Atrial Fibrillation, Vascular Risk
Conditions
Keywords
Atrial fibrillation, Anticoagulant therapy, Thromboembolic prevention
Brief summary
The purpose of this study is to determine if the combination of clopidogrel 75mg once daily (od) plus aspirin 100mg daily (recommended dose) is better than aspirin alone (100mg daily recommended dose) for preventing vascular events such as stroke and heart attack during approximately three years of follow-up in patients with atrial fibrillation associated with at least one major risk factor of vascular event such as elderly, blood pressure increase, history of stroke or transient ischemic attack or left ventricular dysfunction etc. The study will also accept patients with atrial fibrillation and unwilling to take oral anticoagulant therapy.
Interventions
oral administration (tablets)
DRUGplacebo
oral administration (tablets)
Sponsors
Bristol-Myers Squibb
Sanofi
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
To be eligible for ACTIVE A patients must have in same time the three following conditions : * Evidence of atrial fibrillation either on one current Electrocardiogram (ECG) or two ECGs recorded at two weeks a part during 6 months prior to study enrollment. * Evidence of high risk of vascular events : at least one of the following risk criteria must be present : * are 75 years greater; * on treatment for systemic hypertension; * prior stroke, Transient Ischemic Attack (TIA) or non-Central Nervous System (non-CNS) systemic embolus; * left ventricular dysfunction with left ventricular ejection fraction (EF) estimated by echocardiogram or angiogram (radionuclide or contrast) to be \< 45%; * peripheral vascular disease (previous peripheral artery revascularization, limb and foot amputation, or the combination of current intermittent claudication and ankle arm systolic blood pressure ratio \< 0.9); * age 55 to 74 years and either; f1) diabetes mellitus requiring drug therapy, or f2) documented previous myocardial infarction or documented coronary artery disease. * To have either a contraindication to use an oral anticoagulant treatment or they are unwilling to take an oral anticoagulant treatment.
Exclusion criteria
Patients will be excluded from ACTIVE if any of the following are present : * requirement for clopidogrel (such as recent coronary stent procedure) * requirement for oral anticoagulant (such as prosthetic mechanical heart valve); * prior intolerance to ASA or clopidogrel; * documented peptic ulcer disease within the previous 6 months; * prior intracerebral hemorrhage; * significant thrombocytopenia; (platelet count \< 50 x 10(9)/L) * psychosocial reason making study participation impractical; * geographic reason making study participation impractical; * ongoing alcohol abuse; * mitral stenosis, * pregnant or nursing woman or woman of child bearing potential and not on effective birth control for at least one month prior to start of study or not willing to continue on birth control for duration of study; (severe comorbid condition such that the patient is not expected to survive 6 months; * patient currently receiving an investigational pharmacologic agent;
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| First Occurence of Any Component of the Composite of Stroke, Non-Central Nervous System (Non-CNS) Systemic Embolism, Myocardial Infarction or Vascular Death as Per Adjudication | expected median follow-up of approximately 3 years | The primary event is the first occurence of any adjudicated component of the following cluster over the duration of follow-up : * stroke (nonfatal or fatal) * myocardial infarction (nonfatal or fatal) * non-CNS systemic embolism * vascular death The primary efficacy analysis is performed on the time from randomization to this primary event. Numbers of patients with the composite event over the duration of the follow-up are presented by arm group. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Occurrence of Stroke | expected median follow-up of approximately 3 years | The event is the occurence of stroke (nonfatal or fatal, ischemic, hemorrhagic or of uncertain type) after validation of the Event Adjudication Committee . The analysis is performed on the time from randomization to the occurrence of this event. Numbers of patients with the event over the duration of the follow-up are presented by arm group. |
| Death From Any Cause (Cardiovascular and Noncardiovascular) | expected median follow-up of approximately 3 years | The considered event is death from any cause. The analysis is performed on the time from randomization to this event. Numbers of patients with the event over the duration of the follow-up are presented by arm group. |
| Adjudicated Major Bleedings | expected median follow-up of approximately 3 years | The number of participants with at least one major bleeding, validated by the Event Adjudication Committee are counted over the duration of the follow-up (including after permanent discontinuation of the study drug). |
Countries
Argentina, Australia, Austria, Belgium, Brazil, Canada, Chile, Czechia, Denmark, Finland, France, Germany, Greece, Hong Kong, Hungary, Italy, Malaysia, Mexico, Netherlands, Norway, Poland, Portugal, Singapore, South Africa, Spain, Sweden, Switzerland, Taiwan, United Kingdom, United States
Participant flow
Recruitment details
Patients were enrolled from June 2003 until May 2006. The study was conducted at 580 centers in 33 countries. The planned final follow-up visit date ensuring a median follow-up of three years was November 2008. The follow-up of the study was actually completed on March 2009 corresponding to an actual median follow-up of 3.5 years.
