Acute Coronary Syndrome
Conditions
Keywords
Acute Coronary Syndrome, Myocardial infarction, Unstable angina, Acetylsalicylic acid, Rivaroxaban, JNJ-39039039, Bay 59-7939, Xarelto, Clopidogrel, Ticagrelor, Plavix, Brilinta, Effient
Brief summary
The purpose of this study is to estimate the risk of bleeding with rivaroxaban, compared with acetylsalicylic acid (ASA), in addition to a single antiplatelet/ platelet adenosine diphosphate P2Y12 receptor antagonist (P2Y12 inhibitor agent: clopidogrel or ticagrelor), in participants with a recent acute coronary syndrome (ACS: including ST segment elevation myocardial infarction \[STEMI\] and non-ST-segment elevation acute coronary syndrome \[NSTE-ACS\]).
Detailed description
This is a prospective, randomized (the study drug is assigned by chance), double-blind (neither physician nor participant knows the treatment that the participant receives), active-controlled (study in which the experimental treatment or procedure is compared to a standard treatment or procedure), parallel group (each group of participants will be treated at the same time), multicenter (when more than one hospital or medical school team work on a medical research study) study in participants with a recent ACS (STEMI or NSTE-ACS). All the eligible participants receiving background treatment of ASA plus clopidogrel (Stratum 1) or ASA plus ticagrelor (Stratum 2) will be randomly assigned to either receive ASA or rivaroxaban on background of P2Y12 receptor antagonists treatment. This study will include 3 phases: Screening Phase (up to 10 days, before study start on Day 1), Double-blind Treatment Phase (up to either 180 days after randomization of the last enrolled participant in the study or Day 360, whichever occurs earlier), and Follow-up Phase (up to 30 days). Participants' safety will be monitored throughout the study.
Interventions
DRUGAcetylsalicylic acid
ASA 100 mg enteric-coated tablet once daily orally.
DRUGRivaroxaban
Rivaroxaban 2.5 mg tablet twice daily orally.
DRUGClopidogrel
Clopidogrel 75 mg once daily orally.
DRUGTicagrelor
Ticagrelor 90 mg twice daily orally.
Sponsors
Bayer
Duke Clinical Research Institute
Harvard Medical School (HMS and HSDM)
Janssen Research & Development, LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Participants, 18 years or older, must have symptoms suggestive of acute coronary syndrome (ACS) (angina, or symptoms thought to be equivalent) within 48 hours of hospital presentation, or developed ACS while being hospitalized, and has a diagnosis of: a) ST segment elevation myocardial infarction (STEMI); b) non-ST-segment elevation acute coronary syndrome (NSTE-ACS). However, participant who is 54 years of age or younger must also have either diabetes mellitus or a history of a prior myocardial infarction (MI), in addition to the presenting ACS event * Participant must be randomized within the screening window of 10 days after hospital admission for the index ACS event. Participant should have received acute phase treatment for the index ACS, such as intravenous anticoagulant or antiplatelet, and are receiving maintenance dual antiplatelet therapy (DAPT) with either clopidogrel plus acetyl salicylic acid (ASA), or ticagrelor plus ASA, with the intent to continue the treatment with a platelet adenosine diphosphate P2Y12 receptor antagonist (P2Y12 inhibitor) after randomization * Participants must agree to provide a pharmacogenomics deoxyribonucleic acid (DNA) sample
Exclusion criteria
* Participant has any conditions that, in the opinion of the investigator, contraindicates anticoagulant therapy or would have an unacceptable risk * Participant with a prior stroke of any etiology or transient ischemic attack (TIA) * Participant who received thrombolytic therapy as treatment for the index ACS event cannot be enrolled in the ticagrelor stratum * Participant has anticipated need for chronic administration of omeprazole or esomeprazole concomitantly with clopidogrel * Participant has known allergy or intolerance to ASA or rivaroxaban
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Non Coronary Artery Bypass Graft-Related (Non CABG-related) Thrombolysis in Myocardial Infarction (TIMI) Clinically Significant Bleeding Events | From start of study treatment until follow-up (up to 390 days) | Non CABG-related TIMI clinically significant bleeding events are sum of non CABG-related TIMI major bleeding events, TIMI minor bleeding events and TIMI bleeding events requiring medical attention. Major: any symptomatic intracranial bleeding: clinically overt signs of hemorrhage with hemoglobin (Hb) drop of greater than or equal to (\>=)5 gram per deciliter (g/dl) (or absolute drop in hematocrit of \>=15%) and fatal bleeding (results in death within 7 days); Minor: clinically overt sign of hemorrhage with Hb drop of 3 - \<5 g/dl (or drop in hematocrit of 9 - \<15%); requiring medical attention: bleeding event that required medical, surgical treatment/laboratory evaluation and did not meet criteria for major/minor bleeding event. |
Countries
Argentina, Australia, Belgium, Brazil, Bulgaria, Canada, Czechia, Denmark, France, Hungary, Japan, Netherlands, Poland, Russia, South Korea, Spain, Sweden, Turkey (Türkiye), Ukraine, United States
Participant flow
Pre-assignment details
A total of 3,145 participants were screened for eligibility, of these 108 participants were screening failures and the remaining 3,037 participants were randomized.
