Comparison of Antiplatelet and Anti-inflammatory Effects of High Dose Statin Monotherapy Versus Moderate Dose Statin Plus Ezetimibe
Overview
- Phase
- Not Applicable
- Intervention
- Simvastatin 80 mg/day for 6 weeks
- Conditions
- Stable Angina
- Sponsor
- University of Sao Paulo
- Enrollment
- 78
- Locations
- 1
- Primary Endpoint
- C-reactive Protein
- Status
- Completed
- Last Updated
- 15 years ago
Overview
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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Stable angina
- •Low-density lipoprotein (LDL) cholesterol 70-160 mg/dl
Exclusion Criteria
- •Renal failure
- •Simvastatin current treatment\>20mg
- •Hepatic disease
- •Inflammatory diseases
Arms & Interventions
Simvastatin 80 mg
Patients were treated with simvastatin 80 mg for 6 weeks
Intervention: Simvastatin 80 mg/day for 6 weeks
Ezetimibe 10 mg / Simvastatin 20 mg
Patients were treated with daily Ezetimibe 10 mg / Simvastatin 20 mg for 6 weeks
Intervention: Ezetimibe 10 mg / Simvastatin 20 mg
Outcomes
Primary Outcomes
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).
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.
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.
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).
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)
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).
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 Outcomes
- 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.)