Aortic Stenosis
Conditions
Brief summary
The purpose of this study is to evaluate whether treatment with an investigational drug as compared to placebo will reduce the risk of major cardiovascular events in patients with aortic stenosis.
Interventions
Duration of Treatment: 4 years
DRUGComparator: Placebo
matching Placebo
Sponsors
Organon and Co
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
45 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
* Patients aged 45 to 85 with mild abnormalities of the aortic valve as confirmed by an echocardiogram.
Exclusion criteria
* Patients previously in a trial using the study drug, or currently taking any medications that are not allowed in this study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants That Experienced One or More Components of the Composite Clinical Endpoint of MCE (Major Cardiovascular Events) | Entire follow-up (median = 4.35 years) | Composite endpoint of MCE consists of cardiovascular death, AVR (aortic valve replacement) surgery, CHF(congestive heart failure) as a result of progression of aortic stenosis, nonfatal MI (myocardial infarction), CABG (coronary artery bypass) surgery, PCI (percutaneous coronary intervention), hospitalized unstable angina, and nonhemorrhagic stroke |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants That Experienced One or More Components of the Composite Clinical Endpoint of AVE (Aortic Valve Events) | Entire follow-up (median = 4.35 years) | Composite endpoint of AVE (aortic valve events) consists of AVR surgery, CHF (as a result of progression of AS), or cardiovascular death |
| Number of Participants That Experienced One or More Components of the Composite Clinical Endpoint of ICE (Ischemic Cardiovascular Events) | Entire follow-up (median = 4.35 years) | Composite endpoint of ICE (ischemic cardiovascular events) consists of cardiovascular death, nonfatal MI, CABG, PCI, hospitalized unstable angina, and nonhemorrhagic stroke |
| Change From Baseline in Peak Transaortic Jet Velocity | Baseline to End of follow-up (median = 4.35 years) or pre-aortic valve replacement | Mean change from baseline in peak transaortic jet velocity |
Other
| Measure | Time frame | Description |
|---|---|---|
| Coronary Artery Bypass Grafting (CABG) | Entire follow-up (median = 4.35 years) | Number of participants that experienced coronary artery bypass grafting (CABG) |
| Percutaneous Coronary Intervention (PCI) | Entire follow-up (median = 4.35 years) | Number of participants that experienced percutaneous coronary intervention (PCI) |
| Hospitalization for Unstable Angina | Entire follow-up (median = 4.35 years) | Number of participants that experienced hospitalization for unstable angina |
| Nonhemorrhagic Stroke | Entire follow-up (median = 4.35 years) | Number of participants that experienced nonhemorrhagic stroke |
| Cardiovascular Death | Entire follow-up (median = 4.35 years) | Number of participants that experienced cardiovascular death |
| Percent Change in Time Weighted Average Total Cholesterol From Baseline to End of Follow-up | Baseline to End of follow-up (median = 4.35 years) | Mean percent change (time-weighted average over follow-up) from baseline: Time-weighted average calculated using values at week 8, week 24, year 1 and every 6 months with time interval (days) between 2 successive values used as the weighting factor. For the first follow-up value, the weight was the number of days from randomization. |
| Percent Change in Time Weighted Average Low-density Lipoprotein Cholesterol (LDL-C) From Baseline to End of Follow-up | Baseline to End of follow-up (median = 4.35 years) | Mean percent change (time-weighted average over follow-up) from baseline: Time-weighted average calculated using values at week 8, week 24, year 1 and every 6 months with time interval (days) between 2 successive values used as the weighting factor. For the first follow-up value, the weight was the number of days from randomization. |
