Trial Outcomes & Findings for Explore the Efficacy and Safety of Once-daily Oral Rivaroxaban for the Prevention of Cardiovascular Events in Subjects With Nonvalvular Atrial Fibrillation Scheduled for Cardioversion (NCT NCT01674647)

Last Updated: 2015-04-30

Results Overview

Stroke, TIA, Non-CNS Embolism, MI and cardiovascular death were adjudicated and confirmed by Clinical Endpoints Committee (CEC). Stroke included hemorrhagic and ischemic infarction. TIA including information if with or without matching lesion. Non CNS systemic embolism included emboli in peripheral arterial of the upper and lower extremities, ocular and retinal (pulmonary embolism and MI were excluded from the category). MI was assessed based on either cardiac biomarkers, new abnormal Q waves appeared on electrocardiogram for \>= 2 leads, or autopsy confirmation. Cardiovascular death included death in subjects with non-valvular atrial fibrillation (AF). Number of subjects with composite events were reported.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

1504 participants

Primary outcome timeframe

From randomization to the date of last dose of study drug +2 days for subjects who completed planned treatment or the earlier date [last planned dose, follow-up visit at the end of 30-day follow-up period] for subjects who prematurely stopped treatment

Results posted on

2015-04-30

Participant Flow

The study was conducted at 141 centers (involving 144 investigators) in Europe, South Africa, North America, and Asia Pacific.

Overall, 1584 subjects were screened and 80 subjects did not complete or pass screening. 1504 subjects were randomized; 1002 were assigned to rivaroxaban and 502 to vitamin K antagonist (VKA).

Participant milestones

Participant milestones
Measure	Rivaroxaban (Xarelto, BAY59-7939) Subjects randomized to treatment with rivaroxaban received rivaroxaban 20 milligram (mg) orally once daily. Subjects with moderate renal impairment \[i.e., Creatinine clearance (CrCl) of 30 to 49 milliliter per minute (mL/min), inclusive\] at screening received the adjusted dose of 15 mg once daily. The duration of the treatment period for a given subject depended on the cardioversion strategy. For subjects in the Direct Cardioversion Strategy, the cardioversion procedure was performed within 1-5 days after randomization. Rivaroxaban was given for 1-5 days before planned direct cardioversion and for 42 days thereafter. Subjects in the Delayed Cardioversion Strategy received rivaroxaban for 21 (+4) to 56 (+4) days prior to cardioversion and for 42 days thereafter. The investigator assessed whether or not long-term anticoagulation was warranted and treated the subject according to standard of care. Then subjects entered 30-day follow-up period.	Vitamin K Antagonist (VKA) Subjects assigned to treatment with VKA received VKA orally once daily titrated to a target INR of 2.5 (range 2.0-3.0, inclusive). The specific VKA was given by the investigator based on local standard of practice. For all subjects randomized to receive VKA, the investigator assessed if a parenteral anticoagulant drug, particularly before cardioversion, was needed as bridging therapy with VKA as standard of care (until target INR was achieved). The duration depended on the cardioversion strategy. For subjects in the Direct Cardioversion Strategy, cardioversion was performed within 1-5 days after randomization. VKA was given for 1-5 days before it and for 42 days thereafter. Subjects in the Delayed Cardioversion Strategy received VKA for 21 (+4) to 56 (+4) days before cardioversion and for 42 days thereafter. The investigator assessed if long-term anticoagulation was warranted and treated the subject according to standard of care or not. Then subjects entered 30-day follow-up period.
Treatment Period STARTED	1002	502
Treatment Period Subjects Received Treatment	988	499
Treatment Period COMPLETED	846	400
Treatment Period NOT COMPLETED	156	102
30-day Safety Follow-up Period STARTED	982	487
30-day Safety Follow-up Period COMPLETED	924	446
30-day Safety Follow-up Period NOT COMPLETED	58	41

Reasons for withdrawal

Reasons for withdrawal
Measure	Rivaroxaban (Xarelto, BAY59-7939) Subjects randomized to treatment with rivaroxaban received rivaroxaban 20 milligram (mg) orally once daily. Subjects with moderate renal impairment \[i.e., Creatinine clearance (CrCl) of 30 to 49 milliliter per minute (mL/min), inclusive\] at screening received the adjusted dose of 15 mg once daily. The duration of the treatment period for a given subject depended on the cardioversion strategy. For subjects in the Direct Cardioversion Strategy, the cardioversion procedure was performed within 1-5 days after randomization. Rivaroxaban was given for 1-5 days before planned direct cardioversion and for 42 days thereafter. Subjects in the Delayed Cardioversion Strategy received rivaroxaban for 21 (+4) to 56 (+4) days prior to cardioversion and for 42 days thereafter. The investigator assessed whether or not long-term anticoagulation was warranted and treated the subject according to standard of care. Then subjects entered 30-day follow-up period.	Vitamin K Antagonist (VKA) Subjects assigned to treatment with VKA received VKA orally once daily titrated to a target INR of 2.5 (range 2.0-3.0, inclusive). The specific VKA was given by the investigator based on local standard of practice. For all subjects randomized to receive VKA, the investigator assessed if a parenteral anticoagulant drug, particularly before cardioversion, was needed as bridging therapy with VKA as standard of care (until target INR was achieved). The duration depended on the cardioversion strategy. For subjects in the Direct Cardioversion Strategy, cardioversion was performed within 1-5 days after randomization. VKA was given for 1-5 days before it and for 42 days thereafter. Subjects in the Delayed Cardioversion Strategy received VKA for 21 (+4) to 56 (+4) days before cardioversion and for 42 days thereafter. The investigator assessed if long-term anticoagulation was warranted and treated the subject according to standard of care or not. Then subjects entered 30-day follow-up period.
Treatment Period Death	4	1
Treatment Period Efficacy outcome reached	0	1
Treatment Period Physician Decision	3	1
Treatment Period Adverse Event	60	22
Treatment Period Non-compliance with study drug	3	0
Treatment Period Lost to Follow-up	1	1
Treatment Period Withdrawal by Subject	19	16
Treatment Period Switching to other therapy	5	2
Treatment Period Logistical difficulties	5	8
Treatment Period Treatment failure	0	14
Treatment Period Protocol Violation	56	36
30-day Safety Follow-up Period Death	3	2
30-day Safety Follow-up Period Non-compliance with study drug	0	1
30-day Safety Follow-up Period Protocol Violation	39	22
30-day Safety Follow-up Period Logistical difficulties	1	3
30-day Safety Follow-up Period Withdrawal by Subject	7	8
30-day Safety Follow-up Period Lost to Follow-up	8	5

