Antiplatelet and Anti-inflammatory Effects of Statins and Ezetimibe

Not Applicable

Completed

Conditions: Stable Angina

Interventions: Drug: Ezetimibe 10 mg / Simvastatin 20 mg
Drug: Simvastatin 80 mg/day for 6 weeks

Registration Number: NCT00474123

Lead Sponsor: University of Sao Paulo

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 78

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Ezetimibe 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
Simvastatin 80 mg	Simvastatin 80 mg/day for 6 weeks	Patients were treated with simvastatin 80 mg for 6 weeks

Primary Outcome Measures

Name	Time	Method
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.
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).
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.

Secondary Outcome Measures

Name	Time	Method
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	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.