Acute Coronary Syndromes
Conditions
Brief summary
The purpose of this study is to determine if Apixaban is safer than a Vitamin K Antagonist given for 6 months in terms of bleeding in patients with an irregular heart beat (atrial fibrillation) and a recent heart attack or a recent procedure to open up a blood vessel in the heart. All patients would also be taking a class of medicines called P2Y12 inhibitors (such as clopidogrel/Plavix) and be treated for up to 6 months. The primary focus will be a comparison of the bleeding risk of Apixaban, with or without aspirin, versus a Vitamin K antagonist, such as warfarin, with or without aspirin.
Detailed description
Patients will be recruited from either inpatient coronary care or general medical units, or recruited from outpatient cardiology offices. Masking: Apixaban: Open label. VKA: Open label. Acetylsalicylic acid film coated tablet: Double Blinded. Placebo matching Acetylsalicylic acid film coated tablet: Double Blinded.
Interventions
Sponsors
Pfizer
Duke Clinical Research Institute
Bristol-Myers Squibb
Study design
Allocation
RANDOMIZED
Intervention model
FACTORIAL
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 95 Years
Healthy volunteers
No
Inclusion criteria
For more information regarding BMS clinical trial participation, please visit www.BMSStudyConnect.com Inclusion Criteria: * Adults with either active or a history of non-valvular atrial fibrillation or flutter with the planned or existing use of an oral anticoagulant for prophylaxis of thromboembolism. In addition, subjects must have had an acute coronary syndrome or percutaneous coronary intervention with a stent within the prior 14 days * Planned use of antiplatelet agents for at least 1 to 6 months * Males and Females ≥ 18 years of age * Women of childbearing potential must have a negative serum or urine pregnancy test within 24 hours prior to the start of study drug
Exclusion criteria
* Conditions other than atrial fibrillation that require chronic anticoagulation. (e.g. prosthetic mechanical heart valve) * Severe renal insufficiency (serum creatinine \> 2.5 mg/dL or a calculated creatinine clearance \< 30 mL/min * Patients with a history of intracranial hemorrhage * Patients have had or will undergo Coronary arterial bypass graft (CABG) for their index acute coronary syndrome (ACS) event * Patients with known ongoing bleeding and patients with known coagulopathies * Any contraindications or allergies to VKA, apixaban, or to intended P2Y12 antagonists or to aspirin
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Rate of International Society on Thrombosis and Haemostasis (ISTH) Major or Clinically Relevant Non-Major (CRNM) Bleeding With Apixaban Versus Vitamin K Antagonist (VKA) During the Treatment Period | Approximately 6 months | Time to first ISTH major or CRNM bleeding during the 6-month period of treatment with Apixaban or VKA. N is the number of participants treated with Apixaban or VKA. n is the number of participants treated with Apixaban or VKA with major or CRNM bleeding in each treatment group during the 6-month period of treatment. Event rates are calculated based on the number of participants with major or CRNM bleeding divided by the sum of the number of days from the first dose of study drug to the event date or censoring date and expressed as percentage per year. |
| The Rate of ISTH Major or CRNM Bleeding With Aspirin Versus no Aspirin During the Treatment Period | Approximately 6 months | Time to first ISTH major or CRNM bleeding during the treatment period of 6 months with aspirin or placebo. N is the number of participants with aspirin or placebo. n is the number of participants treated with aspirin or placebo with major or CRNM bleeding in each treatment group during the 6-month period of treatment. Event rates are calculated based on the number of participants with event of interest divided by the sum of the number of days from the first dose of study drug to the event date or censoring date and expressed as percentage per year. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The Rate of All-cause Death or All-cause Rehospitalization With Aspirn Versus no Aspirin | Approximately 6 months | Time to first all-cause death or all-cause hospitalization during the 6-month period of treatment with aspirin or placebo. N is the number of participants treated with aspirin or placebo. n is the number of participants treated with aspirin or placebo with all-cause death or all-cause hospitalization in each treatment group during the 6-month period of treatment. Event rates are calculated based on the number of participants with all-cause death or all-cause hospitalization divided by the sum of the number of days from the first dose of study drug to the event date or censoring date and expressed as percentage per year. |
