Acute Coronary Syndrome
Conditions
Keywords
Acute Coronary Syndrome (ACS), Myocardial Ischemia, Rivaroxaban (BAY59-7939), Anti-platelet agents, Aspirin, Thienopyridine, Clopidogrel
Brief summary
The purpose of this study is to evaluate the safety of rivaroxaban in patients with recent acute coronary syndrome (ACS) and to assess the ability of rivaroxaban to reduce the occurrence of death, myocardial infarction (heart attack), repeat myocardial infarctions, stroke, and ischemia (inadequate blood supply to a local area) in patients with recent ACS.
Detailed description
This is a randomized (patients will be assigned to study treatment by chance), double-blind (neither the patient nor the study doctor will know the identity of the assigned study treatment) study to evaluate the safety and efficacy of rivaroxaban (study drug) compared to placebo (a tablet identical in appearance to study drug but contains no active drug) in patients with acute coronary syndrome (ACS \[a condition where blood flow in a blood vessel in the heart is restricted because of a blood clot\]). Rivaroxaban is a drug that acts as a blood thinner and is being tested to see if it will be safe and effective in patients diagnosed ACS. The goal of this study is to identify the dose and dosing schedule (once-a-day or twice-a-day dosing) of rivaroxaban that will be safe and effective in preventing adverse cardiovascular outcomes such as death, myocardial infarctions (MI) including repeat myocardial infarction (reMI), stroke, or ischemia (inadequate blood supply to a local area) requiring revascularization (ie, the re-establishment of blood supply to a part or an organ) in patients with ACS who are receiving antiplatelet therapy (ie, aspirin alone or aspirin plus an approved thienopyridine, a type of drug such as clopidogrel that acts to inhibit the formation of blood clots). Approximately 3500 patients are planned to participate in the study for approximately 7 months. At study entry, all patients who are currently receiving treatment for ACS with antiplatelet therapy will be permitted to continue this therapy during the study. Patients will be enrolled and randomized to receive placebo, rivaroxaban administered as a once-daily dose, or rivaroxaban administered as a twice-daily dose at each dose level of rivaroxaban tested. Patients randomized at each dose level will continue to receive the same treatment for 6 months. Near the end of enrollment at the first dose level, available safety and efficacy data from patients will be assessed by an Operations Committee before enrolling and randomizing additional patients to the next higher dose level of rivaroxaban. Increasing dose levels of rivaroxaban are planned; however, progression to each higher dose level will be at the discretion of the Operations Committee. Patient safety will be monitored by evaluating adverse events reported, results from clinical laboratory tests, findings from electrocardiograms (ECGs) and vital signs measurements, findings from physical examinations, and the number of patients with protocol-defined major or minor bleeding, or bleeding requiring medical attention. All patients will take study drug or placebo tablets orally (by mouth) twice daily for 6 months starting at an initial total daily dose of 5 mg. Both once- and twice-daily dosing regimens will be tested at each rivaroxaban dose level planned.
Interventions
DRUGRivaroxaban/Placebo
1 rivaroxaban tablet once daily (and 1 placebo tablet once daily) for 6 months. Safety at each dose level will be confirmed before additional patients are randomized to the next higher dose level.
DRUGPlacebo
1 placebo tablet twice daily for 6 months.
DRUGRivaroxaban
1 rivaroxaban tablet twice daily for 6 months. Safety at each dose level will be confirmed before additional patients are randomized to the next higher dose level.
