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Indian J Med Res. 2019 Jul;150(1):50-61. doi: 10.4103/ijmr.IJMR_782_17.

Aspirin & clopidogrel non-responsiveness & its association with genetic polymorphisms in patients with myocardial infarction.

Author information

1
Divisions of Pharmacology, CSIR-Central Drug Research Institute; Department of Cardiology, King George Medical University, Lucknow, India.
2
Divisions of Pharmacology, CSIR-Central Drug Research Institute, Lucknow, India.
3
Divisions of Toxicology & Experimental Medicine, CSIR-Central Drug Research Institute, Lucknow, India.
4
Divisions of Pharmaceutics & Pharmacokinetics, CSIR-Central Drug Research Institute, Lucknow, India.
5
Department of Cardiology, King George Medical University, Lucknow, India.

Abstract

Background & objectives:

Cytochrome P450, P2Y 12, cyclooxygenase-1 (COX1) and glycoprotein V1 (GPVI) gene polymorphisms are known to affect patient responsiveness towards aspirin and clopidogrel dual antiplatelet therapy (DAPT). The present study was undertaken to identify aspirin and clopidogrel non-responsiveness and its association with genetic polymorphism in patients with myocardial infarction (MI).

Methods:

A total of 207 MI patients who were on DAPT, were included. The DAPT non-responsiveness was determined by light transmittance aggregometry using arachidonic acid and adenosine diphosphate and high platelet reactivity by collagen. Platelet activation biomarkers, thromboxane B2 (TxB2)andsoluble CD40 ligand (sCD40L) were measured in plasma. Patient compliance was checked by estimating drug and its metabolite levels (aspirin and clopidogrel) in plasma using liquid chromatography-mass spectrometry/mass spectrometry. Genomic DNA was extracted, amplified by polymerase chain reaction and subsequently sequenced to identify CYP450, P2Y 12, COX1 and GPVI gene polymorphisms.

Results:

Of the 207 patients, 32 were non-responders. The DAPT non-responsiveness was found in 15.5 per cent patients. The non-responsiveness showed a significant and an independent association with gender [odds ratio (OR)=0.18, 95% confidence interval (CI)=0.01-0.78, P=0.023], TxB2(OR=1.00, 95% CI=1.00-1.01, P=0.013), CYP2C19*2 G>A (OR=3.33, 95% CI=1.04-10.69, P=0.044) and GPVI T>C (OR=0.23, 95% CI=0.08-0.67, P=0.007) after adjusting the demographic, clinical and genetic confounding factors when assessed between non-responder and responder compliant patients.

Interpretation & conclusions:

The study showed a significant association of genetic polymorphisms (CYP2C19*2 G>A and GPVI T>C) with DAPT non-responsiveness in MI patients. The findings of this study need further validation in a large cohort of patients with clinical follow up.

KEYWORDS:

Aspirin; clopidogrel; drug compliance; myocardial infarction; non-responders; platelet activation; platelet aggregation; responders; single-nucleotide polymorphism

PMID:
31571629
DOI:
10.4103/ijmr.IJMR_782_17
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