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

• Published in: Indian journal of medical research (New Delhi, India : 1994) India : 1994), 2019-07, Vol.150 (1), p.50-61
• Main Authors: Pandey, Chandra, Misra, Ankita, Negi, Mahendra, Kanuri, Babu, Chhonker, Yashpal, Bhatta, Rabi, Narain, Varun, Dikshit, Madhu
• Format: Article
• Language: English
• Subjects: Adenosine diphosphate; Aged; Alleles; Arachidonic acid; Aspirin; Aspirin - administration & dosage; Aspirin - adverse effects; ATPases; Blood platelets; Cardiovascular disease; CD40 Ligand - genetics; Clopidogrel; Clopidogrel - administration & dosage; Clopidogrel - adverse effects; Collagen; COX-2 inhibitors; Cyclooxygenase 1 - genetics; Cytochrome; Cytochrome P-450 Enzyme System - genetics; Dosage and administration; Drug therapy; Dual Anti-Platelet Therapy - adverse effects; Enzymes; Fatty acids; Female; Genes; Genetic aspects; Genetic Association Studies; Genetic polymorphisms; Genetic Predisposition to Disease; Genotype; Health aspects; Heart attack; Heart attacks; Humans; Male; Metabolism; Metabolites; Middle Aged; Myocardial Infarction - blood; Myocardial Infarction - drug therapy; Myocardial Infarction - genetics; Myocardial Infarction - pathology; Original; Patient compliance; Patient outcomes; Patients; Platelet Aggregation Inhibitors - adverse effects; Platelet Membrane Glycoproteins - genetics; Polymorphism; Polymorphism, Genetic; Receptors, Purinergic P2Y12 - genetics; Sample size; Thromboxane B2 - genetics; Unsaturated fatty acids
• ISSN: 0971-5916
• DOI: 10.4103/ijmr.IJMR_782_17

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.