| Percent Change in Time Weighted Average High-density Lipoprotein Cholesterol (HDL-C) From Baseline to End of Follow-up | Baseline to End of follow-up (median = 4.35 years) | Mean percent change (time-weighted average over follow-up) from baseline: Time-weighted average calculated using values at week 8, week 24, year 1 and every 6 months with time interval (days) between 2 successive values used as the weighting factor. For the first follow-up value, the weight was the number of days from randomization. |
| Percent Change in Time Weighted Average Triglycerides From Baseline to End of Follow-up | Baseline to End of follow-up (median = 4.35 years) | Mean percent change (time-weighted average over follow-up) from baseline: Time-weighted average calculated using values at week 8, week 24, year 1 and every 6 months with time interval (days) between 2 successive values used as the weighting factor. For the first follow-up value, the weight was the number of days from randomization. |
| Death (Any Cause) | Entire follow-up (median = 4.35 years) | Number of participants that died (any cause) |
| Aortic Valve Replacement (AVR) | Entire follow-up (median = 4.35 years) | Number of participants that experienced aortic valve replacement (AVR) |
| Congestive Heart Failure (CHF) Due to Progression of Aortic Stenosis (AS) | Entire follow-up (median = 4.35 years) | Number of participants that experienced Congestive Heart Failure (CHF) due to progression of aortic stenosis (AS) |
| Nonfatal Myocardial Infarction (MI) | Entire follow-up (median = 4.35 years) | Number of participants that experienced nonfatal myocardial infarction (MI) |
Participant flow
Recruitment details
Phase III. Study Initiation Date (FPI) was 06-Jan-2003 and Study Completion Date (LPO) was 17-Apr-2008. Primary therapy period 02-Mar-2001 to 31-Mar-2008 includes start date of therapy from the Simvastatin in Aortic Stenosis (SAS) study. 173 study centers worldwide (Denmark, Finland, Germany, Great Britain, Ireland, Norway, and Sweden)
Pre-assignment details
Included patients with asymptomatic aortic stenosis as assessed on echocardiography, not requiring lipid-lowering therapy, and without known coronary heart disease or diabetes mellitus. 4 week placebo/diet run-in period was followed by treatment period lasting until 4 years after the last patient was randomized.
Participants by arm
| Arm | Count |
|---|---|
| EZ/Simva 10/40 mg Ezetimibe 10 mg + Simvastatin 40 mg | 944 |
| Placebo | 929 |
| Total | 1,873 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adminstrative | 5 | 9 |
| Overall Study | Lost to Follow-up | 0 | 2 |
Baseline characteristics
| Characteristic | EZ/Simva 10/40 mg | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 67.7 years | 67.4 years | 67.5 years |
| High-density Lipoprotein Cholesterol (HDL-C) | 1.49 mmol/L STANDARD_DEVIATION 0.43 | 1.49 mmol/L STANDARD_DEVIATION 0.43 | 1.49 mmol/L STANDARD_DEVIATION 0.43 |
| Low-density Lipoprotein Cholesterol (LDL-C) | 3.62 mmol/L STANDARD_DEVIATION 0.93 | 3.59 mmol/L STANDARD_DEVIATION 0.91 | 3.60 mmol/L STANDARD_DEVIATION 0.92 |
| Peak Transaortic Jet Velocity | 3.09 m/sec STANDARD_DEVIATION 0.55 | 3.10 m/sec STANDARD_DEVIATION 0.54 | 3.09 m/sec STANDARD_DEVIATION 0.54 |
| Race/Ethnicity, Customized Asian | 3 participants | 1 participants | 4 participants |
| Race/Ethnicity, Customized Other | 1 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized White | 940 participants | 928 participants | 1868 participants |
| Sex: Female, Male Female | 363 Participants | 360 Participants | 723 Participants |
| Sex: Female, Male Male | 581 Participants | 569 Participants | 1150 Participants |
| Total Cholesterol | 5.76 mmol/L STANDARD_DEVIATION 1.04 | 5.73 mmol/L STANDARD_DEVIATION 0.99 | 5.74 mmol/L STANDARD_DEVIATION 1.02 |
| Triglycerides (TG) | 1.42 mmol/L STANDARD_DEVIATION 0.71 | 1.42 mmol/L STANDARD_DEVIATION 0.68 | 1.42 mmol/L STANDARD_DEVIATION 0.69 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 703 / — | 706 / — |
| serious Total, serious adverse events | 471 / — | 465 / — |
Outcome results
Primary
Number of Participants That Experienced One or More Components of the Composite Clinical Endpoint of MCE (Major Cardiovascular Events)
