Stable Angina
Conditions
Keywords
angina, atherosclerosis, simvastatin, ezetimibe, inflammation
Brief summary
Among patients with stable coronary artery disease (CAD), it is not clear if the pleiotropic effects of cholesterol reduction differ between high-dose simvastatin alone and combined ezetimibe/simvastatin. The investigators sought to compare the anti-inflammatory and anti-platelet effects of ezetimibe 10 mg / simvastatin 20 mg (E10/S20) to simvastatin 80 mg (S80).
Detailed description
Introduction Among patients with coronary artery disease (CAD), a robust evidence base supports the beneficial effects of statin therapy on mortality and other adverse cardiovascular outcomes . Recently, two large trials , have demonstrated that compared to standard dose statin therapy, high statin doses reduced Low-density lipoprotein-C (LDL-C) to extremely low levels and decreased coronary events, even in patients with normal levels of Low-density lipoprotein-C (LDL-C). Subsequently, recent guidelines have suggested an Low-density lipoprotein-C (LDL-C) treatment goal of \<70 mg/dL in patients with coronary artery disease (CAD). Achieving such low Low-density lipoprotein-C (LDL-C) levels frequently demands an intensive Low-density lipoprotein-C (LDL-C) reduction, often above 50%. Ezetimibe, an intestinal cholesterol absorption inhibitor, can be used as an additional therapy if statin monotherapy fails to reduce Low-density lipoprotein-C (LDL-C) below the treatment goal. Furthermore, anti-inflammatory and antithrombotic pleiotropic effects of statins might explain, at least in part, the large benefits demonstrated in randomized trials , . For example, in hypercholesterolemic patients treated with statins, a decrease in inflammation-associated markers such as the C-reactive protein (CRP) has been described , although it is debated whether this effect is clearly independent of Low-density lipoprotein-C (LDL-C). Moreover, although inhibition of platelets by statin therapy is a well established effect , , it has not yet been clarified whether platelet inhibition by statin therapy depends on the reduction of Low-density lipoprotein-C (LDL-C) or on the inhibition of intracellular signal pathways accompanied by disaggregating effects. Two alternative pharmacologic strategies are equally effective in reducing Low-density lipoprotein-C (LDL-C): high-dose statin alone and combined treatment with ezetimibe plus moderate-dose statin . It is not known whether these two strategies have different cholesterol-independent pleiotropic effects on inflammation and platelets. We therefore compared the anti-inflammatory and antiplatelet effects of two intensive pharmacologic strategies to reduce cholesterol: 80 mg of simvastatin (S80) versus 10 mg ezetimibe/ 20 mg of simvastatin (E10/S20). Anti-inflammatory effects were assessed by performing serial measurements of the following biomarkers: C-Reactive Protein (CRP), monocyte chemoattractant protein (MCP)-1, oxidized Low-density lipoprotein-C (oxLDL), soluble intercellular adhesion molecule (sICAM)-1. Platelet aggregation was also compared between the two strategies.
Interventions
DRUGSimvastatin 80 mg/day for 6 weeks
Simvastatin 80 mg/day, single dose, for 6 weeks.
