Acute Coronary Syndrome
Conditions
Brief summary
The purpose of this study is to assess the bleeding safety (the composite endpoint of major and clinically relevant non-major bleeding) of 2 doses of apixaban (2.5 mg BID and 5.0 mg BID) or placebo in combination with standard therapy (aspirin and /or additional antiplatelet therapy) over a 24 week treatment period in selected subjects with recent (≤7 days) acute coronary syndrome.
Detailed description
Due to withdraw of global phase 3 study (APPRAISE-2) for safety issue, B0661004 Data monitoring committee (DMC) also recommended terminating this study. Therefore, Pfizer decided to stop this study.
Interventions
DRUGApixaban
Apixaban 2.5 mg tablet BID for 24 weeks
OTHERPlacebo
Placebo tablet for 24 weeks
Sponsors
Bristol-Myers Squibb
Pfizer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
20 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Recent (≤ 7 days) ACS * Clinically stable, and receiving standard treatment (patients must be treated with aspirin ≤ 100 mg/day, with or without clopidogrel 75 mg/day or ticlopidine 200 mg/day) based on the physician's judgment)
Exclusion criteria
* Scheduled/planned cardiac catheterization, PCI, CABG or other invasive procedure planned in the 24 weeks (within treatment period) following randomization * Persistent severe hypertension, defined as systolic blood pressure of ≥180 mm Hg or diastolic pressure of ≥110 mm Hg * Active bleeding or at high risk for bleeding (e.g., cirrhosis of the liver, any history of intracranial hemorrhage).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Had Composite of International Society on Thrombosis and Haemostasis (ISTH)-Defined Major and Clinically-relevant Non-major (CRNM) Bleeding Events Occurring During the Treatment Period. | Week 0 to Week 24 | Major bleeding event was acute clinically overt bleeding accompanied by decrease in hemoglobin of 2 g/dL or more over a 24-hour period, transfusion of 2 or more units of packed red blood cells, or bleeding that occurs in critical site (e.g., intracranial). Fatal bleeding was also major bleeding event. CRNM bleeding was acute or sub-acute clinically overt bleeding that did not satisfy the criteria for major bleeding and that led to either hospital admission for bleeding, physician guided medical or surgical treatment for bleeding or a change in antithrombotic therapy. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Had One or More All Bleeding Occurring During the Treatment Period. | Week 0 to Week 24 | All bleeding included major bleeding (including fatal bleeding), clinically-relevant non-major (CRNM) bleeding, and minor bleeding per international society on thrombosis and haemostasis (ISTH) definitions. |
| Percentage of Participants Who Had Major Bleeding Occurring During the Treatment Period Per International Society on Thrombosis and Haemostasis (ISTH) Definitions. | Week 0 to Week 24 | Major bleeding event was defined as an acute clinically overt bleeding accompanied by decrease in hemoglobin of 2 g/dL or more over a 24-hour period, transfusion of 2 or more units of packed red blood cells, or bleeding that occured in critical site (e.g., intracranial). Fatal bleeding was also major bleeding event. |
| Percentage of Participants Who Had Thrombolysis in Myocardial Infarction (TIMI)-Defined Major Bleeding Occurring During the Treatment Period. | Week 0 to Week 24 | TIMI major bleeding event was difined as an intracranial bleeding or clinically overt bleeding (including bleeding evident on imaging studies) associated with a \>= 5 gm/dL fall in hemoglobin or a 15% fall in hematocrit from baseline, accounting for the effect of transfusions (1 unit packed red blood cells = 1 gm/dL hemoglobin = 3% hematocrit). |
| Percentage of Participants Who Had Composite of All-cause Death, Non-fatal Myocardial Infarction, Unstable Angina and Stroke During 30 Days After Discontinuation of Therapy. | For 30 days after Week 24 or the discontinuation of study drug | — |
| Percentage of Participants Who Had Composite of All-cause Death, Non-fatal Myocardial Infarction (MI), Unstable Angina, and Non-hemorrhagic Stroke Occurring During the Intended Treatment Period. | From the day of randomization to the later date of either 2-days after the last dose of study drug or Day 168/Week 24 after randomization day (or the study termination date [19 November 2010, Japan time]) | Intended treatment period for efficacy endpoints was defined as a period starting on the day of randomization and ending at the later date of either 2-days after the last dose of study drug or Day 168/Week 24 after randomization day (or the study termination date \[19 November 2010, Japan time\]). |
