A comparison of the RE-LY and Rocket AF Trials

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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

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.

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)

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

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.

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)