Elsevier

Thrombosis Research

Volume 134, Issue 5, November 2014, Pages 970-975
Thrombosis Research

Regular Article
Relationship Between ABCB1 Polymorphisms, Thromboelastography and Risk of Bleeding Events in Clopidogrel-Treated Patients With ST-Elevation Myocardial Infarction

https://doi.org/10.1016/j.thromres.2014.08.017Get rights and content

Highlights

  • We enrolled 467 consecutive STEMI patients treated with clopidogrel after PCI.

  • ADP inhibition in TEG has predictive value of bleeding risk.

  • ABCB1 tag SNP rs1045642 is associated with higher risk of bleedings.

  • ABCB1 rs7779562 is associated with lower bleeding risk.

  • We validated the results in a second cohort of 504 STEMI patients.

Abstract

Introduction

This study sought to investigate the relationship of polymorphisms in ABCB1 and the predictive value of thromboelastography (TEG) on bleeding risk in clopidogrel-treated patients with ST-elevation myocardial infarction (STEMI).

Methods

467 consecutive patients with STEMI undergoing percutaneous coronary intervention (PCI) were enrolled. Twenty tag single nucleotide polymorphisms (SNPs) selected from ABCB1 gene and CYP2C19*2, *3, *17 were detected by the ligase detection reaction. Platelet reactivity was assessed by TEG. The follow-up period was 12 months.

Results

By receiver operating characteristic curve analysis, the TEG platelet mapping assay value of ADP inhibition had the best predictive value of bleeding academic research consortium definition (BARC) ≥ 3b bleedings, yielding an area under the curve (AUC) of 0.707 (95% CI 0.662-0.749, p = 0.009; cut-off value > 93.4%). ADP inhibition can also predict BARC  3 bleedings with an AUC of 0.594 (95% CI 0.546-0.640, p = 0.05; cut-off value > 92.5%). After adjustment for established risk factors of bleeding including the gain of function CYP2C19*17 allele, age, female gender, renal function, the multivariable logistic regression model demonstrated that ADP inhibition > 92.5% (OR 2.247, 95%CI 1.082-4.665, P = 0.03), carriage of rs1045642 (OR 2.943, 95%CI 1.195-7.247, P = 0.019) and rs7779562 (OR 0.453, 95%CI 0.219-0.936, P = 0.032) were independent predictors of BARC  3 bleedings. These associations were validated in a second cohort of 504 STEMI patients.

Conclusions

In STEMI patients treated with clopidogrel after PCI, the ABCB1 tag SNP rs1045642 is associated with higher risk of bleedings while rs7779562 is associated with lower bleeding risk, and ADP inhibition in TEG has a predictive value of bleedings.

Introduction

The adenosine diphosphate (ADP) receptor blocker clopidogrel is routinely administered for the prevention of cardiovascular events in patients suffering ST-elevation myocardial infarction (STEMI), especially in those undergoing percutaneous coronary intervention (PCI)[1], [2]. Although new standard of antiplatelet agents such as prasugrel and ticagrelor are available now, clopidogrel is still one of the most frequently prescribed drugs in many countries. However, interindividual variability in pharmacodynamics response to clopidogrel is widespread in patients treated with this medication [3]. Patients with high platelet reactivity (PR) to ADP are more likely to experience ischemic events, while low PR to ADP may contribute to increased risk of bleeding events [4]. Although the mechanisms have not been fully elucidated, many factors have been reported to involve in the clopidogrel response variability. Gene polymorphisms play a critical role in clopidogrel metabolism, strongly affecting the prognosis of patients under clopidogrel treatment [5], [6], [7].

