Acute Coronary Syndrome, Myocardial Infarction, Myocardial Ischemia, Unstable Angina
Conditions
Keywords
Rivaroxaban, Acute Coronary Syndrome, ACS, Aspirin, Thienopyridine, Unstable Angina, Myocardial Infarction, Anticoagulation, Clopidogrel (Plavix)
Brief summary
The purpose of this study is to determine whether rivaroxaban in addition to standard care reduces the risk of the composite of cardiovascular death, myocardial infarction, or stroke in patients with a recent acute coronary syndrome compared with placebo.
Detailed description
Acute coronary syndrome (ACS) is a serious and life threatening condition. Following an acute coronary syndrome event patients are at risk of important additional clinical events such as death, myocardial infarction, and stroke. Six months after patients present with an index event of ST-segment myocardial infarction, approximately 15% will either have died or had another episode of myocardial ischemia, and a similar situation exists for non-ST-segment elevation myocardial infarction/unstable angina patients. This randomized; double-blind; placebo controlled study will evaluate the efficacy and safety of rivaroxaban in addition to standard care in patients with a recent ACS. Patients will be given rivaroxaban (2.5 mg twice daily or 5 mg twice daily) or placebo (twice daily) in addition to standard care.
Interventions
One tablet twice daily
DRUGRivaroxaban 5 mg
One tablet twice daily
DRUGPlacebo
One placebo tablet twice daily
DRUGStandard of care
Sponsors
Bayer
Johnson & Johnson Pharmaceutical Research & Development, L.L.C.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients must be currently receiving aspirin therapy alone or in combination with a thienopyridine per national or local dosing recommendation * Have been hospitalized for symptoms suggestive of acute coronary syndrome that lasted at least 10 minutes at rest and occurred 48 hours or less before going to the hospital
Exclusion criteria
* Any condition that, in the opinion of the investigator, contraindicates anticoagulant therapy or would have an unacceptable risk of bleeding * Need for continued anticoagulant therapy * Significant renal impairment or known significant liver disease
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Percentage of Patients With the Composite Endpoint of Cardiovascular Death, Myocardial Infarction, or Stroke | From the time of randomization (Day 1) up to completion of the treatment phase (Month 6) | The percentage of patients with the first occurrence of the composite of death, myocardial infarction, or stroke. The statistical analysis was based on the time from randomization to the first occurrence of the event while on treatment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The Percentage of Patients With the Composite of All Cause Death, Myocardial Infarction, or Stroke | From the time of randomization (Day 1) up to completion of the treatment phase (Month 6) | The percentage of patients with the first occurrence of the composite endpoint. The statistical analysis was based on the time from randomization to the first occurrence of the event while on treatment. |
| The Percentage of Patients With the Composite of Cardiovascular Death, Myocardial Infarction, Ischemic Stroke, or TIMI Major Bleeding Event Not Associated With Coronary Artery Bypass Graft Surgery | From the time of randomization (Day 1) up to completion of the treatment phase (Month 6) | The percentage of patients with the first occurrence of the composite endpoint. The statistical analysis was based on the time from randomization to the first occurrence of the event while on treatment. |
| The Percentage of Patients With the Composite of Cardiovascular Death, Myocardial Infarction, Stroke, or Severe Recurrent Ischemia Requiring Revascularization | From the time of randomization (Day 1) up to completion of the treatment phase (Month 6) | The percentage of patients with the first occurrence of the composite endpoint. The statistical analysis was based on the time from randomization to the first occurrence of the event while on treatment. |
| The Percentage of Patients With the Composite of Cardiovascular Death, Myocardial Infarction, Stroke, or Severe Recurrent Ischemia Leading to Hospitalization | From the time of randomization (Day 1) up to completion of the treatment phase (Month 6) | The percentage of patients with the first occurrence of the composite endpoint. The statistical analysis was based on the time from randomization to the first occurrence of the event while on treatment. |
Countries
Argentina, Australia, Belgium, Brazil, Bulgaria, Canada, Chile, China, Colombia, Croatia, Czechia, Denmark, Egypt, France, Germany, Greece, Hungary, India, Israel, Japan, Latvia, Lithuania, Malaysia, Mexico, Morocco, Netherlands, New Zealand, Philippines, Poland, Portugal, Romania, Russia, Serbia, Slovakia, South Korea, Spain, Sweden, Thailand, Tunisia, Turkey (Türkiye), Ukraine, United Kingdom, United States
Participant flow
Recruitment details
This study, an efficacy and safety study of rivaroxaban in patients with acute coronary syndrome, was conducted between 26 November 2008 and 19 September 2011. Patients were recruited from 766 study centers located in 44 countries worldwide.