DRUGEzetimibe 10 mg / Simvastatin 20 mg
Ezetimibe 10 mg / Simvastatin 20 mg Patients were treated with daily Ezetimibe 10 mg / Simvastatin 20 mg for 6 weeks
Sponsors
University of Sao Paulo
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Stable angina * Low-density lipoprotein (LDL) cholesterol 70-160 mg/dl
Exclusion criteria
* Renal failure * Age\>80 * Simvastatin current treatment\>20mg * Hepatic disease * Inflammatory diseases
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Interleukin-6 | Fasting venous blood samples were drawn immediately after randomization and after at the conclusions of the six weeks study period. | A commercial ELISA assay detecting IL-6 (Siemens, USA) was applied. |
| Monocyte Chemoattractant Protein (MCP)-1 | Change from baseline at 6 weeks | Serum samples were stored at -70°C and were determined simultaneously by ELISA in order to avoid variation of assay conditions. Commercial ELISA assays detecting MCP-1/ICAM-1 (R&D Systems, Europe, Abingdon, UK). |
| Soluble Intercellular Adhesion Molecule (sICAM)-1 | Change from baseline at 6 weeks | serum samples were stored at -70°C and were determined simultaneously by ELISA in order to avoid variation of assay conditions. Commercial ELISA assays detecting MCP-1/ICAM-1 (R&D Systems, Europe, Abingdon, UK) |
| Soluble CD40 Ligand | Fasting venous blood samples were drawn immediately after randomization and after at the conclusions of the six weeks study period. | A commercial ELISA assay detecting sCD40L (R&D Systems, USA) was applied. Detection limits and intra-assay variability was respectively, as follows: sCD-40L 15.6 pg/mL (intra-assay variability not available). |
| C-reactive Protein | Change from baseline at 6 weeks | Serum was separated by centrifugation from the blood samples. For high-sensitivity C-Reactive Protein measurement, whole venous blood was collected in tubes without anticoagulant and centrifuged at room temperature. Serum C-Reactive Protein was assessed with a high-sensitivity, latex microparticle-enhanced immunoturbidimetric assay (Behring Nephelometer Analyzer System; Behring Diagnostics, Somerville, NJ). |
| Oxidized Low-Density Lipoprotein Cholesterol | Change from baseline at 6 weeks | Serum samples were stored at -70°C and were determined simultaneously by ELISA in order to avoid variation of assay conditions. Commercial ELISA assays detecting oxLDL (Mercodia, USA) were applied. |
| Platelet Function Analyzer [PFA]-100 | Change from baseline at 6 weeks | Samples were collected in 3.8% sodium citrate (buffered, pH 5.5, Vacutainer, Becton Dickinson, Plymouth, UK) for platelet function tests. Platelet function assays were processed within 2 hours of blood collection. The PFA-100 records the closure time (CT), witch means the time in seconds (s) from the start of the test until the platelet plug occludes the aperture. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Triglyceride | Fasting venous blood samples were drawn immediately after randomization and at the conclusions of the six week study period. | — |
| Endothelial Progenitor Cells | Fasting venous blood samples were drawn immediately after randomization and at the conclusions of the six week study period. | Endothelial progenitor cells were evaluated by flow cytometry. Selected cells were positive for CD31, CD34 and VEGFR receptors. |
| LDL Cholesterol | Fasting venous blood samples were drawn immediately after randomization and at the conclusions of the six week study period. | — |
Countries
Brazil
Participant flow
Recruitment details
From July 2006 to January 2009, we randomized 78 patients with stable coronary artery disease (CAD) with LDL-C \> 70 mg/dl, Angiographically documented CAD, stable angina, and age between 18 and 80 years. Patients were assigned randomly to two groups. The one group received Ezetimibe 10 mg/Simvastatin 20 mg the one other received Simvastatin 80 mg.
Pre-assignment details
No wash-out period.
