Prevention & Control
Conditions
Keywords
Cardiovascular events, Rivaroxaban, Xarelto, Anticoagulant, Blood thinner, Aspirin, ASA, Coronary artery disease, CAD, Peripheral artery disease, PAD, Artery disease, Coronary artery bypass graft, Stroke, Heart attack, Angina, Arterial vascular disease, Myocardial infarction, MI, Cardiovascular Death, CV Death, Heart disease
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.
Interventions
DRUGRivaroxaban (Xarelto, BAY59-7939)
Tablet, 2.5 mg, twice daily, oral
DRUGAspirin
Tablet, 100 mg, once daily, oral
DRUGAspirin placebo
Aspirin matching placebo, once daily, oral
Rivaroxaban matching placebo, twice daily, oral
DRUGPantoprazole
Tablet, 40 mg, once daily, oral, for participants who were not on a PPI and who were randomized to pantoprazole
DRUGPantoprazole placebo
Pantoprazole matching placebo, once daily, oral, for participants who were not on a PPI and who were randomized to pantoprazole placebo
Sponsors
Population Health Research Institute
Janssen Research & Development, LLC
Bayer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Participants who consented to COMPASS long-term open-label extension (LTOLE) part received open label rivaroxaban 2.5 mg bid and aspirin 100 mg od in LTOLE part and no blinding procedures were applicable to the LTOLE part.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| The First Occurrence of the Primary Safety Outcome Major Bleeding Based on a Modification of the International Society on Thrombosis and Haemostasis (ISTH) Criteria in LTOLE Part | For each participant, the first occurrence of modified ISTH major bleeding from COMPASS LTOLE initiation visit up until 2 days after the last treatment in LTOLE part was considered. The mean time in follow-up was 421 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 from COMPASS LTOLE initiation visit to the first occurrence of the primary safety outcome major bleeding was evaluated. LTOLE: long-term open-lable extension |
| All-cause Mortality in LTOLE Part | For each participants, death by any cause after COMPASS LTOLE initiation visit up until the the last LTOLE part contact date was considered. The mean time in follow-up until that date was 428 days. | Count of participants from COMPASS LTOLE initiation visit to death by all cause were evaluated. LTOLE: long-term open-lable extension |
| The First Occurrence of the Composite Primary Efficacy Outcome, Myocardial Infarction (MI), Stroke, or Cardiovascular (CV) Death in LTOLE Part | For each participant, the first occurrence of the composite primary efficacy outcome after from COMPASS LTOLE initiation visit up until last LTOLE part contact date was considered. The mean time in follow-up was 428 days. | Count of participants from COMPASS LTOLE initiation visit to the first occurrence of the composite primary efficacy outcome, MI, stroke, or CV death were evaluated. LTOLE: long-term open-lable extension |
Countries
Argentina, Australia, Belgium, Brazil, Canada, Chile, China, Colombia, Czechia, Denmark, Ecuador, Finland, France, Germany, Hungary, Ireland, Israel, Italy, Japan, Malaysia, Netherlands, Philippines, Poland, Romania, Russia, Slovakia, South Africa, South Korea, Sweden, Switzerland, Ukraine, United Kingdom, United States
Participant flow
Recruitment details
Study was conducted at 608 centers with randomized participants in 33 countries between 28 Feb 2013 (first patient first visit) and 15 Jun 2021 (last patient last visit of long-term open-label extension part).
Pre-assignment details
Overall, 29872 participants were screened, of which 2477 participants were screen failures. A total of 27395 participants were randomized to antithrombotic treatment. 17598 participants were randomized to pantoprazole/placebo treatment. 12964 participants joined long-term open-label extension (LTOLE) part.