Baseline Characteristics

Explore the Efficacy and Safety of Once-daily Oral Rivaroxaban for the Prevention of Cardiovascular Events in Subjects With Nonvalvular Atrial Fibrillation Scheduled for Cardioversion

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Rivaroxaban (Xarelto, BAY59-7939) n=1002 Participants Subjects randomized to treatment with rivaroxaban received rivaroxaban 20 milligram (mg) orally once daily. Subjects with moderate renal impairment \[i.e., Creatinine clearance (CrCl) of 30 to 49 milliliter per minute (mL/min), inclusive\] at screening received the adjusted dose of 15 mg once daily. The duration of the treatment period for a given subject depended on the cardioversion strategy. For subjects in the Direct Cardioversion Strategy, the cardioversion procedure was performed within 1-5 days after randomization. Rivaroxaban was given for 1-5 days before planned direct cardioversion and for 42 days thereafter. Subjects in the Delayed Cardioversion Strategy received rivaroxaban for 21 (+4) to 56 (+4) days prior to cardioversion and for 42 days thereafter. The investigator assessed whether or not long-term anticoagulation was warranted and treated the subject according to standard of care. Then subjects entered 30-day follow-up period.	Vitamin K Antagonist (VKA) n=502 Participants Subjects assigned to treatment with VKA received VKA orally once daily titrated to a target INR of 2.5 (range 2.0-3.0, inclusive). The specific VKA was given by the investigator based on local standard of practice. For all subjects randomized to receive VKA, the investigator assessed if a parenteral anticoagulant drug, particularly before cardioversion, was needed as bridging therapy with VKA as standard of care (until target INR was achieved). The duration depended on the cardioversion strategy. For subjects in the Direct Cardioversion Strategy, cardioversion was performed within 1-5 days after randomization. VKA was given for 1-5 days before it and for 42 days thereafter. Subjects in the Delayed Cardioversion Strategy received VKA for 21 (+4) to 56 (+4) days before cardioversion and for 42 days thereafter. The investigator assessed if long-term anticoagulation was warranted and treated the subject according to standard of care or not. Then subjects entered 30-day follow-up period.	Total n=1504 Participants Total of all reporting groups
Age, Continuous	64.9 years STANDARD_DEVIATION 10.6 • n=99 Participants	64.7 years STANDARD_DEVIATION 10.5 • n=107 Participants	64.9 years STANDARD_DEVIATION 10.5 • n=206 Participants
Sex: Female, Male Female	275 Participants n=99 Participants	135 Participants n=107 Participants	410 Participants n=206 Participants
Sex: Female, Male Male	727 Participants n=99 Participants	367 Participants n=107 Participants	1094 Participants n=206 Participants
CHADS 2 score	1.3 units on scale STANDARD_DEVIATION 1.1 • n=99 Participants	1.4 units on scale STANDARD_DEVIATION 1.1 • n=107 Participants	1.4 units on scale STANDARD_DEVIATION 1.1 • n=206 Participants
CHA 2 DS 2 VASc score	2.3 units on scale STANDARD_DEVIATION 1.6 • n=99 Participants	2.3 units on scale STANDARD_DEVIATION 1.6 • n=107 Participants	2.3 units on scale STANDARD_DEVIATION 1.6 • n=206 Participants

PRIMARY outcome

Timeframe: From randomization to the date of last dose of study drug +2 days for subjects who completed planned treatment or the earlier date [last planned dose, follow-up visit at the end of 30-day follow-up period] for subjects who prematurely stopped treatment

Population: The primary population for the efficacy analysis was the modified intention-to-treat (mITT) population. mITT population included all the randomized subjects in whom a left atrial/left atrial appendage (LA/LAA) thrombus was not diagnosed during a transesophageal echocardiogram (TEE) performed before the first planned cardioversion in the study.