Other
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Had International Society on Thrombosis and Haemostasis (ISTH)-Defined Individual Bleeding Endpoints (Clinically-relevant Non-major [CRNM] or Minor Bleeding) During the Treatment Period. | Week 0 to Week 24 | ISTH-defined CRNM bleeding was defined as an acute or sub-acute clinically overt bleeding that did not satisfy the criteria for major bleeding and that led to either hospital admission for bleeding, physician guided medical or surgical treatment for bleeding or a change in antithrombotic therapy. ISTH defined minor bleeding event was defined as all acute clinically overt bleeding events not meeting the criteria for either major bleeding or CRNM bleeding were classified as minor bleeding. |
| Percentage of Participants Who Had Thrombolysis in Myocardial Infarction (TIMI) Defined-individual Bleeding Endpoints (Minor or Minimal Bleeding) During the Treatment Period. | Week 0 to Week 24 | TIMI minor bleeding event was defined as a clinically overt bleeding (including bleeding evident on imaging studies) associated with a \>= 3 gm/dL fall in hemoglobin or a 9% fall in hematocrit from baseline, accounting for the effect of transfusions (1 unit packed red blood cells = 1 gm/dL hemoglobin = 3% hematocrit). TIMI minimal bleeding event was defined as a clinically overt bleeding (including bleeding evident on imaging studies) not meeting criteria for TIMI minor bleeding. |
Countries
Japan
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo was administered twice a day in addition to the standard therapy (aspirin with or without clopidogrel or ticlopidine) for 24 weeks.
Number of participants in baseline characteristics means randomized participants. | 52 |
| Apixaban 2.5 mg BID 2.5 mg was administered twice a day in addition to the standard therapy (aspirin with or without clopidogrel or ticlopidine) for 24 weeks.
Number of participants in baseline characteristics means randomized participants. | 49 |
| Apixaban 5.0 mg BID Apixaban 5.0 mg was administered twice a day in addition to the standard therapy (aspirin with or without clopidogrel or ticlopidine) for 24 weeks.
Number of participants in baseline characteristics means randomized participants. | 50 |
| Total | 151 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 4 | 6 | 4 |
| Overall Study | Death | 0 | 0 | 1 |
| Overall Study | Difficulty in study site visit | 1 | 0 | 0 |
| Overall Study | Protocol Violation | 0 | 0 | 1 |
| Overall Study | Study terminated by sponsor | 2 | 1 | 6 |
| Overall Study | Withdrawal by Subject | 4 | 1 | 2 |
Baseline characteristics
| Characteristic | Placebo | Apixaban 2.5 mg BID | Apixaban 5.0 mg BID | Total |
|---|---|---|---|---|
| Age Continuous | 63.9 years STANDARD_DEVIATION 10.1 | 66.0 years STANDARD_DEVIATION 9 | 64.0 years STANDARD_DEVIATION 9.2 | 64.6 years STANDARD_DEVIATION 9.5 |
| Sex: Female, Male Female | 10 Participants | 6 Participants | 4 Participants | 20 Participants |
| Sex: Female, Male Male | 42 Participants | 43 Participants | 46 Participants | 131 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 | 22 / 51 | 28 / 49 | 22 / 49 |
| serious Total, serious adverse events | 8 / 51 | 11 / 49 | 7 / 49 |
Outcome results
Primary
Percentage of Participants Who Had Composite of International Society on Thrombosis and Haemostasis (ISTH)-Defined Major and Clinically-relevant Non-major (CRNM) Bleeding Events Occurring During the Treatment Period.
Major bleeding event was acute clinically overt bleeding accompanied by decrease in hemoglobin of 2 g/dL or more over a 24-hour period, transfusion of 2 or more units of packed red blood cells, or bleeding that occurs in critical site (e.g., intracranial). Fatal bleeding was also major bleeding event. CRNM bleeding was acute or sub-acute clinically overt bleeding that did not satisfy the criteria for major bleeding and that led to either hospital admission for bleeding, physician guided medical or surgical treatment for bleeding or a change in antithrombotic therapy.