Participants by arm
| Arm | Count |
|---|---|
| Rivaroxaban 2.5mg + Aspirin 100mg 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. | 9,152 |
| Rivaroxaban 5mg + 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. | 9,117 |
| Rivaroxaban Placebo + Aspirin 100mg 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. | 9,126 |
| Total | 27,395 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Antithrombotic Part (Double Blind) | Lost to Follow-up | 10 | 8 | 9 |
| Antithrombotic Part (Double Blind) | Withdrawal by Subject | 10 | 11 | 15 |
| LTOLE Part (Open Label) | Lost to Follow-up | 6 | 2 | 5 |
| LTOLE Part (Open Label) | Missing final visit | 68 | 58 | 62 |
| LTOLE Part (Open Label) | Refused | 5 | 2 | 11 |
Baseline characteristics
| Characteristic | Rivaroxaban 2.5mg + Aspirin 100mg | Rivaroxaban 5mg + Aspirin Placebo | Rivaroxaban Placebo + Aspirin 100mg | Total |
|---|---|---|---|---|
| Age, Continuous | 68.3 Years STANDARD_DEVIATION 7.9 | 68.2 Years STANDARD_DEVIATION 7.9 | 68.2 Years STANDARD_DEVIATION 8 | 68.2 Years STANDARD_DEVIATION 7.9 |
| Race/Ethnicity, Customized Black/African American | 76 Participants | 94 Participants | 92 Participants | 262 Participants |
| Race/Ethnicity, Customized Chinese | 388 Participants | 381 Participants | 376 Participants | 1145 Participants |
| Race/Ethnicity, Customized Hispanic | 1769 Participants | 1751 Participants | 1758 Participants | 5278 Participants |
| Race/Ethnicity, Customized Other | 183 Participants | 179 Participants | 197 Participants | 559 Participants |
| Race/Ethnicity, Customized Other Asian | 956 Participants | 938 Participants | 915 Participants | 2809 Participants |
| Race/Ethnicity, Customized South Asian | 107 Participants | 102 Participants | 106 Participants | 315 Participants |
| Race/Ethnicity, Customized White/Caucasian | 5673 Participants | 5672 Participants | 5682 Participants | 17027 Participants |
| Sex: Female, Male Female | 2059 Participants | 1972 Participants | 1989 Participants | 6020 Participants |
| Sex: Female, Male Male | 7093 Participants | 7145 Participants | 7137 Participants | 21375 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 529 / 9,152 | 566 / 9,117 | 566 / 9,126 | 283 / 12,964 |
| other Total, other adverse events | 557 / 9,134 | 529 / 9,109 | 501 / 9,107 | 49 / 12,903 |
| serious Total, serious adverse events | 692 / 9,134 | 664 / 9,109 | 630 / 9,107 | 292 / 12,903 |
Outcome results
Primary
The First Occurrence of the Composite Primary Efficacy Outcome, Myocardial Infarction (MI), Stroke, or Cardiovascular (CV) Death
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.
Time frame: 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.
Population: ITT: included all participants randomized to antithrombotic treatment for the initial study part. The ITT set comprised both participants randomized to pantoprazole/placebo and participants not randomized to pantoprazole/placebo.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Rivaroxaban 2.5mg + Aspirin 100mg | The First Occurrence of the Composite Primary Efficacy Outcome, Myocardial Infarction (MI), Stroke, or Cardiovascular (CV) Death | 379 Participants |
| Rivaroxaban 5mg + Aspirin Placebo | The First Occurrence of the Composite Primary Efficacy Outcome, Myocardial Infarction (MI), Stroke, or Cardiovascular (CV) Death | 448 Participants |
| Rivaroxaban Placebo + Aspirin 100mg | The First Occurrence of the Composite Primary Efficacy Outcome, Myocardial Infarction (MI), Stroke, or Cardiovascular (CV) Death | 496 Participants |
p-value: 0.0000495% CI: [0.66, 0.86]Log Rank
p-value: 0.114995% CI: [0.79, 1.03]Log Rank
Primary
The First Occurrence of the Primary Safety Outcome Major Bleeding Based on a Modification of the International Society on Thrombosis and Haemostasis (ISTH) Criteria
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.
Time frame: 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.
Population: ITT: included all participants randomized to antithrombotic treatment for the initial study part. The ITT set comprised both participants randomized to pantoprazole/placebo and participants not randomized to pantoprazole/placebo.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Rivaroxaban 2.5mg + Aspirin 100mg | The First Occurrence of the Primary Safety Outcome Major Bleeding Based on a Modification of the International Society on Thrombosis and Haemostasis (ISTH) Criteria | 288 Participants |
| Rivaroxaban 5mg + Aspirin Placebo | The First Occurrence of the Primary Safety Outcome Major Bleeding Based on a Modification of the International Society on Thrombosis and Haemostasis (ISTH) Criteria | 255 Participants |
| Rivaroxaban Placebo + Aspirin 100mg | The First Occurrence of the Primary Safety Outcome Major Bleeding Based on a Modification of the International Society on Thrombosis and Haemostasis (ISTH) Criteria | 170 Participants |
p-value: <0.0000195% CI: [1.4, 2.05]Log Rank
p-value: 0.0000395% CI: [1.25, 1.84]Log Rank
Secondary
All-cause Mortality
Count of participants and time from randomization to death by all cause were evaluated. Hazard ratios were calculated and reported as statistical analysis.
Time frame: 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.
Population: ITT: included all participants randomized to antithrombotic treatment for the initial study part. The ITT set comprised both participants randomized to pantoprazole/placebo and participants not randomized to pantoprazole/placebo.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Rivaroxaban 2.5mg + Aspirin 100mg | All-cause Mortality | 313 Participants |
| Rivaroxaban 5mg + Aspirin Placebo | All-cause Mortality | 366 Participants |
| Rivaroxaban Placebo + Aspirin 100mg | All-cause Mortality | 378 Participants |
p-value: 0.0106295% CI: [0.71, 0.96]Log Rank
p-value: 0.6641895% CI: [0.84, 1.12]Log Rank
Secondary
The First Occurrence of MI, Ischemic Stroke, ALI, or Cardiovascular (CV) Death
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.
