Phase III Acute Coronary Syndrome

Study Overview
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Brief Summary
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The purpose of this study is to determine if apixaban is superior to placebo for preventing cardiovascular death, non-fatal myocardial infarction, or ischemic stroke in subjects with a recent acute coronary syndrome

Official Title
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Apixaban for Prevention of Acute Ischemic Events - 2 A Phase 3, Randomized, Double-Blind, Evaluation of the Safety and Efficacy of Apixaban In Subjects With a Recent Acute Coronary Syndrome

Conditions
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Acute Coronary Syndrome

Intervention / Treatment
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* Drug: Apixaban
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Acute coronary syndrome (ACS) Clinically stable Receiving standard of care for ACS Exclusion Criteria: Severe hypertension Active bleeding or high risk for major bleeding Hemoglobin < 9 g/dL

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Apixaban<br> | Drug: Apixaban<br>* Tablets, Oral, 5 mg, twice daily, until study end<br>* Other names: BSM-562247;|
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* Tablets, Oral, 0 mg, twice daily, until study end<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event Rate of Cardiovascular Death, Myocardial Infarction, or Ischemic Stroke During the Intended Treatment Period - Randomized Participants | Event rate was percent of participants with an event of cardiovascular (CV) death, myocardial infarction (MI), or ischemic stroke (number of participants with event/number randomized) per 100 patient (100-pt) years. Study was terminated early and last patient, last visit was in Year 2. Only events confirmed by the adjudication committee were included in the analyses. CV death included deaths due to CV causes (eg, cardiogenic shock, heart failure, arrhythmia/sudden death, cardiac rupture, ischemic stroke, pulmonary embolism, venous/arterial thrombotic events) and other sudden deaths for which an alternative cause was not identified. Intended Treatment Period: the period that started on the day of randomization and ended at the efficacy cut-off date (cut-off date: the date all sites were informed that study drug should be discontinued for all participants, 18 November 2010). | Randomization (Day 1) to first event (CV death, MI, ischemic stroke), up to March 2011, approximately 2 years | 
| Event Rate of Confirmed Major Bleeding Using Thrombolysis in Myocardial Infarction (TIMI) Criteria During the Treatment Period - Treated Participants | TIMI Major Bleed Criteria: Fatal bleeding, intracranial hemorrhage, and clinically overt bleeding with a hemoglobin (Hgb) drop of ≥ 5 grams per deciliter (g/dL), or ≥15% absolute decrease in hematocrit. To account for transfusions, Hgb measurements were adjusted for transfusions. A transfusion of 1 unit of blood was assumed to result in an increase by 1 g/dL in Hgb or 3% in hematocrit. Event rate was percent of participants with an event of Major Bleed as per TIMI (number of participants with event/number randomized) per 100 patient (100-pt) years. Only events confirmed by the adjudication committee were included in the analyses. Treatment Period=events with onset from first dose to last dose plus 2 days. | From first dose to first occurrence of event (TIMI major bleeding) during Treatment Period (first dose to last dose + 2 days), up to March 2011, approximately 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event Rate of Unstable Angina (UA) During the Intended Treatment Period - Randomized Participants | Unstable Angina (UA) defined as worsening or recurrent severe or repetitive angina symptoms at rest lasting at least 10 minutes with at least 2 of the following: New and dynamic electrocardiogram (ECG) changes; angina symptoms leading to inpatient hospitalization; angina symptoms leading to an unplanned or urgent cardiac catheterization, with or without revascularization, that showed evidence of hemodynamically and clinically significant stenosis. Event rate was percent of participants with an event of unstable angina (number of participants with event/number randomized) per 100 patient (100-pt) years. Only events confirmed by the adjudication committee were included in the analyses. Intended Treatment Period: the period that started on the day of randomization and ended at the efficacy cut-off date (cut-off date: the date all sites were informed that study drug should be discontinued for all participants, 18 November 2010). | Randomization (Day 1) to first event of UA, up to March 2011, approximately 2 years | 