Participants by arm
| Arm | Count |
|---|---|
| Simvastatin 80 mg Patients were treated with simvastatin 80 mg for 6 weeks | 38 |
| Simvastatin 20mg/Ezetimibe 10 mg Patients were treated with Simvastatin 20mg/Ezetimibe 10 mgfor 6 weeks | 40 |
| Total | 78 |
Baseline characteristics
| Characteristic | Simvastatin 20mg/Ezetimibe 10 mg | Simvastatin 80 mg | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 3 Participants | 3 Participants | 6 Participants |
| Age, Categorical Between 18 and 65 years | 37 Participants | 35 Participants | 72 Participants |
| Age Continuous | 64.5 years STANDARD_DEVIATION 9 | 61.7 years STANDARD_DEVIATION 10 | 63.2 years STANDARD_DEVIATION 10 |
| Region of Enrollment Brazil | 40 participants | 38 participants | 78 participants |
| Sex: Female, Male Female | 15 Participants | 18 Participants | 33 Participants |
| Sex: Female, Male Male | 25 Participants | 20 Participants | 45 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 38 | 0 / 40 |
| serious Total, serious adverse events | 0 / 38 | 0 / 40 |
Outcome results
Primary
C-reactive Protein
Serum was separated by centrifugation from the blood samples. For high-sensitivity C-Reactive Protein measurement, whole venous blood was collected in tubes without anticoagulant and centrifuged at room temperature. Serum C-Reactive Protein was assessed with a high-sensitivity, latex microparticle-enhanced immunoturbidimetric assay (Behring Nephelometer Analyzer System; Behring Diagnostics, Somerville, NJ).
Time frame: Change from baseline at 6 weeks
Population: per protocol
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Simvastatin 80 mg | C-reactive Protein | -16 Percentage |
| Simvastatin 20mg/Ezetimibe 10 mg | C-reactive Protein | -11 Percentage |
Comparison: The sample size was determined as 78 patients. Continuous data were presented as means ± SD, or median (interquartile range) when the distribution was non-normal. For qualitative variables, we presented counts and relative frequencies. For between-group comparison we used multiple regression with adjustment for baseline values of the outcome variable (ANCOVA), or Wilcoxon rank-sum test when the variable had a non-normal distribution.p-value: 0.3Wilcoxon (Mann-Whitney)
Primary
Interleukin-6
A commercial ELISA assay detecting IL-6 (Siemens, USA) was applied.
Time frame: Fasting venous blood samples were drawn immediately after randomization and after at the conclusions of the six weeks study period.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Simvastatin 80 mg | Interleukin-6 | 0 percentage |
| Simvastatin 20mg/Ezetimibe 10 mg | Interleukin-6 | 0 percentage |
Primary
Monocyte Chemoattractant Protein (MCP)-1
Serum samples were stored at -70°C and were determined simultaneously by ELISA in order to avoid variation of assay conditions. Commercial ELISA assays detecting MCP-1/ICAM-1 (R&D Systems, Europe, Abingdon, UK).
Time frame: Change from baseline at 6 weeks
Population: per protocol
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Simvastatin 80 mg | Monocyte Chemoattractant Protein (MCP)-1 | 11 percentage | Standard Deviation 47 |
| Simvastatin 20mg/Ezetimibe 10 mg | Monocyte Chemoattractant Protein (MCP)-1 | 10 percentage | Standard Deviation 21 |
Comparison: The sample size was determined as 78 patients. Continuous data were presented as means ± SD, or median (interquartile range) when the distribution was non-normal. For qualitative variables, we presented counts and relative frequencies. For between-group comparison we used multiple regression with adjustment for baseline values of the outcome variable (ANCOVA), or Wilcoxon rank-sum test when the variable had a non-normal distribution.p-value: 0.85ANCOVA
Primary
Oxidized Low-Density Lipoprotein Cholesterol
Serum samples were stored at -70°C and were determined simultaneously by ELISA in order to avoid variation of assay conditions. Commercial ELISA assays detecting oxLDL (Mercodia, USA) were applied.
Time frame: Change from baseline at 6 weeks
Population: per protocol
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Simvastatin 80 mg | Oxidized Low-Density Lipoprotein Cholesterol | -18 Percentage | Standard Deviation 47 |
| Simvastatin 20mg/Ezetimibe 10 mg | Oxidized Low-Density Lipoprotein Cholesterol | -15 Percentage | Standard Deviation 33 |
Comparison: The sample size was determined as 78 patients. Continuous data were presented as means ± SD, or median (interquartile range) when the distribution was non-normal. For qualitative variables, we presented counts and relative frequencies. For between-group comparison we used multiple regression with adjustment for baseline values of the outcome variable (ANCOVA), or Wilcoxon rank-sum test when the variable had a non-normal distribution.p-value: 0.65ANCOVA
Primary
Platelet Function Analyzer [PFA]-100
Samples were collected in 3.8% sodium citrate (buffered, pH 5.5, Vacutainer, Becton Dickinson, Plymouth, UK) for platelet function tests. Platelet function assays were processed within 2 hours of blood collection. The PFA-100 records the closure time (CT), witch means the time in seconds (s) from the start of the test until the platelet plug occludes the aperture.
