An Efficacy and Safety Study of Rivaroxaban With Warfarin for the Prevention of Stroke and Non-Central Nervous System Systemic Embolism in Patients With Non-Valvular Atrial Fibrillation

Conditions

Atrial Fibrillation, Embolism, Stroke

Keywords

Atrial Fibrillation, Stroke, Embolism, Non-central nervous system systemic embolism, Non-valvular atrial fibrillation, Blood Clot, Rivaroxaban, Warfarin, Anticoagulants, Arrhythmias, Cardiac

Brief summary

The purpose of this study is to compare the efficacy and safety of rivaroxaban with warfarin for the prevention of blood clots in the brain (referred to as stroke) and blood clots in other parts of the body referred to as non-central nervous system systemic embolism) in patients with non-valvular atrial fibrillation (a heart rhythm disorder).

Detailed description

Patients with non-valvular atrial fibrillation who are at risk for stroke and non-central nervous system (non-CNS) systemic embolism, will be randomized (assigned by chance) to receive treatment with rivaroxaban or warfarin, two different anticoagulants (substances that prevent blood clots). Treatment will be double-blinded (neither the patient nor study staff will know which study drug is assigned to patients during the study). Patients assigned to rivaroxaban will receive rivaroxaban 20 mg orally (p.o.) once daily (OD) plus warfarin placebo p.o. OD titrated to a target sham international normalized ratio (INR) of 2.5. Patients with moderate renal impairment at screening will receive rivaroxaban 15 mg p.o. OD. Patients assigned to warfarin will receive warfarin p.o. OD titrated to a target INR of 2.5 plus rivaroxaban placebo p.o. OD. The maximum expected length of treatment is up to 32 months but may be extended up to 4 years.

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Interventions

DRUGRivaroxaban

Type=exact number, unit=mg, number=20, form=tablet, route=oral use. One 20 mg tablet once daily for an expected maximum treatment period of up to 32 months that may extend up to 4 years (Patients with moderate renal impairment at screening willl have a dose adaptation to rivaroxaban 15 mg, orally, once daily for an expected maximum treatment period of up to 32 months that may extend up to 4 years)

DRUGWarfarin

Type=exact number, unit=mg, number=1, 2.5, or 5 mg, form=tablet, route=oral use. Number of warfarin tablets to be determined based on target INR values once daily for an expected maximum treatment period of up to 32 months that may extend up to 4 years

DRUGMatching placebo for Rivaroxaban arm (Warfarin placebo)

Form=tablet, route=oral. One warfarin placebo tablet taken orally once daily for up to an expected maximum treatment period of 32 months that may extend up to 4 years

DRUGMatching placebo for Warfarin arm (Rivaroxaban placebo)

Form-tablet, Route=oral administration. Number of rivaroxaban placebo determined by the number of warfarin tablets taken. Duration of treatment is up to an expected maximum treatment period of 32 months that may extend up to 4 years

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

PREVENTION

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

No

Inclusion criteria

* Patients must have documented atrial fibrillation on 2 separate occasions within 6 months before screening * History of a prior stroke, transient ischemic attack or non-neurologic systemic embolism believed to be cardiac in origin, or at least two of the following risk factors: heart failure, hypertension, age 75 years or greater, diabetes mellitus

Exclusion criteria

* Significant mitral stenosis * Transient atrial fibrillation caused by a reversible disorder * Active internal bleeding * Severe disabling stroke * History of intracranial bleeding * Hemorrhagic disorders

Design outcomes

Primary

Measure	Time frame	Description
The Composite Event of Stroke/Non-CNS Systemic Embolism: Primary Efficacy (Non-Inferiority)	Up to 4 years	The number of patients with the first occurrence of a stroke or non-CNS systemic embolism while on treatment (defined as the time interval from the first dose to the last dose of study drug plus 2 days). The statistical analysis is based on time from randomization to the first occurrence of the event while on treatment.
The Composite of Event of Stroke/Non-CNS Systemic Embolism: Primary Efficacy (Superiority)	Up to 4 years	The number of patients with the first occurrence of a stroke or non-CNS systemic embolism while on treatment (defined as the time interval from the first dose to the last dose of study drug plus 2 days). The statistical analysis is based on time from randomization to the first occurrence of the event while on treatment.
The Composite Event of Major/Non-major Clinically Relevant Bleeding Events: Primary Safety	Up to 4 years	The number of patients with the first occurrence of a major or non-major clinically relevant bleeding event while on treatment. The statistical analysis is based on time from the first dose of study drug to the first occurrence of the event while on treatment.