Participants by arm
| Arm | Count |
|---|---|
| Clopidogrel + ASA Clopidogrel 75 mg once daily (od) plus acetylsalicyclic acid (ASA) 75 to 100 mg od recommended (dose at the investigators' discretion) | 3,772 |
| Placebo + ASA Matching placebo of clopidogrel 75 mg od plus ASA 75 to 100 mg od recommended (dose at the investigators' discretion) | 3,782 |
| Total | 7,554 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Angiotensin II receptor blocker required | 1 | 0 |
| Overall Study | Contraindication to oral anticoagulant | 4 | 8 |
| Overall Study | Event related to cardiac condition | 12 | 21 |
| Overall Study | Lost to Follow-up | 4 | 7 |
| Overall Study | Minor bleeding | 99 | 37 |
| Overall Study | Non-compliance | 41 | 46 |
| Overall Study | Not treated | 7 | 8 |
| Overall Study | Open label clopidogrel required | 31 | 42 |
| Overall Study | Oral anticoagulant required | 159 | 157 |
| Overall Study | Other contraindicated medication | 1 | 0 |
| Overall Study | Other non serious Adverse Event | 112 | 108 |
| Overall Study | Other Serious Adverse Event | 86 | 97 |
| Overall Study | Patient not wish to continue after May08 | 3 | 4 |
| Overall Study | Physician withdrew consent | 59 | 60 |
| Overall Study | Qualifying condition not present | 20 | 23 |
| Overall Study | Serious haemorrhagic Adverse Event | 74 | 30 |
| Overall Study | Severe allergic reaction | 8 | 1 |
| Overall Study | Significant thrombocytopenia | 9 | 8 |
| Overall Study | Study drug intolerance | 5 | 0 |
| Overall Study | Surgery/ procedure | 9 | 9 |
| Overall Study | Thromboembolic/outcome event | 82 | 122 |
| Overall Study | Withdrawal by Subject | 504 | 466 |
Baseline characteristics
| Characteristic | Placebo + ASA | Clopidogrel + ASA | Total |
|---|---|---|---|
| Age, Continuous | 71.1 years STANDARD_DEVIATION 10.2 | 70.9 years STANDARD_DEVIATION 10.2 | 71.0 years STANDARD_DEVIATION 10.2 |
| Age, Customized 18 to <65 years | 935 participants | 931 participants | 1866 participants |
| Age, Customized 65 to <75 years | 1258 participants | 1291 participants | 2549 participants |
| Age, Customized >= 75 years | 1589 participants | 1550 participants | 3139 participants |
| Body Mass Index (BMI) | 28.459 kg/m² STANDARD_DEVIATION 6.022 | 28.370 kg/m² STANDARD_DEVIATION 5.575 | 28.415 kg/m² STANDARD_DEVIATION 5.803 |
| CHADS2 Score 0 | 101 participants | 105 participants | 206 participants |
| CHADS2 Score 1 | 1338 participants | 1360 participants | 2698 participants |
| CHADS2 Score 2 | 1315 participants | 1263 participants | 2578 participants |
| CHADS2 Score >2 | 1028 participants | 1040 participants | 2068 participants |
| CHADS2 Score Missing | 0 participants | 4 participants | 4 participants |
| Sex: Female, Male Female | 1597 Participants | 1560 Participants | 3157 Participants |
| Sex: Female, Male Male | 2185 Participants | 2212 Participants | 4397 Participants |
| Sitting Systolic Blood Pressure <120 mmHg | 620 participants | 603 participants | 1223 participants |
| Sitting Systolic Blood Pressure >=120 mmHg | 3159 participants | 3166 participants | 6325 participants |
| Sitting Systolic Blood Pressure Missing | 3 participants | 3 participants | 6 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 2,542 / 3,772 | 2,502 / 3,782 |
| serious Total, serious adverse events | 1,154 / 3,772 | 1,069 / 3,782 |
Outcome results
Primary
First Occurence of Any Component of the Composite of Stroke, Non-Central Nervous System (Non-CNS) Systemic Embolism, Myocardial Infarction or Vascular Death as Per Adjudication
The primary event is the first occurence of any adjudicated component of the following cluster over the duration of follow-up : * stroke (nonfatal or fatal) * myocardial infarction (nonfatal or fatal) * non-CNS systemic embolism * vascular death The primary efficacy analysis is performed on the time from randomization to this primary event. Numbers of patients with the composite event over the duration of the follow-up are presented by arm group.