| Superiority on ISTH Major or CRNM Bleeding for Apixaban Versus VKA | Approximately 6 months | Time to first occurrence during the time the participants were treated with Apixaban or VKA. N is the number of participants treated with Apixaban or VKA. n is the number of participants treated with Apixaban or VKA with major or CRNM bleeding in each treatment group during the 6-month period of treatment. Event rates are calculated based on the number of participants with event of interest divided by the sum of the number of days from the first dose of study drug to the event date or censoring date and expressed as percentage per year. |
| The Composite Endpoints of Death and Ischemic Events (Stroke, Myocardial Infarction, Stent Thrombosis, Urgent Revascularization) With Aspirin Versus no Aspirin | Approximately 6 months | Time to first death or ischenic event during the 6-month treatment period with aspirin or placebo. N is the number of participants treated with aspirin or placebo. n is the number of participants treated with aspirin or placebo with death or ischemic events in each treatment group during the 6-month treatment period. Event rates are calculated based on the number of participants with death or ischemic events divided by the sum of the number of days from the first dose of study drug to the event date or censoring date and expressed as percentage per year. |
| The Rate of the Composite Endpoint of Death or Ischemic Events (Stroke, Myocardial Infarction, Stent Thrombosis, Urgent Revascularization) With Apixaban Versus VKA | Approximately 6 months | Time to first occurrence during the 6-month treatment period with Apixaban or VKA. N is the number of participants treated with Apixaban or VKA. n is the number of participants treated with Apixaban or VKA with death or ischemic events in each treatment group during the during the 6-month period of treatment. Event rates are calculated based on the number of participants with death or ischemic events divided by the sum of the number of days from the first dose of study drug to the event date or censoring date and expressed as percentage per year. |
| The Rate of All-cause Death or All-cause Rehospitalization With Apixaban Versus VKA | Approximately 6 months | Time to first all-cause death or all-cause hospitalization during the during the 6-month treatment period with Apixaban or VKA. N is the number of participants treated with Apixaban or VKA. n is the number of participants treated with Apixaban or VKA with all-cause death or all-cause hospitalization in each treatment group during the 6-month period of treatment. Event rates are calculated based on the number of participants with all-cause death or all-cause hospitalization divided by the sum of the number of days from the first dose of study drug to the event date or censoring date and expressed as percentage per year. |
Countries
Argentina, Australia, Austria, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Croatia, Czechia, Denmark, France, Germany, Hungary, India, Israel, Italy, Mexico, Netherlands, Norway, Peru, Poland, Portugal, Puerto Rico, Romania, Russia, Serbia, Slovakia, South Korea, Spain, Sweden, Switzerland, Ukraine, United Kingdom, United States, Virgin Islands
Participant flow
Pre-assignment details
4683 participants enrolled, 4614 randomized. Reasons not randomized: 2 adverse event; 1 request to stop therapy; 12 withdrew consent; 1 lost to follow-up; 1 poor/non-compliance; 35 no longer met criteria; 2 admin reasons by Sponsor; 10 lack of IP at site; 1 IWRS down; 2 physician recommended; 1 leaving the country; 1 pharmacogenetic sample positive
Participants by arm
| Arm | Count |
|---|---|
| Apixaban With Acetylsalicylic Acid Film Coated Tablet 5 mg or 2.5 mg Apixaban tablets orally twice per day with 81 mg Acetylsalicylic acid film coated tablet orally once daily with concomitant P2Y12 inhibitor therapy | 1,153 |
| Apixaban With Placebo Matching Acetylsalicylic Acid 5 mg or 2.5 mg Apixaban tablets orally twice per day with placebo matching Acetylsalicylic acid film coated tablet orally once daily with concomitant P2Y12 inhibitor therapy | 1,153 |
| Vitamin K Antagonist (VKA) With Acetylsalicylic VKA tablets orally once daily with 81 mg Acetylsalicylic acid film coated tablet orally once daily with concomitant P2Y12 inhibitor therapy | 1,154 |
| VKA With Placebo Matching Acetylsalicylic Acid VKA tablets orally once daily with placebo matching Acetylsalicylic acid film coated tablet orally once daily with concomitant P2Y12 inhibitor therapy | 1,154 |
| Total | 4,614 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 | 1 | 2 |
