STOPCAP: Effect of Statins on Oxidative Stress and Endothelial Progenitor Cells

• Sponsor: Emory University (Other)
• Overall Status: Completed
• CT.gov ID: NCT00166036
• Collaborator: (none)
• Enrollment: 36
• Location: 1
• Arms: 2
• Duration (Months): 55
• Patients Per Site Per Month: 0.7

Study Details

Study Description

Brief Summary

Thirty-six subjects with hyperlipidemia and metabolic syndrome and/or diabetes were randomized in a double-blind manner to either pravastatin 80 mg or atorvastatin 10 mg daily. Oxidative stress (dROMs assay that measures lipid hydroperoxides, plasma thiobarbituric acid reactive substances [TBARS], and aminothiol levels) and brachial artery flow-mediated dilation (FMD) were measured at baseline and after 12 weeks of statin therapy.

Condition or Disease	Intervention/Treatment	Phase
Diabetes Mellitus; Metabolic Syndrome X; Hypercholesterolemia	Drug: Atorvastatin; Drug: Pravastatin	Phase 2

Detailed Description

Individuals with a high cholesterol level, diabetes or metabolic syndrome (collection of abnormalities such as high blood pressure, high triglyceride levels [fat], obesity, high blood glucose level) have an increased risk of developing a hardening of the arteries and heart disease.

A group of medications called statins, commonly used worldwide to lower cholesterol levels, are known to reduce the risk of heart disease through their effects on reducing cholesterol levels. These medications also have effects beyond the lowering of cholesterol that may help mediate their beneficial effects on the heart and blood vessels.

These include a reduced production of molecules that harm the arteries such as reactive oxygen species (ROS) and increasing the number of stem cells that help repair vessels, called endothelial progenitor cells (EPCs).

Recent studies have shown that different statins might have different effects on protecting people from developing heart disease. These differences may be due to differences in these non-cholesterol lowering processes, and are the subject of this study.

Standard of Care:

The two statins that will be used in this study, pravastatin (Pravachol ®) and atorvastatin (Lipitor®), are approved for use in people with a high cholesterol level or heart disease. These medications are generally very well tolerated with minimal side effects. They are not approved for use in patients to increase the level of EPCs or to reduce the production of ROS, and therefore are considered experimental for this indication. Currently there are no drugs that are specifically approved for these indications.

How the Problem Will be Studied:

These statins will be given to patients who have high cholesterol and either diabetes or the metabolic syndrome once a day for 12 weeks. We, the investigators at Emory, will measure the level of EPCs and ROS before and during the administration of the statin. We will also investigate how well the blood vessels dilate in response to these medications by performing an imaging study of the forearm artery using ultrasound.

The study is blinded and there is an equal chance of receiving either atorvastatin 10mg or pravastatin 80mg which are likely to lower cholesterol level by a similar amount.

How Research Will Advance Scientific Knowledge:

The goal of this study is to determine if atorvastatin will increase the number of circulating EPCs and reduce the production of ROS more than pravastatin. This may help explain the differences between these drugs that have been observed in some recently published trials.

Study Design

• Study Type: Interventional
• Actual Enrollment: 36 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Effect of Statins on Oxidative Stress and Endothelial Progenitor Cells: Comparison of Atorvastatin With Pravastatin
• Study Start Date: Sep 1, 2004
• Actual Primary Completion Date: Mar 1, 2008
• Actual Study Completion Date: Apr 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Atorvastatin 10MG	Drug: Atorvastatin; 12 Weeks of Oral Atorvastatin 10 mg therapy.
Experimental: Pravastatin 80mg	Drug: Pravastatin; 12 Weeks of Oral Pravastatin 80 mg therapy.

Outcome Measures

Primary Outcome Measures

1. Change in Plasma Thiobarbituric Acid Reactive Substance (TBARS) Levels [Baseline &12 Weeks]

   Oxidative stress was assessed with plasma thiobarbituric acid reactive substance (TBARS) levels (an index of lipid peroxidation).Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage.We hypothesized that equipotent doses of these two statins will have divergent effects on markers of oxidative stress and endothelial function.

Secondary Outcome Measures

1. Change in Flow-mediated Dilatation (FMD) [Baseline & 12 Weeks]

   Flow-mediated dilatation (FMD) of the brachial artery was used to asses Endothelial Function. The endothelium, by releasing nitric oxide (NO), promotes vasodilation and inhibits inflammation, thrombosis, and vascular smooth muscle cell proliferation.We hypothesized that equipotent doses of these two statins will have divergent effects on markers of oxidative stress and endothelial function.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 21 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Males or females without child bearing potential aged 21-80 years

• Fasting low-density lipoprotein (LDL) level > 120mg/dL.

• Either known to be diabetic or have at least 3 components of metabolic syndrome that are defined below:

• Hypertension defined as blood pressure (BP) > 140 systolic or > 90 mmHg diastolic, or stable medical therapy for documented hypertension;

• Fasting glucose > 110 mg/dL;

• Waist > 40 inches in males, and > 35 inches in females;

• Triglycerides > 150mg/dL; or

• High-density lipoprotein (HDL) cholesterol < 40 mg/dL in males and < 50 mg/dL in females.