Secondary

Measure	Time frame	Description
The Individual Components of the Composite Primary and Major Secondary Efficacy Outcome Measures: Non-CNS Systemic Embolism	Up to 4 years	The number of patients with the first occurrence of a non-CNS systemic embolism while on treatment. The statistical analysis is based on time from randomization to the first occurrence of the event while on treatment.
The Individual Components of the Composite Primary and Major Secondary Efficacy Outcome Measures: Myocardial Infarction	Up to 4 years	The number of patients with the first occurrence of a myocardial infarction while on treatment. The statistical analysis is based on time from randomization to the first occurrence of the event while on treatment.
The Composite Event of Stroke/Non-CNS Systemic Embolism/Vascular Death	Up to 4 years	The number of patients with the first occurrence of a stroke, non-CNS systemic embolism, or vascular death while on treatment. The statistical analysis is based on time from randomization to the first occurrence of the event while on treatment.
All-cause Mortality	Up to 4 years	The number of patients who died due to any cause while on treatment. The statistical analysis is based on time from randomization to the event while on treatment.
The Individual Components of the Composite Primary and Major Secondary Efficacy Outcome Measures: Vascular Death	Up to 4 years	The number of patients with the occurrence of vascular death while on treatment. The statistical analysis is based on time from randomization to the event while on treatment.
The Composite Event of Stroke/Non-CNS Systemic Embolism/Myocardial Infarction/Vascular Death	Up to 4 years	The number of patients with the first occurrence of a stroke, non-CNS systemic embolism, myocardial infarction, or vascular death while on treatment. The statistical analysis is based on time from randomization to the first occurrence of the event while on treatment.
The Individual Components of the Composite Primary and Major Secondary Efficacy Outcome Measures: Stroke	Up to 4 years	The number of patients with the first occurrence of a stroke while on treatment. The statistical analysis is based on time from randomization to the first occurrence of the event while on treatment.

Countries

Argentina, Australia, Austria, Belgium, Brazil, Bulgaria, Canada, Chile, China, Colombia, Czechia, Denmark, Finland, France, Germany, Greece, Hong Kong, Hungary, India, Israel, Lithuania, Malaysia, Mexico, Netherlands, New Zealand, Norway, Peru, Philippines, Poland, Romania, Russia, Singapore, South Africa, South Korea, Spain, Sweden, Switzerland, Taiwan, Thailand, Turkey (Türkiye), Ukraine, United Kingdom, United States, Venezuela

Participant flow

Recruitment details

This study, an efficacy and safety study of Rivaroxaban with Warfarin for the prevention of stroke and non-central nervous system systemic embolism in patients with non-valvular atrial fibrillation, was conducted from 18 December 2006 to 07 September 2010. Patients were recruited at 1,170 study centers located in 45 countries worldwide.

Pre-assignment details

A total of 14,269 patients were randomized in the study. Five patients were randomized twice bringing the number of randomized unique patients to 14,264. A total of 14,236 (7111 and 7125 patients in the rivaroxaban and warfarin groups, respectively) unique patients took at least 1 dose of study medication and were included in the Safety Population.

Participants by arm

Arm	Count
Rivaroxaban Rivaroxaban 15 mg p.o. once daily or Rivaroxaban 20 mg p.o. once daily	7,111
Warfarin Warfarin (1 mg, 2.5 mg, or 5 mg p.o. once daily)	7,125
Total	14,236

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Adverse Event	993	919
Overall Study	Clinical efficacy endpoint reached	300	332
Overall Study	Consent withdrawn	671	673
Overall Study	Investigator dec./not protocol-related	191	178
Overall Study	Lost to Follow-up	6	8
Overall Study	Missing/incomplete data	1	1
Overall Study	Non-compliant with study medication	134	164
Overall Study	Protocol Violation	142	124
Overall Study	Study terminated by sponsor	82	69