| Overall Study | Coagulation values cannot be set | 0 | 0 | 1 | 0 |
| Overall Study | Death | 39 | 41 | 35 | 42 |
| Overall Study | Investigator decision | 0 | 0 | 1 | 1 |
| Overall Study | Lost to Follow-up | 3 | 3 | 2 | 5 |
| Overall Study | No study drug on site | 0 | 1 | 0 | 0 |
| Overall Study | Participant doesn't answer phone | 1 | 0 | 0 | 0 |
| Overall Study | Participant in jail | 0 | 0 | 1 | 0 |
| Overall Study | Participant no longer meets criteria | 2 | 0 | 0 | 1 |
| Overall Study | Participant request to stop therapy | 4 | 3 | 8 | 6 |
| Overall Study | Participant wanted home visits | 1 | 0 | 0 | 0 |
| Overall Study | Participant withdrew consent | 14 | 12 | 30 | 21 |
| Overall Study | Poor/Non-Compliance | 0 | 1 | 3 | 4 |
| Overall Study | Poor treatment monitoring | 0 | 0 | 1 | 0 |
| Overall Study | Randomized in error | 2 | 0 | 0 | 0 |
| Overall Study | Site closure; participant won't transfer | 0 | 0 | 0 | 1 |
| Overall Study | State regulations prevent participation | 0 | 0 | 1 | 0 |
| Overall Study | Stroke and stroke rehabilitation | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Apixaban With Acetylsalicylic Acid Film Coated Tablet | Apixaban With Placebo Matching Acetylsalicylic Acid | Vitamin K Antagonist (VKA) With Acetylsalicylic | VKA With Placebo Matching Acetylsalicylic Acid | Total |
|---|---|---|---|---|---|
| Age, Continuous | 70.2 Years STANDARD_DEVIATION 9.12 | 69.3 Years STANDARD_DEVIATION 9.32 | 70.0 Years STANDARD_DEVIATION 9.09 | 70.0 Years STANDARD_DEVIATION 9.13 | 69.9 Years STANDARD_DEVIATION 9.17 |
| Age, Customized 65-80 years old | 664 Participants | 660 Participants | 662 Participants | 657 Participants | 2643 Participants |
| Age, Customized < 65 years old | 308 Participants | 333 Participants | 311 Participants | 315 Participants | 1267 Participants |
| Age, Customized >=80 | 181 Participants | 160 Participants | 181 Participants | 182 Participants | 704 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 10 Participants | 7 Participants | 5 Participants | 24 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 114 Participants | 123 Participants | 120 Participants | 126 Participants | 483 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1037 Participants | 1020 Participants | 1027 Participants | 1023 Participants | 4107 Participants |
| Race/Ethnicity, Customized American Indian/Alaska Native | 4 Participants | 6 Participants | 2 Participants | 4 Participants | 16 Participants |
| Race/Ethnicity, Customized Asian | 35 Participants | 35 Participants | 39 Participants | 31 Participants | 140 Participants |
| Race/Ethnicity, Customized Black/African American | 17 Participants | 12 Participants | 12 Participants | 18 Participants | 59 Participants |
| Race/Ethnicity, Customized Native Hawaiian/Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Not Reported | 11 Participants | 13 Participants | 20 Participants | 13 Participants | 57 Participants |
| Race/Ethnicity, Customized Other | 47 Participants | 29 Participants | 38 Participants | 43 Participants | 157 Participants |
| Race/Ethnicity, Customized White | 1039 Participants | 1058 Participants | 1043 Participants | 1044 Participants | 4184 Participants |
| Sex: Female, Male Female | 357 Participants | 313 Participants | 339 Participants | 328 Participants | 1337 Participants |
| Sex: Female, Male Male | 796 Participants | 840 Participants | 815 Participants | 826 Participants | 3277 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 | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk |
|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 42 / 1,145 | 46 / 1,143 | 38 / 1,123 | 42 / 1,127 | 0 / 2 | 3 / 10 | 0 / 9 | 0 / 10 |
| other Total, other adverse events | 35 / 1,145 | 21 / 1,143 | 33 / 1,123 | 18 / 1,126 | 0 / 2 | 1 / 10 | 3 / 9 | 0 / 10 |
| serious Total, serious adverse events | 53 / 1,145 | 50 / 1,143 | 52 / 1,123 | 55 / 1,126 | 0 / 2 | 3 / 10 | 0 / 9 | 0 / 10 |
Outcome results
Primary
The Rate of International Society on Thrombosis and Haemostasis (ISTH) Major or Clinically Relevant Non-Major (CRNM) Bleeding With Apixaban Versus Vitamin K Antagonist (VKA) During the Treatment Period
Time to first ISTH major or CRNM bleeding during the 6-month period of treatment with Apixaban or VKA. N is the number of participants treated with Apixaban or VKA. n is the number of participants treated with Apixaban or VKA with major or CRNM bleeding in each treatment group during the 6-month period of treatment. Event rates are calculated based on the number of participants with major or CRNM bleeding divided by the sum of the number of days from the first dose of study drug to the event date or censoring date and expressed as percentage per year.
