Antiplatelet and Anti-inflammatory Effects of Statins and Ezetimibe

• Sponsor: University of Sao Paulo (Other)
• Overall Status: Completed
• CT.gov ID: NCT00474123
• Collaborator: (none)
• Enrollment: 78
• Location: 1
• Arms: 2
• Duration (Months): 43
• Patients Per Site Per Month: 1.8

Study Details

Study Description

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	N/A

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

• Study Type: Interventional
• 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: Jan 1, 2006
• Actual Primary Completion Date: Jan 1, 2009
• Actual Study Completion Date: Aug 1, 2009

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. C-reactive Protein [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 [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 [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 [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 [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 [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 [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 [Fasting venous blood samples were drawn immediately after randomization and at the conclusions of the six week study period.]

2. Triglyceride [Fasting venous blood samples were drawn immediately after randomization and at the conclusions of the six week study period.]

3. Endothelial Progenitor Cells [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

Criteria

• Ages Eligible for Study: 18 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Locations

	Site	City	State	Country	Postal Code
1	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

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

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• ClinicalTrials.gov Identifier: NCT00474123
• Other Study ID Numbers: 893/05
• First Posted: May 16, 2007
• Last Update Posted: Jul 14, 2010
• Last Verified: Feb 1, 2010

• Keywords provided by , ,: angina; atherosclerosis; simvastatin; ezetimibe; inflammation
• Additional relevant MeSH terms: Angina, Stable; Simvastatin; Ezetimibe

Study Results

Participant Flow

Recruitment Details	From July 2006 to January 2009, we randomized 78 patients with stable coronary artery disease (CAD) with LDL-C > 70 mg/dl, Angiographically documented CAD, stable angina, and age between 18 and 80 years. Patients were assigned randomly to two groups. The one group received Ezetimibe 10 mg/Simvastatin 20 mg the one other received Simvastatin 80 mg.
Pre-assignment Detail	No wash-out period.

Arm/Group Title	Simvastatin 80 mg	Simvastatin 20mg/Ezetimibe 10 mg
Arm/Group Description	Patients were treated with simvastatin 80 mg for 6 weeks	Patients were treated with Simvastatin 20mg/Ezetimibe 10 mgfor 6 weeks
Period Title: Overall Study
STARTED	38	40
COMPLETED	38	40
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Simvastatin 80 mg	Simvastatin 20mg/Ezetimibe 10 mg	Total
Arm/Group Description	Patients were treated with simvastatin 80 mg for 6 weeks	Patients were treated with Simvastatin 20mg/Ezetimibe 10 mgfor 6 weeks	Total of all reporting groups
Overall Participants	38	40	78
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	35 92.1%	37 92.5%	72 92.3%
>=65 years	3 7.9%	3 7.5%	6 7.7%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	61.7 (10)	64.5 (9)	63.2 (10)
Sex: Female, Male (Count of Participants)
Female	18 47.4%	15 37.5%	33 42.3%
Male	20 52.6%	25 62.5%	45 57.7%
Region of Enrollment (participants) [Number]
Brazil	38 100%	40 100%	78 100%

Outcome Measures

1. Primary Outcome

Title	C-reactive Protein
Description	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).
Time Frame	Change from baseline at 6 weeks

Outcome Measure Data

Analysis Population Description

per protocol

Arm/Group Title	Simvastatin 80 mg	Simvastatin 20mg/Ezetimibe 10 mg
Arm/Group Description	Patients were treated with simvastatin 80 mg for 6 weeks	Patients were treated with Simvastatin 20mg/Ezetimibe 10 mgfor 6 weeks
Measure Participants	38	40
Median (Inter-Quartile Range) [Percentage]	-16	-11

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Simvastatin 80 mg, Simvastatin 20mg/Ezetimibe 10 mg
	Comments	The sample size was determined as 78 patients. Continuous data were presented as means ± SD, or median (interquartile range) when the distribution was non-normal. For qualitative variables, we presented counts and relative frequencies. For between-group comparison we used multiple regression with adjustment for baseline values of the outcome variable (ANCOVA), or Wilcoxon rank-sum test when the variable had a non-normal distribution.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