Outcome measures

Outcome measures
Measure	Rivaroxaban (Xarelto, BAY59-7939) n=978 Participants Subjects randomized to treatment with rivaroxaban received rivaroxaban 20 milligram (mg) orally once daily. Subjects with moderate renal impairment \[i.e., Creatinine clearance (CrCl) of 30 to 49 milliliter per minute (mL/min), inclusive\] at screening received the adjusted dose of 15 mg once daily. The duration of the treatment period for a given subject depended on the cardioversion strategy. For subjects in the Direct Cardioversion Strategy, the cardioversion procedure was performed within 1-5 days after randomization. Rivaroxaban was given for 1-5 days before planned direct cardioversion and for 42 days thereafter. Subjects in the Delayed Cardioversion Strategy received rivaroxaban for 21 (+4) to 56 (+4) days prior to cardioversion and for 42 days thereafter. The investigator assessed whether or not long-term anticoagulation was warranted and treated the subject according to standard of care. Then subjects entered 30-day follow-up period.	Vitamin K Antagonist (VKA) n=492 Participants Subjects assigned to treatment with VKA received VKA orally once daily titrated to a target INR of 2.5 (range 2.0-3.0, inclusive). The specific VKA was given by the investigator based on local standard of practice. For all subjects randomized to receive VKA, the investigator assessed if a parenteral anticoagulant drug, particularly before cardioversion, was needed as bridging therapy with VKA as standard of care (until target INR was achieved). The duration depended on the cardioversion strategy. For subjects in the Direct Cardioversion Strategy, cardioversion was performed within 1-5 days after randomization. VKA was given for 1-5 days before it and for 42 days thereafter. Subjects in the Delayed Cardioversion Strategy received VKA for 21 (+4) to 56 (+4) days before cardioversion and for 42 days thereafter. The investigator assessed if long-term anticoagulation was warranted and treated the subject according to standard of care or not. Then subjects entered 30-day follow-up period.
Number of Participants With Composite of the Following Events, Adjudicated Centrally: Stroke, Transient Ischemic Attack, Non-central Nervous System Systemic Embolism, Myocardial Infarction and Cardiovascular Death	5 Participants	5 Participants

PRIMARY outcome

Timeframe: From randomization up to the date of the last dose of study drug + 2 days

Population: The safety profile was analyzed using the safety analysis set (SAF) population. SAF population included all randomized subjects who received at least 1 dose of study medication.

Bleeding events were adjudicated and confirmed by CEC blinded to treatment. The CEC categorized the bleeding events as major or non-major. The bleeding events were defined per the International Society on Thrombosis and Hemostasis (ISTH) criteria. Major bleeding was clinically overt bleeding associated with a fall in hemoglobin of 2 gram per deciliter (g/dL) or higher, leading to a transfusion of 2 or more units of packed red blood cells or whole blood, occurring in a critical site or contributing to death. Number of subjects with confirmed adjudicated bleeding events occurring in greater than (\>)1 total subjects were reported.

Outcome measures

Outcome measures
Measure	Rivaroxaban (Xarelto, BAY59-7939) n=988 Participants Subjects randomized to treatment with rivaroxaban received rivaroxaban 20 milligram (mg) orally once daily. Subjects with moderate renal impairment \[i.e., Creatinine clearance (CrCl) of 30 to 49 milliliter per minute (mL/min), inclusive\] at screening received the adjusted dose of 15 mg once daily. The duration of the treatment period for a given subject depended on the cardioversion strategy. For subjects in the Direct Cardioversion Strategy, the cardioversion procedure was performed within 1-5 days after randomization. Rivaroxaban was given for 1-5 days before planned direct cardioversion and for 42 days thereafter. Subjects in the Delayed Cardioversion Strategy received rivaroxaban for 21 (+4) to 56 (+4) days prior to cardioversion and for 42 days thereafter. The investigator assessed whether or not long-term anticoagulation was warranted and treated the subject according to standard of care. Then subjects entered 30-day follow-up period.	Vitamin K Antagonist (VKA) n=499 Participants Subjects assigned to treatment with VKA received VKA orally once daily titrated to a target INR of 2.5 (range 2.0-3.0, inclusive). The specific VKA was given by the investigator based on local standard of practice. For all subjects randomized to receive VKA, the investigator assessed if a parenteral anticoagulant drug, particularly before cardioversion, was needed as bridging therapy with VKA as standard of care (until target INR was achieved). The duration depended on the cardioversion strategy. For subjects in the Direct Cardioversion Strategy, cardioversion was performed within 1-5 days after randomization. VKA was given for 1-5 days before it and for 42 days thereafter. Subjects in the Delayed Cardioversion Strategy received VKA for 21 (+4) to 56 (+4) days before cardioversion and for 42 days thereafter. The investigator assessed if long-term anticoagulation was warranted and treated the subject according to standard of care or not. Then subjects entered 30-day follow-up period.
Number of Participants With Major Bleedings as Per Central Adjudication	6 Participants	4 Participants

SECONDARY outcome

Population: The primary population for the efficacy analysis was the mITT population. mITT population included all the randomized subjects in whom a LA/LAA thrombus was not diagnosed during a TEE performed before the first planned cardioversion in the study.

Stroke and Non-CNS Embolism were adjudicated and confirmed by CEC. Stroke included hemorrhagic and ischemic infarction. Non CNS systemic embolism included emboli in peripheral arterial of the upper and lower extremities, ocular and retinal (pulmonary embolism and MI were excluded from the category). Number of subjects with composite events were reported.

