A comparison of the RE-LY and Rocket AF Trials

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# 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

## 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

## Rocket AF: Baseline Demographics

## 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 naive, whereas 37.5% of Rocket AF patients were warfarin naive

## Impact of Enrolling Higher CHADs Score Patients
Higher CHADs Scores are associated with:
1. Higher rates of major bleeding
2. Lower TTRs

## Trial Execution

## Rates of Drug Discontinuation

## Primary Endpoint of Stroke or Systemic Embolism
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
- 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
- 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
- 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
- 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
- There is no ITT analysis of safety in Rocket AF. There is no on treatment analysis of safety from RE-LY.

## All Cause Mortality
- 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
- Both drugs were non-inferior to warfarin in reducing the primary endpoint of stroke and systemic embolism
- 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)
CME Category::Cardiology