2. Primary Outcome

Title	Oxidized Low-Density Lipoprotein Cholesterol
Description	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.
Time Frame	Change from baseline at 6 weeks

Outcome Measure Data

Analysis Population Description

per protocol

Arm/Group Title	Simvastatin 80 mg	Simvastatin 20mg/Ezetimibe 10 mg
Arm/Group Description	Patients were treated with simvastatin 80 mg for 6 weeks	Patients were treated with Simvastatin 20mg/Ezetimibe 10 mgfor 6 weeks
Measure Participants	38	40
Mean (Standard Deviation) [Percentage]	-18 (47)	-15 (33)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Simvastatin 80 mg, Simvastatin 20mg/Ezetimibe 10 mg
	Comments	The sample size was determined as 78 patients. Continuous data were presented as means ± SD, or median (interquartile range) when the distribution was non-normal. For qualitative variables, we presented counts and relative frequencies. For between-group comparison we used multiple regression with adjustment for baseline values of the outcome variable (ANCOVA), or Wilcoxon rank-sum test when the variable had a non-normal distribution.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.65
	Comments
	Method	ANCOVA
	Comments

3. Primary Outcome

Title	Platelet Function Analyzer [PFA]-100
Description	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.
Time Frame	Change from baseline at 6 weeks

Outcome Measure Data

Analysis Population Description

per protocol

Arm/Group Title	Simvastatin 80 mg	Simvastatin 20mg/Ezetimibe 10 mg
Arm/Group Description	Patients were treated with simvastatin 80 mg for 6 weeks	Patients were treated with Simvastatin 20mg/Ezetimibe 10 mgfor 6 weeks
Measure Participants	38	40
Mean (Standard Deviation) [Percentage]	27 (43)	8 (33)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Simvastatin 80 mg, Simvastatin 20mg/Ezetimibe 10 mg
	Comments	The sample size was determined as 78 patients. Continuous data were presented as means ± SD, or median (interquartile range) when the distribution was non-normal. For qualitative variables, we presented counts and relative frequencies. For between-group comparison we used multiple regression with adjustment for baseline values of the outcome variable (ANCOVA), or Wilcoxon rank-sum test when the variable had a non-normal distribution.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.02
	Comments
	Method	ANCOVA
	Comments

4. Primary Outcome

Title	Monocyte Chemoattractant Protein (MCP)-1
Description	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).
Time Frame	Change from baseline at 6 weeks

Outcome Measure Data

Analysis Population Description

per protocol

Arm/Group Title	Simvastatin 80 mg	Simvastatin 20mg/Ezetimibe 10 mg
Arm/Group Description	Patients were treated with simvastatin 80 mg for 6 weeks	Patients were treated with Simvastatin 20mg/Ezetimibe 10 mgfor 6 weeks
Measure Participants	38	40
Mean (Standard Deviation) [percentage]	11 (47)	10 (21)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Simvastatin 80 mg, Simvastatin 20mg/Ezetimibe 10 mg
	Comments	The sample size was determined as 78 patients. Continuous data were presented as means ± SD, or median (interquartile range) when the distribution was non-normal. For qualitative variables, we presented counts and relative frequencies. For between-group comparison we used multiple regression with adjustment for baseline values of the outcome variable (ANCOVA), or Wilcoxon rank-sum test when the variable had a non-normal distribution.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.85
	Comments
	Method	ANCOVA
	Comments

5. Primary Outcome

Title	Soluble Intercellular Adhesion Molecule (sICAM)-1
Description	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)
Time Frame	Change from baseline at 6 weeks

Outcome Measure Data

Analysis Population Description

per protocol

Arm/Group Title	Simvastatin 80 mg	Simvastatin 20mg/Ezetimibe 10 mg
Arm/Group Description	Patients were treated with simvastatin 80 mg for 6 weeks	Patients were treated with Simvastatin 20mg/Ezetimibe 10 mgfor 6 weeks
Measure Participants	38	40
Mean (Standard Deviation) [percentage]	10 (14)	10 (16)

