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Antiplatelet and Anti-inflammatory Effects of Statins and Ezetimibe

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ClinicalTrials.gov Identifier: NCT00474123
Recruitment Status : Completed
First Posted : May 16, 2007
Results First Posted : July 14, 2010
Last Update Posted : July 14, 2010
Sponsor:
Information provided by:
University of Sao Paulo

Study Description
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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).


Condition or disease Intervention/treatment Phase
Stable Angina Drug: Simvastatin 80 mg/day for 6 weeks Drug: Ezetimibe 10 mg / Simvastatin 20 mg Not Applicable

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 Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 78 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Comparison of Antiplatelet and Anti-inflammatory Effects of High Dose Statin Monotherapy Versus Moderate Dose Statin Plus Ezetimibe
Study Start Date : January 2006
Actual Primary Completion Date : January 2009
Actual Study Completion Date : August 2009

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Arms and Interventions
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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 Name: 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 Name: Vytorin


Outcome Measures
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Primary Outcome Measures :
  1. 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).

  2. 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.

  3. 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.

  4. 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).

  5. 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)

  6. 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).

  7. 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.


Secondary Outcome Measures :
  1. LDL Cholesterol [ Time Frame: Fasting venous blood samples were drawn immediately after randomization and at the conclusions of the six week study period. ]
  2. Triglyceride [ Time Frame: Fasting venous blood samples were drawn immediately after randomization and at the conclusions of the six week study period. ]
  3. 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.


Eligibility Criteria
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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00474123


Locations
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Brazil
Heart Institute (InCor) HOSPITAL DAS CLINICAS DA FACULDADE DE MEDICINA DA UNIVERSIDADE DE SAO PAULO (HCFMUSP)
Sao Paulo, Brazil, 05403-000
Sponsors and Collaborators
University of Sao Paulo
Investigators
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Principal Investigator: CARLOS V SERRANO, PHD Heart Institute (InCor) HOSPITAL DAS CLINICAS DA FACULDADE DE MEDICINA DA UNIVERSIDADE DE SAO PAULO (HCFMUSP)
More Information
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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: São Paulo Research Foundation (FAPESP)
ClinicalTrials.gov Identifier: NCT00474123    
Other Study ID Numbers: 893/05
First Posted: May 16, 2007    Key Record Dates
Results First Posted: July 14, 2010
Last Update Posted: July 14, 2010
Last Verified: February 2010
Keywords provided by University of Sao Paulo:
angina
atherosclerosis
simvastatin
ezetimibe
inflammation
Additional relevant MeSH terms:
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Angina, Stable
Angina Pectoris
Myocardial Ischemia
Heart Diseases
Cardiovascular Diseases
Vascular Diseases
Chest Pain
Pain
Neurologic Manifestations
 Simvastatin
Ezetimibe
Anticholesteremic Agents
Hypolipidemic Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Lipid Regulating Agents
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Enzyme Inhibitors