Time frame: Approximately 6 months
Population: Participants treated with Apixaban or VKA.~Assessment is only for the Apixaban and VKA interventions.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Apixaban | The Rate of International Society on Thrombosis and Haemostasis (ISTH) Major or Clinically Relevant Non-Major (CRNM) Bleeding With Apixaban Versus Vitamin K Antagonist (VKA) During the Treatment Period | 24.66 Percentage per year |
| Vitamin K Antagonist | The Rate of International Society on Thrombosis and Haemostasis (ISTH) Major or Clinically Relevant Non-Major (CRNM) Bleeding With Apixaban Versus Vitamin K Antagonist (VKA) During the Treatment Period | 35.79 Percentage per year |
Comparison: Separate hierarchical testing was performed for apixaban vs VKA: 1) Non-inferiority for the primary endpoint.p-value: <0.00011-sided p-value for NI test
Comparison: Separate hierarchical testing was performed for apixaban vs VKA: 2) Superiority for the primary endpointp-value: <0.000195% CI: [0.58, 0.82]2-sided p-value for superiority test
Primary
The Rate of ISTH Major or CRNM Bleeding With Aspirin Versus no Aspirin During the Treatment Period
Time to first ISTH major or CRNM bleeding during the treatment period of 6 months with aspirin or placebo. N is the number of participants with aspirin or placebo. n is the number of participants treated with aspirin or placebo with major or CRNM bleeding in each treatment group during the 6-month period of treatment. Event rates are calculated based on the number of participants with event of interest divided by the sum of the number of days from the first dose of study drug to the event date or censoring date and expressed as percentage per year.
Time frame: Approximately 6 months
Population: Participants treated with aspirin or placebo.~Assessment is only for the Acetylsalicylic acid film coated tablet or Placebo matching Acetylsalicylic acid film coated tablet interventions.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Apixaban | The Rate of ISTH Major or CRNM Bleeding With Aspirin Versus no Aspirin During the Treatment Period | 40.51 Percentage per year |
| Vitamin K Antagonist | The Rate of ISTH Major or CRNM Bleeding With Aspirin Versus no Aspirin During the Treatment Period | 21.03 Percentage per year |
Comparison: Separate hierarchical testing was performed for aspirin vs placebo: 2) Superiority for the primary endpoint.p-value: <0.000195% CI: [1.58, 2.23]2-sided p-value for superiority test
Secondary
Superiority on ISTH Major or CRNM Bleeding for Apixaban Versus VKA
Time to first occurrence during the time the participants were treated with Apixaban or VKA. N is the number of participants treated with Apixaban or VKA. n is the number of participants treated with Apixaban or VKA with major or CRNM bleeding in each treatment group during the 6-month period of treatment. Event rates are calculated based on the number of participants with event of interest divided by the sum of the number of days from the first dose of study drug to the event date or censoring date and expressed as percentage per year.
Time frame: Approximately 6 months
Population: Participants treated with Apixaban or VKA.~Assessment is only for the Apixaban or VKA interventions.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Apixaban | Superiority on ISTH Major or CRNM Bleeding for Apixaban Versus VKA | 24.66 Percentage per year |
| Vitamin K Antagonist | Superiority on ISTH Major or CRNM Bleeding for Apixaban Versus VKA | 35.79 Percentage per year |
Comparison: Separate hierarchical testing was performed for apixaban vs VKA: 2) Superiority for the primary endpoint.p-value: <0.00012-sided p-value for superiority test
Secondary
The Composite Endpoints of Death and Ischemic Events (Stroke, Myocardial Infarction, Stent Thrombosis, Urgent Revascularization) With Aspirin Versus no Aspirin
Time to first death or ischenic event during the 6-month treatment period with aspirin or placebo. N is the number of participants treated with aspirin or placebo. n is the number of participants treated with aspirin or placebo with death or ischemic events in each treatment group during the 6-month treatment period. Event rates are calculated based on the number of participants with death or ischemic events divided by the sum of the number of days from the first dose of study drug to the event date or censoring date and expressed as percentage per year.