| Event Rate of Stroke During the Intended Treatment Period - Randomized Participants | Event rate was percent of participants with an event of stroke (number of participants with event/number randomized) per 100 patient (100-pt) years. Only events confirmed by the adjudication committee were included in the analyses. Diagnosis of stroke required a new, non-traumatic, focal neurological deficit of sudden onset, lasting at least 24 hours that was not due to a readily identifiable non-vascular cause (ie, brain tumor). All strokes were classified as hemorrhagic (documentation on imaging (eg computed tomography scan or magnetic resonance imaging) of hemorrhage in the cerebral parenchyma, or a subdural or subarachnoid hemorrhage), non-hemorrhagic/ischemic stroke, ischemic stroke with hemorrhagic conversion, or type unknown. Intended Treatment Period: the period that started on the day of randomization (Day 1) and ended at the efficacy cut-off date (notification of study termination). | Randomization (Day 1) to first event (stroke), up to March 2011, approximately 2 years | 
| Event Rate of Myocardial Infarction (MI) During the Intended Treatment Period - Randomized Participants | MI took into account whether the participant had a recent percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG) surgery. Selected key criteria: Elevation of cardiac biomarkers (eg, Creatine Kinase MB fraction (CKMB), Troponin T, Troponin I) above the upper reference limit (URL) plus ischemic symptoms, ECG changes, or imaging evidence of new loss of viable myocardium or new regional wall motion abnormality; Death of CV etiology with new ST-segment elevation or left bundle branch block (LBBB) or fresh intracoronary thrombus by angiography or at autopsy occurring before biomarkers could be obtained or before their appearance in the blood; Following a PCI, elevation of cardiac biomarkers more than 3*URL; Following CABG surgery, elevation of cardiac biomarkers more than 5*URL; New, significant (≥0.04 s) Q waves in ≥2 contiguous leads; Pathologic findings of acute MI. Intended Treatment Period: Day of randomization (Day 1) to efficacy cut-off notice. | Randomization (Day 1) to first event (MI), up to March 2011, approximately 2 years | 
| Event Rate of Stent Thrombosis During the Intended Treatment Period - Randomized Participants | Stent thrombosis: Definite stent thrombosis considered to have occurred by either angiographic or pathological confirmation; Probable stent thrombosis considered to have occurred in the following cases: any unexplained death within the first 30 days after stent implantation; irrespective of the time after the procedure, any MI that was related to documented acute ischemia in the territory of the implanted stent without angiographic confirmation of stent thrombosis and in the absence of any other obvious cause; Possible stent thrombosis considered to have occurred with any unexplained death from 30 days after intracoronary stenting until end of study (in Year 2). Event rate was percent of participants with an event of stent thrombosis (number with event/number randomized) per 100-pt years. Only events confirmed by the adjudication committee were included in the analyses. Intended Treatment Period: Day of randomization (Day 1) to efficacy cut-off notice of study termination. | Randomization (Day 1) to first event (stent thrombosis), up to March 2011, approximately 2 years | 
| Event Rate of Composite of Cardiovascular Death, Myocardial Infarction, Unstable Angina, or Ischemic Stroke During the Intended Treatment Period - Randomized Participants | Event rate was percent of participants with an event of CV death, MI, unstable angina (UA), or ischemic stroke (number of participants with event/number randomized) per 100-pt years. Only events confirmed by the adjudication committee were included in the analyses. Each type of event was counted once per participant, but participants could have been counted in multiple categories. Intended Treatment Period: Day of randomization (Day 1) to efficacy cut-off date (notification of study termination). | Randomization (Day 1) to first event (CV death, MI, UA, Ischemic Stroke, up to March 2011, approximately 2 years | 
| Event Rate of Composite of Cardiovascular Death, Fatal Bleed, Myocardial Infarction, or Stroke During the Intended Treatment Period - Randomized Participants | Event rate was percent of participants with an event of CV death, fatal bleed, MI, or stroke (number of participants with event/number randomized) per 100 patient (100-pt) years. Only events confirmed by the adjudication committee were included in the analyses. CV death included deaths due to CV causes; Diagnosis of stroke required a new, non-traumatic, focal neurological deficit of sudden onset, lasting at least 24 hours that was not due to a readily identifiable non-vascular cause; Fatal bleeding defined as bleeding that Adjudication Committee determined was the primary cause of death or contributed directly to death; MI took into account whether the participant had a recent PCI or CABG surgery. Intended Treatment Period: Day of randomization (Day 1) to efficacy cut-off date (notification of study termination). | Randomization (Day 1) to first event (CV death, Fatal Bleed, MI, or stroke), up to March 2011, approximately 2 years | 
