• C-reactive Protein [ Time Frame: Change from baseline at 6 weeks ] [ Designated as safety issue: No ]
  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 [ Time Frame: Change from baseline at 6 weeks ] [ Designated as safety issue: No ]
  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 [ Time Frame: Change from baseline at 6 weeks ] [ Designated as safety issue: No ]
  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.
  
  
• Monocyte Chemoattractant Protein (MCP)-1 [ Time Frame: Change from baseline at 6 weeks ] [ Designated as safety issue: No ]
  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 [ Time Frame: Change from baseline at 6 weeks ] [ Designated as safety issue: No ]
  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 [ Time Frame: Fasting venous blood samples were drawn immediately after randomization and after at the conclusions of the six weeks study period. ] [ Designated as safety issue: No ]
  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).
  
  
• Interleukin-6 [ Time Frame: Fasting venous blood samples were drawn immediately after randomization and after at the conclusions of the six weeks study period. ] [ Designated as safety issue: No ]
  A commercial ELISA assay detecting IL-6 (Siemens, USA) was applied.
  
  

• LDL Cholesterol [ Time Frame: Fasting venous blood samples were drawn immediately after randomization and at the conclusions of the six week study period. ] [ Designated as safety issue: No ]
  
• Triglyceride [ Time Frame: Fasting venous blood samples were drawn immediately after randomization and at the conclusions of the six week study period. ] [ Designated as safety issue: No ]
  
• Endothelial Progenitor Cells [ Time Frame: Fasting venous blood samples were drawn immediately after randomization and at the conclusions of the six week study period. ] [ Designated as safety issue: No ]
  Endothelial progenitor cells were evaluated by flow cytometry. Selected cells were positive for CD31, CD34 and VEGFR receptors.
  
  

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.