Atrial Fibrillation, Cardiovascular Disease
Conditions
Keywords
Atrial fibrillation, Cardiovascular disease, angiotensin II blocker
Brief summary
The purpose of this study was to determine if Irbesartan compared to Placebo would reduce the risk of vascular events such as heart attack, stroke, non-cerebral thromboembolic event and death in patients with Atrial Fibrillation (AF) and with at least one major risk of vascular events.
Detailed description
ACTIVE I was one of the 3 separate but related trials of the ACTIVE program conducted in AF patients at risk of vascular events. Patients were enrolled first into one of the 2 parallel trials of the ACTIVE program evaluating Clopidogrel: * ACTIVE A comparing clopidogrel + acetylsalicylic acid (ASA) and ASA alone * ACTIVE W comparing clopidogrel + ASA and oral anticoagulant (OAC). Then those satisfying additional criteria related to blood pressure and angiotensin receptor blocking agents were re-randomized in the two ACTIVE I arms according to a separate randomization list.
Interventions
DRUGIrbesartan
oral administration (tablets) once daily
DRUGplacebo
oral administration (tablets) once daily
Sponsors
Bristol-Myers Squibb
Sanofi
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Should fulfill the eligibility criteria for ACTIVE A or ACTIVE W trial and: * have a systolic blood pressure of at least 110 mmHg * not already receiving an angiotensin receptor blocking agent, unless they are willing and able to be changed to another antihypertensive agent * no previous intolerance to angiotensin receptor blocking agents * no proven indication for angiotensin receptor blocking agents, unless an Angiotensin Converting Enzyme (ACE) inhibitor can be substituted
Exclusion criteria
Patients will be excluded from ACTIVE study 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 acetylsalicyclic acid (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 * requirement for chronic (\> 3 months) non-cyclooxygenase-2 (non-COX-2) inhibitor nonsteroidal anti-inflammatory drug (NSAID) therapy unless willing enrolled in ACTIVE A
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| First Occurence of Any Component of the Composite of Myocardial Infarction, Stroke or Vascular Death as Per Adjudication | Median follow-up of 4.5 years | The first co-primary event is the first occurence of any component of the following cluster over the duration of follow-up: myocardial infarction (nonfatal or fatal), stroke (nonfatal or fatal) or vascular death - after validation by the Event Adjudication Committee (EAC). |
| First Occurence of Any Component of the Composite of Myocardial Infarction, Stroke, Vascular Death or Hospitalization for Heart Failure as Per Adjudication | Median follow-up of 4.5 years | The second co-primary event is the first occurence of any component of the following cluster over the duration of follow-up: myocardial infarction (nonfatal or fatal), stroke (nonfatal or fatal), vascular death or hospitalization for heart failure - after validation by the EAC. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| First Occurrence of Any Heart Failure (HF) Episode | Median follow-up of 4.5 years | The considered event is the first occurence of any HF episode defined as evidence of signs and symptoms of HF with or without hospitalization over the duration of follow-up, as reported by the investigator (i.e. not validated by the Event Adjudication Committee). |
| First Occurrence of Stroke | Median follow-up of 4.5 years | The considered event is the first occurrence of stroke (nonfatal or fatal, ischemic, hemorrhagic or of uncertain type) over the duration of follow-up, after validation by the EAC. |
| First Hospitalisation for Other Cardiovascular (CV) Cause | Median follow-up of 4.5 years | The considered event is the overnight hospital stay for any CV cause other than Heart Failure over the duration of follow-up, as reported by the investigator (i.e. not validated by the Event Adjudication Committee). |
| First Hospitalisation for Heart Failure (HF) | Median follow-up of 4.5 years | The considered event is the first overnight hospital stay for HF over the duration of the follow-up, after validation by the EAC. |
| Death From Any Cause | Median follow-up of 4.5 years | The considered event is the death over the duration of the follow-up whatever the cause, cardiovascular or non-cardiovascular. |
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 in 567 centers in 33 countries. They were initially to be followed until November 2008. After a blinded reassessment of the event rate in May 2008, the planned follow-up end date was postponed and was actually completed on August 2009 corresponding to an actual median follow-up of 4.5 years.