Clopidogrel is an inactive prodrug that requires intestinal absorption and subsequent biotransformation to active metabolites by cytochrome P450 enzymes. We have recently observed that the CYP2C19 loss-of-function (LOF) alleles responsible for clopidogrel metabolism had a gene dose effect on the pharmacodynamics and composite ischemic events of clopidogrel in Chinese people after PCI [8]. As for clopidogrel absorption, a key drug transporter involved is the P-glycoprotein at the intestinal barrier, which is encoded by the ABCB1 (ATP-binding cassette, sub-family B, member 1, also called MDR1) gene [9]. The P-glycoprotein is an ATP-dependent efflux pump that transports various molecules across extracellular and intracellular membranes. The increased expression or function of P-glycoprotein on intestinal epithelial cells can affect bioavailability of its substrate drugs, such as clopidogrel. The contribution of the ABCB1 gene to clopidogrel response continues to be of great interest. More than 50 single nucleotide polymorphisms (SNPs) reside in the coding region of ABCB1 gene which can possibly cause altered function [10]. Most studies focused on a synonymous SNP C3435T (rs1045642) in the gene. Previous research has shown that the minor T allele causes altered function of P-glycoprotein to affect the absorption of clopidogrel [11].

Antiplatelet effect can be evaluated through clinical outcomes and laboratory platelet function tests. Although accumulating data from large studies underscore the importance of high on-treatment PR to ADP as a prognostic risk factor of ischemic events, the association between on-treatment PR and bleeding events is less clear[4]. Thus, we are interested in exploring a potential link between thromboelastography (TEG) results and bleeding events. Meanwhile, epidemiological evidence on ABCB1 gene-association with clopidogrel response is largely inconsistent [12], [13], [14]. In contrast to the numerous studies linking ABCB1 polymorphisms to an increased risk of ischemic events, there is less evidence about the relation of ABCB1 gene and bleeding events. We previously found a significant association between ABCB1 C3435T and bleeding events. In order to further investigate the relation of other ABCB1 polymorphisms on the risk of bleeding and ischemic events, we analyzed tag SNPs across the ABCB1 gene in Chinese STEMI patients treated with clopidogrel, and assessed the association of the ABCB1 polymorphisms in the context of CYP2C19 status to reveal an independent relation of ABCB1 gene variants with clinical outcome. Here, we demonstrated that in STEMI patients treated with clopidogrel after PCI, the ABCB1 tag SNP rs1045642 is associated with higher risk of bleedings while rs7779562 is associated with lower bleeding risk, and ADP inhibition in TEG has predictive value of bleeding risk.

Section snippets

Study population

Between January 2011 and July 2012, 467 consecutive patients with STEMI were enrolled in our prospective, randomized, single-center study. The inclusion criteria were: age of > 18 years, had an uneventful PCI, and could be followed up for > 1 year after PCI. The major exclusion criteria were hemodynamic instability, active bleeding and bleeding diatheses, oral anticoagulation therapy, use of intensified antiplatelet agents other than standard dual antiplatelet therapy, contraindication to

Study population

Samples available for genetic analysis were available from 452 STEMI patients (Fig. 1). All patients were from the Chinese Han population. The average age was 59 ± 12 years, 360 (79.6%) were men. PCIs were all performed with drug-eluting stents. Baseline demographics, clinical presentations and treatment were well balanced between the rs1045642 genotype groups (Table 1). Baseline characteristics were also balanced between the rs2235047, rs7779562 and rs7802783 genotype groups.

During one-year

Discussion

To our knowledge, this is the first study to show an association of tag SNPs in ABCB1 gene and TEG results with bleeding events in STEMI patients. Key findings of our study are that, in clopidogrel-treated patients, (1) TEG value of ADP inhibition predicts BARC  3b and BARC  3 bleedings; (2) ABCB1 genetic locus harbors SNPs associated with bleeding events after PCI.

Among the platelet function assays used in clinical practice, TEG platelet mapping assay enables quantitative analysis of hemostatic

Conclusions

In STEMI patients with clopidogrel administration after PCI, SNPs in ABCB1 genetic might have influence on bleedings, and ADP inhibition of TEG is predictive of bleeding risks.

Conflicts of interest

The authors declared no conflict of interest.

Acknowledgement

This study was supported by the National Natural Science Foundation of China (81170194), the National Key Technology R&D Program in the 12th Five-Year Plan of China (No. 2011BAI11B07) and the Janssen Research Council China research fund (2012–02). We are grateful to the Department of Cardiology, Cardiovascular Institute of Fuwai Hospital for its help in recruiting patients. We thank all members who contributed to the study.

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