6. Primary Outcome

Title	Soluble CD40 Ligand
Description	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).
Time Frame	Fasting venous blood samples were drawn immediately after randomization and after at the conclusions of the six weeks study period.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Simvastatin 80 mg	Simvastatin 20mg/Ezetimibe 10 mg
Arm/Group Description	Patients were treated with simvastatin 80 mg for 6 weeks	Patients were treated with Simvastatin 20mg/Ezetimibe 10 mgfor 6 weeks
Measure Participants	38	40
Mean (Standard Deviation) [percentage]	6 (43)	6 (34)

7. Primary Outcome

Title	Interleukin-6
Description	A commercial ELISA assay detecting IL-6 (Siemens, USA) was applied.
Time Frame	Fasting venous blood samples were drawn immediately after randomization and after at the conclusions of the six weeks study period.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Simvastatin 80 mg	Simvastatin 20mg/Ezetimibe 10 mg
Arm/Group Description	Patients were treated with simvastatin 80 mg for 6 weeks	Patients were treated with Simvastatin 20mg/Ezetimibe 10 mgfor 6 weeks
Measure Participants	38	40
Median (Inter-Quartile Range) [percentage]	0	0

8. Secondary Outcome

Title	LDL Cholesterol
Time Frame	Fasting venous blood samples were drawn immediately after randomization and at the conclusions of the six week study period.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Simvastatin 80 mg	Simvastatin 20mg/Ezetimibe 10 mg
Arm/Group Description	Patients were treated with simvastatin 80 mg for 6 weeks	Patients were treated with Simvastatin 20mg/Ezetimibe 10 mgfor 6 weeks
Measure Participants	38	40
Mean (Standard Deviation) [percentage]	-28 (30)	-29 (13)

9. Secondary Outcome

Title	Triglyceride
Time Frame	Fasting venous blood samples were drawn immediately after randomization and at the conclusions of the six week study period.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Simvastatin 80 mg	Simvastatin 20mg/Ezetimibe 10 mg
Arm/Group Description	Patients were treated with simvastatin 80 mg for 6 weeks	Patients were treated with Simvastatin 20mg/Ezetimibe 10 mgfor 6 weeks
Measure Participants	38	40
Mean (Standard Deviation) [percentage]	-4 (32)	-14 (31)

10. Secondary Outcome

Title	Endothelial Progenitor Cells
Description	Endothelial progenitor cells were evaluated by flow cytometry. Selected cells were positive for CD31, CD34 and VEGFR receptors.
Time Frame	Fasting venous blood samples were drawn immediately after randomization and at the conclusions of the six week study period.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Simvastatin 80 mg	Simvastatin 20mg/Ezetimibe 10 mg
Arm/Group Description	Patients were treated with simvastatin 80 mg for 6 weeks	Patients were treated with Simvastatin 20mg/Ezetimibe 10 mgfor 6 weeks
Measure Participants	38	40
Mean (Standard Deviation) [percentage]	0.4 (1.7)	0.1 (2.1)

Adverse Events

Arm/Group Title	Simvastatin 80 mg		Simvastatin 20mg/Ezetimibe 10 mg
Arm/Group Description	Patients were treated with simvastatin 80 mg for 6 weeks		Patients were treated with Simvastatin 20mg/Ezetimibe 10 mgfor 6 weeks
All Cause Mortality
	Simvastatin 80 mg		Simvastatin 20mg/Ezetimibe 10 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Simvastatin 80 mg		Simvastatin 20mg/Ezetimibe 10 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/38 (0%)		0/40 (0%)
Other (Not Including Serious) Adverse Events
	Simvastatin 80 mg		Simvastatin 20mg/Ezetimibe 10 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/38 (0%)		0/40 (0%)

Limitations/Caveats

Adverse Events were assessed, but none were observed.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.