Participants by arm
| Arm | Count |
|---|---|
| Irbesartan 150 mg for 2 weeks, then uptitrated to 300 mg up to final follow-up visit | 4,518 |
| Placebo matching placebo up to final follow-up visit | 4,498 |
| Total | 9,016 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Angiotensin II receptor blocker required | 35 | 58 |
| Overall Study | Event related to cardiac condition | 17 | 16 |
| Overall Study | Hypotension (non-symptomatic) | 5 | 5 |
| Overall Study | Lightheadedness / dizziness | 15 | 11 |
| Overall Study | Lost to Follow-up | 0 | 2 |
| Overall Study | Minor bleeding (e.g.,bruising,epistaxis) | 7 | 3 |
| Overall Study | Missing | 0 | 1 |
| Overall Study | Non-compliance | 71 | 69 |
| Overall Study | Not treated | 16 | 14 |
| Overall Study | Oral anticoagulant required | 2 | 0 |
| Overall Study | Other adverse events (non-serious) | 188 | 159 |
| Overall Study | Other contraindicated medication | 1 | 1 |
| Overall Study | Other Serious Adverse Event | 84 | 93 |
| Overall Study | Patient not wish to continue after May08 | 4 | 6 |
| Overall Study | Physician withdrew consent | 71 | 63 |
| Overall Study | Qualifying condition not present | 26 | 29 |
| Overall Study | Site not agree to continue after May08 | 1 | 1 |
| Overall Study | Study drug intolerance | 3 | 3 |
| Overall Study | Surgery / procedure | 4 | 5 |
| Overall Study | Symptomatic hypotension | 127 | 64 |
| Overall Study | Thromboembolic / outcome event | 39 | 45 |
| Overall Study | Withdrawal by Subject | 678 | 742 |
Baseline characteristics
| Characteristic | Placebo | Total | Irbesartan |
|---|---|---|---|
| ACTIVE A / ACTIVE W ACTIVE A: ASA | 1259 participants | 2504 participants | 1245 participants |
| ACTIVE A / ACTIVE W ACTIVE A: clopidogrel + ASA | 1231 participants | 2494 participants | 1263 participants |
| ACTIVE A / ACTIVE W ACTIVE W: clopidogrel + ASA | 959 participants | 1970 participants | 1011 participants |
| ACTIVE A / ACTIVE W ACTIVE W: OAC | 1049 participants | 2048 participants | 999 participants |
| Age Continuous | 69.6 years STANDARD_DEVIATION 9.7 | 69.6 years STANDARD_DEVIATION 9.7 | 69.5 years STANDARD_DEVIATION 9.7 |
| Age, Customized 18 to <65 years | 1255 participants | 2542 participants | 1287 participants |
| Age, Customized 65 to <75 years | 1673 participants | 3357 participants | 1684 participants |
| Age, Customized >=75 years | 1570 participants | 3117 participants | 1547 participants |
| Body Mass Index (BMI) | 28.867 kg/m² STANDARD_DEVIATION 5.42 | 28.998 kg/m² STANDARD_DEVIATION 5.519 | 29.129 kg/m² STANDARD_DEVIATION 5.614 |
| Congestive heart failure, High blood pressure, Age, Diabetes Stroke 2 (CHADS2) Score 0 | 96 participants | 199 participants | 103 participants |
| Congestive heart failure, High blood pressure, Age, Diabetes Stroke 2 (CHADS2) Score 1 | 1678 participants | 3365 participants | 1687 participants |
| Congestive heart failure, High blood pressure, Age, Diabetes Stroke 2 (CHADS2) Score 2 | 1560 participants | 3076 participants | 1516 participants |
| Congestive heart failure, High blood pressure, Age, Diabetes Stroke 2 (CHADS2) Score > 2 | 1163 participants | 2373 participants | 1210 participants |
| Congestive heart failure, High blood pressure, Age, Diabetes Stroke 2 (CHADS2) Score Missing | 1 participants | 3 participants | 2 participants |
| Sex: Female, Male Female | 1768 Participants | 3541 Participants | 1773 Participants |
| Sex: Female, Male Male | 2730 Participants | 5475 Participants | 2745 Participants |
| Sitting Systolic Blood Pressure <120 mmHg | 500 participants | 1009 participants | 509 participants |
| Sitting Systolic Blood Pressure >=120 mmHg | 3996 participants | 8002 participants | 4006 participants |
| Sitting Systolic Blood Pressure Missing | 2 participants | 5 participants | 3 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 3,303 / 4,518 | 3,277 / 4,498 |
| serious Total, serious adverse events | 1,409 / 4,518 | 1,446 / 4,498 |
Outcome results
Primary
First Occurence of Any Component of the Composite of Myocardial Infarction, Stroke or Vascular Death as Per Adjudication
The first co-primary event is the first occurence of any component of the following cluster over the duration of follow-up: myocardial infarction (nonfatal or fatal), stroke (nonfatal or fatal) or vascular death - after validation by the Event Adjudication Committee (EAC).