Outcome measures

Outcome measures
Measure	Rivaroxaban (Xarelto, BAY59-7939) n=978 Participants Subjects randomized to treatment with rivaroxaban received rivaroxaban 20 milligram (mg) orally once daily. Subjects with moderate renal impairment \[i.e., Creatinine clearance (CrCl) of 30 to 49 milliliter per minute (mL/min), inclusive\] at screening received the adjusted dose of 15 mg once daily. The duration of the treatment period for a given subject depended on the cardioversion strategy. For subjects in the Direct Cardioversion Strategy, the cardioversion procedure was performed within 1-5 days after randomization. Rivaroxaban was given for 1-5 days before planned direct cardioversion and for 42 days thereafter. Subjects in the Delayed Cardioversion Strategy received rivaroxaban for 21 (+4) to 56 (+4) days prior to cardioversion and for 42 days thereafter. The investigator assessed whether or not long-term anticoagulation was warranted and treated the subject according to standard of care. Then subjects entered 30-day follow-up period.	Vitamin K Antagonist (VKA) n=492 Participants Subjects assigned to treatment with VKA received VKA orally once daily titrated to a target INR of 2.5 (range 2.0-3.0, inclusive). The specific VKA was given by the investigator based on local standard of practice. For all subjects randomized to receive VKA, the investigator assessed if a parenteral anticoagulant drug, particularly before cardioversion, was needed as bridging therapy with VKA as standard of care (until target INR was achieved). The duration depended on the cardioversion strategy. For subjects in the Direct Cardioversion Strategy, cardioversion was performed within 1-5 days after randomization. VKA was given for 1-5 days before it and for 42 days thereafter. Subjects in the Delayed Cardioversion Strategy received VKA for 21 (+4) to 56 (+4) days before cardioversion and for 42 days thereafter. The investigator assessed if long-term anticoagulation was warranted and treated the subject according to standard of care or not. Then subjects entered 30-day follow-up period.
Number of Participants With Composite of Strokes and Non-central Nervous System Systemic Embolisms	2 Participants	3 Participants

SECONDARY outcome

Stroke, TIA, Non- CNS systemic embolism, MI and all-cause mortality were adjudicated and confirmed by CEC. Stroke included hemorrhagic and ischemic infarction. TIA including information if with or without matching lesion. Non CNS systemic embolism included emboli in peripheral arterial of the upper and lower extremities, ocular and retinal (pulmonary embolism and MI were excluded from the category). MI was assessed based on either cardiac biomarkers, new abnormal Q waves appeared on electrocardiogram for \>= 2 leads, or autopsy confirmation. All-cause mortality included vascular death and non-vascular death. Number of subjects with composite events were reported.

Outcome measures

Outcome measures
Measure	Rivaroxaban (Xarelto, BAY59-7939) n=978 Participants Subjects randomized to treatment with rivaroxaban received rivaroxaban 20 milligram (mg) orally once daily. Subjects with moderate renal impairment \[i.e., Creatinine clearance (CrCl) of 30 to 49 milliliter per minute (mL/min), inclusive\] at screening received the adjusted dose of 15 mg once daily. The duration of the treatment period for a given subject depended on the cardioversion strategy. For subjects in the Direct Cardioversion Strategy, the cardioversion procedure was performed within 1-5 days after randomization. Rivaroxaban was given for 1-5 days before planned direct cardioversion and for 42 days thereafter. Subjects in the Delayed Cardioversion Strategy received rivaroxaban for 21 (+4) to 56 (+4) days prior to cardioversion and for 42 days thereafter. The investigator assessed whether or not long-term anticoagulation was warranted and treated the subject according to standard of care. Then subjects entered 30-day follow-up period.	Vitamin K Antagonist (VKA) n=492 Participants Subjects assigned to treatment with VKA received VKA orally once daily titrated to a target INR of 2.5 (range 2.0-3.0, inclusive). The specific VKA was given by the investigator based on local standard of practice. For all subjects randomized to receive VKA, the investigator assessed if a parenteral anticoagulant drug, particularly before cardioversion, was needed as bridging therapy with VKA as standard of care (until target INR was achieved). The duration depended on the cardioversion strategy. For subjects in the Direct Cardioversion Strategy, cardioversion was performed within 1-5 days after randomization. VKA was given for 1-5 days before it and for 42 days thereafter. Subjects in the Delayed Cardioversion Strategy received VKA for 21 (+4) to 56 (+4) days before cardioversion and for 42 days thereafter. The investigator assessed if long-term anticoagulation was warranted and treated the subject according to standard of care or not. Then subjects entered 30-day follow-up period.
Number of Participants With Composite of Strokes, Transient Ischemic Attacks, Non-central Nervous System Systemic Embolisms, Myocardial Infarctions and All-cause Mortality	6 Participants	6 Participants

SECONDARY outcome

All events were adjudicated and confirmed by a CEC blinded to treatment. Stroke included hemorrhagic (Stroke with local collections of intraparenchymal blood. Subarachnoid hemorrhage, subdural hemorrhage, and epidural hemorrhage were excluded), ischemic infarction (Stroke without focal collection of intracranial blood) and unknown (No imaging data and anatomic findings were available). Number of subjects with strokes were reported.

