Clopidogrel and CYP2C19

Clopidogrel (Plavix® and generic products) is used for patients with unstable angina, a condition in which your heart does not receive enough blood flow or oxygen which causes chest pain. This can lead to a heart attack. Typically, unstable angina causes chest discomfort as a result of decreased blood flow through the coronary arteries of the heart. The decreased blood flow can damage the heart muscle.

Clopidogrel keeps platelets from sticking together and forming clots that could block blood vessels leading to the heart muscle. This helps blood and oxygen continue to reach the heart muscle. Additionally, some individuals have small tubes, called stents, placed in the coronary arteries of the heart to help maintain blood flow and increase the flow of oxygen to heart muscle. The stents can "clot off", resulting in damage to the heart and possibly a fatal heart attack. Clopidogrel helps prevent this.

Clopidogrel is a prodrug, meaning it is initially inactive and must be metabolized to the active form in the body.

The gene of interest is called cytochrome P450-2C19 (CYP2C19; pronounced sip two see nineteen). This gene, a sequence of DNA bases, forms the molecule (known as an enzyme) that your body uses to convert clopidogrel to its active form.

There are a number of variations that a person can have for the CYP2C19 gene. Some of these differences result in the production of an enzyme that has lost its function. This results in the enzyme not being able to convert clopidogrel to its active form. This means that the medication will not work properly.

It has been shown that there is a relationship between CYP2C19 enzyme function and the risk of clots and heart damage for patients with stents. Individuals that have the loss-of- function form of the enzyme are at increased risk of clot formation and heart attack. A large majority of individuals, about 70%, have normal enzyme activity. However, roughly 30% of individuals have decreased enzyme activity. It is this group of people that do not benefit optimally from clopidogrel treatment and should be switched to another medication that will benefit them.

There is a genetic test that can be used to identify patients that have reduced enzyme activity.

An Asian male, Dallas, has been prescribed clopidogrel in addition to other treatments for his recent heart attack. When told about the therapy by the doctor, it is mentioned that there is the possibility that Dallas may not receive the full treatment benefit if he has a “loss-of- function” CYP2C19 genotype which is more common among patients with Asian ancestry. Dallas decides not to have the genetic test and leaves the hospital on clopidogrel. Two months following the procedure, Dallas has a second heart attack and is readmitted to the hospital. A genetic test confirms that Dallas has a CYP2C19 variant that decreased the effectiveness of clopidogrel for preventing a second heart attack. Dallas’s doctor must now prescribe him more medications to treat his worsened heart health.

Two months later, the same doctor is treating an African American male, Patrick, who needs antiplatelet therapy following a stent placement. After telling Patrick about the risks of the “loss-of-function” CYP2C19 genotype, Patrick agrees to have the genetic test and finds out that he does have this CYP2C19 variant. The doctor is able to prescribe another antiplatelet medication for Patrick. The following year, Patrick is successfully taken off of the antiplatelet without having experienced complications.

CYP2C19 genetic testing does not completely rule out the risks of taking clopidogrel, nor does it guarantee the medication will work for you. Genetic testing is a guide to personalize the treatment of patients, maximizing benefit and minimizing harm.

The links below provide access to important articles and information relative to clopidogrel. The links are to external websites and will be checked regularly for consistency.

• Clopidogrel Prescribing Information
• Clopidogrel Pharmacogenomic Dosing Guidelines
• Pharmacogenomics Knowledge Base: Clopidogrel

DailyMed [Internet]. Bethesda (MD): U.S. National Library of Medicine; c1993-2012. Plavix- clopidogrel bisulfate tablet, film coated; [cited 2012 Oct 9]; [about 4 screens]. Available from: http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=01b14603-8f29- 4fa3-8d7e- 9d523f802e0b#nlm34068-7/.

Johnson JA, Roden DM, Lesko LJ, Ashley E, Klein TE, Shuldiner AR. Clopidogrel: a case for indication- specific pharmacogenetics. Clinical Pharmacology and Therapeutics. 2012 May;91(5):774-6.

National Center for Biotechnology Information [Internet]. Bethesda (MD): National Center for Biotechnology Information; 2012. CYP2C19 cytochrome P450, family 2, subfamily C, polypeptide 19 [ Homo sapiens (humans) ]; [cited 2012 Oct 9]; [about 12 screens]. Available from: http://www.ncbi.nlm.nih.gov/gene/1557/.

PharmGKB [Internet]. Stanford (CA): U.S. Department of Health and Human Services; c2001-2017. Clopidogrel; [updated 2011 Aug 10; cited 2012 Oct 19]; [about 5 screens]. Available from: https://www.pharmgkb.org/chemical/PA448785?previousQuery=Carbamazepene/.

Scott SA, Sangkuhl K, Gardner EE, Stein CM, Hulot JS, Johnson JA, Roden DM, Klein TE, Shuldiner AR. Clinical Pharmacogenetics Implementation Consortium guidelines for cytochrome P450-2C19 (CYP2C19) genotype and clopidogrel therapy. Clinical Pharmacology and Therapeutics. 2011 Aug;90(2):328-32.

Yin T, Miyata T. Pharmacogenomics of clopidogrel: evidence and perspectives. Thrombosis Research. 2011 Oct;128(4):307-16.