Time frame: Week 0 to Week 24
Population: Bleeding endpoint was included in safety evaluations. The safety analysis set was defined as all treated participants (randomized participants who received at least one dose of study drug).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants Who Had Composite of International Society on Thrombosis and Haemostasis (ISTH)-Defined Major and Clinically-relevant Non-major (CRNM) Bleeding Events Occurring During the Treatment Period. | 2.0 Percentage of Participants |
| Apixaban 2.5 mg BID | Percentage of Participants Who Had Composite of International Society on Thrombosis and Haemostasis (ISTH)-Defined Major and Clinically-relevant Non-major (CRNM) Bleeding Events Occurring During the Treatment Period. | 4.1 Percentage of Participants |
| Apixaban 5.0 mg BID | Percentage of Participants Who Had Composite of International Society on Thrombosis and Haemostasis (ISTH)-Defined Major and Clinically-relevant Non-major (CRNM) Bleeding Events Occurring During the Treatment Period. | 4.1 Percentage of Participants |
Secondary
Percentage of Participants Who Had Composite of All-cause Death, Non-fatal Myocardial Infarction (MI), Unstable Angina, and Non-hemorrhagic Stroke Occurring During the Intended Treatment Period.
Intended treatment period for efficacy endpoints was defined as a period starting on the day of randomization and ending at the later date of either 2-days after the last dose of study drug or Day 168/Week 24 after randomization day (or the study termination date \[19 November 2010, Japan time\]).
Time frame: From the day of randomization to the later date of either 2-days after the last dose of study drug or Day 168/Week 24 after randomization day (or the study termination date [19 November 2010, Japan time])
Population: The efficacy analysis set was all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants Who Had Composite of All-cause Death, Non-fatal Myocardial Infarction (MI), Unstable Angina, and Non-hemorrhagic Stroke Occurring During the Intended Treatment Period. | 1.9 Percentage of Participants |
| Apixaban 2.5 mg BID | Percentage of Participants Who Had Composite of All-cause Death, Non-fatal Myocardial Infarction (MI), Unstable Angina, and Non-hemorrhagic Stroke Occurring During the Intended Treatment Period. | 0 Percentage of Participants |
| Apixaban 5.0 mg BID | Percentage of Participants Who Had Composite of All-cause Death, Non-fatal Myocardial Infarction (MI), Unstable Angina, and Non-hemorrhagic Stroke Occurring During the Intended Treatment Period. | 2.0 Percentage of Participants |
Secondary
Percentage of Participants Who Had Composite of All-cause Death, Non-fatal Myocardial Infarction, Unstable Angina and Stroke During 30 Days After Discontinuation of Therapy.
Time frame: For 30 days after Week 24 or the discontinuation of study drug
Population: Bleeding endpoint was included in safety evaluations. The safety analysis set was defined as all treated participants (randomized participants who received at least one dose of study drug).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants Who Had Composite of All-cause Death, Non-fatal Myocardial Infarction, Unstable Angina and Stroke During 30 Days After Discontinuation of Therapy. | 0 Percentage of Participants |
| Apixaban 2.5 mg BID | Percentage of Participants Who Had Composite of All-cause Death, Non-fatal Myocardial Infarction, Unstable Angina and Stroke During 30 Days After Discontinuation of Therapy. | 0 Percentage of Participants |
| Apixaban 5.0 mg BID | Percentage of Participants Who Had Composite of All-cause Death, Non-fatal Myocardial Infarction, Unstable Angina and Stroke During 30 Days After Discontinuation of Therapy. | 2 Percentage of Participants |
Secondary
Percentage of Participants Who Had Major Bleeding Occurring During the Treatment Period Per International Society on Thrombosis and Haemostasis (ISTH) Definitions.
Major bleeding event was defined as an acute clinically overt bleeding accompanied by decrease in hemoglobin of 2 g/dL or more over a 24-hour period, transfusion of 2 or more units of packed red blood cells, or bleeding that occured in critical site (e.g., intracranial). Fatal bleeding was also major bleeding event.