Pre-assignment details
A total of 15,526 patients were randomly allocated to the 3 treatment arms in the study. A total of 15,350 patients (5,115 patients in the rivaroxaban 2.5 mg bid group, 5,110 patients in the rivaroxaban 5 mg bid group and 5,125 patients in the placebo group) who received at least 1 dose of study drug were included in the safety analysis set.
Participants by arm
| Arm | Count |
|---|---|
| Placebo One placebo tablet twice daily | 5,125 |
| Rivaroxaban 2.5 mg Bid One rivaroxaban 2.5 mg tablet twice daily | 5,115 |
| Rivaroxaban 5 mg Bid One rivaroxaban 5 mg tablet twice daily | 5,110 |
| Total | 15,350 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Death | 194 | 147 | 196 |
| Overall Study | Lost to Follow-up | 17 | 10 | 18 |
| Overall Study | Other Reason | 167 | 170 | 189 |
| Overall Study | Withdrawal by Subject | 405 | 448 | 441 |
Baseline characteristics
| Characteristic | Placebo | Rivaroxaban 2.5 mg Bid | Rivaroxaban 5 mg Bid | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1805 Participants | 1876 Participants | 1900 Participants | 5581 Participants |
| Age, Categorical Between 18 and 65 years | 3320 Participants | 3239 Participants | 3210 Participants | 9769 Participants |
| Age, Continuous | 61.5 years STANDARD_DEVIATION 9.38 | 61.8 years STANDARD_DEVIATION 9.22 | 61.9 years STANDARD_DEVIATION 9 | 61.7 years STANDARD_DEVIATION 9.2 |
| Region of Enrollment Argentina | 118 participants | 126 participants | 158 participants | 402 participants |
| Region of Enrollment Australia | 172 participants | 182 participants | 150 participants | 504 participants |
| Region of Enrollment Belgium | 59 participants | 57 participants | 53 participants | 169 participants |
| Region of Enrollment Brazil | 184 participants | 171 participants | 168 participants | 523 participants |
| Region of Enrollment Bulgaria | 258 participants | 264 participants | 268 participants | 790 participants |
| Region of Enrollment Canada | 67 participants | 58 participants | 63 participants | 188 participants |
| Region of Enrollment Chile | 67 participants | 65 participants | 78 participants | 210 participants |
| Region of Enrollment China | 281 participants | 299 participants | 302 participants | 882 participants |
| Region of Enrollment Colombia | 97 participants | 84 participants | 87 participants | 268 participants |
| Region of Enrollment Croatia | 21 participants | 19 participants | 22 participants | 62 participants |
| Region of Enrollment Czech Republic | 154 participants | 158 participants | 170 participants | 482 participants |
| Region of Enrollment Denmark | 35 participants | 21 participants | 41 participants | 97 participants |
| Region of Enrollment Egypt | 63 participants | 47 participants | 46 participants | 156 participants |
| Region of Enrollment France | 68 participants | 67 participants | 72 participants | 207 participants |
| Region of Enrollment Germany | 101 participants | 96 participants | 122 participants | 319 participants |
| Region of Enrollment Greece | 19 participants | 21 participants | 27 participants | 67 participants |
| Region of Enrollment Hungary | 147 participants | 142 participants | 122 participants | 411 participants |
| Region of Enrollment India | 479 participants | 507 participants | 473 participants | 1459 participants |
| Region of Enrollment Israel | 114 participants | 122 participants | 101 participants | 337 participants |
| Region of Enrollment Italy | 78 participants | 77 participants | 77 participants | 232 participants |
| Region of Enrollment Japan | 131 participants | 135 participants | 131 participants | 397 participants |
| Region of Enrollment Latvia | 27 participants | 33 participants | 40 participants | 100 participants |
| Region of Enrollment Lithuania | 59 participants | 51 participants | 66 participants | 176 participants |
| Region of Enrollment Malaysia | 36 participants | 33 participants | 26 participants | 95 participants |
| Region of Enrollment Mexico | 71 participants | 96 participants | 86 participants | 253 participants |
| Region of Enrollment Morocco | 12 participants | 22 participants | 22 participants | 56 participants |
| Region of Enrollment Netherlands | 131 participants | 113 participants | 124 participants | 368 participants |
| Region of Enrollment New Zealand | 28 participants | 31 participants | 38 participants | 97 participants |
| Region of Enrollment Philippines | 19 participants | 11 participants | 8 participants | 38 participants |
| Region of Enrollment Poland | 332 participants | 361 participants | 356 participants | 1049 participants |
| Region of Enrollment Portugal | 36 participants | 36 participants | 43 participants | 115 participants |
| Region of Enrollment Romania | 103 participants | 94 participants | 107 participants | 304 participants |