Baseline characteristics

Characteristic	Rivaroxaban	Warfarin	Total
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	5465 Participants	5483 Participants	10948 Participants
Age, Categorical Between 18 and 65 years	1646 Participants	1642 Participants	3288 Participants
Age, Continuous Age Continuous	71.2 years STANDARD_DEVIATION 9.45	71.2 years STANDARD_DEVIATION 9.39	71.2 years STANDARD_DEVIATION 9.42
Region of Enrollment Argentina	284 participants	285 participants	569 participants
Region of Enrollment Australia	120 participants	122 participants	242 participants
Region of Enrollment Austria	16 participants	16 participants	32 participants
Region of Enrollment Belgium	49 participants	47 participants	96 participants
Region of Enrollment Brazil	241 participants	242 participants	483 participants
Region of Enrollment Bulgaria	337 participants	339 participants	676 participants
Region of Enrollment Canada	372 participants	375 participants	747 participants
Region of Enrollment Chile	144 participants	142 participants	286 participants
Region of Enrollment China	249 participants	246 participants	495 participants
Region of Enrollment Colombia	134 participants	133 participants	267 participants
Region of Enrollment Czech Republic	299 participants	299 participants	598 participants
Region of Enrollment Denmark	60 participants	61 participants	121 participants
Region of Enrollment Finland	9 participants	7 participants	16 participants
Region of Enrollment France	35 participants	36 participants	71 participants
Region of Enrollment Germany	263 participants	265 participants	528 participants
Region of Enrollment Greece	15 participants	14 participants	29 participants
Region of Enrollment Hong Kong	36 participants	37 participants	73 participants
Region of Enrollment Hungary	119 participants	118 participants	237 participants
Region of Enrollment India	133 participants	135 participants	268 participants
Region of Enrollment Israel	94 participants	94 participants	188 participants
Region of Enrollment Italy	69 participants	69 participants	138 participants
Region of Enrollment Korea (South)	103 participants	100 participants	203 participants
Region of Enrollment Lithuania	122 participants	122 participants	244 participants
Region of Enrollment Malaysia	26 participants	25 participants	51 participants
Region of Enrollment Mexico	83 participants	85 participants	168 participants
Region of Enrollment Netherlands	80 participants	81 participants	161 participants
Region of Enrollment New Zealand	58 participants	58 participants	116 participants
Region of Enrollment Norway	25 participants	24 participants	49 participants
Region of Enrollment Peru	42 participants	42 participants	84 participants
Region of Enrollment Philippines	185 participants	183 participants	368 participants
Region of Enrollment Poland	263 participants	264 participants	527 participants
Region of Enrollment Romania	391 participants	391 participants	782 participants
Region of Enrollment Russia	645 participants	645 participants	1290 participants
Region of Enrollment Singapore	21 participants	23 participants	44 participants
Region of Enrollment South Africa	122 participants	125 participants	247 participants
Region of Enrollment Spain	124 participants	124 participants	248 participants
Region of Enrollment Sweden	12 participants	16 participants	28 participants
Region of Enrollment Switzerland	3 participants	4 participants	7 participants
Region of Enrollment Taiwan	78 participants	79 participants	157 participants
Region of Enrollment Thailand	43 participants	44 participants	87 participants
Region of Enrollment Turkey	50 participants	51 participants	101 participants
Region of Enrollment Ukraine	505 participants	504 participants	1009 participants
Region of Enrollment United Kingdom	79 participants	80 participants	159 participants
Region of Enrollment United States	962 participants	964 participants	1926 participants
Region of Enrollment Venezuela	11 participants	9 participants	20 participants
Sex: Female, Male Female	2819 Participants	2826 Participants	5645 Participants
Sex: Female, Male Male	4292 Participants	4299 Participants	8591 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	— / —	— / —
other Total, other adverse events	2,537 / 7,111	2,573 / 7,125
serious Total, serious adverse events	2,649 / 7,111	2,720 / 7,125

Outcome results

Primary

The Composite Event of Major/Non-major Clinically Relevant Bleeding Events: Primary Safety

The number of patients with the first occurrence of a major or non-major clinically relevant bleeding event while on treatment. The statistical analysis is based on time from the first dose of study drug to the first occurrence of the event while on treatment.

Time frame: Up to 4 years

Population: The safety population consisted of all randomized unique patients who took at least 1 dose of study medication after randomization during the double-blind treatment period.

Arm	Measure	Value (NUMBER)
Rivaroxaban	The Composite Event of Major/Non-major Clinically Relevant Bleeding Events: Primary Safety	1475 Patients
Warfarin	The Composite Event of Major/Non-major Clinically Relevant Bleeding Events: Primary Safety	1449 Patients

Comparison: Alternate hypothesis of superiority based on on-treatment data from the safety population.p-value: 0.44295% CI: [0.96, 1.11]Cox Proportional Hazards model

Primary

The Composite Event of Stroke/Non-CNS Systemic Embolism: Primary Efficacy (Non-Inferiority)

The number of patients with the first occurrence of a stroke or non-CNS systemic embolism while on treatment (defined as the time interval from the first dose to the last dose of study drug plus 2 days). The statistical analysis is based on time from randomization to the first occurrence of the event while on treatment.

Time frame: Up to 4 years

Population: The per-protocol (PP) population consisted of all randomized unique patients excluding those who had specific pre-defined major protocol deviations that occurred by the time of enrollment into the study or during the trial. Site 042012 with GCP violation was excluded.

