Ischemic stroke and myocardial ischemia in clopidogrel users and the association with CYP2C19 loss-of-function homozygocity: a real-world study

• Published in: The pharmacogenomics journal 2021-06, Vol.21 (3), p.402-408
• Main Authors: Gronich, Naomi, Lavi, Idit, Lejbkowicz, Flavio, Pinchev, Mila, Zoabi, Yusri, Auriel, Eitan, Saliba, Walid, Rennert, Gad
• Format: Article
• Language: English
• Subjects: 45/43; 631/154/436; 631/208; 631/208/2489/1512; 631/208/721; Aged; Aged, 80 and over; Angioplasty; Biomedical and Life Sciences; Biomedicine; Case-Control Studies; Cerebral infarction; Clopidogrel; Clopidogrel - adverse effects; Clopidogrel - metabolism; Cohort Studies; Complications and side effects; Cytochrome P-450; Cytochrome P-450 CYP2C19 - genetics; Databases, Factual; Endpoint Determination; Female; Gene Expression; Genetic aspects; Genome-Wide Association Study; Genotypes; Health aspects; Heart attacks; Homozygosity; Homozygote; Human Genetics; Humans; Ischemia; Ischemic Stroke - chemically induced; Ischemic Stroke - genetics; Male; Middle Aged; Myocardial infarction; Myocardial Infarction - genetics; Myocardial ischemia; Myocardial Ischemia - chemically induced; Myocardial Ischemia - genetics; Oncology; Patient outcomes; Percutaneous Coronary Intervention; Pharmacology, Experimental; Pharmacotherapy; Physiological aspects; Platelet Aggregation Inhibitors - adverse effects; Platelet Aggregation Inhibitors - metabolism; Prevention; Psychopharmacology; Retrospective Studies; Risk Factors; Stroke; Stroke (Disease); Transluminal angioplasty; Treatment Outcome
• ISSN: 1470-269X; 1473-1150
• DOI: 10.1038/s41397-021-00218-8

Reduced clopidogrel effectiveness in preventing recurrent myocardial ischemia following percutaneous coronary intervention has been demonstrated in CYP2C19 loss-of-function carriers. Less is known about the effect of CYP2C19 genotype on the effectiveness of clopidogrel for stroke prevention, particularly in Caucasians. This is a retrospective cohort study, in which we used the Clalit clinical database to follow genotyped clopidogrel initiators, for up to 3 years. Endpoint was a new primary discharge diagnosis of ischemic stroke; secondary endpoints were new primary discharge diagnoses of coronary angioplasty, myocardial infarction (MI), or a composite endpoint of: stroke, MI, or coronary angioplasty. After 3 years of follow up over 628 clopidogrel initiators, 2 out of 12 (16.7%) poor metabolizers, 9 out of 144 intermediate metabolizers (6.3%), and 29 out of 472 (6.1%) normal/rapid/ultrarapid metabolizers have been newly diagnosed with ischemic stroke. Poor metabolizer status was associated with higher risk for ischemic stroke, marginally significant in univariate analysis and in multivariable models; and higher risk for the composite outcome of stroke, myocardial infarction and coronary angioplasty, HR = 3.32 (1.35–8.17) p  = 0.009, 2.86 (1.16–7.06) p  = 0.02 (univariate and multivariate analyses, respectively). Poor metabolizer status was associated with higher risk for stroke HR = 5.80 (1.33–25.24) p  = 0.019, HR = 4.13 (0.94–18.13) p  = 0.06 (univariate and multivariate analyses, respectively) in patients who “survived” the first year, and were in the cohort 1–3 years. Caucasian treated with clopidogrel who are homozygote for the CYP2C19 loss-of function allele might be at increased risk for ischemic stroke, and for the composite outcome of ischemic stroke, myocardial infarction and coronary angioplasty.