The impact of gene polymorphism and high on-treatment platelet reactivity on clinical follow-up: outcomes in patients with acute coronary syndrome after drug-eluting stent implantation
Selected in EuroIntervention by S. Brugaletta
Liang ZY, Han YL, Zhang XL, Li Y, Yan CH, Kang J
EuroIntervention. 2013 Jul 22;9(3):316-27
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The current study sought to evaluate the clinical impact of newly reported genetic variations and their association with clopidogrel high on-treatment platelet reactivity (HTPR) in acute coronary syndrome (ACS) patients after drug-eluting stent (DES) implantation.
Methods and results
The study enrolled 1,016 consecutive patients with ACS undergoing DES implantation. A total of 19 tag single nucleotide polymorphisms (SNPs) were selected from CYP3A4/5, CYP2C19, P2Y12 and ABCB1 genes. ADP-induced light transmittance aggregometry (LTA) was performed to test the post-procedure maximum platelet agglutination (MPA). The primary endpoint was a composite of cardiovascular death, non-fatal myocardial infarction (MI), stent thrombosis, and ischaemic stroke at one-year follow-up after DES placement. The secondary endpoint was the incidence of bleeding events. The post-procedure MPA was calculated and the cut-off point was determined for the HTPR. Using multivariate logistic regression analysis, the carriage of two CYP2C19 LOF alleles was an independent predictor of the post-procedure HTPR (OR: 2.8, 95% CI: 1.70-7.23, p<0.001). Through multivariate Cox regression analysis, the carriage of two CYP2C19 LOF alleles and the post-procedure HTPR were independent predictors of the primary endpoint (HR: 2.3, 95% CI: 1.40-4.97, p<0.001; HR: 2.9, 95% CI: 1.52-5.57, p<0.001, respectively). However, post-procedure MPA did not predict a bleeding event (HR: 0.9, 95% CI: 0.44-1.59, p=0.532).
In patients with ACS, the CYP2C19 LOF allele was associated with post-procedure HTPR and a subsequently increased risk of adverse clinical events at one-year follow-up following DES implantation and clopidogrel administration.
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What is known
Persistent high platelet reactivity following PCI is reported to occur, even with adequate pre-treatment of clopidogrel, and is related to an increased risk of adverse cardiovascular events. Indeed, platelet activity in response to clopidogrel treatment is highly variable, with clinical, cellular, and genetic factors considered as important reasons for the variability. The present study sought to assess the impact of gene polymorphisms (CYP3A4/5, CYP2C19, P2Y12 and ABCB1) on ADP-induced platelet reactivity, and subsequent clinical follow- up outcomes in Chinese high-risk ACS patients receiving clopidogrel after DES implantation.
- 1016 consecutive patients with ACS undergoing DES implantation were enrolled.
- ADP-induced light transmittance aggregometry was performed to test the post-procedure maximum platelet agglutination (MPA).
- The primary endpoint was a composite of cardiovascular death, non-fatal myocardial infarction (MI), stent thrombosis, and ischaemic stroke at one-year follow-up. The secondary endpoint was the incidence of bleeding events.
- Through multivariate Cox regression analysis, the carriage of two CYP2C19 LOF alleles and the post-procedure high on treatment platelet reactivity were independent predictors of the primary end-point (HR: 2.3, 95% CI: 1.40-4.97, p<0.001; HR: 2.9, 95% CI: 1.52-5.57, p<0.001, respectively).
- Post-procedure MPA did not predict a bleeding event (HR: 0.9, 95% CI: 0.44-1.59, p=0.532).
The present study currently represents the first study conducted in East Asia, demonstrating that high-platelet reactivity, despite administration of clopidogrel, and carrying of two CYP2C19 LOF alleles are associated with an increased risk of adverse clinical events. This study confirms therefore the low responsiveness of patients to clopidogrel, which is already already since several years, extending this finding to Chinese population. New antiplatelet agents, such as prasugrel and ticagrelor, that are more potent than clopidogrel, have been developed and actually recommended by guidelines in treatment of patients with acute coronary syndromes in order to overcome the high response variability to clopidogrel. It would be interesting to know if these guidelines are widely applied in all countries or if, due to economical reasons, prasugrel and ticagrelor are reserved only to those patients at high-risk of ischemic events.