Arm	Measure	Value (NUMBER)
Rivaroxaban	The Composite Event of Stroke/Non-CNS Systemic Embolism: Primary Efficacy (Non-Inferiority)	188 Patients
Warfarin	The Composite Event of Stroke/Non-CNS Systemic Embolism: Primary Efficacy (Non-Inferiority)	241 Patients

p-value: <0.00195% CI: [0.66, 0.96]Cox Proportional Hazards model

Primary

The Composite of Event of Stroke/Non-CNS Systemic Embolism: Primary Efficacy (Superiority)

The number of patients with the first occurrence of a stroke or non-CNS systemic embolism while on treatment (defined as the time interval from the first dose to the last dose of study drug plus 2 days). The statistical analysis is based on time from randomization to the first occurrence of the event while on treatment.

Time frame: Up to 4 years

Population: The safety population consisted of all randomized unique patients who took at least 1 dose of study medication after randomization during the double-blind treatment period. Site 042012 with GCP violation was excluded.

Arm	Measure	Value (NUMBER)
Rivaroxaban	The Composite of Event of Stroke/Non-CNS Systemic Embolism: Primary Efficacy (Superiority)	189 Patients
Warfarin	The Composite of Event of Stroke/Non-CNS Systemic Embolism: Primary Efficacy (Superiority)	243 Patients

Comparison: Alternative hypothesis of superiority based on on-treatment data from the safety population.p-value: 0.01595% CI: [0.65, 0.95]Cox Proportional Hazards model

Secondary

All-cause Mortality

The number of patients who died due to any cause while on treatment. The statistical analysis is based on time from randomization to the event while on treatment.

Time frame: Up to 4 years

Population: The safety population consisted of all randomized unique patients who took at least 1 dose of study medication after randomization during the double-blind treatment period. Site 042012 with GCP violation was excluded.

Arm	Measure	Value (NUMBER)
Rivaroxaban	All-cause Mortality	208 Patients
Warfarin	All-cause Mortality	250 Patients

Comparison: Alternative hypothesis of superiority based on on-treatment data from the safety population.p-value: 0.07395% CI: [0.7, 1.02]Cox Proportional Hazards model

Secondary

The Composite Event of Stroke/Non-CNS Systemic Embolism/Myocardial Infarction/Vascular Death

The number of patients with the first occurrence of a stroke, non-CNS systemic embolism, myocardial infarction, or vascular death while on treatment. The statistical analysis is based on time from randomization to the first occurrence of the event while on treatment.

Time frame: Up to 4 years

Population: The safety population consisted of all randomized unique patients who took at least 1 dose of study medication after randomization during the double-blind treatment period. Site 042012 with GCP violation was excluded.

Arm	Measure	Value (NUMBER)
Rivaroxaban	The Composite Event of Stroke/Non-CNS Systemic Embolism/Myocardial Infarction/Vascular Death	433 Patients
Warfarin	The Composite Event of Stroke/Non-CNS Systemic Embolism/Myocardial Infarction/Vascular Death	519 Patients

Comparison: Alternative hypothesis of superiority based on on-treatment data from the safety population.p-value: 0.0195% CI: [0.74, 0.96]Cox Proportional Hazards model

Secondary

The Composite Event of Stroke/Non-CNS Systemic Embolism/Vascular Death

The number of patients with the first occurrence of a stroke, non-CNS systemic embolism, or vascular death while on treatment. The statistical analysis is based on time from randomization to the first occurrence of the event while on treatment.

Time frame: Up to 4 years

Population: The safety population consisted of all randomized unique patients who took at least 1 dose of study medication after randomization during the double-blind treatment period. Site 042012 with GCP violation was excluded.

Arm	Measure	Value (NUMBER)
Rivaroxaban	The Composite Event of Stroke/Non-CNS Systemic Embolism/Vascular Death	346 Patients
Warfarin	The Composite Event of Stroke/Non-CNS Systemic Embolism/Vascular Death	410 Patients

Comparison: Alternative hypothesis of superiority based on on-treatment data from the safety population.p-value: 0.03495% CI: [0.74, 0.99]Cox Proportional Hazards model

Secondary

The Individual Components of the Composite Primary and Major Secondary Efficacy Outcome Measures: Myocardial Infarction

The number of patients with the first occurrence of a myocardial infarction while on treatment. The statistical analysis is based on time from randomization to the first occurrence of the event while on treatment.

Time frame: Up to 4 years

Population: The safety population consisted of all randomized unique patients who took at least 1 dose of study medication after randomization during the double-blind treatment period. Site 042012 with GCP violation was excluded.