Time frame: Median follow-up of 4.5 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) |
|---|---|---|---|
| Irbesartan | First Occurence of Any Component of the Composite of Myocardial Infarction, Stroke or Vascular Death as Per Adjudication | All components | 963 participants |
| Irbesartan | First Occurence of Any Component of the Composite of Myocardial Infarction, Stroke or Vascular Death as Per Adjudication | - Myocardial Infarction (fatal or not) | 136 participants |
| Irbesartan | First Occurence of Any Component of the Composite of Myocardial Infarction, Stroke or Vascular Death as Per Adjudication | - Stroke (fatal or not) | 367 participants |
| Irbesartan | First Occurence of Any Component of the Composite of Myocardial Infarction, Stroke or Vascular Death as Per Adjudication | - Vascular death | 460 participants |
| Placebo | First Occurence of Any Component of the Composite of Myocardial Infarction, Stroke or Vascular Death as Per Adjudication | - Vascular death | 433 participants |
| Placebo | First Occurence of Any Component of the Composite of Myocardial Infarction, Stroke or Vascular Death as Per Adjudication | All components | 963 participants |
| Placebo | First Occurence of Any Component of the Composite of Myocardial Infarction, Stroke or Vascular Death as Per Adjudication | - Stroke (fatal or not) | 407 participants |
| Placebo | First Occurence of Any Component of the Composite of Myocardial Infarction, Stroke or Vascular Death as Per Adjudication | - Myocardial Infarction (fatal or not) | 123 participants |
p-value: 0.85795% CI: [0.907, 1.085]Log Rank
Primary
First Occurence of Any Component of the Composite of Myocardial Infarction, Stroke, Vascular Death or Hospitalization for Heart Failure as Per Adjudication
The second co-primary event is the first occurence of any component of the following cluster over the duration of follow-up: myocardial infarction (nonfatal or fatal), stroke (nonfatal or fatal), vascular death or hospitalization for heart failure - after validation by the EAC.
