Platelet reactivity index after treatment of clopidogrel versus ticagrelor based on CYP2C19 genotypes among patients undergoing percutaneous coronary intervention: results of a randomized study
Authors: Akkaif M A , Daud N A A , Noor D A M , Sha'aban A , Wahab M J A , Sk Abdul Kader M A , Ibrahim B 
Published: January 2023

Abstract

Funding Acknowledgements
Type of funding sources: None.

Background
Although clopidogrel is the basic drug for antiplatelet therapy in patients with coronary artery disease (CAD). However, loss of function (LOF) allelic variants located within the CYP2C19 gene may reduce the production of clopidogrel active metabolites and weaken the antiplatelet effect, increasing platelet rates reactivity and associated with increased rates of adverse events after percutaneous coronary intervention (PCI). Thus, drug regulatory authorities have warned of clopidogrel's reduced efficacy and suggested using alternative treatments (such as ticagrelor). However, in clinical practice, the strategy of genotype-guided selection for antiplatelet therapy has been limited by the lack of access to immediately available results.

Purpose
We sought to evaluate the effect of point-of-care genetic testing for CYP2C19 genotypes on the antiplatelet choice of therapy (i.e., clopidogrel vs ticagrelor), using platelet reactivity index (PRI) as a proxy of clinical outcome

Method
This study was a prospective, randomized, parallel design, an open-label investigation conducted among Malaysian patients with stable coronary artery disease (SCAD) undergoing PCI. Patients underwent rapid point-of-care genetic testing using the nested allele-specific multiplex PCR assay, which defines CYP2C19 genetic status within 3 hours, allowing patients to be genotyped on the same day before PCI. Patients who were carriers of at least one +LOF or -LOF (*2 or *3) allele was randomized to receive either clopidogrel [600mg loading dose (LD) - 75mg/day maintenance dose (MD)] or ticagrelor (180mg LD - 90mg MD). The induced platelet reactivity index (PRI) was assessed by Vasodilator-Associated Stimulated Phosphoprotein (VASP) Assay to whole blood at one standardized time point after 4 hours of LD. All patients were treated with aspirin. The primary endpoint of the study was the non-inferiority in platelet reactivity, measured as PRI, at 4 hours of clopidogrel vs ticagrelor in +LOF or -LOF allele carriers

Result
In 1638 SCAD patients, 94 underwent PCI and were genotyped and randomized to receive either clopidogrel (n=44) or ticagrelor (n=50). A total of 42 (44.68%) were carriers of at least one +LOF. PRI levels at 4 hours for clopidogrel vs ticagrelor 44 and 40, respectively (mean difference = 23.08; 95% CI: 17 to 30; p=&lt;0.001); this will meet the primary endpoint of superiority in a non-inferiority. Ticagrelor significantly reduced PRI more than clopidogrel. The cross-tabulation of the response classification showed that ticagrelor is superior to clopidogrel based on the -LOF and +LOF (P= 0.005 and &lt;0.001, respectively)

Conclusion
A rapid point-of-care genetic test using a nested allele-specific multiplex PCR assay can be used to personalize antiplatelet therapy and provides timely results for patients undergoing PCI. In addition, the results showed that ticagrelor was superior to clopidogrel in the level of platelet inhibition in both groups (+LOF or -LOF)