CYP2C19 Loss-Of-Function Carriers Treated with Clopidogrel Following PCI

Among patients treated with alternative therapy vs clopidogrel, lower atherothrombotic risk in CYP2C19 loss-of-function (LOF) carriers was demonstrated by real-world data. Among those same patients, similar risk was noted in those without the LOF allele. These findings were published in the Journal of the American Heart Association.

Increased risk for atherothrombotic major events in CYP2C19 loss-of-function (LOF) variant carriers vs non-carriers treated with clopidogrel after percutaneous coronary intervention (PCI) have been demonstrated in previous studies. Researchers sought to evaluate real-world outcomes, since CYP2C19-guided antiplatelet therapy after PCI has been clinically implemented to reduce risk of major adverse cardiovascular events.

To accomplish this, researchers conducted a real-world pragmatic expanded prospective study that included 3342 patients (aged ≥18 years, mean age 63 years; 32% women; 20% African ancestry), of whom 2290 received PCI for acute coronary syndrome (ACS) and 1052 received PCI for a chronic coronary syndrome. These patients were genotyped clinically for CYP2C19 and received a P2Y12 inhibitor (clopidogrel, prasugrel, or ticagrelor). These data were contributed by 9 medical centers who performed genotyping. Composite of major atherothrombotic events (all-cause death, myocardial infarction, ischemic stroke, stent thrombosis, or hospitalization for unstable angina) within 12 months following PCI was the primary outcome. In the same time period, moderate or severe to life-threatening bleeding was the secondary outcome.

A total of 1032 patients were allele carriers, 55% of whom were treated with alternative therapy and 45% with clopidogrel 75 mg/day. In the LOF group, among patients treated with alternative therapy, 337 received prasugrel, 219 received ticagrelor, and 15 received high-dose clopidogrel. In the non-LOF group, 378 were treated with alternative therapy and 1932 were treated with standard-dose clopidogrel. Among LOF carriers, the rate of major atherothrombotic events was lower in patients treated with alternative therapy vs clopidogrel (adjusted hazard ratio [aHR], 0.56; 95% CI 0.39-0.82). Among the non-LOF allele group, no difference was observed (aHR, 1.07; 95% CI 0.71-1.60). Among either group, alternative therapy vs clopidogrel showed no difference in bleeding.

Study limitations included the real-world nature in which patients could choose to follow genotype recommendations, the non-randomized design, and that there was no control group that did not receive genetic testing. Other limitations were that the outcomes were determined based on electronic health record data, the focus was on clinically actionable bleeding, and the sample size in subgroups was too small to compare outcomes.

 “Real-world data demonstrate lower atherothrombotic risk in CYP2C19 LOF carriers treated with alternative therapy versus clopidogrel and similar risk in those without a LOF allele treated with clopidogrel or alternative therapy,” the researchers wrote. “PCI patients treated with clopidogrel should undergo genotyping so that CYP2C19 LOF carriers can be identified and treated with alternative therapy.”

Disclosure: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.


Beitelshees AL, Thomas CD, Empey PE, et al. CYP2C19 genotype-guided antiplatelet therapy after percutaneous coronary intervention in diverse clinical settings. J Am Heart Assoc. Published online February 15, 2022. doi:10.1161/JAHA.121.024159