A step toward precision medicine in genetic-guided testing for blood thinner drugs

A scientific statement from the American Heart Association published in Circulation provides clinicians with guidance regarding the use of CYP2C19 genetic testing when prescribing oral P2Y12 inhibitor therapy. These drugs help prevent the formation of blood clots, which can cause heart attacks and strokes.

The traditional approach is to prescribe clopidogrel, the most commonly prescribed antiplatelet therapy, regardless of a person's genetic makeup. 

However, certain genetic variations in the CYP2C19 gene can affect how well some people metabolize clopidogrel. These variations make the drug less effective and put those people at a higher risk of a stroke or heart attack.

Studies suggest that using CYP2C19 genetic-guided testing to identify poor metabolizers of clopidogrel and prescribing alternative medications can lead to fewer bleeding events as compared to all patients receiving the newer and more potent drugs.

"CYP2C19 genetic-guided testing tailors the choice of blood thinners based on a patient’s genetic variants," says Naveen Pereira, M.D., a Mayo Clinic cardiologist and chair of the group that issued the statement. "The overarching goal is to prescribe the right drug to the right patient to maximize efficacy and minimize toxicity. It is also a cost-effective approach."

Clopidogrel-CYP2C19 is a cardiovascular drug-gene pair with the most comprehensive analysis and clinical trial data. Because of this, clopidogrel has a boxed warning on its drug label stating that CYP2C19 poor metabolizers are at a higher risk for blood clotting events when treated with clopidogrel. The label notes that CYP2C19 genetic testing can identify people with these genetic variations.

Key points from a Scientific Statement from the American Heart Association

• Clopidogrel is inactive when taken into the body. Activation occurs after the CYP2C19 enzyme has metabolized it. There is genetic variation in CYP2C19 that is linked to the loss of enzymatic function and decreased active clopidogrel metabolite levels, and it varies based on racial and ethnic populations.
• A CYP2C19 loss-of-function allele is a variant of the CYP2C19 gene that makes a less functional or nonfunctional enzyme. Compared to non-carriers, CYP2C19 loss-of-function carriers treated with clopidogrel have increased platelet aggregation (platelets clump together). They also have increased blockage of blood flow events, especially after percutaneous coronary intervention, acute coronary syndromes and stroke.
• The oral P2Y12 inhibitor drugs ticagrelor or prasugrel are not dependent on CYP2C19 for its activation. CYP2C19 loss-of-function carriers when treated with ticagrelor or prasugrel have significantly reduced cumulative blockage of blood clotting events compared to those treated with clopidogrel. The CYP2C19 genotype is an important determinant of the significant reduction in blood clotting events observed with ticagrelor or prasugrel drug therapy compared to clopidogrel.

Therefore, approximately 70% of patients who do not have the loss-of-function CYP2C19 genetic variants can safely take clopidogrel, while the 30% of patients who do have it can be prescribed alternative drugs such as prasugrel or ticagrelor.  

"This precision medicine approach allows physicians to use this information to guide treatment decisions," says Dr. Pereira. "The extensive clinical evidence supports CYP2C19 genetic testing, especially for patients with heart attacks and those who have undergone angioplasty or stent procedures."

Whether clinicians request CYP2C19 genetic testing to guide the use of antiplatelet drugs will depend on several guidelines, including recently published evidence, adoption of point-of-care genetic testing, timely availability of results, integration of results in the electronic health record, education to support understanding and interpretation of results and reimbursement by insurance companies.

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