Antiplatelet and Anti-inflammatory Effects of Statins and Ezetimibe

June 18, 2010 updated by: University of Sao Paulo

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

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).

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

78

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Brazil
      • Sao Paulo, Brazil, 05403-000
        • Heart Institute (InCor) HOSPITAL DAS CLINICAS DA FACULDADE DE MEDICINA DA UNIVERSIDADE DE SAO PAULO (HCFMUSP)

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 80 years (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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 Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: TREATMENT
  • Allocation: RANDOMIZED
  • Interventional Model: PARALLEL
  • Masking: NONE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
ACTIVE_COMPARATOR: Simvastatin 80 mg
Patients were treated with simvastatin 80 mg for 6 weeks
Drug: Simvastatin 80 mg/day for 6 weeks
Simvastatin 80 mg/day, single dose, for 6 weeks.
Other Names:
  • Simvastatin 80 mg (Zocor)
ACTIVE_COMPARATOR: Ezetimibe 10 mg / Simvastatin 20 mg
Patients were treated with daily Ezetimibe 10 mg / Simvastatin 20 mg for 6 weeks
Drug: 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

Other Names:
  • Vytorin

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
C-reactive Protein
Time Frame: 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).
Change from baseline at 6 weeks
Oxidized Low-Density Lipoprotein Cholesterol
Time Frame: 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.
Change from baseline at 6 weeks
Platelet Function Analyzer [PFA]-100
Time Frame: 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.
Change from baseline at 6 weeks
Monocyte Chemoattractant Protein (MCP)-1
Time Frame: 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).
Change from baseline at 6 weeks
Soluble Intercellular Adhesion Molecule (sICAM)-1
Time Frame: 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)
Change from baseline at 6 weeks
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.
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
Time Frame: 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.
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
Time Frame: Fasting venous blood samples were drawn immediately after randomization and at the conclusions of the six week study period.
Fasting venous blood samples were drawn immediately after randomization and at the conclusions of the six week study period.
Triglyceride
Time Frame: Fasting venous blood samples were drawn immediately after randomization and at the conclusions of the six week study period.
Fasting venous blood samples were drawn immediately after randomization and at the conclusions of the six week study period.
Endothelial Progenitor Cells
Time Frame: 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.
Fasting venous blood samples were drawn immediately after randomization and at the conclusions of the six week study period.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Sao Paulo

Investigators

  • Principal Investigator: CARLOS V SERRANO, PHD, Heart Institute (InCor) HOSPITAL DAS CLINICAS DA FACULDADE DE MEDICINA DA UNIVERSIDADE DE SAO PAULO (HCFMUSP)

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

January 1, 2006

Primary Completion (ACTUAL)

January 1, 2009

Study Completion (ACTUAL)

August 1, 2009

Study Registration Dates

First Submitted

May 15, 2007

First Submitted That Met QC Criteria

May 15, 2007

First Posted (ESTIMATE)

May 16, 2007

Study Record Updates

Last Update Posted (ESTIMATE)

July 14, 2010

Last Update Submitted That Met QC Criteria

June 18, 2010

Last Verified

February 1, 2010

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 893/05

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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