Composite endpoint of MCE consists of cardiovascular death, AVR (aortic valve replacement) surgery, CHF(congestive heart failure) as a result of progression of aortic stenosis, nonfatal MI (myocardial infarction), CABG (coronary artery bypass) surgery, PCI (percutaneous coronary intervention), hospitalized unstable angina, and nonhemorrhagic stroke
Time frame: Entire follow-up (median = 4.35 years)
Population: Intention-to-Treat
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| EZ/Simva 10/40 mg | Number of Participants That Experienced One or More Components of the Composite Clinical Endpoint of MCE (Major Cardiovascular Events) | 333 Participants |
| Placebo | Number of Participants That Experienced One or More Components of the Composite Clinical Endpoint of MCE (Major Cardiovascular Events) | 355 Participants |
p-value: 0.59195% CI: [0.826, 1.115]Regression, Cox
Secondary
Change From Baseline in Peak Transaortic Jet Velocity
Mean change from baseline in peak transaortic jet velocity
Time frame: Baseline to End of follow-up (median = 4.35 years) or pre-aortic valve replacement
Population: Full Analysis Set: All patients who were randomized, took at least one dose of blinded study therapy and had a baseline and at least one post-randomization assessment without regard to protocol violations or compliance with study medication. 180 patients were excluded from peak transaortic jet velocity due to missing measurements.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| EZ/Simva 10/40 mg | Change From Baseline in Peak Transaortic Jet Velocity | 0.613 m/sec | Standard Deviation 0.586 |
| Placebo | Change From Baseline in Peak Transaortic Jet Velocity | 0.618 m/sec | Standard Deviation 0.612 |
p-value: 0.82995% CI: [-0.063, 0.051]ANCOVA
Secondary
Number of Participants That Experienced One or More Components of the Composite Clinical Endpoint of AVE (Aortic Valve Events)
Composite endpoint of AVE (aortic valve events) consists of AVR surgery, CHF (as a result of progression of AS), or cardiovascular death
Time frame: Entire follow-up (median = 4.35 years)
Population: Intention-to-Treat
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| EZ/Simva 10/40 mg | Number of Participants That Experienced One or More Components of the Composite Clinical Endpoint of AVE (Aortic Valve Events) | 308 Participants |
| Placebo | Number of Participants That Experienced One or More Components of the Composite Clinical Endpoint of AVE (Aortic Valve Events) | 326 Participants |
p-value: 0.73295% CI: [0.833, 1.137]Regression, Cox
Secondary
Number of Participants That Experienced One or More Components of the Composite Clinical Endpoint of ICE (Ischemic Cardiovascular Events)
Composite endpoint of ICE (ischemic cardiovascular events) consists of cardiovascular death, nonfatal MI, CABG, PCI, hospitalized unstable angina, and nonhemorrhagic stroke
Time frame: Entire follow-up (median = 4.35 years)
Population: Intention-to-Treat
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| EZ/Simva 10/40 mg | Number of Participants That Experienced One or More Components of the Composite Clinical Endpoint of ICE (Ischemic Cardiovascular Events) | 148 Participants |
| Placebo | Number of Participants That Experienced One or More Components of the Composite Clinical Endpoint of ICE (Ischemic Cardiovascular Events) | 187 Participants |
p-value: 0.02495% CI: [0.628, 0.967]Regression, Cox
Other Pre-specified
Aortic Valve Replacement (AVR)
Number of participants that experienced aortic valve replacement (AVR)
Time frame: Entire follow-up (median = 4.35 years)
Population: Intention-to-Treat
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| EZ/Simva 10/40 mg | Aortic Valve Replacement (AVR) | 267 Participants |
| Placebo | Aortic Valve Replacement (AVR) | 278 Participants |
p-value: 0.96895% CI: [0.842, 1.179]Regression, Cox
Other Pre-specified
Cardiovascular Death
Number of participants that experienced cardiovascular death
Time frame: Entire follow-up (median = 4.35 years)
Population: Intention-to-Treat
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| EZ/Simva 10/40 mg | Cardiovascular Death | 47 Participants |
| Placebo | Cardiovascular Death | 56 Participants |