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 75 Years
Healthy volunteers
No
Inclusion criteria
* Have symptoms suggestive of ACS that lasted at least 10 minutes at rest occurring within 7 days of randomization * Have a diagnosis of ST-elevation myocardial infarction or non-ST elevation myocardial infarction/unstable angina (ie, chest pain or discomfort) (ST elevation is an abnormal finding from an ECG test) with at least 1 protocol-defined high risk feature
Exclusion criteria
* Active bleeding or high risk of bleeding or intracranial hemorrhage (bleeding within the skull enclosing the brain) * Need for continued anticoagulant therapy * Significantly impaired renal (kidney) or hepatic (liver) function * Severe concomitant diseases such as cardiogenic shock (heart damage that results in insufficient blood supply to other parts or organs of the body), refractory ventricular arrhythmias (irregular contractions of the heart unresponsive to treatment), or any severe condition that would limit life expectancy of the patient to less than 6 months
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Thrombolysis in Myocardial Infarction (TIMI) Clinically Significant Bleeding Events (Primary Safety) | Day 1 to Day 210 | The number of patients with a first occurrence of a TIMI clinically significant bleeding event that occurred from the time of randomization to the time of the last patient contact. TIMI clinically significant bleeding events included TIMI minor bleeding events, TIMI major bleeding events, or any bleeding that required medical attention. |
| The Composite Endpoint of All Cause Death, Myocardial Infarction (MI) (Including Repeat MI), Stroke (Ischemic, Hemorrhagic or Unknown), or Severe Recurrent Ischemia Requiring Revascularization (Primary Efficacy) | Day 1 to Day 210 | The number of patients who died due to any cause or had a first occurrence of MI (including repeat MI) or stroke (ischemic, hemorrhagic or unknown) or severe recurrent ischemia requiring revascularization from the time of randomization to the last date of patient contact. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The Composite Endpoint of Death (All Cause), Myocardial Infarction (MI) (or Repeat MI), or Stroke | Day 1 to Day 210 | The number of patients who died due to any cause or had a first occurrence of MI (or repeat MI) or stroke from the time of randomization to the last date of patient contact. |
| The Composite Endpoint of Cardiovascular Death, Myocardial Infarction (MI), or Stroke | Day 1 to Day 210 | The number of patients with the composite endpoint of cardiovascular death or MI or stroke that occurred from the time of randomization to the last date of patient contact. |
| The Number of Deaths (All Cause) | Day 1 to Day 210 | The number of patients who died due to any cause from the time of randomization to the last date of patient contact. |
| The Composite Endpoint of Death (All Cause), MI (or reMI), Stroke, Severe Recurrent Ischemia Requiring Revascularization, or Thrombolysis in Myocardial Infarction (TIMI) (Major or Minor Bleeding) to Assess the Net Clinical Benefit | Day 1 to Day 210 | The number of patients who died due to any cause or had a first occurrence of MI (or repeat MI), or stroke, or severe recurrent ischemia requiring revascularization, or TIMI (major or minor bleeding) from the time of randomization to the last date of patient contact to assess the net clinical benefit of rivaroxaban. |
Participant flow
Recruitment details
NCT00402597: Study 39039039ACS2001 (ATLAS ACS TIMI 46 Trial) was conducted at 297 centers in 27 countries between 17 November 2006 and 19 September 2008. A total of 3576 patients were screened for study and 3491 patients were randomly assigned to treatment.
Pre-assignment details
Of the 3576 patients screened for study, 85 patients were screening failures and 3491 patients were randomly assigned to treatment. All randomized patients were included in the intent-to-treat (ITT) analysis set and were eligible for efficacy analyses. Of the 3491 patients, 29 never took study drug, leaving 3462 patients valid for safety analysis.
Participants by arm
| Arm | Count |
|---|---|
| Placebo One placebo tablet twice daily for 6 months. | 1,153 |
| Riva 5 mg Total Daily Dose (TDD) Rivaroxaban 5 mg (2.5 mg twice a day or 5 mg once daily) | 307 |
| Riva 10 mg TDD Rivaroxaban 10 mg (5 mg twice a day or 10 mg once daily) for 6 months. | 1,046 |
| Riva 15 mg TDD Rivaroxaban 15 mg (7.5 mg twice a day or 15 mg once daily) for 6 months. | 353 |
| Riva 20 mg TDD Rivaroxaban 20 mg (10 mg twice a day or 20 mg once daily) for 6 months. | 603 |
| Total | 3,462 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 81 | 18 | 106 | 39 | 71 |
| Overall Study | Death | 15 | 7 | 6 | 4 | 6 |
| Overall Study | Lost to Follow-up | 8 | 1 | 8 | 2 | 3 |
| Overall Study | reason not specified | 30 | 4 | 27 | 14 | 20 |
| Overall Study | Withdrawal by Subject | 57 | 16 | 65 | 15 | 24 |
Baseline characteristics
| Characteristic | Placebo | Riva 5 mg Total Daily Dose (TDD) | Riva 10 mg TDD | Riva 15 mg TDD | Riva 20 mg TDD | Total |
|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 306 Participants | 89 Participants | 260 Participants | 70 Participants | 145 Participants | 870 Participants |
