a comparison of re-ly and rocket af trial designs and outcomes

A Comparison of RE-LY and ROCKET AFTrial Designs and Outcomes

C. Michael Gibson, M.S., MD.

RE-LY: Study Design

Atrial fibrillation ≥1 Risk Factor

Absence of contra-indications951 centers in 44 countries

R

Warfarinadjusted

(INR 2.0-3.0)N=6000

Dabigatran Etexilate

110 mg BIDN=6000

Dabigatran Etexilate

150 mg BIDN=6000

Blinded Event Adjudication.

Open Blinded

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: 1.Previous stroke or transient ischemic attack2.a left ventricular ejection fraction of less than 40%3.New York Heart Association class II or higher heart-failure symptoms within 6 months before screening4.An age of at least 75 years or an age of 65 to 74 years plus diabetes mellitus, hypertension, or coronary artery disease.

Connolly SJ, et al. N Engl J Med. 2009;361:1139-1151

Rivaroxaban Warfarin

Primary Endpoint: Stroke or non-CNS Systemic Embolism

INR target - 2.5 (2.0-3.0 inclusive)

20 mg daily15 mg for Cr Cl 30-49 ml/min

Atrial Fibrillation

RandomizeDouble Blind / Double Dummy

(n ~ 14,000)

Monthly MonitoringAdherence to standard of care guidelines

Rocket AF Study Design

* Enrollment of patients without prior Stroke, TIA or systemic embolism and only 2 factors capped at 10%

Risk Factors• CHF • Hypertension • Age 75 • Diabetes OR• Stroke, TIA or Systemic embolus

At least 2 or 3 required*

Rocket AF Investigators, AHA 2010

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;361:1139-1151

Trial 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)

Sham INR

1/07 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 4576 165

SPORTIF V CHADS ≥ 1 Sham INR

8/2000 17 3922 409

ENGAGE CHADS > 2 Sham INR

10/2008 24 20,500 ~1400

Comparison of Study Designs in Other Trials


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


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.


The primary efficacy outcome is the composite of strokeStroke 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 embolismNon-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 Definitions of Stroke


RE-LY: Baseline Characteristics

Characteristic 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 (%) 2 (%) 3+ (%)

2.1

32.634.732.7

2.2

32.235.232.6

2.1

30.937.032.1

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


Rivaroxaban (N=7081)

Warfarin (N=7090)

CHADS2 Score (mean) 2 (%)

3 (%)

4 (%)

5 (%)

6 (%)

3.48134329132

3.46134428122

Prior VKA Use (%) 62 63

Congestive Heart Failure (%) 63 62

Hypertension (%) 90 91

Diabetes Mellitus (%) 40 39

Prior Stroke/TIA/Embolism (%) 55 55

Prior Myocardial Infarction (%) 17 18

Based on Intention-to-Treat Population

Rocket AF: Baseline Demographics


• 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

Rocket AF was a Higher Risk Patient Population


Impact of Enrolling Higher CHADs Score Patients

Higher CHADs scores are associated with:

1.Higher rates of major bleeding2.Lower TTRs

C. Michael Gibson, M.S., M.D. Personal communication RE-LY Investigators. Connolly SJ, et al. N Engl J Med. 2009;361:1139-1151

Comparison of Trial MetricsComparison of Trial MetricsRE-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-experienced61% warfarin-naïve

57.8%


Rates of Drug DiscontinuationRE-LY

1 Year:

Dabigatran 110 mg: 14.5%


Warfarin: 10.2%

2 Years:


Dabigatran 150 mg: 21.2%,

Warfarin: 16.6%

Rocket AF

Rivaroxaban: 23.9%

Warfarin: 22.4%C. Michael Gibson, M.S., M.D. Rocket AF Investigators, AHA 2010; Connolly SJ, et al. N Engl J Med. 2009;361:1139-1151

RE-LYDabigatran 110 mg 1.53% per yearDabigatran 150 mg 1.11% per yearWarfarin 1.69% per year

Rocket AFRivaroxaban 20mg 2.12% per yearWarfarin 2.42% per year

Primary Endpoint of Stroke or Systemic Embolism: Non-inferiority Analysis

p<0.001

p<0.001

p<0.001

Non Inferiorirtyp vs warfarin

ITT Analysis

Per ProtocolAnalysis

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.


RE-LYDabigatran 110 mg 1.53% per yearDabigatran 150 mg 1.11% per yearWarfarin 1.69% per year

Rocket AFRivaroxaban 20mg 2.12% per yearWarfarin 2.42% per year

Primary Endpoint of Stroke or Systemic Embolism: Superiority Analysis

p=0.117*

p<0.001

p=0.34

Superiorityp vs warfarinITT Analysis


*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

Dabigatran 110 mg 0.12% / yr 0.31 <0.001Dabigatran 150 mg 0.10% / yr 0.26 <0.001

Warfarin 0.38% / yr

HRITT

P-value

Rivaroxaban 20 mg 0.26% / yr 0.59 0.012*

Warfarin 0.44% / yr

Rocket AF

RELY


*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

Dabigatran 110 mg 1.34% / yr 1.20 0.35Dabigatran 150 mg 0.92% / yr 0.76 0.03

Warfarin 1.20% / yr

HRITT

P-value


Warfarin 1.64% / yr

Rocket AF

RELY


*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


Warfarin 0.53% / yr

HRITT

P-value


Warfarin 1.11% / yr

Rocket AF

RELY


*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.


Warfarin 3.36150 mg Dabigatran vs 110 mg Dabigatran = HR of 1.16 (1.00–1.34) p = 0.052

Major Bleeding

HRITT

P-valueRE-LY


Warfarin 3.45% / yr

Rocket AF


*There is no ITT analysis of safety in Rocket AF. There is no on treatment analysis of safety from RE-LY.

On TreatmentP-value

All Cause Mortality


Warfarin 4.13% / yr

HRITT

P-value


Warfarin 4.91% / yr

Rocket AF

RELY


*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.


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)

Conclusions: RE-LY vs Rocket AF Regarding Stroke


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.

Conclusions: RE-LY vs Rocket AF Regarding Bleeding


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)


a comparison of re-ly and rocket af trial designs and outcomes

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