Outcome measures

Outcome measures
Measure	Rivaroxaban (Xarelto, BAY59-7939) n=978 Participants Subjects randomized to treatment with rivaroxaban received rivaroxaban 20 milligram (mg) orally once daily. Subjects with moderate renal impairment \[i.e., Creatinine clearance (CrCl) of 30 to 49 milliliter per minute (mL/min), inclusive\] at screening received the adjusted dose of 15 mg once daily. The duration of the treatment period for a given subject depended on the cardioversion strategy. For subjects in the Direct Cardioversion Strategy, the cardioversion procedure was performed within 1-5 days after randomization. Rivaroxaban was given for 1-5 days before planned direct cardioversion and for 42 days thereafter. Subjects in the Delayed Cardioversion Strategy received rivaroxaban for 21 (+4) to 56 (+4) days prior to cardioversion and for 42 days thereafter. The investigator assessed whether or not long-term anticoagulation was warranted and treated the subject according to standard of care. Then subjects entered 30-day follow-up period.	Vitamin K Antagonist (VKA) n=492 Participants Subjects assigned to treatment with VKA received VKA orally once daily titrated to a target INR of 2.5 (range 2.0-3.0, inclusive). The specific VKA was given by the investigator based on local standard of practice. For all subjects randomized to receive VKA, the investigator assessed if a parenteral anticoagulant drug, particularly before cardioversion, was needed as bridging therapy with VKA as standard of care (until target INR was achieved). The duration depended on the cardioversion strategy. For subjects in the Direct Cardioversion Strategy, cardioversion was performed within 1-5 days after randomization. VKA was given for 1-5 days before it and for 42 days thereafter. Subjects in the Delayed Cardioversion Strategy received VKA for 21 (+4) to 56 (+4) days before cardioversion and for 42 days thereafter. The investigator assessed if long-term anticoagulation was warranted and treated the subject according to standard of care or not. Then subjects entered 30-day follow-up period.
Number of Participants With Strokes	2 Participants	2 Participants

SECONDARY outcome

All events were adjudicated and confirmed by a CEC blinded to treatment. Number of subjects with TIA were reported.

Outcome measures

Outcome measures
Measure	Rivaroxaban (Xarelto, BAY59-7939) n=978 Participants Subjects randomized to treatment with rivaroxaban received rivaroxaban 20 milligram (mg) orally once daily. Subjects with moderate renal impairment \[i.e., Creatinine clearance (CrCl) of 30 to 49 milliliter per minute (mL/min), inclusive\] at screening received the adjusted dose of 15 mg once daily. The duration of the treatment period for a given subject depended on the cardioversion strategy. For subjects in the Direct Cardioversion Strategy, the cardioversion procedure was performed within 1-5 days after randomization. Rivaroxaban was given for 1-5 days before planned direct cardioversion and for 42 days thereafter. Subjects in the Delayed Cardioversion Strategy received rivaroxaban for 21 (+4) to 56 (+4) days prior to cardioversion and for 42 days thereafter. The investigator assessed whether or not long-term anticoagulation was warranted and treated the subject according to standard of care. Then subjects entered 30-day follow-up period.	Vitamin K Antagonist (VKA) n=492 Participants Subjects assigned to treatment with VKA received VKA orally once daily titrated to a target INR of 2.5 (range 2.0-3.0, inclusive). The specific VKA was given by the investigator based on local standard of practice. For all subjects randomized to receive VKA, the investigator assessed if a parenteral anticoagulant drug, particularly before cardioversion, was needed as bridging therapy with VKA as standard of care (until target INR was achieved). The duration depended on the cardioversion strategy. For subjects in the Direct Cardioversion Strategy, cardioversion was performed within 1-5 days after randomization. VKA was given for 1-5 days before it and for 42 days thereafter. Subjects in the Delayed Cardioversion Strategy received VKA for 21 (+4) to 56 (+4) days before cardioversion and for 42 days thereafter. The investigator assessed if long-term anticoagulation was warranted and treated the subject according to standard of care or not. Then subjects entered 30-day follow-up period.
Number of Participants With Transient Ischemic Attacks	0 Participants	0 Participants

SECONDARY outcome

All events were adjudicated and confirmed by a CEC blinded to treatment. Non CNS systemic embolism included emboli in peripheral arterial of the upper and lower extremities, ocular and retinal (pulmonary embolism and MI were excluded from the category). Number of subjects with non-CNS embolism were reported.

Outcome measures

Outcome measures
Measure	Rivaroxaban (Xarelto, BAY59-7939) n=978 Participants Subjects randomized to treatment with rivaroxaban received rivaroxaban 20 milligram (mg) orally once daily. Subjects with moderate renal impairment \[i.e., Creatinine clearance (CrCl) of 30 to 49 milliliter per minute (mL/min), inclusive\] at screening received the adjusted dose of 15 mg once daily. The duration of the treatment period for a given subject depended on the cardioversion strategy. For subjects in the Direct Cardioversion Strategy, the cardioversion procedure was performed within 1-5 days after randomization. Rivaroxaban was given for 1-5 days before planned direct cardioversion and for 42 days thereafter. Subjects in the Delayed Cardioversion Strategy received rivaroxaban for 21 (+4) to 56 (+4) days prior to cardioversion and for 42 days thereafter. The investigator assessed whether or not long-term anticoagulation was warranted and treated the subject according to standard of care. Then subjects entered 30-day follow-up period.	Vitamin K Antagonist (VKA) n=492 Participants Subjects assigned to treatment with VKA received VKA orally once daily titrated to a target INR of 2.5 (range 2.0-3.0, inclusive). The specific VKA was given by the investigator based on local standard of practice. For all subjects randomized to receive VKA, the investigator assessed if a parenteral anticoagulant drug, particularly before cardioversion, was needed as bridging therapy with VKA as standard of care (until target INR was achieved). The duration depended on the cardioversion strategy. For subjects in the Direct Cardioversion Strategy, cardioversion was performed within 1-5 days after randomization. VKA was given for 1-5 days before it and for 42 days thereafter. Subjects in the Delayed Cardioversion Strategy received VKA for 21 (+4) to 56 (+4) days before cardioversion and for 42 days thereafter. The investigator assessed if long-term anticoagulation was warranted and treated the subject according to standard of care or not. Then subjects entered 30-day follow-up period.
Number of Participants With Non-central Nervous System Systemic Embolisms	0 Participants	1 Participants

SECONDARY outcome

All events were adjudicated and confirmed by a CEC blinded to treatment. MI was assessed based onmeither cardiac biomarkers, new abnormal Q waves appeared on electrocardiogram for \>= 2 leads, or autopsy confirmation. Number of subjects with MI were reported.

