Clinical trial NCT00474123: Antiplatelet and Anti-inflammatory Effects of Statins and Ezetimibe
Official title: Comparison of Antiplatelet and Anti-inflammatory Effects of High Dose Statin Monotherapy Versus Moderate Dose Statin Plus Ezetimibe
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Stable Angina
Keywords: angina
atherosclerosis
simvastatin
ezetimibe
inflammation
Lead sponsor: University of Sao Paulo
Sponsor class: OTHER
First posted: 2007-05-16
Enrollment: 78
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility 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

Primary outcomes:
measure: C-reactive Protein
timeFrame: Change from baseline at 6 weeks
measure: Oxidized Low-Density Lipoprotein Cholesterol
timeFrame: Change from baseline at 6 weeks
measure: Platelet Function Analyzer [PFA]-100
timeFrame: Change from baseline at 6 weeks
measure: Monocyte Chemoattractant Protein (MCP)-1
timeFrame: Change from baseline at 6 weeks
measure: Soluble Intercellular Adhesion Molecule (sICAM)-1
timeFrame: Change from baseline at 6 weeks
measure: Soluble CD40 Ligand
timeFrame: Fasting venous blood samples were drawn immediately after randomization and after at the conclusions of the six weeks study period.
measure: Interleukin-6
timeFrame: Fasting venous blood samples were drawn immediately after randomization and after at the conclusions of the six weeks study period.
Secondary outcomes:
measure: LDL Cholesterol
timeFrame: Fasting venous blood samples were drawn immediately after randomization and at the conclusions of the six week study period.
measure: Triglyceride
timeFrame: Fasting venous blood samples were drawn immediately after randomization and at the conclusions of the six week study period.
measure: Endothelial Progenitor Cells
timeFrame: Fasting venous blood samples were drawn immediately after randomization and at the conclusions of the six week study period.
Other outcomes:
Locations:
city: Sao Paulo
country: Brazil
facility: Heart Institute (InCor) HOSPITAL DAS CLINICAS DA FACULDADE DE MEDICINA DA UNIVERSIDADE DE SAO PAULO (HCFMUSP)
Study officials:
affiliation: Heart Institute (InCor) HOSPITAL DAS CLINICAS DA FACULDADE DE MEDICINA DA UNIVERSIDADE DE SAO PAULO (HCFMUSP)
name: CARLOS V SERRANO, PHD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Pesaro AE, Serrano CV Jr, Katz M, Marti L, Fernandes JL, Parra PR, Campos AH. Increasing doses of simvastatin versus combined ezetimibe/simvastatin: effect on circulating endothelial progenitor cells. J Cardiovasc Pharmacol Ther. 2013 Sep;18(5):447-52. doi: 10.1177/1074248413489771. Epub 2013 Jun 5.
citation: Pesaro AE, Serrano CV Jr, Katz M, Campos AH, Lopes RD, Marti LC, Martins HS, Sunahara RS, Maranhao RC, Nicolau JC. Inflammation and circulating endothelial progenitor cells in patients with coronary artery disease and residual platelet reactivity. Clinics (Sao Paulo). 2012 Sep;67(9):1117-21. doi: 10.6061/clinics/2012(09)21. No abstract available.