• Able to provide written informed consent

• Non-smoker

Exclusion Criteria:

• On any oral antioxidants or lipid lowering medications in the previous 8 weeks

• Age < 21 or > 80 years

• Premenopausal females with potential for pregnancy

• LDL cholesterol level < 120 mg/dl

• Initiation or change in dose of any concomitant medical therapy within 2 months before the study

• Uncontrolled hypertension with BP > 180 mmHg systolic and > 120 mmHg diastolic

• Current smoker

• Previous intolerance or allergy to statins

• Acute infection in previous 4 weeks

• History of substance abuse

• Uninterpretable Brachial Artery Reactivity Study

• Current neoplasm

• Chronic renal failure (creatinine > 2.5 mg/dL) or liver failure (liver enzymes > 2X normal)

• Acute coronary syndrome, heart failure, cerebrovascular accident (CVA), or coronary intervention within 3 months

• Known aortic stenosis, hypertrophic cardiomyopathy, or symptomatic heart failure.

• Inability to give informed consent

• Inability to return to Emory for follow-up

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Emory University Hospital	Atlanta	Georgia	United States	30322

Sponsors and Collaborators

• Emory University

Investigators

• Principal Investigator: Arshed A Quyyumi, MD, Emory University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Arshed A. Quyyumi, Professor, Emory University
• ClinicalTrials.gov Identifier: NCT00166036
• Other Study ID Numbers: 1038-2004
• First Posted: Sep 14, 2005
• Last Update Posted: Sep 8, 2014
• Last Verified: Aug 1, 2014

• Additional relevant MeSH terms: Metabolic Syndrome; Hypercholesterolemia; Atorvastatin; Pravastatin

Study Results

Participant Flow

Pre-assignment Detail	Previous statin or other lipid lowering medications will be discontinued for 2 months. Subjects will be on stable medical therapy for at least 2 months before recruitment.

Arm/Group Title	Atorvastatin 10 mg	Pravastatin 80 mg
Arm/Group Description	Once Daily for 12 Weeks	Once Daily for 12 Weeks
Period Title: Overall Study
STARTED	17	19
COMPLETED	17	19
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Atorvastatin 10 mg	Pravastatin 80 mg	Total
Arm/Group Description	Subject treated with oral Atorvastatin 10 mg for 12 Weeks.	Subject treated with oral Pravastatin 80 mg for 12 Weeks.	Total of all reporting groups
Overall Participants	17	19	36
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	16 94.1%	18 94.7%	34 94.4%
>=65 years	1 5.9%	1 5.3%	2 5.6%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	54.2 (6.6)	51.7 (10.8)	52.9 (9.1)
Sex: Female, Male (Count of Participants)
Female	09 52.9%	14 73.7%	23 63.9%
Male	08 47.1%	05 26.3%	13 36.1%

Outcome Measures

1. Primary Outcome

Title	Change in Plasma Thiobarbituric Acid Reactive Substance (TBARS) Levels
Description	Oxidative stress was assessed with plasma thiobarbituric acid reactive substance (TBARS) levels (an index of lipid peroxidation).Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage.We hypothesized that equipotent doses of these two statins will have divergent effects on markers of oxidative stress and endothelial function.
Time Frame	Baseline &12 Weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Atorvastatin 10 mg	Pravastatin 80 mg
Arm/Group Description	Atorvastatin 10 mg taken daily	Pravastatin 80 mg daily
Measure Participants	17	19
Mean (Standard Error) [nmol/mL]	2.1 (0.8)	2.5 (1.0)

2. Secondary Outcome

Title	Change in Flow-mediated Dilatation (FMD)
Description	Flow-mediated dilatation (FMD) of the brachial artery was used to asses Endothelial Function. The endothelium, by releasing nitric oxide (NO), promotes vasodilation and inhibits inflammation, thrombosis, and vascular smooth muscle cell proliferation.We hypothesized that equipotent doses of these two statins will have divergent effects on markers of oxidative stress and endothelial function.
Time Frame	Baseline & 12 Weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Atorvastatin 10 mg	Pravastatin 80 mg
Arm/Group Description	Atorvastatin 10 mg daily	Pravastatin 80 mg daily
Measure Participants	17	19
Mean (Standard Error) [Percentage of brachial artery diameter]	5.9 (2.9)	6.0 (2.3)

Adverse Events

Arm/Group Title	Atorvastatin 10 mg		Pravastatin 80 mg
Arm/Group Description	Subject treated with oral Atorvastatin 10 mg for 12 Weeks.		Subject treated with oral Pravastatin 80 mg for 12 Weeks.
All Cause Mortality
	Atorvastatin 10 mg		Pravastatin 80 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Atorvastatin 10 mg		Pravastatin 80 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/17 (0%)		0/19 (0%)
Other (Not Including Serious) Adverse Events
	Atorvastatin 10 mg		Pravastatin 80 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/17 (0%)		0/19 (0%)

Limitations/Caveats

Detection of changes in Oxidative stress with significance requires a much larger cohort study.

More Information

Certain Agreements

Principal Investigators are NOT 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.