Time frame: Median follow-up of 4.5 years
Population: The intent-to-treat (ITT) population was used for this analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Irbesartan | First Occurence of Any Component of the Composite of Myocardial Infarction, Stroke, Vascular Death or Hospitalization for Heart Failure as Per Adjudication | - Myocardial Infarction (fatal or not) | 122 participants |
| Irbesartan | First Occurence of Any Component of the Composite of Myocardial Infarction, Stroke, Vascular Death or Hospitalization for Heart Failure as Per Adjudication | All components | 1236 participants |
| Irbesartan | First Occurence of Any Component of the Composite of Myocardial Infarction, Stroke, Vascular Death or Hospitalization for Heart Failure as Per Adjudication | - Stroke (fatal or not) | 340 participants |
| Irbesartan | First Occurence of Any Component of the Composite of Myocardial Infarction, Stroke, Vascular Death or Hospitalization for Heart Failure as Per Adjudication | - Hospitalization for heart failure | 443 participants |
| Irbesartan | First Occurence of Any Component of the Composite of Myocardial Infarction, Stroke, Vascular Death or Hospitalization for Heart Failure as Per Adjudication | - Vascular death | 331 participants |
| Placebo | First Occurence of Any Component of the Composite of Myocardial Infarction, Stroke, Vascular Death or Hospitalization for Heart Failure as Per Adjudication | - Hospitalization for heart failure | 513 participants |
| Placebo | First Occurence of Any Component of the Composite of Myocardial Infarction, Stroke, Vascular Death or Hospitalization for Heart Failure as Per Adjudication | - Vascular death | 291 participants |
| Placebo | First Occurence of Any Component of the Composite of Myocardial Infarction, Stroke, Vascular Death or Hospitalization for Heart Failure as Per Adjudication | All components | 1291 participants |
| Placebo | First Occurence of Any Component of the Composite of Myocardial Infarction, Stroke, Vascular Death or Hospitalization for Heart Failure as Per Adjudication | - Myocardial Infarction (fatal or not) | 112 participants |
| Placebo | First Occurence of Any Component of the Composite of Myocardial Infarction, Stroke, Vascular Death or Hospitalization for Heart Failure as Per Adjudication | - Stroke (fatal or not) | 375 participants |
p-value: 0.1295% CI: [0.869, 1.016]Log Rank
Secondary
Death From Any Cause
The considered event is the death over the duration of the follow-up whatever the cause, cardiovascular or non-cardiovascular.
Time frame: Median follow-up of 4.5 years
Population: The intent-to-treat (ITT) population was used for the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Irbesartan | Death From Any Cause | 949 participants |
| Placebo | Death From Any Cause | 929 participants |
p-value: 0.75995% CI: [0.927, 1.11]Log Rank
Secondary
First Hospitalisation for Heart Failure (HF)
The considered event is the first overnight hospital stay for HF over the duration of the follow-up, after validation by the EAC.
Time frame: Median follow-up of 4.5 years
Population: The intent-to-treat (ITT) population was used for this analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Irbesartan | First Hospitalisation for Heart Failure (HF) | 482 participants |
| Placebo | First Hospitalisation for Heart Failure (HF) | 551 participants |
p-value: 0.017595% CI: [0.763, 0.975]Log Rank
Secondary
First Hospitalisation for Other Cardiovascular (CV) Cause
The considered event is the overnight hospital stay for any CV cause other than Heart Failure over the duration of follow-up, as reported by the investigator (i.e. not validated by the Event Adjudication Committee).
Time frame: Median follow-up of 4.5 years
Population: The intent-to-treat (ITT) population was used for the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Irbesartan | First Hospitalisation for Other Cardiovascular (CV) Cause | 1186 participants |
| Placebo | First Hospitalisation for Other Cardiovascular (CV) Cause | 1174 participants |
p-value: 0.837795% CI: [0.93, 1.093]Log Rank
Secondary
First Occurrence of Any Heart Failure (HF) Episode
The considered event is the first occurence of any HF episode defined as evidence of signs and symptoms of HF with or without hospitalization over the duration of follow-up, as reported by the investigator (i.e. not validated by the Event Adjudication Committee).
Time frame: Median follow-up of 4.5 years
Population: The intent-to-treat (ITT) population was used for the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Irbesartan | First Occurrence of Any Heart Failure (HF) Episode | 699 participants |
| Placebo | First Occurrence of Any Heart Failure (HF) Episode | 767 participants |
p-value: 0.036995% CI: [0.809, 0.993]Log Rank
Secondary
First Occurrence of Stroke
The considered event is the first occurrence of stroke (nonfatal or fatal, ischemic, hemorrhagic or of uncertain type) over the duration of follow-up, after validation by the EAC.
Time frame: Median follow-up of 4.5 years
Population: The intent-to-treat (ITT) population was used for this analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Irbesartan | First Occurrence of Stroke | 379 participants |
| Placebo | First Occurrence of Stroke | 411 participants |
p-value: 0.216295% CI: [0.796, 1.053]Log Rank