Investigation of the Athero-Protective Effects of Clopidogrel

Phase 4

Completed

Conditions: Coronary Artery Disease

Interventions: Drug: Clopidogrel
Drug: Placebo

Registration Number: NCT01283282

Lead Sponsor: Emory University

Brief Summary: The investigators would like to investigate whether clopidogrel will help lower the level of harmful markers in patients with coronary artery disease, and at the same time will help increase the cells that are useful in repairing the damaged blood vessels. The investigators will give half of the patients clopidogrel and the other half a sugar pill, placebo, and check the levels of these markers and helpful cells in each group. At the same time the investigators will check how well these patient's blood vessels work using ultrasound imaging of the forearm to see how blood vessels relax and tonometry to see how stiff the patient's blood vessels are. After 6 weeks of drug therapy, the patients will switch to the other drug and these same tests will be performed after an additional 6 weeks of therapy. The drug taken by the patient will not be known to the patient or the researchers. The patients will continue on their prescribed medical therapy during the duration of the 12 week study.

Detailed Description: Blockages in the blood vessels of the heart are caused by atherosclerosis. Atherosclerosis is the main cause for chest pain and heart attacks. Gradual narrowing of the vessels of the heart caused by blockages causes chronic symptoms, such as chest pain. Those with these findings often have a cardiac catheterization to detect these blockages. Additionally these patients may have an angioplasty or stent placed to help relieve these symptoms. With this angioplasty/stent procedure, patients are placed on the drug clopidogrel to help prevent clots from forming and narrowing of the blood vessels. Clopidogrel is a blood thinner that prevents clots from forming similar to an aspirin, but is more powerful and effective. Markers, or substances, have been identified that cause worsening of the blockages in the blood vessels of the heart. Many of these substances have been shown to decrease with the use of clopidogrel. This occurs separately from clopidogrel's ability to prevent clots. Endothelial progenitor cells, or EPCs, come mostly from the bone marrow and is helpful in repairing damage to the lining of the blood vessels of the heart. The EPCs help balance out the damage incurred in the blood vessels from those harmful markers. Several other drugs commonly used in heart disease have recently been shown to improve EPCs function. With this in mind, it is important to understand more of clopidogrel's function. A decrease in markers that cause worsening of the blockages, and an increase in the number of cells that will help repair damaged blood vessels of the heart is important in avoiding future chest pain and heart attacks. This may be how clopidogrel is currently protecting patients from developing new blockages. The investigators would like to investigate whether clopidogrel will help lower the level of harmful markers in patients with coronary artery disease, and at the same time will help increase the cells that are useful in repairing the damaged blood vessels. The investigators will give half of the patients clopidogrel and the other half a sugar pill, placebo, and check the levels of these markers and helpful cells in each group. At the same time the investigators will check how well these patient's blood vessels work using ultrasound imaging of the forearm to see how blood vessels relax and tonometry to see how stiff the patient's blood vessels are. After 6 weeks of drug therapy, the patients will switch to the other drug and these same tests will be performed after an additional 6 weeks of therapy. The drug taken by the patient will not be known to the patient or the researchers. The patients will continue on their prescribed medical therapy during the duration of the 12 week study.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 48

Inclusion Criteria

Male or females without child bearing potential aged 21-80 years
Known coronary artery disease by angiogram or documented myocardial infarction.
Able to provide written informed consent

Exclusion Criteria

Treated with clopidogrel or ticlodipine in the previous 3 months
Age < 21 or >80 years
Premenopausal females with potential for pregnancy
Allergy to clopidogrel or aspirin
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
Treated with coumadin therapy
Intolerance or allergy to statins
Acute infection in previous 4 weeks
History of substance abuse
Uninterpretable PAT test
Current neoplasm
Chronic renal failure [creatinine > 2.5 mg/dL] or liver failure (Liver enzymes >2X normal)
Acute coronary syndrome, heart failure, CVA, coronary intervention within 3 months
Known aortic stenosis, hypertrophic cardiomyopathy, symptomatic heart failure.
Inability to give informed consent
Inability to return to Emory for follow-up

Study & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Clopidogrel/Placebo	Placebo	Subjects were randomized to clopidogrel 75 mg daily for 6 weeks. Then immediately transitioned to a placebo daily for 6 weeks.
Clopidogrel/Placebo	Clopidogrel	Subjects were randomized to clopidogrel 75 mg daily for 6 weeks. Then immediately transitioned to a placebo daily for 6 weeks.
Placebo/Clopidogrel	Clopidogrel	Subjects were randomized to a placebo daily for 6 weeks. Then immediately transitioned to clopidogrel 75 mg daily for 6 weeks.
Placebo/Clopidogrel	Placebo	Subjects were randomized to a placebo daily for 6 weeks. Then immediately transitioned to clopidogrel 75 mg daily for 6 weeks.

Primary Outcome Measures

Name	Time	Method
Nitroglycerin-mediated Vasodilation	Baseline, Week 12	Nitroglycerin (NTG)-mediated vasodilation was measured after 0.4 mg of NTG was administered sublingually. Brachial artery images were obtained via ultrasound after three minutes of NTG administration. Measurements from the twelve frames will be averaged to calculate the percent change in diameter of the brachial artery from baseline to 12 weeks.
Endothelial Progenitor Cells (EPCs)	Week 12	The circulating progenitor-enriched population of cells was measured by the expression of surface antigens using direct flow cytometry for CD34+, CD34+/CD133+, CD34+/ VEGF2R+ and CD34+/CD133+/VEGF2R+
Flow-mediated Dilation (FMD)	Baseline, Week 12	Flow-mediated dilation (FMD) collected by an ultrasound and is measured by the percent change in diameter of the brachial artery from baseline to 12 weeks.

Secondary Outcome Measures

Name	Time	Method
Oxidative Stress Markers	Week 12	Oxidative stress was measured by using liquid chromatography to collect plasma cystine, cysteine, gluthione, and oxidized glutathione levels.
Pulse Wave Velocity (PWV)	Week 12	PWV was measured between the carotid and femoral arteries using the SphygmoCor device. Pressure waveforms at the carotid and femoral arteries were acquired using EKG gating. Velocity (distance per time in seconds) was calculated using the foot-to-foot method and the distance between the sites was measured manually.
Inflammatory Marker High-sensitivity C-reactive Protein (hsCRP)	Week 12	High-sensitivity C-reactive protein (hsCRP) was measured. The hsCRP levels were measured by Dade Behring nephelometry.
Inflammatory Marker CD40 Ligand	Week 12	CD40 ligand levels were measured. The level of CD40 ligand were measured using the Flurokine MultiAnalyte profiling (MAP) Human Base Kit B.