Time frame: Week 0 to Week 24
Population: Bleeding endpoint was included in safety evaluations. The safety analysis set was defined as all treated participants (randomized participants who received at least one dose of study drug).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants Who Had Major Bleeding Occurring During the Treatment Period Per International Society on Thrombosis and Haemostasis (ISTH) Definitions. | 0 Percentage of Participants |
| Apixaban 2.5 mg BID | Percentage of Participants Who Had Major Bleeding Occurring During the Treatment Period Per International Society on Thrombosis and Haemostasis (ISTH) Definitions. | 2.0 Percentage of Participants |
| Apixaban 5.0 mg BID | Percentage of Participants Who Had Major Bleeding Occurring During the Treatment Period Per International Society on Thrombosis and Haemostasis (ISTH) Definitions. | 4.1 Percentage of Participants |
Secondary
Percentage of Participants Who Had One or More All Bleeding Occurring During the Treatment Period.
All bleeding included major bleeding (including fatal bleeding), clinically-relevant non-major (CRNM) bleeding, and minor bleeding per international society on thrombosis and haemostasis (ISTH) definitions.
Time frame: Week 0 to Week 24
Population: Bleeding endpoint was included in safety evaluations. The safety analysis set was defined as all treated participants (randomized participants who received at least one dose of study drug).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants Who Had One or More All Bleeding Occurring During the Treatment Period. | 33.3 Percentage of Participants |
| Apixaban 2.5 mg BID | Percentage of Participants Who Had One or More All Bleeding Occurring During the Treatment Period. | 38.8 Percentage of Participants |
| Apixaban 5.0 mg BID | Percentage of Participants Who Had One or More All Bleeding Occurring During the Treatment Period. | 44.9 Percentage of Participants |
Secondary
Percentage of Participants Who Had Thrombolysis in Myocardial Infarction (TIMI)-Defined Major Bleeding Occurring During the Treatment Period.
TIMI major bleeding event was difined as an intracranial bleeding or clinically overt bleeding (including bleeding evident on imaging studies) associated with a \>= 5 gm/dL fall in hemoglobin or a 15% fall in hematocrit from baseline, accounting for the effect of transfusions (1 unit packed red blood cells = 1 gm/dL hemoglobin = 3% hematocrit).
Time frame: Week 0 to Week 24
Population: Bleeding endpoint was included in safety evaluations. The safety analysis set was defined as all treated participants (randomized participants who received at least one dose of study drug).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants Who Had Thrombolysis in Myocardial Infarction (TIMI)-Defined Major Bleeding Occurring During the Treatment Period. | 0 Percentage of Participants |
| Apixaban 2.5 mg BID | Percentage of Participants Who Had Thrombolysis in Myocardial Infarction (TIMI)-Defined Major Bleeding Occurring During the Treatment Period. | 2.0 Percentage of Participants |
| Apixaban 5.0 mg BID | Percentage of Participants Who Had Thrombolysis in Myocardial Infarction (TIMI)-Defined Major Bleeding Occurring During the Treatment Period. | 2.0 Percentage of Participants |
Other Pre-specified
Percentage of Participants Who Had International Society on Thrombosis and Haemostasis (ISTH)-Defined Individual Bleeding Endpoints (Clinically-relevant Non-major [CRNM] or Minor Bleeding) During the Treatment Period.
ISTH-defined CRNM bleeding was defined as an acute or sub-acute clinically overt bleeding that did not satisfy the criteria for major bleeding and that led to either hospital admission for bleeding, physician guided medical or surgical treatment for bleeding or a change in antithrombotic therapy. ISTH defined minor bleeding event was defined as all acute clinically overt bleeding events not meeting the criteria for either major bleeding or CRNM bleeding were classified as minor bleeding.
