Hypercholesterolemia, Myocardial Infarction
Conditions
Keywords
hypercholesterolemia, myocardial infarction, cholesterol, randomized controlled trials, acute coronary syndrome, angina
Brief summary
This is a randomized, active-control, double-blind study of subjects with stabilized high-risk acute coronary syndrome (ACS). The primary objective is to evaluate the clinical benefit of Ezetimibe/Simvastatin Combination 10/40 (single tablet, under the brand VYTORIN in the United States) compared with Simvastatin 40 mg. As per the original protocol, if low-density lipoprotein cholesterol (LDL-C) response was inadequate, the dose of simvastatin in the VYTORIN arm or simvastatin arm, could be increased to 80 mg (Note: per June 2011 protocol amendment, criteria for continued use of 80 mg simvastatin were modified and new increases of simvastatin dose to 80 mg were stopped). Clinical benefit will be defined as the reduction in the risk of the occurrence of the composite endpoint of cardiovascular (CV) death, major coronary events, and stroke.
Interventions
Ezetimibe/simvastatin 10/40 mg per day from randomization through the end of participation. As per the original protocol, if LDL-C response was inadequate, the dose of simvastatin in the VYTORIN arm or simvastatin arm, could be increased to 80 mg (Note: per June 2011 protocol amendment, criteria for continued use of 80 mg simvastatin were modified and new increases of simvastatin dose to 80 mg were stopped).
DRUGsimvastatin
Simvastatin 40 mg per day from randomization through the end of participation. As per the original protocol, if LDL-C response was inadequate, the dose of simvastatin in the VYTORIN arm or simvastatin arm, could be increased to 80 mg (Note: per June 2011 protocol amendment, criteria for continued use of 80 mg simvastatin were modified and new increases of simvastatin dose to 80 mg were stopped).
DRUGPlacebo for simvastatin 40 mg
one or two tablets orally daily
DRUGPlacebo for ezetimibe 10 mg/simvastatin 40 mg combination
one tablet orally daily.
Sponsors
Organon and Co
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Clinically stable participants may be eligible to enroll within 10 days following hospital admission with high-risk acute coronary syndrome (either ST-elevation myocardial infarction \[STEMI\] or Non-STEMI or unstable angina) * Participants not taking a statin must have an LDL-C of 125 mg/dl or less. Participants taking a statin must have an LDL-C of 100 mg/dl or less.
Exclusion criteria
* Pregnant or lactating woman, or intending to become pregnant * Participant with active liver disease or persistent unexplained serum transaminase elevation * History of alcohol or drug abuse * History of sensitivity to statin or ezetimibe * A participant for whom discontinuation of existing lipid lowering regimen poses an unacceptable risk.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to First Occurrence of Cardiovascular Death, Major Coronary Event, or Non-fatal Stroke (Kaplan-Meier Estimate of Percentage of Participants Experiencing a Qualifying Event) | Up to approximately 9 years | The time (in months) from study start to the first occurrence of any of the following clinical outcomes was recorded: cardiovascular death, major coronary Event (non-fatal myocardial infarction \[MI\], documented unstable angina \[UA\] requiring hospitalization, or coronary revascularization with percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) ≥ 30 days after randomization), or non-fatal Stroke. A Clinical Endpoints Committee (CEC) reviewed and adjudicated each suspected efficacy endpoint event while blinded to treatment. Participants who did not have any endpoint event until last visit or who were lost to follow-up and had no event were censored at the time of last available information (last study visit). The Kaplan-Meier estimate reports the percentage of participants who experienced cardiovascular death, major coronary event, or non-fatal stroke within 7 years from randomization. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to First Occurrence of Death From Any Cause, Major Coronary Event, or Non-fatal Stroke (Kaplan-Meier Estimate of Percentage of Participants Experiencing a Qualifying Event) | Up to approximately 9 years | The time (in months) from study start to the first occurrence of any of the following clinical outcomes was recorded: death from any cause, major coronary event (non-fatal myocardial infarction, documented unstable angina requiring hospitalization, or coronary revascularization with percutaneous coronary intervention or coronary artery bypass grafting ≥ 30 days after randomization), or non-fatal stroke. A Clinical Endpoints Committee (CEC) reviewed and adjudicated each suspected efficacy endpoint event while blinded to treatment. Participants who did not have any endpoint event until last visit or who were lost to follow-up and had no event were censored at the time of last available information (last study visit). The Kaplan-Meier estimate reports the percentage of participants who experienced death from any cause, major coronary event, or non-fatal stroke within 7 years from randomization. |
| Time to First Occurrence of Coronary Heart Disease (CHD) Death, Non-fatal MI, or Urgent Coronary Revascularization With PCI or CABG ≥ 30 Days After Randomization (Kaplan-Meier Estimate of Percentage of Participants Experiencing a Qualifying Event) | Up to approximately 9 years | The time (in months) from study start to the first occurrence of any of the following clinical outcomes was recorded: CHD death, non-fatal MI, or urgent coronary revascularization with PCI or CABG ≥ 30 days after randomization. A Clinical Endpoints Committee (CEC) reviewed and adjudicated each suspected efficacy endpoint event while blinded to treatment. Participants who did not have any endpoint event until last visit or who were lost to follow-up and had no event were censored at the time of last available information (last study visit). The Kaplan-Meier estimate reports the percentage of participants who experienced CHD death, non-fatal MI, or urgent coronary revascularization with PCI or CABG ≥ 30 days after randomization within 7 years from randomization. |