Time frame: Change from baseline at 6 weeks
Population: per protocol
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Simvastatin 80 mg | Platelet Function Analyzer [PFA]-100 | 27 Percentage | Standard Deviation 43 |
| Simvastatin 20mg/Ezetimibe 10 mg | Platelet Function Analyzer [PFA]-100 | 8 Percentage | Standard Deviation 33 |
Comparison: The sample size was determined as 78 patients. Continuous data were presented as means ± SD, or median (interquartile range) when the distribution was non-normal. For qualitative variables, we presented counts and relative frequencies. For between-group comparison we used multiple regression with adjustment for baseline values of the outcome variable (ANCOVA), or Wilcoxon rank-sum test when the variable had a non-normal distribution.p-value: 0.02ANCOVA
Primary
Soluble CD40 Ligand
A commercial ELISA assay detecting sCD40L (R&D Systems, USA) was applied. Detection limits and intra-assay variability was respectively, as follows: sCD-40L 15.6 pg/mL (intra-assay variability not available).
Time frame: Fasting venous blood samples were drawn immediately after randomization and after at the conclusions of the six weeks study period.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Simvastatin 80 mg | Soluble CD40 Ligand | 6 percentage | Standard Deviation 43 |
| Simvastatin 20mg/Ezetimibe 10 mg | Soluble CD40 Ligand | 6 percentage | Standard Deviation 34 |
Primary
Soluble Intercellular Adhesion Molecule (sICAM)-1
serum samples were stored at -70°C and were determined simultaneously by ELISA in order to avoid variation of assay conditions. Commercial ELISA assays detecting MCP-1/ICAM-1 (R&D Systems, Europe, Abingdon, UK)
Time frame: Change from baseline at 6 weeks
Population: per protocol
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Simvastatin 80 mg | Soluble Intercellular Adhesion Molecule (sICAM)-1 | 10 percentage | Standard Deviation 14 |
| Simvastatin 20mg/Ezetimibe 10 mg | Soluble Intercellular Adhesion Molecule (sICAM)-1 | 10 percentage | Standard Deviation 16 |
Secondary
Endothelial Progenitor Cells
Endothelial progenitor cells were evaluated by flow cytometry. Selected cells were positive for CD31, CD34 and VEGFR receptors.
Time frame: Fasting venous blood samples were drawn immediately after randomization and at the conclusions of the six week study period.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Simvastatin 80 mg | Endothelial Progenitor Cells | 0.4 percentage | Standard Deviation 1.7 |
| Simvastatin 20mg/Ezetimibe 10 mg | Endothelial Progenitor Cells | 0.1 percentage | Standard Deviation 2.1 |
Secondary
LDL Cholesterol
Time frame: Fasting venous blood samples were drawn immediately after randomization and at the conclusions of the six week study period.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Simvastatin 80 mg | LDL Cholesterol | -28 percentage | Standard Deviation 30 |
| Simvastatin 20mg/Ezetimibe 10 mg | LDL Cholesterol | -29 percentage | Standard Deviation 13 |
Secondary
Triglyceride
Time frame: Fasting venous blood samples were drawn immediately after randomization and at the conclusions of the six week study period.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Simvastatin 80 mg | Triglyceride | -4 percentage | Standard Deviation 32 |
| Simvastatin 20mg/Ezetimibe 10 mg | Triglyceride | -14 percentage | Standard Deviation 31 |