Clopidogrel resistance associated with gene polymorphism tied to adverse clinical outcomes following PCI: Study

A recent study published in the Indian Heart Journal has emphasized the association between gene polymorphisms, clopidogrel resistance, and negative clinical outcomes after percutaneous coronary intervention (PCI).

Clopidogrel is a cornerstone in ACS treatment, helping to prevent thrombotic events by inhibiting platelet aggregation. CYP2C19 is a highly polymorphic enzyme that leads to varied responses to clopidogrel in ACS patients. Variants that result in loss of function (LOF) are linked to decreased efficacy or a complete lack of activity for clopidogrel. The relationship between LOF variants and reduced platelet inhibition has significant clinical implications. Factors such as patient demographics, genetic variations, and drug interactions are essential for understanding individual responses to clopidogrel.

In India, the prevalence of clopidogrel resistance ranges from 5% to 44%. Ischemic and bleeding events risk can be significantly minimized by tailoring antiplatelet therapy based on platelet function testing (PFT), genetic profiles, and clinical characteristics, the researchers noted.

Against the above background, Heemanshu Lodhi, Department of Cardiology, Army Hospital Research and Referral, Delhi Cantonment, New Delhi, and colleagues aimed to assess the association between CYP2C19 metabolization status and clopidogrel resistance by PFT based on platelet reactivity units (PRUs).

The study included 668 individuals undergoing PCI, approved by the Institutional Review Board (IRB) with informed consent. Samples were collected per ICMR and AHRR guidelines, focusing on patients with acute coronary syndrome based on criteria from previous studies. Eligible participants were those willing to undergo follow-up assessments. DNA was isolated using the QIAGEN DNA Mini Kit, and platelet function was evaluated using the Verify PRU test according to the manufacturer’s protocol.

The key findings of the study were as follows:

• 54.64% of the patients who carried the LOF variants were categorized as poor metabolizers for clopidogrel, while the rest individuals belong to ultra (18.26%) and extensive (27.1%) metabolizers.
• To examine the association between genetic testing results related to clopidogrel metabolization status and PRU values, platelet function testing (PFT) was randomly conducted for 143 individuals, of whom 45%, 12%, and 43% exhibited good, intermediate, and poor drug effects, respectively.
• There was a significant statistical correlation between genetic test results and PRU values with an Odds ratio (OR) of 10.4.
• In TVR and TLR cases, 75% and 88.85% were clopidogrel resistant (Intermediate Metabolizers and Poor Metabolizers) respectively.
• 88.80% of the individuals had PRU values above 160, indicating increased platelet reactivity in TLR individuals.
• Among patients with ISR, 80% had PRU values above 160, and 80% were clopidogrel resistant.
• All individuals with stent thrombosis were clopidogrel resistant, and 100% had PRU values above 160.
• Twelve patients died due to cardiovascular disease, 75% were clopidogrel resistant, and 83.32% had more than 160 PRU values.

"The study demonstrates the association between CYP2C19 LOF polymorphisms and adverse clinical outcomes in ACS patients following PCI. This emphasizes the need for personalized treatment approaches based on genetic findings to optimize antiplatelet therapy and enhance patient outcomes," the researchers concluded.

Reference:

Lodhi, H., Bhat, K. G., Guleria, V. S., Pillai, R. K. J., Goel, R., Sharma, N., Sharma, A., & Sharma, V. (2024). Clopidogrel Resistance and its effect on clinical outcomes in Acute Coronary Syndrome. Indian Heart Journal. https://doi.org/10.1016/j.ihj.2024.07.003