Rivaroxaban for the Prevention of Major Cardiovascular Events in Coronary or Peripheral Artery Disease

Phase 3

Completed

• Conditions: Prevention & Control
• Interventions: Drug: Rivaroxaban (Xarelto, BAY59-7939); Drug: Rivaroxaban placebo; Drug: Aspirin placebo; Drug: Aspirin; Drug: Pantoprazole; Drug: Pantoprazole placebo

• Registration Number: NCT01776424
• Lead Sponsor: Bayer

Brief Summary

The primary objectives of this study are:

* To determine whether rivaroxaban 2.5 mg twice daily (bid) + aspirin 100 mg once daily (od) compared with aspirin 100 mg od reduces the risk of a composite of myocardial infarction, stroke, or cardiovascular death in subjects with coronary artery disease (CAD) or peripheral artery disease (PAD);

* To determine whether rivaroxaban 5 mg bid compared with aspirin 100 mg od reduces the risk of a composite of myocardial infarction, stroke or cardiovascular death in subjects with CAD or PAD.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2013-01-24
• Study First Submitted QC: 2013-01-25
• Study First Posted: 2013-01-28
• Study Start: 2013-02-28
• Primary Completion: 2017-07-21
• Results First Submitted: 2018-07-16
• Results First Submitted QC: 2018-09-06
• Results First Posted: 2018-10-05
• Study Completion: 2021-06-15
• Status Verified: 2022-11
• Last Update Submitted: 2022-11-03
• Last Update Posted: 2022-11-28

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 27395

Inclusion Criteria

• Meet criteria for CAD and/or PAD

Subjects with CAD must also meet at least one of the following criteria:

• Age ≥65, or
• Age <65 and documented atherosclerosis or revascularization involving at least 2 vascular beds, or at least 2 additional risk factors

Exclusion Criteria

• Stroke within 1 month or any history of hemorrhagic or lacunar stroke
• Severe heart failure with known ejection fraction <30% or New York Heart Association (NYHA) class III or IV symptoms
• Estimated glomerular filtration rate (eGFR)<15 mL/min
• Need for dual antiplatelet therapy, other non-aspirin antiplatelet therapy, or oral anticoagulant therapy

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Rivaroxaban 2.5mg + Aspirin 100mg	Rivaroxaban (Xarelto, BAY59-7939)	Participants received rivaroxaban 2.5 mg twice daily (bid) and aspirin 100 mg once daily (od). All doses were provided in tablet form for oral administration. Participants who did not have a continuous need to take a proton pump inhibitor (PPI), were additionally randomized 1:1 to receive pantoprazole 40 mg (tablet form for oral administration, od) or matching placebo od. Participants who consented to LTOLE part received open label rivaroxaban 2.5 mg bid and aspirin 100 mg od in LTOLE part.
Rivaroxaban 5mg + Aspirin Placebo	Rivaroxaban (Xarelto, BAY59-7939)	Participants received rivaroxaban 5 mg bid and aspirin placebo od. All doses were provided in tablet form for oral administration. Participants who did not have a continuous need to take a PPI, were additionally randomized 1:1 to receive pantoprazole 40 mg (tablet form for oral administration, od) or matching placebo od. Participants who consented to LTOLE part received open label rivaroxaban 2.5 mg bid and aspirin 100 mg od in LTOLE part.
Rivaroxaban Placebo + Aspirin 100mg	Rivaroxaban placebo	Participants received rivaroxaban placebo bid and aspirin 100 mg od. All doses were provided in tablet form for oral administration. Participants who did not have a continuous need to take a PPI, were randomized 1:1 to receive pantoprazole 40 mg (tablet form for oral administration, od) or matching placebo od. Participants who consented to LTOLE part received open label rivaroxaban 2.5 mg bid and aspirin 100 mg od in LTOLE part.
Rivaroxaban 5mg + Aspirin Placebo	Aspirin placebo	Participants received rivaroxaban 5 mg bid and aspirin placebo od. All doses were provided in tablet form for oral administration. Participants who did not have a continuous need to take a PPI, were additionally randomized 1:1 to receive pantoprazole 40 mg (tablet form for oral administration, od) or matching placebo od. Participants who consented to LTOLE part received open label rivaroxaban 2.5 mg bid and aspirin 100 mg od in LTOLE part.
Rivaroxaban 5mg + Aspirin Placebo	Pantoprazole placebo	Participants received rivaroxaban 5 mg bid and aspirin placebo od. All doses were provided in tablet form for oral administration. Participants who did not have a continuous need to take a PPI, were additionally randomized 1:1 to receive pantoprazole 40 mg (tablet form for oral administration, od) or matching placebo od. Participants who consented to LTOLE part received open label rivaroxaban 2.5 mg bid and aspirin 100 mg od in LTOLE part.
Rivaroxaban Placebo + Aspirin 100mg	Pantoprazole placebo	Participants received rivaroxaban placebo bid and aspirin 100 mg od. All doses were provided in tablet form for oral administration. Participants who did not have a continuous need to take a PPI, were randomized 1:1 to receive pantoprazole 40 mg (tablet form for oral administration, od) or matching placebo od. Participants who consented to LTOLE part received open label rivaroxaban 2.5 mg bid and aspirin 100 mg od in LTOLE part.
Rivaroxaban 2.5mg + Aspirin 100mg	Pantoprazole placebo	Participants received rivaroxaban 2.5 mg twice daily (bid) and aspirin 100 mg once daily (od). All doses were provided in tablet form for oral administration. Participants who did not have a continuous need to take a proton pump inhibitor (PPI), were additionally randomized 1:1 to receive pantoprazole 40 mg (tablet form for oral administration, od) or matching placebo od. Participants who consented to LTOLE part received open label rivaroxaban 2.5 mg bid and aspirin 100 mg od in LTOLE part.
Rivaroxaban 2.5mg + Aspirin 100mg	Aspirin	Participants received rivaroxaban 2.5 mg twice daily (bid) and aspirin 100 mg once daily (od). All doses were provided in tablet form for oral administration. Participants who did not have a continuous need to take a proton pump inhibitor (PPI), were additionally randomized 1:1 to receive pantoprazole 40 mg (tablet form for oral administration, od) or matching placebo od. Participants who consented to LTOLE part received open label rivaroxaban 2.5 mg bid and aspirin 100 mg od in LTOLE part.
Rivaroxaban 2.5mg + Aspirin 100mg	Pantoprazole	Participants received rivaroxaban 2.5 mg twice daily (bid) and aspirin 100 mg once daily (od). All doses were provided in tablet form for oral administration. Participants who did not have a continuous need to take a proton pump inhibitor (PPI), were additionally randomized 1:1 to receive pantoprazole 40 mg (tablet form for oral administration, od) or matching placebo od. Participants who consented to LTOLE part received open label rivaroxaban 2.5 mg bid and aspirin 100 mg od in LTOLE part.
Rivaroxaban 5mg + Aspirin Placebo	Pantoprazole	Participants received rivaroxaban 5 mg bid and aspirin placebo od. All doses were provided in tablet form for oral administration. Participants who did not have a continuous need to take a PPI, were additionally randomized 1:1 to receive pantoprazole 40 mg (tablet form for oral administration, od) or matching placebo od. Participants who consented to LTOLE part received open label rivaroxaban 2.5 mg bid and aspirin 100 mg od in LTOLE part.
Rivaroxaban Placebo + Aspirin 100mg	Aspirin	Participants received rivaroxaban placebo bid and aspirin 100 mg od. All doses were provided in tablet form for oral administration. Participants who did not have a continuous need to take a PPI, were randomized 1:1 to receive pantoprazole 40 mg (tablet form for oral administration, od) or matching placebo od. Participants who consented to LTOLE part received open label rivaroxaban 2.5 mg bid and aspirin 100 mg od in LTOLE part.
Rivaroxaban Placebo + Aspirin 100mg	Pantoprazole	Participants received rivaroxaban placebo bid and aspirin 100 mg od. All doses were provided in tablet form for oral administration. Participants who did not have a continuous need to take a PPI, were randomized 1:1 to receive pantoprazole 40 mg (tablet form for oral administration, od) or matching placebo od. Participants who consented to LTOLE part received open label rivaroxaban 2.5 mg bid and aspirin 100 mg od in LTOLE part.

