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Genetic profiling has become of increasing interest to eventually detect poor responders to clopidogrel therapy. Multiple studies have shown that disorders in the CYP2C19 gene are associated with a higher adverse atherothrombotic event rate in patients under dual antiplatelet therapy after PCI and stenting, including stent thrombosis. Less frequent and inconsistent for results are reports about genetic disorders in genes related to absorption of the drug (ABCB1).
Clopidogrel is an ADP receptor inhibitor prodrug. After intestinal absorption (ABCB1 gene), the majority (85%) of the prodrug is metabolized and inactivated by esterases and only the remaining 15% of clopidogrel is transformed into the intermediate 2-oxo-clopidogrel metabolite by 3 isoenzymes (CYP1A2, CYP2B6 and CYP2C19). This intermediate non-active metabolite is further hydrolyzed into the highly unstable active thiol derivative R-130964 by involvement of 4 isoenzymes (CYP2B6, CYP2C9, CYP2C19 and CYP3A4) and inhibits platelet aggregation through an irreversible blockage of the ADP P2Y12 receptors on the platelet surface. In contrast, ticagrelor metabolism is not affected by such genetic variabilities.
The current presentation of Wallentin and co-workers focused on genetic disorders influencing absorption as well as metabolism by investigating loss-of-function (LOF)-genes (probably associated with atherothombotic complications) as well as genes associated with an increased metabolism of clopidogrel and therefore possibly related to bleeding complications in a huge PLATO genetic substudy in more than 10,000 patients with acute coronary syndromes, referred for angiography and PCI, and randomly treated with clopidogrel or ticagrelor. Objectives were to investigate if CYP2C19 and/or ABCB1 polymorphisms influences primary (CV death, MI and stroke) and secondary efficacy outcomes as well as safety outcomes when comparing treatments with ticagrelor versus clopidogrel in PLATO.
While genetic variants in the ABCB1 gene had no statistical impact on different clinical endpoints, the presence of any LOF allele in the CYP2C19 gene was associated with a higher combined endpoint rate in clopidogrel but not ticagrelor treated patients, which was statistically different after 30 days but lost significance after 1 year (clopidogrel: 11.2 vs. 10.0%; ticagrelor: 8.6 vs. 8.8%). The presence of any LOF allele, however, was not responsible for the statistical benefit of ticagrelor over clopidgrel (interaction p-value 0.46). In addition, ticagrelor vs. clopidogrel bleeding comparisons were unaffected by CYP2C19 and ABCB1 genotypes, whereas with clopidogrel carriers of CYP2C19 GOF allele had a tendency for higher bleeding rates.
In this elegant and important investigation, Wallentin et al were able to confirm earlier results from smaller trials with respect to the importance of disorders in the CYP2C19 gene. From these data, it might be concluded that personalized therapy targeting patients who carry these genetic variants might help to improve clinical outcome after stent implantation. However, for the clinical role of genetic profiling, multiple unknown factors still remain: While in the majority of trials CYP2C19 genetic polymorphisms have been shown to reduce clopidogrel metabolism and its clinical effectiveness while other genetic variants (with few exceptions) remained less important, there are no prospective studies demonstrating a clinical beneﬁt to personalizing antiplatelet therapy based on genotyping.
Commercially available genetic tests that can determine CYP2C19 genotype (and other) variants are not routinely reimbursed and point of care assays (e.g. for patients with ACS) are lacking at the moment. Moreover, it is important to point out that CYP2C19 polymorphisms account for only approximately 12% of variability in clopidogrel platelet response, the positive predictive value of CYP2C19 loss-of-function polymorphisms for cardiovascular events in patients with ACS undergoing PCI is low, approximately 12% to 20% and other clinical factors and risk constellations might be of greater clinical importance.
Finally, it is unknown whether a specific genetic polymorphism is capable of inﬂuencing outcome for the individual patient. Accordingly, genetic profiling should not be recommended for routine use at present but will remain of increased scientific interest.