| Event Rate of Composite of All-Cause Death, Myocardial Infarction, or Stroke During the Intended Treatment Period - Randomized Participants | Cause of death was determined by the principal condition that caused the death, not the immediate mode of death. CV death: included deaths due to CV causes. Non-CV death: included non-CV deaths caused primarily by a malignancy, infection, bleeding, trauma, non-CV system organ failure, or non-CV surgery. Unknown: included deaths that were not attributable to one of the above categories of CV death or to a non-CV cause. MI accounted whether the participant had a recent PCI or CABG surgery. Diagnosis of stroke required a new, non-traumatic, focal neurological deficit of sudden onset, lasting at least 24 hours that was not due to a readily identifiable non-vascular cause. Only events confirmed by the adjudication committee were included in analyses. Intended Treatment Period: Day of randomization (Day 1) to efficacy cut-off date (notification of study termination). | Randomization (Day 1) to first event (All Cause Death, MI, or Stroke), up to March 2011, approximately 2 years | 
| Event Rate of Confirmed Major Bleeding Using International Society on Thrombosis and Hemostasis (ISTH) Criteria During the Treatment Period - Treated Participants | ISTH Criteria: Acute clinically overt bleeding defined as new onset, visible bleeding or signs or symptoms suggestive of bleeding confirmed by imaging techniques, which can detect the presence of blood (eg, ultrasound, CT, MRI). Major bleeding: acute clinically overt bleeding accompanied by one or more of the following: A decrease in Hgb of 2 g/dL or more over 24 hours; A transfusion of 2 or more units of packed red blood cells (RBCs); Bleeding that occurs in at least one of the following sites: intracranial, intraspinal, intraocular (within the corpus of the eye; thus, a conjunctival bleed is not an intraocular bleed), pericardial, intra-articular, intramuscular with compartment syndrome, retroperitoneal; Bleeding that was fatal. Bleeding events were adjudicated by the Adjudication Committee. Event rate was percent of participants with an event (number with event/number randomized) per 100-pt years. Treatment Period=events with onset from first dose to last dose plus 2 days. | From first dose to first occurrence of event (ISTH major bleed) during Treatment Period (first dose to last dose + 2 days), up to March 2011, approximately 2 years | 
| Event Rate of Confirmed Major Bleeding or Clinically Relevant Non-Major Bleeding (CRNM) Using ISTH Criteria During the Treatment Period - Treated Participants | ISTH Major bleed: acute clinically overt bleeding accompanied by one or more of the following: A decrease in Hgb of 2 g/dL or more over 24 hours; A transfusion of 2 or more units of packed RBCs; Bleeding that occurs in at least one of the following critical sites: intracranial, intraspinal, intraocular (within the corpus of the eye), pericardial, intra-articular, intramuscular with compartment syndrome, retroperitoneal; Bleeding that was fatal. CRNM: acute clinically overt bleeding that did not satisfy additional criteria required for the bleeding event to be defined as a major bleeding event and meets at least one of the following: Hospital admission for bleeding; Physician guided medical or surgical treatment for bleeding; Change in anti-thrombotic treatment (anticoagulant or antiplatelet) therapy. Bleeding events were adjudicated by the Adjudication Committee. Treatment Period=events with onset from first dose to last dose plus 2 days. | From first dose to first occurrence of event (ISTH major or CRNM bleed) during Treatment Period (first dose to last dose + 2 days), up to March 2011, approximately 2 years | 
| Event Rate of All Bleeding Reported by the Investigator During the Treatment Period - Treated Participants | Bleeding events were adjudicated by the Adjudication Committee and classified according to Thrombolysis in Myocardial Infarction (TIMI) major, minor, minimal, and International Society on Thrombosis and Hemostasis (ISTH) major and clinically relevant non-major bleeding (CRNM) criteria. The adjudicated results based on TIMI and ISTH classifications, and programmatically identified events (not adjudicated) according to Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) classification were used in the analyses of bleeding endpoints. GUSTO Bleed Criteria included Severe or life-threatening: Intracranial hemorrhage, or bleeding that causes hemodynamic compromise requiring intervention; Moderate: Bleeding that requires a blood transfusion, but does not result in hemodynamic compromise; Mild: Bleeding that does not meet criteria for either severe or moderate bleeding. Treatment Period=events with onset from first dose to last dose plus 2 days. | From first dose to first occurrence of event (Bleeding) during Treatment Period (first dose to last dose + 2 days), up to March 2011, approximately 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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