Investigation of the Athero-Protective Effects of Clopidogrel (APECS)

Phase 4 Study of Clopidogrel in Patients With Stable Coronary Artery Disease to Determine Effects on Vascular Function, Biomarkers and Endothelial Progrenitor Cells

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.

Study Overview

• Status: Completed
• Conditions: Coronary Artery Disease
• Intervention / Treatment: Drug: Clopidogrel; Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 48
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Clopidogrel/Placebo; Subjects were randomized to clopidogrel 75 mg daily for 6 weeks. Then immediately transitioned to a placebo daily for 6 weeks.	Drug: Clopidogrel; Clopidogrel 75 mg PO qday for 6 weeks; Other Names: Plavix; Drug: Placebo; Placebo PO qday for 6 weeks
Active Comparator: Placebo/Clopidogrel; Subjects were randomized to a placebo daily for 6 weeks. Then immediately transitioned to clopidogrel 75 mg daily for 6 weeks.	Drug: Clopidogrel; Clopidogrel 75 mg PO qday for 6 weeks; Other Names: Plavix; Drug: Placebo; Placebo PO qday for 6 weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Flow-mediated Dilation (FMD)	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.	Baseline, Week 12
Nitroglycerin-mediated Vasodilation	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.	Baseline, Week 12
Endothelial Progenitor Cells (EPCs)	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+	Week 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pulse Wave Velocity (PWV)	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.	Week 12
Oxidative Stress Markers	Oxidative stress was measured by using liquid chromatography to collect plasma cystine, cysteine, gluthione, and oxidized glutathione levels.	Week 12
Inflammatory Marker High-sensitivity C-reactive Protein (hsCRP)	High-sensitivity C-reactive protein (hsCRP) was measured. The hsCRP levels were measured by Dade Behring nephelometry.	Week 12
Inflammatory Marker CD40 Ligand	CD40 ligand levels were measured. The level of CD40 ligand were measured using the Flurokine MultiAnalyte profiling (MAP) Human Base Kit B.	Week 12

Collaborators and Investigators

• Sponsor: Emory University
• Investigators: Principal Investigator: Ziyad Ghazzal, MD, American University of Beirut, Emory University

Publications and helpful links

General Publications

• Ramadan R, Dhawan SS, Syed H, Pohlel FK, Binongo JN, Ghazzal ZB, Quyyumi AA. Effects of clopidogrel therapy on oxidative stress, inflammation, vascular function, and progenitor cells in stable coronary artery disease. J Cardiovasc Pharmacol. 2014 Apr;63(4):369-74. doi: 10.1097/FJC.0000000000000057.

Study record dates

Study Major Dates

• Study Start: January 1, 2008
• Primary Completion (Actual): December 1, 2010
• Study Completion (Actual): December 1, 2010

Study Registration Dates

• First Submitted: January 24, 2011
• First Submitted That Met QC Criteria: January 24, 2011
• First Posted (Estimate): January 25, 2011

Study Record Updates

• Last Update Posted (Estimate): May 1, 2015
• Last Update Submitted That Met QC Criteria: April 15, 2015
• Last Verified: April 1, 2015

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Coronary Artery Disease; Myocardial Ischemia; Coronary Disease; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Purinergic P2 Receptor Antagonists; Purinergic Antagonists; Purinergic Agents; Clopidogrel
• Other Study ID Numbers: IRB00005145; APECS (Other Identifier: Other)