Chronic Heart Failure
Conditions
Brief summary
The primary objective of this study is to demonstrate the superiority of ivabradine over placebo in the reduction of cardiovascular mortality or hospitalisation for worsening heart failure in patients with moderate to severe symptoms of chronic heart failure, a reduced left ventricular ejection fraction and currently receiving recommended therapy for this disease.
Interventions
DRUGIvabradine
2.5mg, 5mg or 7.5mg tablets to be taken orally twice daily, at 12-hours intervals, in the morning and in the evening during meals up to 42 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 42 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
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Symptomatic Chronic heart failure (NYHA II, III or IV) * Left ventricular systolic dysfunction (LVEF ≤ 35%) * Sinus rhythm and resting heart rate ≥ 70 bpm * Optimal and unchanged CHF medications or dosages
Exclusion criteria
* Unstable condition within previous 4 weeks * Myocardial infarction or coronary revascularisation within previous 2 months * Stroke or transient cerebral ischaemia within previous 4 weeks * Congenital heart disease * Severe valvular disease * Active myocarditis * Permanent atrial fibrillation or flutter
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Primary Composite Endpoint: First Event Among Cardiovascular Death (Including Death of Unknown Cause) or Hospitalization for Worsening Heart Failure. | All over the study (up to 42 months). | Number of patients having experienced the Primary Composite Endpoint. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Hospitalisation for Worsening Heart Failure | From the date of randomization to the date of first documented hospitalisation, up to 42 months | — |
| All-cause Mortality | From the date of randomisation to death, up to 42 months. | — |
| Death From Heart Failure | From the date of randomisation to death, up to 42 months. | Component of cardiovascular death |
| Hospitalisation for Any Cause | From the date of randomisation to the date of first documented hospitalisation, up to 42 months | — |
| Cardiovascular Death | From the date of randomization until the date of death, up to 42 months | Component of the primary composite endpoint |
| Unplanned Hospitalisation for Any Cause | From the date of randomisation to the first documented hospitalisation, up to 42 months | — |
| Unplanned Hospitalisation for CV Reason | From the date of randomisation to the first documented hospitalisation, up to 42 months. | — |
| Secondary Composite Endpoint | From the date of randomisation to the date of the first event, up to 42 months | CV death, hospitalisation for worsening HF or hospitalisation for non-fatal myocardial infarction |
| Hospitalisation for Cardiovascular Reason | From the date of randomisation to the first documented hospitalisation, up to 42 months | — |
Countries
France, Sweden
Participant flow
Recruitment details
The target population was adult patients with stable, moderate to severe chronic heart failure (CHF) and left ventricular systolic dysfunction, with optimal and unchanged CHF medications and dosages for ≥ 4 weeks.
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 Ivabradine: 2.5mg, 5mg or 7.5mg tablets to be taken orally twice daily, at 12-hours intervals, in the morning and in the evening during meals up to 42 months. | 3,241 |
| 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 42 months. | 3,264 |
| Total | 6,505 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 503 | 553 |
| Overall Study | Lost to Follow-up | 2 | 1 |
| Overall Study | Withdrawal by Subject | 73 | 58 |
Baseline characteristics
| Characteristic | Ivabradine | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 60.7 years STANDARD_DEVIATION 11.2 | 60.1 years STANDARD_DEVIATION 11.5 | 60.4 years STANDARD_DEVIATION 11.4 |
| Beta-blocker intake at randomization No | 344 participants | 341 participants | 685 participants |
| Beta-blocker intake at randomization Yes | 2897 participants | 2923 participants | 5820 participants |
| Sex: Female, Male Female | 779 Participants | 756 Participants | 1535 Participants |
| Sex: Female, Male Male | 2462 Participants | 2508 Participants | 4970 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 2,062 / 3,232 | 2,020 / 3,260 |
| serious Total, serious adverse events | 1,369 / 3,232 | 1,481 / 3,260 |
Outcome results
Primary
Primary Composite Endpoint: First Event Among Cardiovascular Death (Including Death of Unknown Cause) or Hospitalization for Worsening Heart Failure.