| Age, Categorical Between 18 and 65 years | 847 Participants | 218 Participants | 786 Participants | 283 Participants | 458 Participants | 2592 Participants |
| Age Continuous | 57.8 years STANDARD_DEVIATION 9.58 | 58.1 years STANDARD_DEVIATION 9.76 | 57.2 years STANDARD_DEVIATION 9.71 | 56.4 years STANDARD_DEVIATION 9.38 | 57.4 years STANDARD_DEVIATION 9.06 | 57.4 years STANDARD_DEVIATION 9.53 |
| Region of Enrollment Australia | 75 participants | 14 participants | 73 participants | 15 participants | 29 participants | 206 participants |
| Region of Enrollment Belgium | 19 participants | 3 participants | 34 participants | 9 participants | 12 participants | 77 participants |
| Region of Enrollment Brazil | 11 participants | 0 participants | 26 participants | 0 participants | 0 participants | 37 participants |
| Region of Enrollment Bulgaria | 78 participants | 47 participants | 85 participants | 7 participants | 41 participants | 258 participants |
| Region of Enrollment Canada | 34 participants | 2 participants | 28 participants | 7 participants | 17 participants | 88 participants |
| Region of Enrollment China | 2 participants | 0 participants | 2 participants | 0 participants | 0 participants | 4 participants |
| Region of Enrollment Czech Republic | 48 participants | 0 participants | 58 participants | 33 participants | 41 participants | 180 participants |
| Region of Enrollment Denmark | 18 participants | 16 participants | 14 participants | 7 participants | 9 participants | 64 participants |
| Region of Enrollment Finland | 3 participants | 0 participants | 7 participants | 0 participants | 6 participants | 16 participants |
| Region of Enrollment France | 16 participants | 1 participants | 21 participants | 5 participants | 6 participants | 49 participants |
| Region of Enrollment Germany | 31 participants | 3 participants | 35 participants | 11 participants | 12 participants | 92 participants |
| Region of Enrollment Hungary | 11 participants | 0 participants | 14 participants | 7 participants | 4 participants | 36 participants |
| Region of Enrollment Israel | 43 participants | 0 participants | 26 participants | 16 participants | 11 participants | 96 participants |
| Region of Enrollment Italy | 43 participants | 3 participants | 56 participants | 17 participants | 17 participants | 136 participants |
| Region of Enrollment Korea (South) | 17 participants | 0 participants | 9 participants | 10 participants | 11 participants | 47 participants |
| Region of Enrollment Netherlands | 28 participants | 0 participants | 39 participants | 9 participants | 11 participants | 87 participants |
| Region of Enrollment New Zealand | 57 participants | 22 participants | 37 participants | 8 participants | 24 participants | 148 participants |
| Region of Enrollment Norway | 8 participants | 3 participants | 5 participants | 0 participants | 5 participants | 21 participants |
| Region of Enrollment Poland | 174 participants | 4 participants | 109 participants | 86 participants | 124 participants | 497 participants |
| Region of Enrollment Russia | 136 participants | 90 participants | 105 participants | 17 participants | 82 participants | 430 participants |
| Region of Enrollment Slovakia | 49 participants | 1 participants | 32 participants | 13 participants | 21 participants | 116 participants |
| Region of Enrollment South Africa | 6 participants | 0 participants | 7 participants | 0 participants | 4 participants | 17 participants |
| Region of Enrollment Spain | 35 participants | 5 participants | 36 participants | 12 participants | 15 participants | 103 participants |
| Region of Enrollment Sweden | 13 participants | 2 participants | 17 participants | 6 participants | 9 participants | 47 participants |
| Region of Enrollment Ukraine | 57 participants | 21 participants | 37 participants | 11 participants | 33 participants | 159 participants |
| Region of Enrollment United Kingdom | 9 participants | 1 participants | 19 participants | 15 participants | 8 participants | 52 participants |
| Region of Enrollment United States | 132 participants | 69 participants | 115 participants | 32 participants | 51 participants | 399 participants |
| Sex: Female, Male Female | 272 Participants | 78 Participants | 228 Participants | 67 Participants | 143 Participants | 788 Participants |
| Sex: Female, Male Male | 881 Participants | 229 Participants | 818 Participants | 286 Participants | 460 Participants | 2674 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 223 / 1,153 | 67 / 307 | 293 / 1,046 | 108 / 353 | 148 / 603 |
| serious Total, serious adverse events | 247 / 1,153 | 74 / 307 | 208 / 1,046 | 72 / 353 | 128 / 603 |
Outcome results
Primary
The Composite Endpoint of All Cause Death, Myocardial Infarction (MI) (Including Repeat MI), Stroke (Ischemic, Hemorrhagic or Unknown), or Severe Recurrent Ischemia Requiring Revascularization (Primary Efficacy)
The number of patients who died due to any cause or had a first occurrence of MI (including repeat MI) or stroke (ischemic, hemorrhagic or unknown) or severe recurrent ischemia requiring revascularization from the time of randomization to the last date of patient contact.