Time frame: 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.
Population: ITT: included all participants randomized to antithrombotic treatment for the initial study part. The ITT set comprised both participants randomized to pantoprazole/placebo and participants not randomized to pantoprazole/placebo.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Rivaroxaban 2.5mg + Aspirin 100mg | The First Occurrence of MI, Ischemic Stroke, ALI, or Cardiovascular (CV) Death | 389 Participants |
| Rivaroxaban 5mg + Aspirin Placebo | The First Occurrence of MI, Ischemic Stroke, ALI, or Cardiovascular (CV) Death | 453 Participants |
| Rivaroxaban Placebo + Aspirin 100mg | The First Occurrence of MI, Ischemic Stroke, ALI, or Cardiovascular (CV) Death | 516 Participants |
p-value: 0.0000195% CI: [0.65, 0.85]Log Rank
p-value: 0.0399595% CI: [0.77, 0.99]Log Rank
Secondary
The First Occurrence of Myocardial Infarction (MI), Ischemic Stroke, Acute Limb Ischemia (ALI), or Coronary Heart Disease (CHD) Death
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.
Time frame: 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.
Population: ITT: included all participants randomized to antithrombotic treatment for the initial study part. The ITT set comprised both participants randomized to pantoprazole/placebo and participants not randomized to pantoprazole/placebo.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Rivaroxaban 2.5mg + Aspirin 100mg | The First Occurrence of Myocardial Infarction (MI), Ischemic Stroke, Acute Limb Ischemia (ALI), or Coronary Heart Disease (CHD) Death | 329 Participants |
| Rivaroxaban 5mg + Aspirin Placebo | The First Occurrence of Myocardial Infarction (MI), Ischemic Stroke, Acute Limb Ischemia (ALI), or Coronary Heart Disease (CHD) Death | 397 Participants |
| Rivaroxaban Placebo + Aspirin 100mg | The First Occurrence of Myocardial Infarction (MI), Ischemic Stroke, Acute Limb Ischemia (ALI), or Coronary Heart Disease (CHD) Death | 450 Participants |
p-value: 0.0000195% CI: [0.63, 0.83]Log Rank
p-value: 0.0643795% CI: [0.77, 1.01]Log Rank
Other Pre-specified
All-cause Mortality in LTOLE Part
Count of participants from COMPASS LTOLE initiation visit to death by all cause were evaluated. LTOLE: long-term open-lable extension
Time frame: For each participants, death by any cause after COMPASS LTOLE initiation visit up until the the last LTOLE part contact date was considered. The mean time in follow-up until that date was 428 days.
Population: LTOLE ITT: included all participants who completed COMPASS LTOLE initiation visit (LTOLE initiation visit date entered).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Rivaroxaban 2.5mg + Aspirin 100mg | All-cause Mortality in LTOLE Part | 282 Participants |
Other Pre-specified
The First Occurrence of the Composite Primary Efficacy Outcome, Myocardial Infarction (MI), Stroke, or Cardiovascular (CV) Death in LTOLE Part
Count of participants from COMPASS LTOLE initiation visit to the first occurrence of the composite primary efficacy outcome, MI, stroke, or CV death were evaluated. LTOLE: long-term open-lable extension
Time frame: For each participant, the first occurrence of the composite primary efficacy outcome after from COMPASS LTOLE initiation visit up until last LTOLE part contact date was considered. The mean time in follow-up was 428 days.
Population: LTOLE ITT: included all participants who completed COMPASS LTOLE initiation visit (LTOLE initiation visit date entered).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Rivaroxaban 2.5mg + Aspirin 100mg | The First Occurrence of the Composite Primary Efficacy Outcome, Myocardial Infarction (MI), Stroke, or Cardiovascular (CV) Death in LTOLE Part | 353 Participants |
Other Pre-specified
The First Occurrence of the Primary Safety Outcome Major Bleeding Based on a Modification of the International Society on Thrombosis and Haemostasis (ISTH) Criteria in LTOLE Part
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 from COMPASS LTOLE initiation visit to the first occurrence of the primary safety outcome major bleeding was evaluated. LTOLE: long-term open-lable extension
Time frame: For each participant, the first occurrence of modified ISTH major bleeding from COMPASS LTOLE initiation visit up until 2 days after the last treatment in LTOLE part was considered. The mean time in follow-up was 421 days.
Population: LTOLE SAF: included all participants who completed COMPASS LTOLE initiation visit and who received at least one dose of medication in LTOLE part.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Rivaroxaban 2.5mg + Aspirin 100mg | The First Occurrence of the Primary Safety Outcome Major Bleeding Based on a Modification of the International Society on Thrombosis and Haemostasis (ISTH) Criteria in LTOLE Part | 138 Participants |