Coronary Artery Disease
Conditions
Brief summary
The purpose of this study is to evaluate the effect of ivabradine on cardiovascular events in patients with coronary artery disease.
Interventions
DRUGIvabradine
5 mg, 7.5 mg or 10 mg tablets to be taken orally twice daily, at 12-hours intervals, in the morning and in the evening during meals up to 48 months.
DRUGPlacebo
Matching placebo tablets to be taken orally twice daily, at 12-hours intervals, in the morning and in the evening during meals up to 48 months.
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
55 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Evidence of coronary artery disease * Sinus rhythm and resting heart rate equal or higher than 70 bpm
Exclusion criteria
* Unstable cardiovascular condition * Known hypersensitivity to ivabradine or current treatment with marketed ivabradine
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Primary Composite Endpoint | The events are expressed as the time to occurrence of the first event, defined as the duration between the date of randomisation and the date of first occurrence of event, assessed up to 48 months. | First event among cardiovascular death or non-fatal myocardial infarction |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cardiovascular Mortality | From the date of randomisation to death, up to 48 months | Component of the primary composite endpoint |
| Coronary Mortality | From the date of randomisation to death, up to 48 months | Coronary mortality including sudden death of unknown cause, death from myocardial infarction, death from heart failure, death from coronary artery procedure, presumed arrhythmic death |
| Fatal Myocardial Infarction | From the date of randomisation to death, up to 48 months | Non-composite secondary endpoint |
| All-cause Mortality | From the date of randomisation to death, up to 48 months | — |
| Elective Coronary Revascularisation | From the date of randomisation to the date of first occurrence of the event, up to 48 months | Non-composite secondary endpoint |
| Coronary Revascularisation (Elective or Not) | From the date of randomisation to the date of first occurrence of the event, up to 48 months | Non-composite secondary endpoint |
| Secondary Composite Endpoint | From the date of randomisation to the date of first occurrence of the event, up to 48 months | Fatal or non-fatal myocardial infarction |
| Non-fatal Myocardial Infarction | From the date of randomisation to the date of first occurrence of the event, up to 48 months | Component of the primary composite endpoint |
Countries
Italy, United Kingdom
Participant flow
Recruitment details
A total of 1181 centres in 51 countries screened at least one patient and 1139 centres included at least one patient.
Pre-assignment details
A total of 23 164 patients were screened, 21 862 were selected and 19 107 were included. The Randomised Set comprised 19 102 patients: 9550 patients in the ivabradine group and 9552 in the placebo group. Of the 19 102 patients in the Randomised Set, 17 724 completed the study: 8830 patients in the ivabradine group and 8894 in the placebo group.
Participants by arm
| Arm | Count |
|---|---|
| Ivabradine Ivabradine: 5 mg, 7.5 mg or 10 mg tablets to be taken orally twice daily, at 12-hours intervals, in the morning and in the evening during meals up to 48 months. | 9,550 |
| Placebo Placebo: Matching placebo tablets to be taken orally twice daily, at 12-hours intervals, in the morning and in the evening during meals up to 48 months. | 9,552 |
| Total | 19,102 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 485 | 458 |
| Overall Study | Lost to Follow-up | 3 | 1 |
| Overall Study | Physician Decision | 1 | 0 |
| Overall Study | Withdrawal by Subject | 231 | 199 |
Baseline characteristics
| Characteristic | Ivabradine | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 4441 Participants | 4456 Participants | 8897 Participants |
| Age, Categorical Between 18 and 65 years | 5109 Participants | 5096 Participants | 10205 Participants |
| Age, Continuous | 65 years STANDARD_DEVIATION 7.2 | 65 years STANDARD_DEVIATION 7.3 | 65 years STANDARD_DEVIATION 7.2 |
| Sex: Female, Male Female | 2601 Participants | 2662 Participants | 5263 Participants |
| Sex: Female, Male Male | 6949 Participants | 6890 Participants | 13839 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 6,207 / 9,539 | 5,525 / 9,544 |
| serious Total, serious adverse events | 3,379 / 9,539 | 3,263 / 9,544 |
Outcome results
Primary
Primary Composite Endpoint
First event among cardiovascular death or non-fatal myocardial infarction
Time frame: The events are expressed as the time to occurrence of the first event, defined as the duration between the date of randomisation and the date of first occurrence of event, assessed up to 48 months.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ivabradine | Primary Composite Endpoint | 654 participants |
| Placebo | Primary Composite Endpoint | 611 participants |
p-value: 0.196995% CI: [0.96, 1.2]Regression, Cox
Secondary
All-cause Mortality
Time frame: From the date of randomisation to death, up to 48 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ivabradine | All-cause Mortality | 485 participants |