| Time to First Occurrence of CV Death, Nonfatal MI, UA With Hospitalization, All Revascularization Occurring ≥30 Days After Randomization, and Non-fatal Stroke (Kaplan-Meier Estimate of Percentage of Participants Experiencing a Qualifying Event) | Up to approximately 9 years | The time (in months) from study start to the first occurrence of any of the following clinical outcomes was recorded: CV death, non-fatal MI, documented UA that requires admission into a hospital, all revascularization (including non-coronary) occurring at least 30 days after randomization, and non-fatal stroke. A Clinical Endpoints Committee (CEC) reviewed and adjudicated each suspected efficacy endpoint event while blinded to treatment. Participants who did not have any endpoint event until last visit or who were lost to follow-up and had no event were censored at the time of last available information (last study visit). The Kaplan-Meier estimate reports the percentage of participants who experienced CV death, non-fatal MI, unstable angina with hospitalization, all revascularization occurring ≥ 30 days after randomization, and non-fatal stroke within 7 Years from randomization. |
Participant flow
Recruitment details
Adult men and women presenting with non-ST segment elevation myocardial infarction (NSTEMI) , STEMI, or hospitalized, documented unstable angina (UA) whom a percutaneous coronary intervention (PCI) was planned as management for the qualifying acute coronary syndrome (ACS) event were eligible for entry into the trial.
Pre-assignment details
Study continued until a minimum of 5,250 participants had a primary endpoint event and each participant was followed for a minimum of 2.5 years.
Participants by arm
| Arm | Count |
|---|---|
| Ezetimibe/Simvastatin One Ezetimibe 10 mg/simvastatin 40 mg combination tablet and two simvastatin 40 mg placebo tablets once per day. | 9,067 |
| Simvastatin One simvastatin 40 mg tablet, one ezetimibe/simvastatin combination 10/40 placebo tablet and one simvastatin 40 mg placebo tablet once per day. | 9,077 |
| Total | 18,144 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 964 | 968 |
| Overall Study | Lost to Follow-up | 44 | 49 |
| Overall Study | Only Vital Status Known | 357 | 356 |
| Overall Study | Site Closure | 39 | 36 |
| Overall Study | Withdrawal by Subject | 795 | 808 |
Baseline characteristics
| Characteristic | Ezetimibe/Simvastatin | Simvastatin | Total |
|---|---|---|---|
| Age, Continuous | 63.6 years STANDARD_DEVIATION 9.7 | 63.6 years STANDARD_DEVIATION 9.8 | 63.6 years STANDARD_DEVIATION 9.8 |
| Sex: Female, Male Female | 2225 Participants | 2191 Participants | 4416 Participants |
| Sex: Female, Male Male | 6842 Participants | 6886 Participants | 13728 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 5,486 / 9,067 | 5,472 / 9,077 |
| serious Total, serious adverse events | 3,640 / 9,067 | 3,649 / 9,077 |
Outcome results
Primary
Time to First Occurrence of Cardiovascular Death, Major Coronary Event, or Non-fatal Stroke (Kaplan-Meier Estimate of Percentage of Participants Experiencing a Qualifying Event)
The time (in months) from study start to the first occurrence of any of the following clinical outcomes was recorded: cardiovascular death, major coronary Event (non-fatal myocardial infarction \[MI\], documented unstable angina \[UA\] requiring hospitalization, or coronary revascularization with percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) ≥ 30 days after randomization), or non-fatal Stroke. A Clinical Endpoints Committee (CEC) reviewed and adjudicated each suspected efficacy endpoint event while blinded to treatment. Participants who did not have any endpoint event until last visit or who were lost to follow-up and had no event were censored at the time of last available information (last study visit). The Kaplan-Meier estimate reports the percentage of participants who experienced cardiovascular death, major coronary event, or non-fatal stroke within 7 years from randomization.
Time frame: Up to approximately 9 years
Population: All participants who were randomly assigned to a treatment arm.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ezetimibe/Simvastatin | Time to First Occurrence of Cardiovascular Death, Major Coronary Event, or Non-fatal Stroke (Kaplan-Meier Estimate of Percentage of Participants Experiencing a Qualifying Event) | 32.72 Percentage of Participants |
| Simvastatin | Time to First Occurrence of Cardiovascular Death, Major Coronary Event, or Non-fatal Stroke (Kaplan-Meier Estimate of Percentage of Participants Experiencing a Qualifying Event) | 34.67 Percentage of Participants |
p-value: 0.01695% CI: [0.887, 0.988]Cox proportional hazard model
Secondary
Time to First Occurrence of Coronary Heart Disease (CHD) Death, Non-fatal MI, or Urgent Coronary Revascularization With PCI or CABG ≥ 30 Days After Randomization (Kaplan-Meier Estimate of Percentage of Participants Experiencing a Qualifying Event)
The time (in months) from study start to the first occurrence of any of the following clinical outcomes was recorded: CHD death, non-fatal MI, or urgent coronary revascularization with PCI or CABG ≥ 30 days after randomization. A Clinical Endpoints Committee (CEC) reviewed and adjudicated each suspected efficacy endpoint event while blinded to treatment. Participants who did not have any endpoint event until last visit or who were lost to follow-up and had no event were censored at the time of last available information (last study visit). The Kaplan-Meier estimate reports the percentage of participants who experienced CHD death, non-fatal MI, or urgent coronary revascularization with PCI or CABG ≥ 30 days after randomization within 7 years from randomization.
