Stable AnginaNCT00474123
Antiplatelet and Anti-inflammatory Effects of Statins and Ezetimibe
A study testing Simvastatin 80 mg/day for 6 weeks and Ezetimibe 10 mg / Simvastatin 20 mg in people with Stable Angina, run by University of Sao Paulo at 1 site in Brazil.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 80 years
- Conditions the study is for
- Stable Angina
- What is being tested?
- Simvastatin 80 mg/day for 6 weeks and Ezetimibe 10 mg / Simvastatin 20 mg
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 78 participants
- Where
- 1 siteBrazil
- Study dates
- Jan 2006to Aug 2009
- Phase
- Interventional
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 80 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Stable angina
- Low-density lipoprotein (LDL) cholesterol 70-160 mg/dl
Who cannot join
- Renal failure
- Age>80
- Simvastatin current treatment>20mg
- Hepatic disease
- Inflammatory diseases
Trial locations and contacts
1 site in 1 country.
Brazil1 site
Heart Institute (InCor) HOSPITAL DAS CLINICAS DA FACULDADE DE MEDICINA DA UNIVERSIDADE DE SAO PAULO (HCFMUSP)
São Paulo, São Paulo, 05403-000
About this study
Official title: 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).
Read the 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.
- Conditions
- Stable Angina
- Being tested
- Simvastatin 80 mg/day for 6 weeks, Ezetimibe 10 mg / Simvastatin 20 mg
- Keywords
- angina, atherosclerosis, simvastatin, ezetimibe, inflammation
- Medical subject headings
- Angina, Stable, Angina Pectoris, Atherosclerosis, Inflammation
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Simvastatin 80 mg/day for 6 weeksDrug
Also called Simvastatin 80 mg (Zocor)
Simvastatin 80 mg/day, single dose, for 6 weeks.
Ezetimibe 10 mg / Simvastatin 20 mgDrug
Also called Vytorin
Ezetimibe 10 mg / Simvastatin 20 mg
Patients were treated with daily Ezetimibe 10 mg / Simvastatin 20 mg for 6 weeks
| Study group | Role | What they receive |
|---|---|---|
| Simvastatin 80 mg | Active comparator | Patients were treated with simvastatin 80 mg for 6 weeks Receives: Drug: Simvastatin 80 mg/day for 6 weeks |
| Ezetimibe 10 mg / Simvastatin 20 mg | Active comparator | Patients were treated with daily Ezetimibe 10 mg / Simvastatin 20 mg for 6 weeks Receives: Drug: Ezetimibe 10 mg / Simvastatin 20 mg |
What is being measured
The primary outcome is the main question the study is designed to answer.
C-reactive Protein
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).
Measured: Change from baseline at 6 weeks
Oxidized Low-Density Lipoprotein Cholesterol
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.
Measured: Change from baseline at 6 weeks
Platelet Function Analyzer [PFA]-100
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.
Measured: Change from baseline at 6 weeks
Monocyte Chemoattractant Protein (MCP)-1
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).
Measured: Change from baseline at 6 weeks
Soluble Intercellular Adhesion Molecule (sICAM)-1
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)
Measured: Change from baseline at 6 weeks
Soluble CD40 Ligand
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).
Measured: Fasting venous blood samples were drawn immediately after randomization and after at the conclusions of the six weeks study period.
Interleukin-6
A commercial ELISA assay detecting IL-6 (Siemens, USA) was applied.
Measured: Fasting venous blood samples were drawn immediately after randomization and after at the conclusions of the six weeks study period.
Secondary outcomes (3)
LDL Cholesterol
Measured: Fasting venous blood samples were drawn immediately after randomization and at the conclusions of the six week study period.
Triglyceride
Measured: Fasting venous blood samples were drawn immediately after randomization and at the conclusions of the six week study period.
Endothelial Progenitor Cells
Endothelial progenitor cells were evaluated by flow cytometry. Selected cells were positive for CD31, CD34 and VEGFR receptors.
Measured: Fasting venous blood samples were drawn immediately after randomization and at the conclusions of the six week study period.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted16 May 2007 (estimated)
- Study startJan 2006
- Primary completionJan 2009
- Study completionAug 2009
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Stable AnginaStudies of the same condition, open and under way.
