Implementation of CYP2C19 Genotyping to Guide Antiplatelet Therapy

Implementation of CYP2C19 Genotyping to Guide Antiplatelet Therapy for Patients Undergoing Cardiac Catheterization at UF Health Jacksonville

It is well established that clopidogrel-induced antiplatelet effects is suboptimal in many patients who are thus exposed to an increased risk of adverse cardiovascular events. Studies have shown that genotypes of the cytochrome P450 (CYP) 2C19 enzyme, which is a key determinant of clopidogrel metabolism, contribute to these findings. Prasugrel and ticagrelor are alternative agents whose effectiveness is not dependent on CYP2C19 genotype. A boxed warning on the Food and Drug Administration (FDA)-approved clopidogrel labeling warns of reduced effectiveness in patients with the LOF genotype and recommends alternative therapies in these patients. The availability of an assay recently approved by the FDA, SpartanRX, which provides results within one-hour facilitates performing genetic testing as a clinical test in real-world practice. We therefore propose to 1) examine the feasibility of implementing CYP2C19 genotyping using SpartanRX as standard of care for patients undergoing cardiac catheterization at UF Health Jacksonville providing the opportunity for clinicians to embrace genotype-guided antiplatelet therapy in those who proceed to PCI and 2) determine if CYP2C19 genotype-guided antiplatelet therapy reduces the risk for major adverse cardiovascular outcomes after PCI.

Study Overview

• Status: Completed
• Conditions: Coronary Artery Disease
• Intervention / Treatment: Device: SpartanRX

Detailed Description

Dual antiplatelet therapy with aspirin and a P2Y12 receptor inhibitor represents the standard of care treatment for the prevention of major adverse cardiovascular events in patients undergoing percutaneous coronary intervention (PCI). Currently, 3 oral P2Y12 receptor inhibitors (clopidogrel, prasugrel, and ticagrelor) are available for clinical use. Clopidogrel remains the most broadly used P2Y12 receptor inhibitor. However, it is well established that clopidogrel-induced antiplatelet effects is suboptimal in many patients who are thus exposed to an increased risk of adverse cardiovascular events. Studies have shown that genotypes of the cytochrome P450 (CYP) 2C19 enzyme, which is a key determinant of clopidogrel metabolism, contribute to these findings. In fact, clopidogrel is a prodrug that requires bioactivation by the CYP2C19 enzyme. Approximately 30-40% of individuals have the loss-of-function (LOF) CYP2C19 genotype and cannot sufficiently convert clopidogrel to its active form, thereby gaining little to no benefit from the drug. Prasugrel and ticagrelor are alternative agents whose effectiveness is not dependent on CYP2C19 genotype. A boxed warning on the Food and Drug Administration (FDA)-approved clopidogrel labeling warns of reduced effectiveness in patients with the LOF genotype and recommends alternative therapies in these patients. Guidelines from the Clinical Pharmacogenetics Implementation Consortium (CPIC) specifically recommend prasugrel or ticagrelor over clopidogrel for patients with a LOF CYP2C19 genotype who undergo PCI. In turn, these recommendations have led to the use in clinical practice of genetic testing of CYP2C19 genotypes as an aid to clinicians in determining therapeutic strategies for patients undergoing PCI. However, the uptake of genetic testing in real-world clinical practice has been limited by the availability of assays able to provide genetic results in a timely fashion. The availability of an assay recently approved by the FDA, SpartanRX, which provides results within one-hour facilitates performing genetic testing as a clinical test in real-world practice. We therefore propose to 1) examine the feasibility of implementing CYP2C19 genotyping using SpartanRX as standard of care for patients undergoing cardiac catheterization at UF Health Jacksonville providing the opportunity for clinicians to embrace genotype-guided antiplatelet therapy in those who proceed to PCI and 2) determine if CYP2C19 genotype-guided antiplatelet therapy reduces the risk for major adverse cardiovascular outcomes after PCI.

• Study Type: Observational
• Enrollment (Actual): 1000

Contacts and Locations

Study Locations

• United States
  • Florida
    • Jacksonville, Florida, United States, 32209
      • University of Florida

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

Patients presenting to the UF Health Jacksonville cardiac catheterization laboratory for left heart catheterization for suspected coronary artery disease (CAD) and intent to undergo PCI will be targeted for enrollment.

Description

Inclusion Criteria:

• Age ≥18 years
• Undergoing left heart catheterization for signs and symptoms suggestive for CAD

Exclusion Criteria:

• Inability to provide written informed consent.

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Left heart catheterization patients; Patients presenting to the UF Health Jacksonville cardiac catheterization laboratory for left heart catheterization for suspected coronary artery disease and intent to undergo percutaneous coronary intervention will be targeted for enrollment and will be genotyped by SpartanRX	Device: SpartanRX; A buccal swap genetic sample will be collected from eligible patients who provide written informed consent for CYP2C19 testing. Genotyping will be performed by the SpartanRX system as a clinical test at the UF Health Pathology Laboratory in Jacksonville.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent of patients approached who consent to study participation and are genotyped successfully	Patients undergoing elective procedures will be approached for CYP2C19 genetic testing prior to undergoing left heart catheterization, while patients requiring emergent procedures will be tested prior to hospital discharge.	48 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Major adverse cardiac events (MACE)	A composite rate of death, myocardial infarction, stroke, stent thrombosis, and ischemia-driven revascularization	12 months

Collaborators and Investigators

• Sponsor: University of Florida
• Collaborators: National Institutes of Health (NIH); National Human Genome Research Institute (NHGRI)
• Investigators: Principal Investigator: Dominick J Angiolillo, MD, PhD, University of Florida College of Medicine-Jacksonville

Publications and helpful links

General Publications

• Cavallari LH, Franchi F, Rollini F, Been L, Rivas A, Agarwal M, Smith DM, Newsom K, Gong Y, Elsey AR, Starostik P, Johnson JA, Angiolillo DJ. Clinical implementation of rapid CYP2C19 genotyping to guide antiplatelet therapy after percutaneous coronary intervention. J Transl Med. 2018 Apr 11;16(1):92. doi: 10.1186/s12967-018-1469-8.

Study record dates

Study Major Dates

• Study Start (Actual): May 1, 2016
• Primary Completion (Actual): November 20, 2020
• Study Completion (Actual): December 31, 2021

Study Registration Dates

• First Submitted: March 8, 2016
• First Submitted That Met QC Criteria: March 24, 2016
• First Posted (Estimate): March 31, 2016

Study Record Updates

• Last Update Posted (Actual): June 2, 2022
• Last Update Submitted That Met QC Criteria: May 31, 2022
• Last Verified: May 1, 2022

More Information

Terms related to this study

• Keywords: percutaneous coronary intervention; clopidogrel; loss-of-function allele
• Additional Relevant MeSH Terms: Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Coronary Disease; Coronary Artery Disease
• Other Study ID Numbers: IRB201703131 (Other Identifier: Univeristy of Florida); U01HG007269 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Patients will be asked to also have a single blood sample collected which will be stored for future research, and the option to share data to the public NIH database of Genotypes and Phenotypes (dbGaP). dbGaP was developed to archive and distribute the data and results from studies that have investigated the interaction of genotype and phenotype in Humans.