| Region of Enrollment Russian Federation | 586 participants | 596 participants | 569 participants | 1751 participants |
| Region of Enrollment Serbia | 43 participants | 45 participants | 29 participants | 117 participants |
| Region of Enrollment Slovakia | 67 participants | 58 participants | 53 participants | 178 participants |
| Region of Enrollment South Korea | 57 participants | 40 participants | 49 participants | 146 participants |
| Region of Enrollment Spain | 71 participants | 73 participants | 76 participants | 220 participants |
| Region of Enrollment Sweden | 58 participants | 41 participants | 44 participants | 143 participants |
| Region of Enrollment Thailand | 52 participants | 50 participants | 38 participants | 140 participants |
| Region of Enrollment Tunisia | 60 participants | 62 participants | 52 participants | 174 participants |
| Region of Enrollment Turkey | 37 participants | 39 participants | 41 participants | 117 participants |
| Region of Enrollment Ukraine | 205 participants | 210 participants | 213 participants | 628 participants |
| Region of Enrollment United Kingdom | 79 participants | 91 participants | 75 participants | 245 participants |
| Region of Enrollment United States | 243 participants | 211 participants | 224 participants | 678 participants |
| Sex: Female, Male Female | 1280 Participants | 1283 Participants | 1316 Participants | 3879 Participants |
| Sex: Female, Male Male | 3845 Participants | 3832 Participants | 3794 Participants | 11471 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 140 / 5,125 | 259 / 5,115 | 341 / 5,110 |
| serious Total, serious adverse events | 1,018 / 5,125 | 1,033 / 5,115 | 1,083 / 5,110 |
Outcome results
Primary
The Percentage of Patients With the Composite Endpoint of Cardiovascular Death, Myocardial Infarction, or Stroke
The percentage of patients with the first occurrence of the composite of death, myocardial infarction, or stroke. The statistical analysis was based on the time from randomization to the first occurrence of the event while on treatment.
Time frame: From the time of randomization (Day 1) up to completion of the treatment phase (Month 6)
Population: The Modified Intent-to-Treat (mITT) population consisted of all randomized patients, regardless of treatment exposure, excluding sites 091001, 091019, and 091026 (excluded due to potential trial misconduct). The mITT population was also subject to censoring of events that occurred on, or after, the global treatment end date.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | The Percentage of Patients With the Composite Endpoint of Cardiovascular Death, Myocardial Infarction, or Stroke | 7.4 Percentage of patients |
| Rivaroxaban 2.5 mg Bid | The Percentage of Patients With the Composite Endpoint of Cardiovascular Death, Myocardial Infarction, or Stroke | 6.1 Percentage of patients |
| Rivaroxaban 5 mg Bid | The Percentage of Patients With the Composite Endpoint of Cardiovascular Death, Myocardial Infarction, or Stroke | 6.1 Percentage of patients |
p-value: 0.0295% CI: [0.72, 0.97]Log Rank
p-value: 0.02895% CI: [0.73, 0.98]Log Rank
Secondary
The Percentage of Patients With the Composite of All Cause Death, Myocardial Infarction, or Stroke
The percentage of patients with the first occurrence of the composite endpoint. The statistical analysis was based on the time from randomization to the first occurrence of the event while on treatment.
Time frame: From the time of randomization (Day 1) up to completion of the treatment phase (Month 6)
Population: The Modified Intent-to-Treat (mITT) population consisted of all randomized patients, regardless of treatment exposure, excluding sites 091001, 091019, and 091026 (excluded due to potential trial misconduct). The mITT population was also subject to censoring of events that occurred on, or after, the global treatment end date.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | The Percentage of Patients With the Composite of All Cause Death, Myocardial Infarction, or Stroke | 7.5 Percentage of patients |
| Rivaroxaban 2.5 mg Bid | The Percentage of Patients With the Composite of All Cause Death, Myocardial Infarction, or Stroke | 6.3 Percentage of patients |
| Rivaroxaban 5 mg Bid | The Percentage of Patients With the Composite of All Cause Death, Myocardial Infarction, or Stroke | 6.3 Percentage of patients |
p-value: 0.01695% CI: [0.72, 0.97]Log Rank
p-value: 0.02595% CI: [0.73, 0.98]Log Rank
Secondary
The Percentage of Patients With the Composite of Cardiovascular Death, Myocardial Infarction, Ischemic Stroke, or TIMI Major Bleeding Event Not Associated With Coronary Artery Bypass Graft Surgery
The percentage of patients with the first occurrence of the composite endpoint. The statistical analysis was based on the time from randomization to the first occurrence of the event while on treatment.