Time frame: Week 0 to Week 24
Population: Bleeding endpoint was included in safety evaluations. The safety analysis set was defined as all treated participants (randomized participants who received at least one dose of study drug).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Percentage of Participants Who Had International Society on Thrombosis and Haemostasis (ISTH)-Defined Individual Bleeding Endpoints (Clinically-relevant Non-major [CRNM] or Minor Bleeding) During the Treatment Period. | ISTH defined CRNM | 2.0 Percentage of Participants |
| Placebo | Percentage of Participants Who Had International Society on Thrombosis and Haemostasis (ISTH)-Defined Individual Bleeding Endpoints (Clinically-relevant Non-major [CRNM] or Minor Bleeding) During the Treatment Period. | ISTH defined minor bleeding | 31.4 Percentage of Participants |
| Apixaban 2.5 mg BID | Percentage of Participants Who Had International Society on Thrombosis and Haemostasis (ISTH)-Defined Individual Bleeding Endpoints (Clinically-relevant Non-major [CRNM] or Minor Bleeding) During the Treatment Period. | ISTH defined CRNM | 2.0 Percentage of Participants |
| Apixaban 2.5 mg BID | Percentage of Participants Who Had International Society on Thrombosis and Haemostasis (ISTH)-Defined Individual Bleeding Endpoints (Clinically-relevant Non-major [CRNM] or Minor Bleeding) During the Treatment Period. | ISTH defined minor bleeding | 36.7 Percentage of Participants |
| Apixaban 5.0 mg BID | Percentage of Participants Who Had International Society on Thrombosis and Haemostasis (ISTH)-Defined Individual Bleeding Endpoints (Clinically-relevant Non-major [CRNM] or Minor Bleeding) During the Treatment Period. | ISTH defined CRNM | 0 Percentage of Participants |
| Apixaban 5.0 mg BID | Percentage of Participants Who Had International Society on Thrombosis and Haemostasis (ISTH)-Defined Individual Bleeding Endpoints (Clinically-relevant Non-major [CRNM] or Minor Bleeding) During the Treatment Period. | ISTH defined minor bleeding | 40.8 Percentage of Participants |
Other Pre-specified
Percentage of Participants Who Had Thrombolysis in Myocardial Infarction (TIMI) Defined-individual Bleeding Endpoints (Minor or Minimal Bleeding) During the Treatment Period.
TIMI minor bleeding event was defined as a clinically overt bleeding (including bleeding evident on imaging studies) associated with a \>= 3 gm/dL fall in hemoglobin or a 9% fall in hematocrit from baseline, accounting for the effect of transfusions (1 unit packed red blood cells = 1 gm/dL hemoglobin = 3% hematocrit). TIMI minimal bleeding event was defined as a clinically overt bleeding (including bleeding evident on imaging studies) not meeting criteria for TIMI minor bleeding.
Time frame: Week 0 to Week 24
Population: Bleeding endpoint was included in safety evaluations. The safety analysis set was defined as all treated participants (randomized participants who received at least one dose of study drug).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Percentage of Participants Who Had Thrombolysis in Myocardial Infarction (TIMI) Defined-individual Bleeding Endpoints (Minor or Minimal Bleeding) During the Treatment Period. | TIMI defined minor bleeding | 0 Percentage of Participants |
| Placebo | Percentage of Participants Who Had Thrombolysis in Myocardial Infarction (TIMI) Defined-individual Bleeding Endpoints (Minor or Minimal Bleeding) During the Treatment Period. | TIMI defined minimal bleeding | 33.3 Percentage of Participants |
| Apixaban 2.5 mg BID | Percentage of Participants Who Had Thrombolysis in Myocardial Infarction (TIMI) Defined-individual Bleeding Endpoints (Minor or Minimal Bleeding) During the Treatment Period. | TIMI defined minor bleeding | 2.0 Percentage of Participants |
| Apixaban 2.5 mg BID | Percentage of Participants Who Had Thrombolysis in Myocardial Infarction (TIMI) Defined-individual Bleeding Endpoints (Minor or Minimal Bleeding) During the Treatment Period. | TIMI defined minimal bleeding | 38.8 Percentage of Participants |
| Apixaban 5.0 mg BID | Percentage of Participants Who Had Thrombolysis in Myocardial Infarction (TIMI) Defined-individual Bleeding Endpoints (Minor or Minimal Bleeding) During the Treatment Period. | TIMI defined minor bleeding | 2.0 Percentage of Participants |
| Apixaban 5.0 mg BID | Percentage of Participants Who Had Thrombolysis in Myocardial Infarction (TIMI) Defined-individual Bleeding Endpoints (Minor or Minimal Bleeding) During the Treatment Period. | TIMI defined minimal bleeding | 40.8 Percentage of Participants |