Outcome measures

Outcome measures
Measure	Rivaroxaban (Xarelto, BAY59-7939) n=978 Participants Subjects randomized to treatment with rivaroxaban received rivaroxaban 20 milligram (mg) orally once daily. Subjects with moderate renal impairment \[i.e., Creatinine clearance (CrCl) of 30 to 49 milliliter per minute (mL/min), inclusive\] at screening received the adjusted dose of 15 mg once daily. The duration of the treatment period for a given subject depended on the cardioversion strategy. For subjects in the Direct Cardioversion Strategy, the cardioversion procedure was performed within 1-5 days after randomization. Rivaroxaban was given for 1-5 days before planned direct cardioversion and for 42 days thereafter. Subjects in the Delayed Cardioversion Strategy received rivaroxaban for 21 (+4) to 56 (+4) days prior to cardioversion and for 42 days thereafter. The investigator assessed whether or not long-term anticoagulation was warranted and treated the subject according to standard of care. Then subjects entered 30-day follow-up period.	Vitamin K Antagonist (VKA) n=492 Participants Subjects assigned to treatment with VKA received VKA orally once daily titrated to a target INR of 2.5 (range 2.0-3.0, inclusive). The specific VKA was given by the investigator based on local standard of practice. For all subjects randomized to receive VKA, the investigator assessed if a parenteral anticoagulant drug, particularly before cardioversion, was needed as bridging therapy with VKA as standard of care (until target INR was achieved). The duration depended on the cardioversion strategy. For subjects in the Direct Cardioversion Strategy, cardioversion was performed within 1-5 days after randomization. VKA was given for 1-5 days before it and for 42 days thereafter. Subjects in the Delayed Cardioversion Strategy received VKA for 21 (+4) to 56 (+4) days before cardioversion and for 42 days thereafter. The investigator assessed if long-term anticoagulation was warranted and treated the subject according to standard of care or not. Then subjects entered 30-day follow-up period.
Number of Participants With Myocardial Infarctions	1 Participants	1 Participants

SECONDARY outcome

All events were adjudicated and confirmed by a CEC blinded to treatment. Any death that was not clearly non-vascular (e.g., deaths due to spontaneous bleeding, myocardial infarction, stroke, cardiac failure, and arrhythmia). Number of subjects with cardiovascular deaths were reported.

Outcome measures

Outcome measures
Measure	Rivaroxaban (Xarelto, BAY59-7939) n=978 Participants Subjects randomized to treatment with rivaroxaban received rivaroxaban 20 milligram (mg) orally once daily. Subjects with moderate renal impairment \[i.e., Creatinine clearance (CrCl) of 30 to 49 milliliter per minute (mL/min), inclusive\] at screening received the adjusted dose of 15 mg once daily. The duration of the treatment period for a given subject depended on the cardioversion strategy. For subjects in the Direct Cardioversion Strategy, the cardioversion procedure was performed within 1-5 days after randomization. Rivaroxaban was given for 1-5 days before planned direct cardioversion and for 42 days thereafter. Subjects in the Delayed Cardioversion Strategy received rivaroxaban for 21 (+4) to 56 (+4) days prior to cardioversion and for 42 days thereafter. The investigator assessed whether or not long-term anticoagulation was warranted and treated the subject according to standard of care. Then subjects entered 30-day follow-up period.	Vitamin K Antagonist (VKA) n=492 Participants Subjects assigned to treatment with VKA received VKA orally once daily titrated to a target INR of 2.5 (range 2.0-3.0, inclusive). The specific VKA was given by the investigator based on local standard of practice. For all subjects randomized to receive VKA, the investigator assessed if a parenteral anticoagulant drug, particularly before cardioversion, was needed as bridging therapy with VKA as standard of care (until target INR was achieved). The duration depended on the cardioversion strategy. For subjects in the Direct Cardioversion Strategy, cardioversion was performed within 1-5 days after randomization. VKA was given for 1-5 days before it and for 42 days thereafter. Subjects in the Delayed Cardioversion Strategy received VKA for 21 (+4) to 56 (+4) days before cardioversion and for 42 days thereafter. The investigator assessed if long-term anticoagulation was warranted and treated the subject according to standard of care or not. Then subjects entered 30-day follow-up period.
Number of Participants With Cardiovascular Deaths	4 Participants	2 Participants

SECONDARY outcome

All events were adjudicated and confirmed by a CEC blinded to treatment. All-cause mortality included vascular death and non-vascular death. Number of subjects with all-cause mortality were reported.

