A comparison of the RE-LY and Rocket AF Trials
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
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Media:ROCKET_vs_RELY_comparison.ppt
Comparison of RE-LY and Rocket AF Trial Designs and Outcomes
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
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
RE-LY: 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.
Statistical Methods: Safety
RE-LY:
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
| 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
| 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
| 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
| 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
| 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
| 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
| RE-LY | 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
| RE-LY | 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
| RE-LY | 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 |
- In an on treatment analysis in Rocket AF MI rates were 0.91% / yr for rivaroxaban and 1.12% / yr for warfarin, p=0.121. No on treatment analysis is available from RE-LY.
Major Bleeding
| RE-LY | HR | ITT p-value | |
|---|---|---|---|
| Dabigatran 110 mg | 2.71% / yr | 0.8 | 0.003 |
| Dabigatran 150 mg | 3.11% / yr | 0.93 | 0.31 |
| Warfarin | 3.36% / year | ||
| 150 mg Dabigatran vs 110 mg Dabigatran = HR of 1.16 (1.00–1.34) p = 0.052 | |||
| 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
| RE-LY | 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.
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)