Time frame: From the time of randomization (Day 1) up to completion of the treatment phase (Month 6)
Population: The Modified Intent-to-Treat (mITT) population consisted of all randomized patients, regardless of treatment exposure, excluding sites 091001, 091019, and 091026 (excluded due to potential trial misconduct). The mITT population was also subject to censoring of events that occurred on, or after, the global treatment end date.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | The Percentage of Patients With the Composite of Cardiovascular Death, Myocardial Infarction, Ischemic Stroke, or TIMI Major Bleeding Event Not Associated With Coronary Artery Bypass Graft Surgery | 7.6 Percentage of patients |
| Rivaroxaban 2.5 mg Bid | The Percentage of Patients With the Composite of Cardiovascular Death, Myocardial Infarction, Ischemic Stroke, or TIMI Major Bleeding Event Not Associated With Coronary Artery Bypass Graft Surgery | 7.1 Percentage of patients |
| Rivaroxaban 5 mg Bid | The Percentage of Patients With the Composite of Cardiovascular Death, Myocardial Infarction, Ischemic Stroke, or TIMI Major Bleeding Event Not Associated With Coronary Artery Bypass Graft Surgery | 7.2 Percentage of patients |
p-value: 0.3295% CI: [0.81, 1.07]Log Rank
p-value: 0.50895% CI: [0.83, 1.1]Log Rank
Secondary
The Percentage of Patients With the Composite of Cardiovascular Death, Myocardial Infarction, Stroke, or Severe Recurrent Ischemia Leading to Hospitalization
The percentage of patients with the first occurrence of the composite endpoint. The statistical analysis was based on the time from randomization to the first occurrence of the event while on treatment.
Time frame: From the time of randomization (Day 1) up to completion of the treatment phase (Month 6)
Population: The Modified Intent-to-Treat (mITT) population consisted of all randomized patients, regardless of treatment exposure, excluding sites 091001, 091019, and 091026 (excluded due to potential trial misconduct). The mITT population was also subject to censoring of events that occurred on, or after, the global treatment end date.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | The Percentage of Patients With the Composite of Cardiovascular Death, Myocardial Infarction, Stroke, or Severe Recurrent Ischemia Leading to Hospitalization | 8.7 Percentage of patients |
| Rivaroxaban 2.5 mg Bid | The Percentage of Patients With the Composite of Cardiovascular Death, Myocardial Infarction, Stroke, or Severe Recurrent Ischemia Leading to Hospitalization | 7.3 Percentage of patients |
| Rivaroxaban 5 mg Bid | The Percentage of Patients With the Composite of Cardiovascular Death, Myocardial Infarction, Stroke, or Severe Recurrent Ischemia Leading to Hospitalization | 7.6 Percentage of patients |
p-value: 0.01195% CI: [0.73, 0.96]Log Rank
p-value: 0.0795% CI: [0.78, 1.01]Log Rank
Secondary
The Percentage of Patients With the Composite of Cardiovascular Death, Myocardial Infarction, Stroke, or Severe Recurrent Ischemia Requiring Revascularization
The percentage of patients with the first occurrence of the composite endpoint. The statistical analysis was based on the time from randomization to the first occurrence of the event while on treatment.
Time frame: From the time of randomization (Day 1) up to completion of the treatment phase (Month 6)
Population: The Modified Intent-to-Treat (mITT) population consisted of all randomized patients, regardless of treatment exposure, excluding sites 091001, 091019, and 091026 (excluded due to potential trial misconduct). The mITT population was also subject to censoring of events that occurred on, or after, the global treatment end date.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | The Percentage of Patients With the Composite of Cardiovascular Death, Myocardial Infarction, Stroke, or Severe Recurrent Ischemia Requiring Revascularization | 9.4 Percentage of patients |
| Rivaroxaban 2.5 mg Bid | The Percentage of Patients With the Composite of Cardiovascular Death, Myocardial Infarction, Stroke, or Severe Recurrent Ischemia Requiring Revascularization | 8.5 Percentage of patients |
| Rivaroxaban 5 mg Bid | The Percentage of Patients With the Composite of Cardiovascular Death, Myocardial Infarction, Stroke, or Severe Recurrent Ischemia Requiring Revascularization | 8.2 Percentage of patients |
p-value: 0.18595% CI: [0.8, 1.04]Log Rank
p-value: 0.08195% CI: [0.78, 1.01]Log Rank