Outcome measures

Outcome measures
Measure	Rivaroxaban (Xarelto, BAY59-7939) n=978 Participants Subjects randomized to treatment with rivaroxaban received rivaroxaban 20 milligram (mg) orally once daily. Subjects with moderate renal impairment \[i.e., Creatinine clearance (CrCl) of 30 to 49 milliliter per minute (mL/min), inclusive\] at screening received the adjusted dose of 15 mg once daily. The duration of the treatment period for a given subject depended on the cardioversion strategy. For subjects in the Direct Cardioversion Strategy, the cardioversion procedure was performed within 1-5 days after randomization. Rivaroxaban was given for 1-5 days before planned direct cardioversion and for 42 days thereafter. Subjects in the Delayed Cardioversion Strategy received rivaroxaban for 21 (+4) to 56 (+4) days prior to cardioversion and for 42 days thereafter. The investigator assessed whether or not long-term anticoagulation was warranted and treated the subject according to standard of care. Then subjects entered 30-day follow-up period.	Vitamin K Antagonist (VKA) n=492 Participants Subjects assigned to treatment with VKA received VKA orally once daily titrated to a target INR of 2.5 (range 2.0-3.0, inclusive). The specific VKA was given by the investigator based on local standard of practice. For all subjects randomized to receive VKA, the investigator assessed if a parenteral anticoagulant drug, particularly before cardioversion, was needed as bridging therapy with VKA as standard of care (until target INR was achieved). The duration depended on the cardioversion strategy. For subjects in the Direct Cardioversion Strategy, cardioversion was performed within 1-5 days after randomization. VKA was given for 1-5 days before it and for 42 days thereafter. Subjects in the Delayed Cardioversion Strategy received VKA for 21 (+4) to 56 (+4) days before cardioversion and for 42 days thereafter. The investigator assessed if long-term anticoagulation was warranted and treated the subject according to standard of care or not. Then subjects entered 30-day follow-up period.
Number of Participants With All-cause Mortality	5 Participants	3 Participants

SECONDARY outcome

Timeframe: From randomization up to the date of the last dose of study drug + 2 days

Population: The safety profile was analyzed using the SAF population. SAF population included all randomized subjects who received at least 1 dose of study medication.

All events were adjudicated and confirmed by a CEC blinded to treatment. The CEC categorized the bleeding events as major or non-major. The bleeding events were defined per the ISTH criteria. Clinically relevant bleeding included major bleeding (overt bleeding associated with 2 g/dL or greater fall in hemoglobin, leading to a transfusion of 2 or more units of packed red blood cells or whole blood, occurring in a critical site or contributing to death) and non-major bleeding associated with medical intervention, unscheduled physician contact, (temporary) cessation of study treatment, discomfort for the participants such as pain, or impairment of activities of daily life. Number of subjects with clinically relevant major and non-major bleeding events were reported.

Outcome measures

Outcome measures
Measure	Rivaroxaban (Xarelto, BAY59-7939) n=988 Participants Subjects randomized to treatment with rivaroxaban received rivaroxaban 20 milligram (mg) orally once daily. Subjects with moderate renal impairment \[i.e., Creatinine clearance (CrCl) of 30 to 49 milliliter per minute (mL/min), inclusive\] at screening received the adjusted dose of 15 mg once daily. The duration of the treatment period for a given subject depended on the cardioversion strategy. For subjects in the Direct Cardioversion Strategy, the cardioversion procedure was performed within 1-5 days after randomization. Rivaroxaban was given for 1-5 days before planned direct cardioversion and for 42 days thereafter. Subjects in the Delayed Cardioversion Strategy received rivaroxaban for 21 (+4) to 56 (+4) days prior to cardioversion and for 42 days thereafter. The investigator assessed whether or not long-term anticoagulation was warranted and treated the subject according to standard of care. Then subjects entered 30-day follow-up period.	Vitamin K Antagonist (VKA) n=499 Participants Subjects assigned to treatment with VKA received VKA orally once daily titrated to a target INR of 2.5 (range 2.0-3.0, inclusive). The specific VKA was given by the investigator based on local standard of practice. For all subjects randomized to receive VKA, the investigator assessed if a parenteral anticoagulant drug, particularly before cardioversion, was needed as bridging therapy with VKA as standard of care (until target INR was achieved). The duration depended on the cardioversion strategy. For subjects in the Direct Cardioversion Strategy, cardioversion was performed within 1-5 days after randomization. VKA was given for 1-5 days before it and for 42 days thereafter. Subjects in the Delayed Cardioversion Strategy received VKA for 21 (+4) to 56 (+4) days before cardioversion and for 42 days thereafter. The investigator assessed if long-term anticoagulation was warranted and treated the subject according to standard of care or not. Then subjects entered 30-day follow-up period.
Number of Participants With Composite of Major and Non-major Bleeding Events	33 Participants	14 Participants

Adverse Events

Rivaroxaban (Xarelto; BAY59-7939)

Serious events: 93 serious events

Other events: 272 other events

Deaths: 0 deaths

Vitamin K Antagonist

Serious events: 38 serious events

Other events: 126 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Bayer HealthCare AG

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The Consultant agrees not to publish or cause to be published any works of authorship relating to the Project rendered pursuant to this Agreement without first notifying Bayer in writing and obtaining Bayer's written consent. Bayer will respond to such notification within sixty (60) days of receipt.Bayer reserves the right to insist on the removal of all or any of its Confidential Information from any such work prior to publication
Publication restrictions are in place