Time frame: Approximately 6 months
Population: Participants randomized to aspirin or placebo.~Assessment is only for the Acetylsalicylic acid film coated tablet or Placebo matching Acetylsalicylic acid film coated tablet interventions.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Apixaban | The Composite Endpoints of Death and Ischemic Events (Stroke, Myocardial Infarction, Stent Thrombosis, Urgent Revascularization) With Aspirin Versus no Aspirin | 15.28 Percentage per year |
| Vitamin K Antagonist | The Composite Endpoints of Death and Ischemic Events (Stroke, Myocardial Infarction, Stent Thrombosis, Urgent Revascularization) With Aspirin Versus no Aspirin | 17.73 Percentage per year |
Comparison: Separate hierarchical testing was performed for aspirin vs placebo: 4) Superiority for all-cause death and ischemic events.p-value: 0.174295% CI: [0.7, 1.07]2-sided p-value
Secondary
The Rate of All-cause Death or All-cause Rehospitalization With Apixaban Versus VKA
Time to first all-cause death or all-cause hospitalization during the during the 6-month treatment period with Apixaban or VKA. N is the number of participants treated with Apixaban or VKA. n is the number of participants treated with Apixaban or VKA with all-cause death or all-cause hospitalization in each treatment group during the 6-month period of treatment. Event rates are calculated based on the number of participants with all-cause death or all-cause hospitalization divided by the sum of the number of days from the first dose of study drug to the event date or censoring date and expressed as percentage per year.
Time frame: Approximately 6 months
Population: Participants randomized to Apixaban or VKA.~Assessment is only for the Apixaban or VKA interventions.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Apixaban | The Rate of All-cause Death or All-cause Rehospitalization With Apixaban Versus VKA | 57.24 Percentage per year |
| Vitamin K Antagonist | The Rate of All-cause Death or All-cause Rehospitalization With Apixaban Versus VKA | 69.19 Percentage per year |
Comparison: Separate hierarchical testing was performed for apixaban vs VKA: 3) Superiority for all-cause death and all-cause rehospitalization.p-value: 0.003395% CI: [0.75, 0.94]2-sided p-value
Secondary
The Rate of All-cause Death or All-cause Rehospitalization With Aspirn Versus no Aspirin
Time to first all-cause death or all-cause hospitalization during the 6-month period of treatment with aspirin or placebo. N is the number of participants treated with aspirin or placebo. n is the number of participants treated with aspirin or placebo with all-cause death or all-cause hospitalization in each treatment group during the 6-month period of treatment. Event rates are calculated based on the number of participants with all-cause death or all-cause hospitalization divided by the sum of the number of days from the first dose of study drug to the event date or censoring date and expressed as percentage per year.
Time frame: Approximately 6 months
Population: Participants randomized to aspirin or placebo.~Assessment is only for the Acetylsalicylic acid film coated tablet or Placebo matching Acetylsalicylic acid film coated tablet interventions.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Apixaban | The Rate of All-cause Death or All-cause Rehospitalization With Aspirn Versus no Aspirin | 65.72 Percentage per year |
| Vitamin K Antagonist | The Rate of All-cause Death or All-cause Rehospitalization With Aspirn Versus no Aspirin | 60.56 Percentage per year |
Comparison: Separate hierarchical testing was performed for aspirin vs placebo: 3) Superiority for all-cause death and all-cause rehospitalization.p-value: 0.221995% CI: [0.96, 1.2]2-sided p-value
Secondary
The Rate of the Composite Endpoint of Death or Ischemic Events (Stroke, Myocardial Infarction, Stent Thrombosis, Urgent Revascularization) With Apixaban Versus VKA
Time to first occurrence during the 6-month treatment period with Apixaban or VKA. N is the number of participants treated with Apixaban or VKA. n is the number of participants treated with Apixaban or VKA with death or ischemic events in each treatment group during the during the 6-month period of treatment. Event rates are calculated based on the number of participants with death or ischemic events divided by the sum of the number of days from the first dose of study drug to the event date or censoring date and expressed as percentage per year.
Time frame: Approximately 6 months
Population: Participants randomized to Apixaban or VKA.~Assessment is only for the Apixaban or VKA interventions.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Apixaban | The Rate of the Composite Endpoint of Death or Ischemic Events (Stroke, Myocardial Infarction, Stent Thrombosis, Urgent Revascularization) With Apixaban Versus VKA | 15.85 Percentage per year |
| Vitamin K Antagonist | The Rate of the Composite Endpoint of Death or Ischemic Events (Stroke, Myocardial Infarction, Stent Thrombosis, Urgent Revascularization) With Apixaban Versus VKA | 17.17 Percentage per year |
Comparison: Separate hierarchical testing was performed for apixaban vs VKA: 4) Superiority for all-cause death and ischemic events.p-value: 0.43795% CI: [0.75, 1.13]2-sided p-value