p-value: 0.34495% CI: [0.563, 1.222]Regression, Cox
Other Pre-specified
Congestive Heart Failure (CHF) Due to Progression of Aortic Stenosis (AS)
Number of participants that experienced Congestive Heart Failure (CHF) due to progression of aortic stenosis (AS)
Time frame: Entire follow-up (median = 4.35 years)
Population: Intention-to-Treat
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| EZ/Simva 10/40 mg | Congestive Heart Failure (CHF) Due to Progression of Aortic Stenosis (AS) | 25 Participants |
| Placebo | Congestive Heart Failure (CHF) Due to Progression of Aortic Stenosis (AS) | 23 Participants |
p-value: 0.77195% CI: [0.617, 1.917]Regression, Cox
Other Pre-specified
Coronary Artery Bypass Grafting (CABG)
Number of participants that experienced coronary artery bypass grafting (CABG)
Time frame: Entire follow-up (median = 4.35 years)
Population: Intention-to-Treat
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| EZ/Simva 10/40 mg | Coronary Artery Bypass Grafting (CABG) | 69 Participants |
| Placebo | Coronary Artery Bypass Grafting (CABG) | 100 Participants |
p-value: 0.01595% CI: [0.503, 0.929]Regression, Cox
Other Pre-specified
Death (Any Cause)
Number of participants that died (any cause)
Time frame: Entire follow-up (median = 4.35 years)
Population: Intention-to-Treat
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| EZ/Simva 10/40 mg | Death (Any Cause) | 105 Participants |
| Placebo | Death (Any Cause) | 100 Participants |
p-value: 0.79995% CI: [0.788, 1.363]Regression, Cox
Post Hoc
Death Due to Cancer
Number of participants that died due to cancer
Time frame: Entire follow-up (median = 4.35 years)
Population: Intention-to-Treat
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| EZ/Simva 10/40 mg | Death Due to Cancer | 39 Participants |
| Placebo | Death Due to Cancer | 23 Participants |
p-value: 0.05295% CI: [0.996, 2.791]Regression, Cox
Other Pre-specified
Hospitalization for Unstable Angina
Number of participants that experienced hospitalization for unstable angina
Time frame: Entire follow-up (median = 4.35 years)
Population: Intention-to-Treat
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| EZ/Simva 10/40 mg | Hospitalization for Unstable Angina | 5 Participants |
| Placebo | Hospitalization for Unstable Angina | 8 Participants |
95% CI: [0.199, 1.86]Regression, Cox
Post Hoc
Incident Cancer
Number of participants with incident cancer
Time frame: Entire follow-up (median = 4.35 years)
Population: One patient from the 944 patients randomized to ezetimibe/simvastatin 10/40 mg did not receive study medication and was not included.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| EZ/Simva 10/40 mg | Incident Cancer | 105 Participants |
| Placebo | Incident Cancer | 70 Participants |
p-value: 0.00895% CI: [1.111, 2.035]Regression, Cox
Other Pre-specified
Nonfatal Myocardial Infarction (MI)
Number of participants that experienced nonfatal myocardial infarction (MI)
Time frame: Entire follow-up (median = 4.35 years)
Population: Intention-to-Treat
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| EZ/Simva 10/40 mg | Nonfatal Myocardial Infarction (MI) | 17 Participants |
| Placebo | Nonfatal Myocardial Infarction (MI) | 26 Participants |
p-value: 0.14795% CI: [0.345, 1.173]Regression, Cox
Other Pre-specified
Nonhemorrhagic Stroke
Number of participants that experienced nonhemorrhagic stroke
Time frame: Entire follow-up (median = 4.35 years)
Population: Intention-to-Treat
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| EZ/Simva 10/40 mg | Nonhemorrhagic Stroke | 33 Participants |
| Placebo | Nonhemorrhagic Stroke | 29 Participants |
p-value: 0.64795% CI: [0.682, 1.85]Regression, Cox
Other Pre-specified
Percent Change in Time Weighted Average High-density Lipoprotein Cholesterol (HDL-C) From Baseline to End of Follow-up
Mean percent change (time-weighted average over follow-up) from baseline: Time-weighted average calculated using values at week 8, week 24, year 1 and every 6 months with time interval (days) between 2 successive values used as the weighting factor. For the first follow-up value, the weight was the number of days from randomization.
