Coronary Disease, Ventricular Dysfunction, Left
Conditions
Brief summary
The aim of this study is to test whether ivabradine is able to reduce cardiovascular events when given to patients with coronary artery disease and impaired heart function.
Interventions
DRUGIvabradine
DRUGPlacebo
Sponsors
Institut de Recherches Internationales Servier
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Coronary artery disease * Left ventricular systolic dysfunction * Sinus rhythm: heart rate (HR) \>= 60 beats per minute (bpm)
Exclusion criteria
* Unstable cardiovascular condition * Severe congestive heart failure
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Primary Composite Endpoint | From the date of randomisation to the date of the first occurrence of the first event, up to 3 years. | First event among cardiovascular death, hospitalisation for acute myocardial infarction (fatal or not), or hospitalisation for new onset or worsening heart failure (fatal or not). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Hospitalisation for Acute Myocardial Infarction | From the date of randomisation to the date of first occurrence of the event, up to 3 years. | — |
| Hospitalisation for New Onset or Worsening Heart Failure | From the date of randomisation to the date of first occurrence of the event, up to 3 years. | — |
| All-cause of Mortality | From the date of randomisation to death, up to 3 years. | — |
| Coronary Artery Disease Death | From the date of randomisation to death, up to 3 years. | Death due to heart failure, acute myocardial infarction or cardiac procedure |
| Hospitalisation for Coronary Revascularisation | From the date of randomisation to the date of first occurrence of the event, up to 3 years. | — |
| Cardiovascular Death | From the date of randomisation to death, up to 3 years. | Cardiovascular death including sudden death of unknown cause |
| Hospitalisation for Acute Coronary Syndrome (Unstable Angina or Acute Myocardial Infarction) | From the date of randomisation to the date of first occurrence of the first event, up to 3 years. | — |
| Hospitalisation for Acute Coronary Syndrome, or Coronary Revascularisation | From the date of randomisation to the date of first occurrence of the first event, up to 3 years. | — |
| Hospitalisation for Acute Coronary Syndrome, New Onset or Worsening Heart Failure or Coronary Revascularisation | From the date of randomisation to the date of first occurrence of the first event, up to 3 years. | — |
| Cardiovascular Death, or Hospitalisation for New Onset or Worsening Heart Failure | From the date of randomisation to the date of first occurrence of the first event, up to 3 years. | — |
| Cardiovascular Death, or Hospitalisation for Acute Myocardial Infarction | From the date of randomisation to the date of the first occurrence of the first event, up to 3 years. | — |
| Hospitalisation for Unstable Angina | From the date of randomisation to the date of first occurrence of the event, up to 3 years. | — |
Countries
United Kingdom
Participant flow
Recruitment details
Eligible participants were men and women, with documented history of coronary artery disease, associated with left ventricular systolic dysfunction. Angina and/or heart failure symptoms should have been stable for ≥ 3 months, with optimal conventional cardiovascular medication on appropriate stable doses for at least 1 month.
Pre-assignment details
Following a run-in period of two weeks during which no study treatment was dispensed, the participants were randomised to receive ivabradine or placebo in addition to their usual cardiovascular treatment in double-blind treatment period.
Participants by arm
| Arm | Count |
|---|---|
| Ivabradine Patients received ivabradine at starting dose of 5 mg twice daily, with a target dose, if HR tolerance criteria were met after two weeks (at the D15 visit), of 7.5 mg twice daily. | 5,479 |
| Placebo Patients received placebo twice daily. | 5,438 |
| Total | 10,917 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 572 | 547 |
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Withdrawal by Subject | 114 | 102 |
| Overall Study | Withdrawn by sponsor's decision | 0 | 3 |
Baseline characteristics
| Characteristic | Ivabradine | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 65.3 years STANDARD_DEVIATION 8.5 | 65 years STANDARD_DEVIATION 8.4 | 65.2 years STANDARD_DEVIATION 8.5 |
| Beta-blocker intake No | 730 participants | 700 participants | 1430 participants |
| Beta-blocker intake Yes | 4749 participants | 4738 participants | 9487 participants |
| Sex: Female, Male Female | 939 Participants | 931 Participants | 1870 Participants |
| Sex: Female, Male Male | 4540 Participants | 4507 Participants | 9047 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 2,570 / 5,477 | 2,221 / 5,430 |
| serious Total, serious adverse events | 1,625 / 5,477 | 1,770 / 5,430 |
Outcome results
Primary
Primary Composite Endpoint
First event among cardiovascular death, hospitalisation for acute myocardial infarction (fatal or not), or hospitalisation for new onset or worsening heart failure (fatal or not).