Time frame: expected median follow-up of approximately 3 years
Population: The intent-to-treat (ITT) population was used for all analyses. This consisted of all randomized patients irrespective of whether or not the patient actually received study drug or the patient's compliance with the study protocol. All patients were included in the treatment group to which they were originally allocated.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Clopidogrel + ASA | First Occurence of Any Component of the Composite of Stroke, Non-Central Nervous System (Non-CNS) Systemic Embolism, Myocardial Infarction or Vascular Death as Per Adjudication | - Myocardial Infarction (fatal or not) | 84 participants |
| Clopidogrel + ASA | First Occurence of Any Component of the Composite of Stroke, Non-Central Nervous System (Non-CNS) Systemic Embolism, Myocardial Infarction or Vascular Death as Per Adjudication | - Non-CNS systemic embolism | 50 participants |
| Clopidogrel + ASA | First Occurence of Any Component of the Composite of Stroke, Non-Central Nervous System (Non-CNS) Systemic Embolism, Myocardial Infarction or Vascular Death as Per Adjudication | - Stroke (fatal or not) | 285 participants |
| Clopidogrel + ASA | First Occurence of Any Component of the Composite of Stroke, Non-Central Nervous System (Non-CNS) Systemic Embolism, Myocardial Infarction or Vascular Death as Per Adjudication | - Vascular death | 413 participants |
| Clopidogrel + ASA | First Occurence of Any Component of the Composite of Stroke, Non-Central Nervous System (Non-CNS) Systemic Embolism, Myocardial Infarction or Vascular Death as Per Adjudication | All components | 832 participants |
| Placebo + ASA | First Occurence of Any Component of the Composite of Stroke, Non-Central Nervous System (Non-CNS) Systemic Embolism, Myocardial Infarction or Vascular Death as Per Adjudication | - Vascular death | 380 participants |
| Placebo + ASA | First Occurence of Any Component of the Composite of Stroke, Non-Central Nervous System (Non-CNS) Systemic Embolism, Myocardial Infarction or Vascular Death as Per Adjudication | All components | 924 participants |
| Placebo + ASA | First Occurence of Any Component of the Composite of Stroke, Non-Central Nervous System (Non-CNS) Systemic Embolism, Myocardial Infarction or Vascular Death as Per Adjudication | - Myocardial Infarction (fatal or not) | 105 participants |
| Placebo + ASA | First Occurence of Any Component of the Composite of Stroke, Non-Central Nervous System (Non-CNS) Systemic Embolism, Myocardial Infarction or Vascular Death as Per Adjudication | - Stroke (fatal or not) | 391 participants |
| Placebo + ASA | First Occurence of Any Component of the Composite of Stroke, Non-Central Nervous System (Non-CNS) Systemic Embolism, Myocardial Infarction or Vascular Death as Per Adjudication | - Non-CNS systemic embolism | 48 participants |
p-value: 0.013395% CI: [0.81, 0.98]Log Rank
Secondary
Adjudicated Major Bleedings
The number of participants with at least one major bleeding, validated by the Event Adjudication Committee are counted over the duration of the follow-up (including after permanent discontinuation of the study drug).
Time frame: expected median follow-up of approximately 3 years
Population: The intent-to-treat (ITT) population was used for the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Clopidogrel + ASA | Adjudicated Major Bleedings | 251 participants |
| Placebo + ASA | Adjudicated Major Bleedings | 162 participants |
p-value: <0.001Chi-squared
Secondary
Death From Any Cause (Cardiovascular and Noncardiovascular)
The considered event is death from any cause. The analysis is performed on the time from randomization to this event. Numbers of patients with the event over the duration of the follow-up are presented by arm group.
Time frame: expected median follow-up of approximately 3 years
Population: The intent-to-treat (ITT) population was used for the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Clopidogrel + ASA | Death From Any Cause (Cardiovascular and Noncardiovascular) | 825 participants |
| Placebo + ASA | Death From Any Cause (Cardiovascular and Noncardiovascular) | 841 participants |
p-value: 0.69695% CI: [0.89, 1.08]Log Rank
Secondary
Occurrence of Stroke
The event is the occurence of stroke (nonfatal or fatal, ischemic, hemorrhagic or of uncertain type) after validation of the Event Adjudication Committee . The analysis is performed on the time from randomization to the occurrence of this event. Numbers of patients with the event over the duration of the follow-up are presented by arm group.
Time frame: expected median follow-up of approximately 3 years
Population: The intent-to-treat (ITT) population was used for this analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Clopidogrel + ASA | Occurrence of Stroke | 296 participants |
| Placebo + ASA | Occurrence of Stroke | 408 participants |
p-value: <0.00195% CI: [0.62, 0.83]Log Rank