Number of patients having experienced the Primary Composite Endpoint.
Time frame: All over the study (up to 42 months).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ivabradine | Primary Composite Endpoint: First Event Among Cardiovascular Death (Including Death of Unknown Cause) or Hospitalization for Worsening Heart Failure. | 793 participants |
| Placebo | Primary Composite Endpoint: First Event Among Cardiovascular Death (Including Death of Unknown Cause) or Hospitalization for Worsening Heart Failure. | 937 participants |
p-value: <0.000195% CI: [0.75, 0.9]Regression, Cox
Secondary
All-cause Mortality
Time frame: From the date of randomisation to death, up to 42 months.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ivabradine | All-cause Mortality | 503 participants |
| Placebo | All-cause Mortality | 552 participants |
p-value: 0.09295% CI: [0.8, 1.02]Regression, Cox
Secondary
Cardiovascular Death
Component of the primary composite endpoint
Time frame: From the date of randomization until the date of death, up to 42 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ivabradine | Cardiovascular Death | 449 participants |
| Placebo | Cardiovascular Death | 491 participants |
p-value: 0.12895% CI: [0.8, 1.03]Regression, Cox
Secondary
Death From Heart Failure
Component of cardiovascular death
Time frame: From the date of randomisation to death, up to 42 months.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ivabradine | Death From Heart Failure | 113 participants |
| Placebo | Death From Heart Failure | 151 participants |
p-value: 0.01495% CI: [0.58, 0.94]Regression, Cox
Secondary
Hospitalisation for Any Cause
Time frame: From the date of randomisation to the date of first documented hospitalisation, up to 42 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ivabradine | Hospitalisation for Any Cause | 1231 participants |
| Placebo | Hospitalisation for Any Cause | 1356 participants |
p-value: 0.002795% CI: [0.82, 0.96]Regression, Cox
Secondary
Hospitalisation for Cardiovascular Reason
Time frame: From the date of randomisation to the first documented hospitalisation, up to 42 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ivabradine | Hospitalisation for Cardiovascular Reason | 977 participants |
| Placebo | Hospitalisation for Cardiovascular Reason | 1122 participants |
p-value: 0.000295% CI: [0.78, 0.92]Regression, Cox
Secondary
Hospitalisation for Worsening Heart Failure
Time frame: From the date of randomization to the date of first documented hospitalisation, up to 42 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ivabradine | Hospitalisation for Worsening Heart Failure | 514 participants |
| Placebo | Hospitalisation for Worsening Heart Failure | 672 participants |
p-value: <0.000195% CI: [0.66, 0.83]Regression, Cox
Secondary
Secondary Composite Endpoint
CV death, hospitalisation for worsening HF or hospitalisation for non-fatal myocardial infarction
Time frame: From the date of randomisation to the date of the first event, up to 42 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ivabradine | Secondary Composite Endpoint | 825 participants |
| Placebo | Secondary Composite Endpoint | 979 participants |
p-value: <0.000195% CI: [0.74, 0.89]Regression, Cox
Secondary
Unplanned Hospitalisation for Any Cause
Time frame: From the date of randomisation to the first documented hospitalisation, up to 42 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ivabradine | Unplanned Hospitalisation for Any Cause | 1137 participants |
| Placebo | Unplanned Hospitalisation for Any Cause | 1264 participants |
p-value: 0.001395% CI: [0.81, 0.95]Regression, Cox
Secondary
Unplanned Hospitalisation for CV Reason
Time frame: From the date of randomisation to the first documented hospitalisation, up to 42 months.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ivabradine | Unplanned Hospitalisation for CV Reason | 909 participants |
| Placebo | Unplanned Hospitalisation for CV Reason | 1047 participants |
p-value: 0.000295% CI: [0.77, 0.92]Regression, Cox