Time frame: Up to approximately 9 years
Population: All participants who were randomly assigned to a treatment arm.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ezetimibe/Simvastatin | Time to First Occurrence of Coronary Heart Disease (CHD) Death, Non-fatal MI, or Urgent Coronary Revascularization With PCI or CABG ≥ 30 Days After Randomization (Kaplan-Meier Estimate of Percentage of Participants Experiencing a Qualifying Event) | 17.52 Percentage of Participants |
| Simvastatin | Time to First Occurrence of Coronary Heart Disease (CHD) Death, Non-fatal MI, or Urgent Coronary Revascularization With PCI or CABG ≥ 30 Days After Randomization (Kaplan-Meier Estimate of Percentage of Participants Experiencing a Qualifying Event) | 18.88 Percentage of Participants |
p-value: 0.01695% CI: [0.847, 0.983]Cox proportional hazard model
Secondary
Time to First Occurrence of CV Death, Nonfatal MI, UA With Hospitalization, All Revascularization Occurring ≥30 Days After Randomization, and Non-fatal Stroke (Kaplan-Meier Estimate of Percentage of Participants Experiencing a Qualifying Event)
The time (in months) from study start to the first occurrence of any of the following clinical outcomes was recorded: CV death, non-fatal MI, documented UA that requires admission into a hospital, all revascularization (including non-coronary) occurring at least 30 days after randomization, and non-fatal stroke. A Clinical Endpoints Committee (CEC) reviewed and adjudicated each suspected efficacy endpoint event while blinded to treatment. Participants who did not have any endpoint event until last visit or who were lost to follow-up and had no event were censored at the time of last available information (last study visit). The Kaplan-Meier estimate reports the percentage of participants who experienced CV death, non-fatal MI, unstable angina with hospitalization, all revascularization occurring ≥ 30 days after randomization, and non-fatal stroke within 7 Years from randomization.
Time frame: Up to approximately 9 years
Population: All participants who were randomly assigned to a treatment arm.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ezetimibe/Simvastatin | Time to First Occurrence of CV Death, Nonfatal MI, UA With Hospitalization, All Revascularization Occurring ≥30 Days After Randomization, and Non-fatal Stroke (Kaplan-Meier Estimate of Percentage of Participants Experiencing a Qualifying Event) | 34.49 Percentage of Participants |
| Simvastatin | Time to First Occurrence of CV Death, Nonfatal MI, UA With Hospitalization, All Revascularization Occurring ≥30 Days After Randomization, and Non-fatal Stroke (Kaplan-Meier Estimate of Percentage of Participants Experiencing a Qualifying Event) | 36.20 Percentage of Participants |
p-value: 0.03595% CI: [0.897, 0.996]Cox proportional hazard model
Secondary
Time to First Occurrence of Death From Any Cause, Major Coronary Event, or Non-fatal Stroke (Kaplan-Meier Estimate of Percentage of Participants Experiencing a Qualifying Event)
The time (in months) from study start to the first occurrence of any of the following clinical outcomes was recorded: death from any cause, major coronary event (non-fatal myocardial infarction, documented unstable angina requiring hospitalization, or coronary revascularization with percutaneous coronary intervention or coronary artery bypass grafting ≥ 30 days after randomization), or non-fatal stroke. A Clinical Endpoints Committee (CEC) reviewed and adjudicated each suspected efficacy endpoint event while blinded to treatment. Participants who did not have any endpoint event until last visit or who were lost to follow-up and had no event were censored at the time of last available information (last study visit). The Kaplan-Meier estimate reports the percentage of participants who experienced death from any cause, major coronary event, or non-fatal stroke within 7 years from randomization.
Time frame: Up to approximately 9 years
Population: All participants who were randomly assigned to a treatment arm.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ezetimibe/Simvastatin | Time to First Occurrence of Death From Any Cause, Major Coronary Event, or Non-fatal Stroke (Kaplan-Meier Estimate of Percentage of Participants Experiencing a Qualifying Event) | 38.65 Percentage of Participants |
| Simvastatin | Time to First Occurrence of Death From Any Cause, Major Coronary Event, or Non-fatal Stroke (Kaplan-Meier Estimate of Percentage of Participants Experiencing a Qualifying Event) | 40.25 Percentage of Participants |
p-value: 0.03595% CI: [0.903, 0.996]Cox proportional hazard model