Primary Outcome Measures

Name	Time	Method
The First Occurrence of the Composite Primary Efficacy Outcome, Myocardial Infarction (MI), Stroke, or Cardiovascular (CV) Death	For each participant, the first occurrence of the composite primary efficacy outcome after randomization up until the global rivaroxaban/aspirin outcomes cut-off date (06 FEB 2017) was considered. The mean time in follow-up until that date was 702 days.	Count of participants and time from randomization to the first occurrence of the composite primary efficacy outcome, MI, stroke, or CV death were evaluated. Hazard ratios were calculated and reported as statistical analysis.
The First Occurrence of the Primary Safety Outcome Major Bleeding Based on a Modification of the International Society on Thrombosis and Haemostasis (ISTH) Criteria	For each participant, the first occurrence of modified ISTH major bleeding after randomization up until the global rivaroxaban/aspirin outcomes cut-off date (06 FEB 2017) was considered. The mean time in follow-up until that date was 702 days.	Modified ISTH major bleeding is defined as: i) Fatal bleeding, or ii) Symptomatic bleeding in a critical area or organ, such as intraarticular, intracranial, intramuscular with compartment syndrome, intraocular, intraspinal, liver, pancreas, pericardial, respiratory, retroperitoneal, adrenal gland or kidney; or bleeding into the surgical site requiring reoperation, or iii) Bleeding leading to hospitalization (major bleeding also includes presentation to an acute care facility with discharge on the same day).; Count of participants and time from randomization to the first occurrence of the primary safety outcome major bleeding were evaluated. Hazard ratios were calculated and reported as statistical analysis.

Secondary Outcome Measures

Name	Time	Method
The First Occurrence of MI, Ischemic Stroke, ALI, or Cardiovascular (CV) Death	For each participant, the first occurrence of MI, ischemic stroke, ALI, or CV death after randomization up until the global rivaroxaban/aspirin outcomes cut-off date (06 FEB 2017) was considered. The mean time in follow-up until that date was 702 days.	Count of participants and time from randomization to the first occurrence of MI, ischemic stroke, ALI, or CV death were evaluated. Hazard ratios were calculated and reported as statistical analysis.
The First Occurrence of Myocardial Infarction (MI), Ischemic Stroke, Acute Limb Ischemia (ALI), or Coronary Heart Disease (CHD) Death	For each participant, the first occurrence of MI, ALI, or CHD death after randomization up until the global rivaroxaban/aspirin outcomes cut-off date (06 FEB 2017) was considered. The mean time in follow-up until that date was 702 days.	Count of participants and time from randomization to the first occurrence of MI, ischemic stroke, ALI, or CHD death were evaluated. Hazard ratios were calculated and reported as statistical analysis.
All-cause Mortality	For each participants, death by any cause after randomization up until the global rivaroxaban/aspirin outcomes cut-off date (06 FEB 2017) was considered. The mean time in follow-up until that date was 702 days.	Count of participants and time from randomization to death by all cause were evaluated. Hazard ratios were calculated and reported as statistical analysis.