Clustering of ABCB1 and CYP2C19 Genetic Variants Predicts Risk of Major Bleeding and Thrombotic Events in Elderly Patients with Acute Coronary Syndrome Receiving Dual Antiplatelet Therapy with Aspirin and Clopidogrel

Abstract

ObjectiveThe clinical efficacy of clopidogrel in secondary prevention of vascular events is hampered by marked inter-patient variability in drug response, which partially depends on genetic make-up. The aim of this pilot prospective study was to evaluate 12-month cardiovascular outcomes in elderly patients with acute coronary syndrome (ACS) receiving dual antiplatelet therapy (aspirin and clopidogrel) according to the clustering of CYP2C19 and ABCB1 genetic variants.MethodsParticipants were 100 consecutive ACS patients who were genotyped for CYP2C19 (G681A and C-806T) and ABCB1 (C3435T) polymorphisms, which affect clopidogrel metabolism and bioavailability, using PCR-restriction fragment length polymorphism. They were then grouped as poor, extensive and ultra-rapid metabolisers based on the combination of CYP2C19 loss-of-function (CYP2C19*2) and gain-of-function (CYP2C19*17) alleles and ABCB1 alleles. The predictive value of each phenotype for acute vascular events was estimated based on 12-month cardiovascular outcomes.ResultsThe poor metabolisers were at an increased risk of thrombotic events (OR 1.26; 95% CI 1.099–1.45; χ2 = 5.676; p = 0.027), whereas the ultra-rapid metabolisers had a 1.31-fold increased risk of bleeding events compared with the poor and extensive metabolisers (OR 1.31; 95% CI 1.033–1.67; χ2 = 5.676; p = 0.048). Logistic regression model, including age, sex, BMI and smoking habit, confirmed the differential risk of major events in low and ultra-rapid metabolisers.ConclusionsOur findings suggest that ACS patients classified as ‘poor or ultra-rapid’ metabolisers based on CYP2C19 and ABCB1 genotypes should receive alternative antiplatelet therapies to clopidogrel.Electronic supplementary materialThe online version of this article (10.1007/s40266-018-0555-1) contains supplementary material, which is available to authorized users.

<p>Increased Risk of Clopidogrel-Induced Gastric Mucosal Erosion in Elderly Chinese Men Harboring the <em>ABCB1 3435T</em> Allele</p>

“…In contrast, CYP2C19 *17, known as a functional acquired gene mutation, is associated with an increased risk of bleeding. 29 Our study did not observe that the CYP2C19 2 *3 * and 17 * alleles were associated with gastric mucosal erosion but found that ABCB1 3435T allele carriers had a higher incidence of gastric mucosal erosion after long-term clopidogrel use. ABCB1 is also known as the multidrug resistance gene MDR1, and its encoded P-glycoprotein can pump harmful substances or substrates, such as drugs, out of the cell.…”

“…In contrast, CYP2C19 *17 , known as a functional acquired gene mutation, is associated with an increased risk of bleeding. 29 …”

Impact of genetic variants on major bleeding after percutaneous coronary intervention based on a prospective multicenter registry

“…Previous studies that evaluated the association between genetic variations and clinical outcomes have mainly focused on ischemic outcomes such as cardiac death, myocardial infarction, stent thrombosis, and target lesion revascularization 12 . CYP2C19 is the most commonly studied gene, and several studies on this gene have shown that the gain-of-function group had a higher occurrence of bleeding events than the loss-of-function group 7 , 13 . However, the prevalence of gain-of-function in Asians with the CYP2C19 variant is very low compared to that in Caucasians with the CYP2C19 variant 8 , 14 , 15 .…”

Pharmacogenetics of Antithrombotic Drugs: Status Update on the Problem

“…Помимо аллельных вариантов, ответственных за ослабление эффекта клопидогрела, был выявлен полиморфизм CYP2C19*17, гомозиготный вариант которого ассоциировался с повышением риска кровотечений [39][40][41][42]. Возможно, однако, что для данного аллельного варианта имеет значение этническая принадлежность.…”