Antiplatelet and Anti-inflammatory Effects of Statins and Ezetimibe

Study Overview
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Brief Summary
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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
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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.

Official Title
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Comparison of Antiplatelet and Anti-inflammatory Effects of High Dose Statin Monotherapy Versus Moderate Dose Statin Plus Ezetimibe

Conditions
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Stable Angina

Intervention / Treatment
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* Drug: Simvastatin 80 mg/day for 6 weeks
* Drug: Ezetimibe 10 mg / Simvastatin 20 mg


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Simvastatin 80 mg<br>Patients were treated with simvastatin 80 mg for 6 weeks | Drug: Simvastatin 80 mg/day for 6 weeks<br>* Simvastatin 80 mg/day, single dose, for 6 weeks.<br>* Other names: Simvastatin 80 mg (Zocor);|
| Active Comparator: Ezetimibe 10 mg / Simvastatin 20 mg<br>Patients were treated with daily Ezetimibe 10 mg / Simvastatin 20 mg for 6 weeks | Drug: Ezetimibe 10 mg / Simvastatin 20 mg<br>* Ezetimibe 10 mg / Simvastatin 20 mg Patients were treated with daily Ezetimibe 10 mg / Simvastatin 20 mg for 6 weeks<br>* Other names: Vytorin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | Change from baseline at 6 weeks | 
| 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. | Change from baseline at 6 weeks | 
| 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. | Change from baseline at 6 weeks | 
| 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). | Change from baseline at 6 weeks | 
| 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) | Change from baseline at 6 weeks | 
| 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). | Fasting venous blood samples were drawn immediately after randomization and after at the conclusions of the six weeks study period. | 
| Interleukin-6 | A commercial ELISA assay detecting IL-6 (Siemens, USA) was applied. | Fasting venous blood samples were drawn immediately after randomization and after at the conclusions of the six weeks study period. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| LDL Cholesterol |  | Fasting venous blood samples were drawn immediately after randomization and at the conclusions of the six week study period. | 
| Triglyceride |  | Fasting venous blood samples were drawn immediately after randomization and at the conclusions of the six week study period. | 
| Endothelial Progenitor Cells | Endothelial progenitor cells were evaluated by flow cytometry. Selected cells were positive for CD31, CD34 and VEGFR receptors. | Fasting venous blood samples were drawn immediately after randomization and at the conclusions of the six week study period. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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angina, atherosclerosis, simvastatin, ezetimibe, inflammation