- More trials run by University of Sao PauloThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 78 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Sao Paulo
- Sponsor type
- University, hospital or other
- Investigators
- CARLOS V SERRANO, PHD, Principal investigator, Heart Institute (InCor) HOSPITAL DAS CLINICAS DA FACULDADE DE MEDICINA DA UNIVERSIDADE DE SAO PAULO (HCFMUSP)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00474123
- Sponsor's protocol ID
- 893/05
- Status last verified
- Feb 2010
- First submitted
- 15 May 2007
- Last updated
- 14 Jul 2010
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
Publications
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.
PubMed 23739650Pesaro 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.
PubMed 23018312
Study at a glance
From the registry record, last updated by the sponsor on 14 Jul 2010. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Comparison of Antiplatelet and Anti-inflammatory Effects of High Dose Statin Monotherapy Versus Moderate Dose Statin Plus Ezetimibe
- ClinicalTrials.gov ID
- NCT00474123
- Acronym / sponsor ID
- 893/05
- Conditions
- Stable Angina
- Keywords
- angina, atherosclerosis, simvastatin, ezetimibe, inflammation
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 78 participants (actual)
- Lead sponsor
- University of Sao PauloUniversity, hospital or other
- Study start
- Jan 2006
- Primary completion
- Jan 2009 (actual)
- Study completion
- Aug 2009 (actual)
- First posted
- 16 May 2007 (estimated)
- Results
- Posted 14 Jul 2010
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Simvastatin 80 mg | Active comparator | Drug: Simvastatin 80 mg/day for 6 weeksPatients were treated with simvastatin 80 mg for 6 weeks |
| Ezetimibe 10 mg / Simvastatin 20 mg | Active comparator | Drug: Ezetimibe 10 mg / Simvastatin 20 mgPatients were treated with daily Ezetimibe 10 mg / Simvastatin 20 mg for 6 weeks |
Who may qualify
- Ages
- 18 to 80 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (2 listed)
- Stable angina
- Low-density lipoprotein (LDL) cholesterol 70-160 mg/dl
Key exclusion criteria (5 listed)
- Renal failure
- Age>80
- Simvastatin current treatment>20mg
- Hepatic disease
- Inflammatory diseases
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Simvastatin 80 mg/day for 6 weeksAlso: Simvastatin 80 mg (Zocor)Simvastatin 80 mg/day, single dose, for 6 weeks. | Drug | Simvastatin 80 mg |
| Ezetimibe 10 mg / Simvastatin 20 mgAlso: VytorinEzetimibe 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 |
Primary outcome
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.
3 secondary outcomes
LDL Cholesterol
Time frame: 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.
Endothelial Progenitor Cells
Time frame: Fasting venous blood samples were drawn immediately after randomization and at the conclusions of the six week study period.
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 14 Jul 2010.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 23739650Pesaro 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.
- Derived from this study: PubMed 23018312Pesaro 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.
Related trials for Stable Angina
Recruiting
Intracoronary Cryotherapy Effect on Stabilization of Vulnerable Plaque in Patients With Stable Angina or ACS - A Traditional Feasibility Study
Coronary Arterial Disease (CAD), Plaque
Recruiting
Multivessel Balloon Occlusion to Investigate Obstructive Coronary Artery Disease and aNgina
Stable Angina, Multivessel Coronary Artery Disease
Recruiting
Study of Lesion-Specific Invasive Haemodynamic Angina Thresholds
Angina (Stable), Coronary Artery Disease(CAD)
Active, not recruitingObservational study
REDUCER-I: An Observational Study of the Neovasc Reducer™ System
Angina Pectoris, Angina Pectoris, Stable
RecruitingObservational study
Identification of Lesion Characteristics in Coronary Plaques Using Multimodality Intravascular Imaging and Novel Photon-counting CT in Stable Angina
Coronary Artery Disease (CAD), Stable Angina Pectoris
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
CARLOS V SERRANO, PHD principal investigator
Heart Institute (InCor) HOSPITAL DAS CLINICAS DA FACULDADE DE MEDICINA DA UNIVERSIDADE DE SAO PAULO (HCFMUSP)
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Simvastatin 80 mg/day for 6 weeks and Ezetimibe 10 mg / Simvastatin 20 mg in people with Stable Angina, run by University of Sao Paulo at 1 site in Brazil.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 2 inclusion and 5 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 14 Jul 2010. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Brazil. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Yes. Results are posted in the registry (first posted 14 Jul 2010). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
C-reactive Protein (time frame: Change from baseline at 6 weeks). The study lists 7 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00474123, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 14 Jul 2010.