Time frame: From the date of randomisation to the date of the first occurrence of the first event, up to 3 years.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ivabradine | Primary Composite Endpoint | 844 participants |
| Placebo | Primary Composite Endpoint | 832 participants |
p-value: 0.94595% CI: [0.91, 1.1]Regression, Cox
Secondary
All-cause of Mortality
Time frame: From the date of randomisation to death, up to 3 years.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ivabradine | All-cause of Mortality | 572 participants |
| Placebo | All-cause of Mortality | 547 participants |
p-value: 0.54795% CI: [0.92, 1.16]Regression, Cox
Secondary
Cardiovascular Death
Cardiovascular death including sudden death of unknown cause
Time frame: From the date of randomisation to death, up to 3 years.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ivabradine | Cardiovascular Death | 469 participants |
| Placebo | Cardiovascular Death | 435 participants |
p-value: 0.31695% CI: [0.94, 1.22]Regression, Cox
Secondary
Cardiovascular Death, or Hospitalisation for Acute Myocardial Infarction
Time frame: From the date of randomisation to the date of the first occurrence of the first event, up to 3 years.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ivabradine | Cardiovascular Death, or Hospitalisation for Acute Myocardial Infarction | 606 participants |
| Placebo | Cardiovascular Death, or Hospitalisation for Acute Myocardial Infarction | 593 participants |
p-value: 0.83595% CI: [0.9, 1.13]Regression, Cox
Secondary
Cardiovascular Death, or Hospitalisation for New Onset or Worsening Heart Failure
Time frame: From the date of randomisation to the date of first occurrence of the first event, up to 3 years.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ivabradine | Cardiovascular Death, or Hospitalisation for New Onset or Worsening Heart Failure | 757 participants |
| Placebo | Cardiovascular Death, or Hospitalisation for New Onset or Worsening Heart Failure | 723 participants |
p-value: 0.48495% CI: [0.94, 1.15]Regression, Cox
Secondary
Coronary Artery Disease Death
Death due to heart failure, acute myocardial infarction or cardiac procedure
Time frame: From the date of randomisation to death, up to 3 years.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ivabradine | Coronary Artery Disease Death | 136 participants |
| Placebo | Coronary Artery Disease Death | 151 participants |
p-value: 0.33195% CI: [0.71, 1.12]Regression, Cox
Secondary
Hospitalisation for Acute Coronary Syndrome, New Onset or Worsening Heart Failure or Coronary Revascularisation
Time frame: From the date of randomisation to the date of first occurrence of the first event, up to 3 years.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ivabradine | Hospitalisation for Acute Coronary Syndrome, New Onset or Worsening Heart Failure or Coronary Revascularisation | 681 participants |
| Placebo | Hospitalisation for Acute Coronary Syndrome, New Onset or Worsening Heart Failure or Coronary Revascularisation | 704 participants |
p-value: 0.41195% CI: [0.86, 1.06]Regression, Cox
Secondary
Hospitalisation for Acute Coronary Syndrome, or Coronary Revascularisation
Time frame: From the date of randomisation to the date of first occurrence of the first event, up to 3 years.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ivabradine | Hospitalisation for Acute Coronary Syndrome, or Coronary Revascularisation | 364 participants |
| Placebo | Hospitalisation for Acute Coronary Syndrome, or Coronary Revascularisation | 401 participants |
p-value: 0.14195% CI: [0.78, 1.04]Regression, Cox
Secondary
Hospitalisation for Acute Coronary Syndrome (Unstable Angina or Acute Myocardial Infarction)
Time frame: From the date of randomisation to the date of first occurrence of the first event, up to 3 years.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ivabradine | Hospitalisation for Acute Coronary Syndrome (Unstable Angina or Acute Myocardial Infarction) | 303 participants |
| Placebo | Hospitalisation for Acute Coronary Syndrome (Unstable Angina or Acute Myocardial Infarction) | 317 participants |
p-value: 0.50195% CI: [0.81, 1.11]Regression, Cox
Secondary
Hospitalisation for Acute Myocardial Infarction
Time frame: From the date of randomisation to the date of first occurrence of the event, up to 3 years.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ivabradine | Hospitalisation for Acute Myocardial Infarction | 199 Participants |
| Placebo | Hospitalisation for Acute Myocardial Infarction | 226 Participants |
p-value: 0.15995% CI: [0.72, 1.06]Regression, Cox
Secondary
Hospitalisation for Coronary Revascularisation
Time frame: From the date of randomisation to the date of first occurrence of the event, up to 3 years.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ivabradine | Hospitalisation for Coronary Revascularisation | 155 participants |
| Placebo | Hospitalisation for Coronary Revascularisation | 186 participants |
p-value: 0.07895% CI: [0.67, 1.02]Regression, Cox
Secondary
Hospitalisation for New Onset or Worsening Heart Failure
Time frame: From the date of randomisation to the date of first occurrence of the event, up to 3 years.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ivabradine | Hospitalisation for New Onset or Worsening Heart Failure | 426 participants |
| Placebo | Hospitalisation for New Onset or Worsening Heart Failure | 427 participants |
p-value: 0.8595% CI: [0.86, 1.13]Regression, Cox
Secondary
Hospitalisation for Unstable Angina
Time frame: From the date of randomisation to the date of first occurrence of the event, up to 3 years.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ivabradine | Hospitalisation for Unstable Angina | 114 participants |
| Placebo | Hospitalisation for Unstable Angina | 105 participants |
p-value: 0.58395% CI: [0.83, 1.4]Regression, Cox