Restriction type: OTHER

Measure	Rivaroxaban (Xarelto; BAY59-7939) n=988 participants at risk Subjects randomized to treatment with rivaroxaban received rivaroxaban 20 milligram (mg) orally once daily. Subjects with moderate renal impairment \[i.e., Creatinine clearance (CrCl) of 30 to 49 milliliter per minute (mL/min), inclusive\] at screening received the adjusted dose of 15 mg once daily. The duration of the treatment period for a given subject depended on the cardioversion strategy. For subjects in the Direct Cardioversion Strategy, the cardioversion procedure was performed within 1-5 days after randomization. Rivaroxaban was given for 1-5 days before planned direct cardioversion and for 42 days thereafter. Subjects in the Delayed Cardioversion Strategy received rivaroxaban for 21 (+4) to 56 (+4) days prior to cardioversion and for 42 days thereafter. The investigator assessed whether or not long-term anticoagulation was warranted and treated the subject according to standard of care. Then subjects entered 30-day follow-up period.	Vitamin K Antagonist n=499 participants at risk Subjects assigned to treatment with VKA received VKA orally once daily titrated to a target INR of 2.5 (range 2.0-3.0, inclusive). The specific VKA was given by the investigator based on local standard of practice. For all subjects randomized to receive VKA, the investigator assessed if a parenteral anticoagulant drug, particularly before cardioversion, was needed as bridging therapy with VKA as standard of care (until target INR was achieved). The duration depended on the cardioversion strategy. For subjects in the Direct Cardioversion Strategy, cardioversion was performed within 1-5 days after randomization. VKA was given for 1-5 days before it and for 42 days thereafter. Subjects in the Delayed Cardioversion Strategy received VKA for 21 (+4) to 56 (+4) days before cardioversion and for 42 days thereafter. The investigator assessed if long-term anticoagulation was warranted and treated the subject according to standard of care or not. Then subjects entered 30-day follow-up period.
Cardiac disorders Atrial fibrillation	0.20% 2/988 • From first administration of study drug to date of last study drug + 2 days	1.4% 7/499 • From first administration of study drug to date of last study drug + 2 days
Cardiac disorders Atrial thrombosis	1.6% 16/988 • From first administration of study drug to date of last study drug + 2 days	1.2% 6/499 • From first administration of study drug to date of last study drug + 2 days
Cardiac disorders Atrioventricular block first degree	4.0% 40/988 • From first administration of study drug to date of last study drug + 2 days	5.0% 25/499 • From first administration of study drug to date of last study drug + 2 days
Cardiac disorders Bradycardia	3.0% 30/988 • From first administration of study drug to date of last study drug + 2 days	2.6% 13/499 • From first administration of study drug to date of last study drug + 2 days
Cardiac disorders Sinus bradycardia	2.5% 25/988 • From first administration of study drug to date of last study drug + 2 days	2.4% 12/499 • From first administration of study drug to date of last study drug + 2 days
Gastrointestinal disorders Constipation	1.0% 10/988 • From first administration of study drug to date of last study drug + 2 days	0.60% 3/499 • From first administration of study drug to date of last study drug + 2 days
Gastrointestinal disorders Diarrhoea	1.8% 18/988 • From first administration of study drug to date of last study drug + 2 days	0.60% 3/499 • From first administration of study drug to date of last study drug + 2 days
Gastrointestinal disorders Nausea	1.7% 17/988 • From first administration of study drug to date of last study drug + 2 days	0.20% 1/499 • From first administration of study drug to date of last study drug + 2 days
General disorders Fatigue	1.4% 14/988 • From first administration of study drug to date of last study drug + 2 days	1.8% 9/499 • From first administration of study drug to date of last study drug + 2 days
General disorders Oedema peripheral	2.0% 20/988 • From first administration of study drug to date of last study drug + 2 days	1.0% 5/499 • From first administration of study drug to date of last study drug + 2 days
Infections and infestations Influenza	0.30% 3/988 • From first administration of study drug to date of last study drug + 2 days	1.0% 5/499 • From first administration of study drug to date of last study drug + 2 days
Infections and infestations Nasopharyngitis	1.2% 12/988 • From first administration of study drug to date of last study drug + 2 days	1.0% 5/499 • From first administration of study drug to date of last study drug + 2 days
Infections and infestations Urinary tract infection	0.71% 7/988 • From first administration of study drug to date of last study drug + 2 days	1.0% 5/499 • From first administration of study drug to date of last study drug + 2 days
Injury, poisoning and procedural complications Contusion	0.30% 3/988 • From first administration of study drug to date of last study drug + 2 days	1.0% 5/499 • From first administration of study drug to date of last study drug + 2 days
Investigations International normalised ratio increased	0.10% 1/988 • From first administration of study drug to date of last study drug + 2 days	1.8% 9/499 • From first administration of study drug to date of last study drug + 2 days
Nervous system disorders Dizziness	2.5% 25/988 • From first administration of study drug to date of last study drug + 2 days	1.8% 9/499 • From first administration of study drug to date of last study drug + 2 days
Nervous system disorders Headache	2.5% 25/988 • From first administration of study drug to date of last study drug + 2 days	1.4% 7/499 • From first administration of study drug to date of last study drug + 2 days
Respiratory, thoracic and mediastinal disorders Cough	1.3% 13/988 • From first administration of study drug to date of last study drug + 2 days	0.60% 3/499 • From first administration of study drug to date of last study drug + 2 days
Respiratory, thoracic and mediastinal disorders Dyspnoea	1.6% 16/988 • From first administration of study drug to date of last study drug + 2 days	2.4% 12/499 • From first administration of study drug to date of last study drug + 2 days
Respiratory, thoracic and mediastinal disorders Epistaxis	3.0% 30/988 • From first administration of study drug to date of last study drug + 2 days	1.8% 9/499 • From first administration of study drug to date of last study drug + 2 days
Skin and subcutaneous tissue disorders Rash	1.2% 12/988 • From first administration of study drug to date of last study drug + 2 days	1.0% 5/499 • From first administration of study drug to date of last study drug + 2 days
Vascular disorders Hypertension	2.2% 22/988 • From first administration of study drug to date of last study drug + 2 days	0.80% 4/499 • From first administration of study drug to date of last study drug + 2 days