Time frame: Day 1 to Day 210
Population: The intent-to-treat (ITT) population consisted of all patients who were randomized to treatment, regardless of study drug intake.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | The Composite Endpoint of All Cause Death, Myocardial Infarction (MI) (Including Repeat MI), Stroke (Ischemic, Hemorrhagic or Unknown), or Severe Recurrent Ischemia Requiring Revascularization (Primary Efficacy) | 83 Patients |
| Riva 5 mg Total Daily Dose (TDD) | The Composite Endpoint of All Cause Death, Myocardial Infarction (MI) (Including Repeat MI), Stroke (Ischemic, Hemorrhagic or Unknown), or Severe Recurrent Ischemia Requiring Revascularization (Primary Efficacy) | 23 Patients |
| Riva 10 mg TDD | The Composite Endpoint of All Cause Death, Myocardial Infarction (MI) (Including Repeat MI), Stroke (Ischemic, Hemorrhagic or Unknown), or Severe Recurrent Ischemia Requiring Revascularization (Primary Efficacy) | 55 Patients |
| Riva 15 mg TDD | The Composite Endpoint of All Cause Death, Myocardial Infarction (MI) (Including Repeat MI), Stroke (Ischemic, Hemorrhagic or Unknown), or Severe Recurrent Ischemia Requiring Revascularization (Primary Efficacy) | 27 Patients |
| Riva 20 mg TDD | The Composite Endpoint of All Cause Death, Myocardial Infarction (MI) (Including Repeat MI), Stroke (Ischemic, Hemorrhagic or Unknown), or Severe Recurrent Ischemia Requiring Revascularization (Primary Efficacy) | 36 Patients |
Primary
Thrombolysis in Myocardial Infarction (TIMI) Clinically Significant Bleeding Events (Primary Safety)
The number of patients with a first occurrence of a TIMI clinically significant bleeding event that occurred from the time of randomization to the time of the last patient contact. TIMI clinically significant bleeding events included TIMI minor bleeding events, TIMI major bleeding events, or any bleeding that required medical attention.
Time frame: Day 1 to Day 210
Population: The safety population consisted of all randomized patients who took at least 1 dose of study medication after randomization during the double-blind treatment period.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Thrombolysis in Myocardial Infarction (TIMI) Clinically Significant Bleeding Events (Primary Safety) | 36 Patients |
| Riva 5 mg Total Daily Dose (TDD) | Thrombolysis in Myocardial Infarction (TIMI) Clinically Significant Bleeding Events (Primary Safety) | 17 Patients |
| Riva 10 mg TDD | Thrombolysis in Myocardial Infarction (TIMI) Clinically Significant Bleeding Events (Primary Safety) | 109 Patients |
| Riva 15 mg TDD | Thrombolysis in Myocardial Infarction (TIMI) Clinically Significant Bleeding Events (Primary Safety) | 43 Patients |
| Riva 20 mg TDD | Thrombolysis in Myocardial Infarction (TIMI) Clinically Significant Bleeding Events (Primary Safety) | 89 Patients |
Secondary
The Composite Endpoint of Cardiovascular Death, Myocardial Infarction (MI), or Stroke
The number of patients with the composite endpoint of cardiovascular death or MI or stroke that occurred from the time of randomization to the last date of patient contact.