| Placebo | All-cause Mortality | 458 participants |
p-value: 0.346195% CI: [0.94, 1.21]Regression, Cox
Secondary
Cardiovascular Mortality
Component of the primary composite endpoint
Time frame: From the date of randomisation to death, up to 48 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ivabradine | Cardiovascular Mortality | 329 participants |
| Placebo | Cardiovascular Mortality | 301 participants |
p-value: 0.249395% CI: [0.94, 1.28]Regression, Cox
Secondary
Coronary Mortality
Coronary mortality including sudden death of unknown cause, death from myocardial infarction, death from heart failure, death from coronary artery procedure, presumed arrhythmic death
Time frame: From the date of randomisation to death, up to 48 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ivabradine | Coronary Mortality | 263 participants |
| Placebo | Coronary Mortality | 249 participants |
p-value: 0.516295% CI: [0.89, 1.26]Regression, Cox
Secondary
Coronary Revascularisation (Elective or Not)
Non-composite secondary endpoint
Time frame: From the date of randomisation to the date of first occurrence of the event, up to 48 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ivabradine | Coronary Revascularisation (Elective or Not) | 562 participants |
| Placebo | Coronary Revascularisation (Elective or Not) | 564 participants |
p-value: 0.97995% CI: [0.89, 1.12]Regression, Cox
Secondary
Elective Coronary Revascularisation
Non-composite secondary endpoint
Time frame: From the date of randomisation to the date of first occurrence of the event, up to 48 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ivabradine | Elective Coronary Revascularisation | 270 participants |
| Placebo | Elective Coronary Revascularisation | 305 participants |
p-value: 0.145895% CI: [0.75, 1.04]Regression, Cox
Secondary
Fatal Myocardial Infarction
Non-composite secondary endpoint
Time frame: From the date of randomisation to death, up to 48 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ivabradine | Fatal Myocardial Infarction | 51 participants |
| Placebo | Fatal Myocardial Infarction | 38 participants |
p-value: 0.164795% CI: [0.88, 2.05]Regression, Cox
Secondary
Non-fatal Myocardial Infarction
Component of the primary composite endpoint
Time frame: From the date of randomisation to the date of first occurrence of the event, up to 48 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ivabradine | Non-fatal Myocardial Infarction | 351 participants |
| Placebo | Non-fatal Myocardial Infarction | 339 participants |
p-value: 0.602495% CI: [0.9, 1.21]Regression, Cox
Secondary
Secondary Composite Endpoint
Non-fatal myocardial infarction, coronary revascularisation, unstable angina
Time frame: From the date of randomisation to the date of first occurrence of the event, up to 48 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ivabradine | Secondary Composite Endpoint | 734 participants |
| Placebo | Secondary Composite Endpoint | 759 participants |
p-value: 0.528595% CI: [0.87, 1.07]Regression, Cox
Secondary
Secondary Composite Endpoint
Fatal or non-fatal myocardial infarction, coronary revascularisation
Time frame: From the date of randomisation to the date of first occurrence of the event, up to 48 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ivabradine | Secondary Composite Endpoint | 718 participants |
| Placebo | Secondary Composite Endpoint | 739 participants |
p-value: 0.591695% CI: [0.88, 1.08]Regression, Cox
Secondary
Secondary Composite Endpoint
Fatal or non-fatal myocardial infarction, coronary revascularisation, unstable angina
Time frame: From the date of randomisation to the date of first occurrence of the event, up to 48 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ivabradine | Secondary Composite Endpoint | 766 participants |
| Placebo | Secondary Composite Endpoint | 782 participants |
p-value: 0.696395% CI: [0.89, 1.08]Regression, Cox
Secondary
Secondary Composite Endpoint
Cardiovascular death, non-fatal myocardial infarction, non-fatal stroke
Time frame: From the date of randomisation to the date of first occurrence of the event, up to 48 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ivabradine | Secondary Composite Endpoint | 774 participants |
| Placebo | Secondary Composite Endpoint | 731 participants |
p-value: 0.222295% CI: [0.96, 1.18]Regression, Cox
Secondary
Secondary Composite Endpoint
Coronary death, non-fatal myocardial infarction
Time frame: From the date of randomisation to the date of first occurrence of the event, up to 48 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ivabradine | Secondary Composite Endpoint | 590 participants |
| Placebo | Secondary Composite Endpoint | 562 participants |
p-value: 0.367195% CI: [0.94, 1.18]Regression, Cox
Secondary
Secondary Composite Endpoint
Fatal or non-fatal myocardial infarction
Time frame: From the date of randomisation to the date of first occurrence of the event, up to 48 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ivabradine | Secondary Composite Endpoint | 392 participants |
| Placebo | Secondary Composite Endpoint | 372 participants |
p-value: 0.429995% CI: [0.92, 1.22]Regression, Cox