Effect of CYP2C19 genetic variants on bleeding and major adverse cardiovascular events in a cohort of Arab patients undergoing percutaneous coronary intervention and stent implantation

Abstract

Introduction One-third of patients have clopidogrel resistance that may lead to major adverse cardiac events (MACEs). By contrast, it was found that some clopidogreltreated patients have hyperresponsive platelets that are associated with higher bleeding risk. Several studies have shown that polymorphisms in the gene encoding the CYP2C19 contribute to the variability in response to clopidogrel. Data on genetic and nongenetic factors affecting clopidogrel response in the Arab population are scarce. In this prospective cohort study, we sought to assess the association between the increased function allele (CYP2C19*17) and bleeding events, and validate the effect of the CYP2C19 genetic variants and nongenetic factors on the incidence of MACEs. Methods Blood samples were collected from patients that were undergoing percutaneous coronary intervention and receiving clopidogrel at the Heart Hospital, a specialist tertiary hospital in Doha, Qatar. Patients were followed for 12 months. Genotyping was performed for CYP2C19*2, *3, and *17 using TaqMan assays. ResultsIn 254 patients, the minor allele frequencies were 0.13, 0.004, and 0.21 for *2, *3, and *17, respectively. Over a 12-month follow-up period, there were 21 bleeding events (8.5 events/100 patient-year). CYP2C19*17 carriers were found to be associated with increased risk of bleeding (OR, 21.6; 95% CI,; P < 0.0001). CYP2C19*2 or *3 carriers were found to be associated with increased risk of baseline and incident MACE combined (OR, 8.4; 95% CI, 3.2-23.9; P < 0.0001). ConclusionThis study showed a significant association between CYP2C19*17 allele and the increased risk of bleeding, and CYP2C19*2 or *3 with MACE outcomes.

‘Effect of CYP2C19 genetic variants on bleeding and major adverse cardiovascular events in a cohort of Arab patients undergoing percutaneous coronary intervention and stent implantation’ by Ali et al. – reassess the evidence, shall we?

“…We have previously shown that CYP2C19 ultrarapid metabolizers neurointervened patients who had increased bleeding risk [12][13][14], in concordance with the work by Ali et al that found a significant odds ratio of 21.6 (95% confidence interval, 4.8-96.8) for bleeding in cardiovascular patients carriers of the CYP2C19*17 allele [1]. Therefore, as the CPIC therapeutic guideline does not include the work by Ali et al, we think it is prudent to suggest a review of the current evidence on the risk of bleeding in patients carrying the CYP2C19*17 polymorphism, whether the indication is cardiovascular or neurovascular.…”

“…On 1 July 2022, Pharmacogenetics and Genomics published a research article, by Ali et al , in which a cohort of Arab patients having percutaneous coronary intervention and stent implantation was studied to determine the effect of cytochrome p450 (CYP) isoform 2C19 genetic variations on bleeding and significant adverse cardiovascular events [1]. Authors found a significant association between CYP2C19 *17 allele and the increased risk of bleeding and CYP2C19 *2 or *3 with major adverse cardiac events [1].…”

Post‐percutaneous coronary intervention CYP2C19 genotyping in an Irish population: The potential role in identifying clopidogrel therapy‐related bleeding risks

“…The findings from our study are supported by results from recent studies which also demonstrate increased bleeding risk in CYP2C19*17 allele carriers. Ali et al investigated the impact of CYP2C19 polymorphisms on bleeding outcomes within an Arab population ( n = 254) receiving clopidogrel therapy after PCI and demonstrated a similar trend of increasing total bleeding incidence with increasing CYP2C19 activity: IM/PM (0.0%), NM (1.7%), RM/UM (25.0%) 11 . The risk of experiencing a bleeding event was significantly higher when RM/UM was compared with NM (hazard ratio [HR] 18.83, 95% CI 4.24‐83.67, P < 0.0001) 11 .…”

“…Carriers of the increased function (CYP2C19*17) allele have increased response to clopidogrel therapy and are phenotypically classified as rapid metabolizers (RM) or ultrarapid metabolizers (UM) depending on whether they carry one or two copies of the gene 7 . An increased production of the pharmacologically active metabolite results in higher bleeding risk and lower incidence of MACE following PCI 9–12 . Interestingly, mixed carriers of one increased function (CYP2C19*17) allele and one loss‐of‐function (CYP2C19*2) allele are also classified as IM since there is no evidence that the increased function from the CYP2C19*17 allele compensates for the loss of function from the CYP2C19*2 allele 7 .…”

“…Our trend reflects the impact of variable CYP2C19 activity (based on corresponding genotypes) on clopidogrel bioactivation and activity. Carriers of the CYP2C19*17 allele (RM/UM) have higher bleeding risks due to increased pharmacologically active metabolite, while carriers of the CYP2C19*2 allele (IM/PM) are less prone to bleeding due to reduced bioactivation of clopidogrel 6,[8][9][10][11][12]. Since ticagrelor is not bioactivated by CYP2C19, this trend of increasing bleeding with CYP2C19 activity was not replicated in the ticagrelor group (IM/PM [5.0%], NM [6.1%], RM/UM [4.3%], P = 0.911).…”