Participants by arm
| Arm | Count |
|---|---|
| Rivaroxaban 2.5 mg Twice Daily (BID) Participants received oral dose of 2.5 mg rivaroxaban BID and acetylsalicylic acid (ASA) placebo once daily (OD) along with either clopidogrel 75 mg OD or ticagrelor 90 mg BID for a minimum of 180 days, and up to 360 days of treatment. | 1,519 |
| Acetylsalicylic Acid 100 mg Once Daily (OD) Participants received oral dose of 100 mg ASA OD and rivaroxaban placebo BID along with either clopidogrel 75 mg OD or ticagrelor 90 mg BID for a minimum of 180 days, and up to 360 days of treatment. | 1,518 |
| Total | 3,037 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Withdrawal by Subject | 8 | 7 |
Baseline characteristics
| Characteristic | Rivaroxaban 2.5 mg Twice Daily (BID) | Total | Acetylsalicylic Acid 100 mg Once Daily (OD) |
|---|---|---|---|
| Age, Continuous | 62.7 years STANDARD_DEVIATION 9.14 | 62.8 years STANDARD_DEVIATION 8.98 | 62.9 years STANDARD_DEVIATION 8.82 |
| Race/Ethnicity, Customized Asian | 54 Participants | 117 Participants | 63 Participants |
| Race/Ethnicity, Customized Black | 24 Participants | 40 Participants | 16 Participants |
| Race/Ethnicity, Customized Others | 24 Participants | 56 Participants | 32 Participants |
| Race/Ethnicity, Customized White | 1417 Participants | 2824 Participants | 1407 Participants |
| Region of Enrollment ARGENTINA | 66 participants | 131 participants | 65 participants |
| Region of Enrollment AUSTRALIA | 18 participants | 35 participants | 17 participants |
| Region of Enrollment BELGIUM | 49 participants | 89 participants | 40 participants |
| Region of Enrollment BRAZIL | 77 participants | 162 participants | 85 participants |
| Region of Enrollment BULGARIA | 83 participants | 161 participants | 78 participants |
| Region of Enrollment CANADA | 37 participants | 84 participants | 47 participants |
| Region of Enrollment CZECH REPUBLIC | 34 participants | 71 participants | 37 participants |
| Region of Enrollment DENMARK | 1 participants | 3 participants | 2 participants |
| Region of Enrollment FRANCE | 28 participants | 57 participants | 29 participants |
| Region of Enrollment HUNGARY | 101 participants | 201 participants | 100 participants |
| Region of Enrollment ITALY | 75 participants | 134 participants | 59 participants |
| Region of Enrollment JAPAN | 26 participants | 59 participants | 33 participants |
| Region of Enrollment Korea, Republic Of | 24 participants | 54 participants | 30 participants |
| Region of Enrollment NETHERLANDS | 69 participants | 134 participants | 65 participants |
| Region of Enrollment POLAND | 158 participants | 333 participants | 175 participants |
| Region of Enrollment RUSSIA | 237 participants | 481 participants | 244 participants |
| Region of Enrollment SPAIN | 62 participants | 122 participants | 60 participants |
| Region of Enrollment SWEDEN | 42 participants | 79 participants | 37 participants |
| Region of Enrollment TURKEY | 102 participants | 200 participants | 98 participants |
| Region of Enrollment UKRAINE | 137 participants | 266 participants | 129 participants |
| Region of Enrollment UNITED STATES | 93 participants | 181 participants | 88 participants |
| Sex: Female, Male Female | 385 Participants | 762 Participants | 377 Participants |
| Sex: Female, Male Male | 1134 Participants | 2275 Participants | 1141 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 81 / 1,510 | 84 / 1,506 |
| serious Total, serious adverse events | 125 / 1,510 | 138 / 1,506 |
Outcome results
Primary
Number of Participants With Non Coronary Artery Bypass Graft-Related (Non CABG-related) Thrombolysis in Myocardial Infarction (TIMI) Clinically Significant Bleeding Events
Non CABG-related TIMI clinically significant bleeding events are sum of non CABG-related TIMI major bleeding events, TIMI minor bleeding events and TIMI bleeding events requiring medical attention. Major: any symptomatic intracranial bleeding: clinically overt signs of hemorrhage with hemoglobin (Hb) drop of greater than or equal to (\>=)5 gram per deciliter (g/dl) (or absolute drop in hematocrit of \>=15%) and fatal bleeding (results in death within 7 days); Minor: clinically overt sign of hemorrhage with Hb drop of 3 - \<5 g/dl (or drop in hematocrit of 9 - \<15%); requiring medical attention: bleeding event that required medical, surgical treatment/laboratory evaluation and did not meet criteria for major/minor bleeding event.
Time frame: From start of study treatment until follow-up (up to 390 days)
Population: Population analyzed included all randomized participants who had received at least one dose of study agent and had events that occurred between randomization and the last dose of the study agent plus 2 days or untreated participants who had events that occurred between randomization to 2 days thereafter.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rivaroxaban 2.5 mg Twice Daily (BID) | Number of Participants With Non Coronary Artery Bypass Graft-Related (Non CABG-related) Thrombolysis in Myocardial Infarction (TIMI) Clinically Significant Bleeding Events | 80 participants |
| Acetylsalicylic Acid 100 mg Once Daily (OD) | Number of Participants With Non Coronary Artery Bypass Graft-Related (Non CABG-related) Thrombolysis in Myocardial Infarction (TIMI) Clinically Significant Bleeding Events | 74 participants |
p-value: 0.58495% CI: [0.8, 1.5]Log Rank