Time frame: Baseline to End of follow-up (median = 4.35 years)
Population: Full Analysis Set: All patients who were randomized, took at least one dose of blinded study therapy and had a baseline and at least one post-randomization assessment without regard to protocol violations or compliance with study medication.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| EZ/Simva 10/40 mg | Percent Change in Time Weighted Average High-density Lipoprotein Cholesterol (HDL-C) From Baseline to End of Follow-up | 6.5 Percent change | Standard Deviation 17.7 |
| Placebo | Percent Change in Time Weighted Average High-density Lipoprotein Cholesterol (HDL-C) From Baseline to End of Follow-up | 2.5 Percent change | Standard Deviation 16.1 |
p-value: <=0.00195% CI: [2.4, 5.5]ANOVA
Other Pre-specified
Percent Change in Time Weighted Average Low-density Lipoprotein Cholesterol (LDL-C) From Baseline to End of Follow-up
Mean percent change (time-weighted average over follow-up) from baseline: Time-weighted average calculated using values at week 8, week 24, year 1 and every 6 months with time interval (days) between 2 successive values used as the weighting factor. For the first follow-up value, the weight was the number of days from randomization.
Time frame: Baseline to End of follow-up (median = 4.35 years)
Population: Full Analysis Set: All patients who were randomized, took at least one dose of blinded study therapy and had a baseline and at least one post-randomization assessment without regard to protocol violations or compliance with study medication.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| EZ/Simva 10/40 mg | Percent Change in Time Weighted Average Low-density Lipoprotein Cholesterol (LDL-C) From Baseline to End of Follow-up | -53.8 Percent Change | Standard Deviation 18.7 |
| Placebo | Percent Change in Time Weighted Average Low-density Lipoprotein Cholesterol (LDL-C) From Baseline to End of Follow-up | -3.8 Percent Change | Standard Deviation 20.6 |
p-value: <=0.00195% CI: [-51.8, -48.2]ANOVA
Other Pre-specified
Percent Change in Time Weighted Average Total Cholesterol From Baseline to End of Follow-up
Mean percent change (time-weighted average over follow-up) from baseline: Time-weighted average calculated using values at week 8, week 24, year 1 and every 6 months with time interval (days) between 2 successive values used as the weighting factor. For the first follow-up value, the weight was the number of days from randomization.
Time frame: Baseline to End of follow-up (median = 4.35 years)
Population: Full Analysis Set: All patients who were randomized, took at least one dose of blinded study therapy and had a baseline and at least one post-randomization assessment without regard to protocol violations or compliance with study medication.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| EZ/Simva 10/40 mg | Percent Change in Time Weighted Average Total Cholesterol From Baseline to End of Follow-up | -34.8 Percent Change | Standard Deviation 13.5 |
| Placebo | Percent Change in Time Weighted Average Total Cholesterol From Baseline to End of Follow-up | -2.7 Percent Change | Standard Deviation 11.8 |
p-value: <=0.00195% CI: [-33.3, -31]ANOVA
Other Pre-specified
Percent Change in Time Weighted Average Triglycerides From Baseline to End of Follow-up
Mean percent change (time-weighted average over follow-up) from baseline: Time-weighted average calculated using values at week 8, week 24, year 1 and every 6 months with time interval (days) between 2 successive values used as the weighting factor. For the first follow-up value, the weight was the number of days from randomization.
Time frame: Baseline to End of follow-up (median = 4.35 years)
Population: Full Analysis Set: All patients who were randomized, took at least one dose of blinded study therapy and had a baseline and at least one post-randomization assessment without regard to protocol violations or compliance with study medication.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| EZ/Simva 10/40 mg | Percent Change in Time Weighted Average Triglycerides From Baseline to End of Follow-up | -14.9 Percent Change | Standard Deviation 27.6 |
| Placebo | Percent Change in Time Weighted Average Triglycerides From Baseline to End of Follow-up | 5.1 Percent Change | Standard Deviation 30.4 |
p-value: <=0.00195% CI: [-22.6, -17.3]ANOVA
Other Pre-specified
Percutaneous Coronary Intervention (PCI)
Number of participants that experienced percutaneous coronary intervention (PCI)
Time frame: Entire follow-up (median = 4.35 years)
Population: Intention-to-Treat
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| EZ/Simva 10/40 mg | Percutaneous Coronary Intervention (PCI) | 8 Participants |
| Placebo | Percutaneous Coronary Intervention (PCI) | 17 Participants |
95% CI: [0.197, 1.057]Regression, Cox