Time frame: Day 1 to Day 210
Population: The ITT population consisted of all patients who were randomized to treatment regardless of study drug intake.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | The Composite Endpoint of Cardiovascular Death, Myocardial Infarction (MI), or Stroke | 63 Patients |
| Riva 5 mg Total Daily Dose (TDD) | The Composite Endpoint of Cardiovascular Death, Myocardial Infarction (MI), or Stroke | 18 Patients |
| Riva 10 mg TDD | The Composite Endpoint of Cardiovascular Death, Myocardial Infarction (MI), or Stroke | 40 Patients |
| Riva 15 mg TDD | The Composite Endpoint of Cardiovascular Death, Myocardial Infarction (MI), or Stroke | 21 Patients |
| Riva 20 mg TDD | The Composite Endpoint of Cardiovascular Death, Myocardial Infarction (MI), or Stroke | 21 Patients |
Secondary
The Composite Endpoint of Death (All Cause), MI (or reMI), Stroke, Severe Recurrent Ischemia Requiring Revascularization, or Thrombolysis in Myocardial Infarction (TIMI) (Major or Minor Bleeding) to Assess the Net Clinical Benefit
The number of patients who died due to any cause or had a first occurrence of MI (or repeat MI), or stroke, or severe recurrent ischemia requiring revascularization, or TIMI (major or minor bleeding) from the time of randomization to the last date of patient contact to assess the net clinical benefit of rivaroxaban.
Time frame: Day 1 to Day 210
Population: The ITT population consisted of all patients who were randomized to treatment, regardless of study drug intake.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | The Composite Endpoint of Death (All Cause), MI (or reMI), Stroke, Severe Recurrent Ischemia Requiring Revascularization, or Thrombolysis in Myocardial Infarction (TIMI) (Major or Minor Bleeding) to Assess the Net Clinical Benefit | 88 Patients |
| Riva 5 mg Total Daily Dose (TDD) | The Composite Endpoint of Death (All Cause), MI (or reMI), Stroke, Severe Recurrent Ischemia Requiring Revascularization, or Thrombolysis in Myocardial Infarction (TIMI) (Major or Minor Bleeding) to Assess the Net Clinical Benefit | 24 Patients |
| Riva 10 mg TDD | The Composite Endpoint of Death (All Cause), MI (or reMI), Stroke, Severe Recurrent Ischemia Requiring Revascularization, or Thrombolysis in Myocardial Infarction (TIMI) (Major or Minor Bleeding) to Assess the Net Clinical Benefit | 71 Patients |
| Riva 15 mg TDD | The Composite Endpoint of Death (All Cause), MI (or reMI), Stroke, Severe Recurrent Ischemia Requiring Revascularization, or Thrombolysis in Myocardial Infarction (TIMI) (Major or Minor Bleeding) to Assess the Net Clinical Benefit | 35 Patients |
| Riva 20 mg TDD | The Composite Endpoint of Death (All Cause), MI (or reMI), Stroke, Severe Recurrent Ischemia Requiring Revascularization, or Thrombolysis in Myocardial Infarction (TIMI) (Major or Minor Bleeding) to Assess the Net Clinical Benefit | 48 Patients |
Secondary
The Composite Endpoint of Death (All Cause), Myocardial Infarction (MI) (or Repeat MI), or Stroke
The number of patients who died due to any cause or had a first occurrence of MI (or repeat MI) or stroke from the time of randomization to the last date of patient contact.
Time frame: Day 1 to Day 210
Population: The ITT population consisted of all patients who were randomized to treatment, regardliess of study drug intake.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | The Composite Endpoint of Death (All Cause), Myocardial Infarction (MI) (or Repeat MI), or Stroke | 66 Patients |
| Riva 5 mg Total Daily Dose (TDD) | The Composite Endpoint of Death (All Cause), Myocardial Infarction (MI) (or Repeat MI), or Stroke | 18 Patients |
| Riva 10 mg TDD | The Composite Endpoint of Death (All Cause), Myocardial Infarction (MI) (or Repeat MI), or Stroke | 40 Patients |
| Riva 15 mg TDD | The Composite Endpoint of Death (All Cause), Myocardial Infarction (MI) (or Repeat MI), or Stroke | 21 Patients |
| Riva 20 mg TDD | The Composite Endpoint of Death (All Cause), Myocardial Infarction (MI) (or Repeat MI), or Stroke | 22 Patients |
Secondary
The Number of Deaths (All Cause)
The number of patients who died due to any cause from the time of randomization to the last date of patient contact.
Time frame: Day 1 to Day 210
Population: The ITT population consisted of all patients who were randomized to treatment, regardless of study drug intake.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | The Number of Deaths (All Cause) | 18 Patients |
| Riva 5 mg Total Daily Dose (TDD) | The Number of Deaths (All Cause) | 11 Patients |
| Riva 10 mg TDD | The Number of Deaths (All Cause) | 9 Patients |
| Riva 15 mg TDD | The Number of Deaths (All Cause) | 4 Patients |
| Riva 20 mg TDD | The Number of Deaths (All Cause) | 9 Patients |