michael Gibson, M.S., M.D.
Rocket AF Investigators, AHA 2010; Connolly SJ, et al. N Engl J Med. 2009;361: