Meta-analyses of the association between cytochrome CYP2C19 loss- and gain-of-function polymorphisms and cardiovascular outcomes in patients with coronary artery disease treated with clopidogrel

Abstract

Not only CYP2C19 loss-of-function but also gain-of-function alleles should be considered to define the pharmacogenetic response to clopidogrel. The results question the relevance of the CYP2C19 loss-of-function alleles in the prediction of major cardiovascular events beyond stent thrombosis in coronary patients treated with clopidogrel. The gain-of-function variant is associated with a lower risk of cardiovascular events but a higher risk of bleeding.

A systematic review and critical assessment of 11 discordant meta-analyses on reduced-function CYP2C19 genotype and risk of adverse clinical outcomes in clopidogrel users

“…Six meta-analyses reduced heterogeneity by excluding one or more studies, 5,8,[24][25][26]29 and four of these found that the resulting pooled effect estimate remained unchanged. 5,8,24,26 Five meta-analyses performed stratified meta-analyses by study and population characteristics, 7,8,25,26,29 two performed metaregression, 5,20 and one inspected primary study characteristics. 5 Higher sample size and poorer quality of the primary studies were associated with lower effect sizes, 7,25 but other studies did not find an impact of study characteristics.…”

“…Five of these eight concluded that there was an association between CYP2C19 loss-of-function alleles and the clinical end point, 24,26-29 two inferred that there was a possible association, 7,8 whereas one concluded that the association was not proven because of publication bias ( Table 2; Supplementary Table S4 and Supplementary Appendix S1 online). 6 The remaining three meta-analyses found no statistically significant pooled effect 5,25 or did not pool the data because of between-study heterogeneity. 30 Of the four meta-analyses that concluded absence of association, three were among the five most recently published.…”

“…The percentage of all studies that were included in the meta-analysis, calculated as the percentage of all available studies at the date of the study selection, ranged from 25 to 90% for the clinical end point and from 9 to 82% for ST (Supplementary Tables S1 and S2; Supplementary Appendix S1 online). Five meta-analyses did not include conference abstracts, 5,25,[28][29][30] and all but one of the metaanalyses left out data from one or more full articles that were included in other meta-analyses (Supplementary Table S1 and Supplementary Appendix S1 online). [34][35][36][37][38][39][40][41] For example, the post hoc genetic analysis of the ACTIVE-A trial was included in only two of the seven meta-analyses that did their literature searches after the publication of the trial, 6,24 and one meta-analysis had limited the inclusion to only primary studies with a follow-up time of 6-12 months.…”

“…[5][6][7][8][24][25][26][27][28][29][30] Mean effect sizes (fixedeffects models) ranged from 1.77 to 3.82. One meta-analysis concluded that there was a possible association, 6 and one other meta-analysis observed the presence of heterogeneity and publication bias and downgraded the evidence ( Table 2; Supplementary Table S4 and Supplementary Appendix S1 online).…”

“…ST was typically defined according to the Academic Research Consortium definitions. 23 Five meta-analyses used a checklist to assess the quality of the primary studies, 5,7,8,24,25 and three meta-analyses used their own approach 6,26,27 or did not check the quality.…”