Arm	Measure	Value (NUMBER)
Rivaroxaban	The Individual Components of the Composite Primary and Major Secondary Efficacy Outcome Measures: Myocardial Infarction	101 Patients
Warfarin	The Individual Components of the Composite Primary and Major Secondary Efficacy Outcome Measures: Myocardial Infarction	126 Patients

Comparison: Alternative hypothesis of superiority based on on-treatment data from the safety population.p-value: 0.12195% CI: [0.63, 1.06]Cox Proportional Hazards model

Secondary

The Individual Components of the Composite Primary and Major Secondary Efficacy Outcome Measures: Non-CNS Systemic Embolism

The number of patients with the first occurrence of a non-CNS systemic embolism while on treatment. The statistical analysis is based on time from randomization to the first occurrence of the event while on treatment.

Time frame: Up to 4 years

Population: The safety population consisted of all randomized unique patients who took at least 1 dose of study medication after randomization during the double-blind treatment period. Site 042012 with GCP violation was excluded.

Arm	Measure	Value (NUMBER)
Rivaroxaban	The Individual Components of the Composite Primary and Major Secondary Efficacy Outcome Measures: Non-CNS Systemic Embolism	5 Patients
Warfarin	The Individual Components of the Composite Primary and Major Secondary Efficacy Outcome Measures: Non-CNS Systemic Embolism	22 Patients

Comparison: Alternative hypothesis of superiority based on on-treatment data from the safety population.p-value: 0.00395% CI: [0.09, 0.61]Cox Proportional Hazards model

Secondary

The Individual Components of the Composite Primary and Major Secondary Efficacy Outcome Measures: Stroke

The number of patients with the first occurrence of a stroke while on treatment. The statistical analysis is based on time from randomization to the first occurrence of the event while on treatment.

Time frame: Up to 4 years

Population: The safety population consisted of all randomized unique patients who took at least 1 dose of study medication after randomization during the double-blind treatment period. Site 042012 with GCP violation was excluded.

Arm	Measure	Value (NUMBER)
Rivaroxaban	The Individual Components of the Composite Primary and Major Secondary Efficacy Outcome Measures: Stroke	184 Patients
Warfarin	The Individual Components of the Composite Primary and Major Secondary Efficacy Outcome Measures: Stroke	221 Patients

Comparison: Alternative hypothesis of superiority based on on-treatment data from the safety population.p-value: 0.09295% CI: [0.7, 1.03]Cox Proportional Hazards model

Secondary

The Individual Components of the Composite Primary and Major Secondary Efficacy Outcome Measures: Vascular Death

The number of patients with the occurrence of vascular death while on treatment. The statistical analysis is based on time from randomization to the event while on treatment.

Time frame: Up to 4 years

Population: The safety population consisted of all randomized unique patients who took at least 1 dose of study medication after randomization during the double-blind treatment period. Site 042012 with GCP violation was excluded.

Arm	Measure	Value (NUMBER)
Rivaroxaban	The Individual Components of the Composite Primary and Major Secondary Efficacy Outcome Measures: Vascular Death	170 Patients
Warfarin	The Individual Components of the Composite Primary and Major Secondary Efficacy Outcome Measures: Vascular Death	193 Patients

Comparison: Alternative hypothesis of superiority based on on-treatment data from the safety population.p-value: 0.28995% CI: [0.73, 1.1]Cox Proportional Hazards model

An Efficacy and Safety Study of Rivaroxaban With Warfarin for the Prevention of Stroke and Non-Central Nervous System Systemic Embolism in Patients With Non-Valvular Atrial Fibrillation

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The Composite Event of Major/Non-major Clinically Relevant Bleeding Events: Primary Safety

The Composite Event of Stroke/Non-CNS Systemic Embolism: Primary Efficacy (Non-Inferiority)

The Composite of Event of Stroke/Non-CNS Systemic Embolism: Primary Efficacy (Superiority)

All-cause Mortality

The Composite Event of Stroke/Non-CNS Systemic Embolism/Myocardial Infarction/Vascular Death

The Composite Event of Stroke/Non-CNS Systemic Embolism/Vascular Death

The Individual Components of the Composite Primary and Major Secondary Efficacy Outcome Measures: Myocardial Infarction

The Individual Components of the Composite Primary and Major Secondary Efficacy Outcome Measures: Non-CNS Systemic Embolism

The Individual Components of the Composite Primary and Major Secondary Efficacy Outcome Measures: Stroke

The Individual Components of the Composite Primary and Major Secondary Efficacy Outcome Measures: Vascular Death