Pharmacogenomics of Antiplatelet Response - I (PARes-I)

PHARMACOGENOMICS OF ANTI-PLATELET RESPONSE - I

This clinical trial is examining the role of genetic polymorphism on the effect of clopidogrel (with or without aspirin) on platelet response in persons at high-risk for myocardial infarction or stroke due to family history of early-onset coronary artery disease.

Study Overview

• Status: Completed
• Conditions: Coronary Artery Disease; Platelet Aggregation; Platelet Transcriptome
• Intervention / Treatment: Drug: Clopidogrel; Drug: Aspirin

Detailed Description

The main goal of this study is to explore the impact of the PEAR1 genetic variant (rs12041331) on responsiveness to clopidogrel. The investigators will further assess the role of other genetic variants in determining the response to single or dual anti-platelet therapy. Apparently healthy subjects (N= 2108) from high-risk families are being (a) identified from a proband with early-onset CAD and (b) genotyped on the Illumina 1 million platform, with imputation to 2.5 million single nucleotide polymorphisms. The investigators plan to characterize the variance in platelet aggregation to multiple agonists (ADP, collagen, and arachidonic acid) after 1-week therapy with clopidogrel in a high-risk subset of GeneSTAR subjects (N=100). The investigators further plan to determine the extent to which variants identified in the PEAR1 gene modify platelet responsiveness to inhibition by clopidogrel in this high-risk subset. In addition, the investigators aim is to determine the extent to which variants in other recently discovered genes, by themselves, and in combination with PEAR1, modify platelet responsiveness to clopidogrel alone and with aspirin in this high-risk subset. Lastly, the investigators also want to determine what changes in platelet mRNA are produced by aspirin alone and by aspirin with clopidogrel.

• Study Type: Interventional
• Enrollment (Actual): 19
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins University School of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 45 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Participants from the GeneSTAR cohort
• Unaffected with no overt coronary artery disease or serious vascular event (stroke or peripheral vascular disease diagnosis
• Presence of an occult coronary artery disease phenotype as defined by coronary artery calcium scores about the MESA (Multiethnic Study of Atherosclerosis) 75th percentile for age sex, and race or ≥ 1 stenoses in any of the major coronary arteries or main branches of > 50%, or coronary plaque volumetric scores above our own 75th percentile, or any combination on cardiac computed tomographic angiography (performed recently as part of the GeneSTAR study and present for all persons being recruited)/
• Presence of occult cerebrovascular disease defined as presence of white matter hyperintensities (WMH) thought to represent ischemic small vessel cerebrovascular disease, and /or the presence of lacunes (old small strokes), or the presence of an Atherosclerosis Risk in Communities Study (ARIC) silent stroke score on a visual analogue scales of 4 or more (on a scale of 0-9).
• Women who are postmenopausal.
• Women who use a reliable contraceptive method; a reliable contraceptive method will be defined as personal history of tubal ligation, ongoing use of intra-uterine device, or ongoing use of oral contraceptive pills.

Exclusion Criteria:

• Presence of any CAD or stroke, transient ischemic attacks, peripheral arterial disease
• Persons taking aspirin, NSAIDS, or any anti-coagulants who are medically unable to stop them for a two week pre-trial
• A history of allergy to aspirin or clopidogrel
• Weight < 60kg
• Age < 45 and > 75 years of age
• A history of recent or any active bleeding
• Serious or current co-morbidity (AIDS, cancer)
• Pregnant women as determined by urine dipstick pregnancy test
• Any aneurysms on cranial magnetic resonance imaging/magnetic resonance angiography (obtained recently in the GeneSTAR participants)
• Blood pressure above >=159/95mmHg
• History of a gastric or duodenal ulcer, or significant gastrointestinal disease, like regional enteritis
• Mental incompetence to make a decision to participate (developmentally disabled, and persons with diagnosed psychiatric disorders-documented in primary care records).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Clopidogrel; Clopidogrel 75 mg daily by mouth for 1 week then Clopidogrel 75 mg daily with aspirin 81 mg daily	Drug: Clopidogrel; Clopidogrel 75 mg daily; Other Names: Plavix; Drug: Aspirin; Aspirin 81 mg daily

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Difference in ADP-induced Platelet Aggregation	ADP-induced platelet aggregation will be measured using impedance aggregometry in whole blood before and after 1-week of clopidogrel. The difference between the baseline and after clopidogrel therapy will be determined. Higher impedance represent higher platelet aggregation.	at baseline and at 1 week

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Difference in Arachidonic Acid-induced Platelet Aggregation	Arachidonic Acid-induced platelet aggregation will be measured using impedance aggregometry in whole blood before and after 1-week of clopidogrel. The difference between the baseline and after clopidogrel therapy will be determined	At baseline and after 1-week
Difference in Collagen-induced Platelet Aggregation	Collagen-induced platelet aggregation will be measured using impedance aggregometry in whole blood before and after 1-week of clopidogrel. The difference between the baseline and after clopidogrel therapy will be determined	At Baseline and at 1 week
Changes in Platelet Transcriptome With Clopidogrel	Platelet transcriptome will be examined before and after 1 week of therapy with clopidogrel and differences will be determined	At baseline and at 1 week

Collaborators and Investigators

• Sponsor: Johns Hopkins University
• Investigators: Principal Investigator: Rehan Qayyum, MD, Johns Hopkins University

Publications and helpful links

Helpful Links

• GeneSTAR Research Program

Study record dates

Study Major Dates

• Study Start: October 1, 2012
• Primary Completion (Actual): June 1, 2014
• Study Completion (Actual): June 1, 2014

Study Registration Dates

• First Submitted: March 18, 2013
• First Submitted That Met QC Criteria: March 19, 2013
• First Posted (Estimate): March 20, 2013

Study Record Updates

• Last Update Posted (Estimate): January 9, 2017
• Last Update Submitted That Met QC Criteria: November 10, 2016
• Last Verified: November 1, 2016

More Information

Terms related to this study

• Keywords: Clopidogrel; Platelet aggregation; Platelet transcriptome
• Additional Relevant MeSH Terms: Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Coronary Disease; Coronary Artery Disease; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Fibrinolytic Agents; Fibrin Modulating Agents; Platelet Aggregation Inhibitors; Cyclooxygenase Inhibitors; Antipyretics; Purinergic P2Y Receptor Antagonists; Purinergic P2 Receptor Antagonists; Purinergic Antagonists; Purinergic Agents; Aspirin; Clopidogrel
• Other Study ID Numbers: K23HL105897-PARes-I; K23HL105897 (U.S. NIH Grant/Contract)