Risk Factor For Clopidogrel Resistance Research Articles

Genetic variability in stroke patients: CYP2C19 polymorphisms unraveled

ObjectiveTo study the distribution characteristics of CYP2C19 polymorphisms in patients suffering from stroke in Han Chinese patients.MethodPCR and DNA microarray chip technology were used to detect the CYP2C19 genotype of 549 patients with stroke, and the genotype, allele frequency and metabolic type of patients with different sexes, ages and types of infarctions and the independent risk factors for clopidogrel resistance were analyzed.ResultsSix genotypes were detected in these 549 patients. A total of 233 (42.44%) patients had the heterozygous allele *1/*2, which was the most prevalent, followed by the homozygous wild-type allele *1/*1 (191, 34.79%). A total of 30 (5.46%) patients possessed the heterozygous allele *1/*3, and 65 (11.84%) patients had the homozygous mutant allele *2/*2. Twenty-nine (5.28%) patients had the compound heterozygous mutant allele *2/*3, and only 1 patient had the homozygous mutant allele *3/*3. The distribution of genotypes, alleles, and metabolic types did not change significantly (P > 0.05) by sex, age, or type of stroke. In addition, no independent risk factors for clopidogrel resistance were found in this analysis.ConclusionThe distribution of CYP2C19 genotypes, allele frequencies, and metabolic types in patients with stroke in Han Chinese patients were not correlated with sex, age, or infarction type. The possibilities of hyperglycemia, hypercholesterolemia, hypertriglyceridemia, hypo-HDL-cholesterolemia, hyper-LDL-cholesterolemia and high blood pressure were not statistically associated with CYP2C19 genotypes. CYP2C19 gene polymorphism detection is recommended for patients who are available, and during treatment, the CYP2C19 genotype can be used to guide personalized precise medication use in patients with stroke.

Factors associated with clopidogrel resistance and clinical outcomes in ischemic cerebrovascular disease: A retrospective study

ObjectiveClopidogrel resistance may lead to the recurrence of cerebrovascular diseases. We aimed to identify potential factors associated with clopidogrel resistance and evaluate the clinical outcomes of the patients. Materials and methodsIn this retrospective study, patients with ischemic cerebrovascular disease treated with clopidogrel were included and classified into 2 groups according to the adenosine diphosphate (ADP)-induced platelet aggregation. Patients with the ADP inhibition rate of <30 % were included in clopidogrel resistance group, otherwise were included in clopidogrel sensitive group. CYP2C19 genotype and other clinical data were analyzed to identify factors and clinical features in the multivariate analysis. The outcomes were vascular events in 6 months. ResultsIn total, 139 patients were enrolled with 81 (58.27 %) in clopidogrel sensitive group and 58 (41.73 %) in clopidogrel resistance group. Female and CYP2C19 *2*3 carrying were risk factors for clopidogrel resistance, and female was an independent risk factor (OR 2.481, 95 % CI 1.066-5.771, P=0.035). The clopidogrel resistance group showed a higher use rate of argatroban (P=0.030) and a lower arachidonic acid-induced inhibition of platelet aggregation (P=0.036). Clopidogrel resistance was related to the progressing stroke (HR 3.521, 95 % CI 1.352-9.170, P=0.010), but had no influence on the bleeding events (P>0.05). ConclusionsThe risk of clopidogrel resistance increased significantly in female patients. Patients with clopidogrel resistance may have an increased incidence of stroke progression in the acute phase.

Analysis of CYP2C19 gene polymorphism and influencing factors of pharmacological response of clopidogrel in patients with cerebral infarction in Zhejiang, China.

Certain genetic and non-genetic factors may cause damaged platelet inhibition by clopidogrel. We aimed to determine the effect of cytochrome P4502C19 (CYP2C19) polymorphism, along with other clinical factors, on the platelet response to clopidogrel in patients with acute ischemic stroke (AIS). A total of 214 patients with AIS receiving clopidogrel at a maintenance dose of 75 mg daily admitted to the Ningbo First Hospital between 1 January 2020, and 31 December 2021, were enrolled. Platelet aggregation analysis was performed to determine clopidogrel resistance. Quantitative real-time polymerase chain reaction (QRT-PCR) was used to determine CYP2C19 genotype. Other laboratory data on complete blood count and biochemical parameters were taken from patient medical files. Among the 214 AIS patients treated with clopidogrel in the Ningbo population, the incidence of clopidogrel resistance was approximately 43.9%, and the distribution of CYP2C19 genotypes was highest for CYP2C19(*1/*2) (43.0%), followed by CYP2C19 (*1/*1) (38.8%). The distribution of alleles *1, *2, *3, and *17 was 62.1, 32.5, 4.9, and 0.5%, respectively. A chi-squared test showed that the gene frequencies of alleles *2 and *3 were significantly higher in the clopidogrel-resistant group than in the clopidogrel-sensitive group (p < 0.001), and a Mann-Whitney U-test showed that high HCY levels were significantly correlated with clopidogrel resistance (p < 0.001). Multi-factor logistic regression analysis demonstrated that mutant heterozygous genotype [OR 2.893; 95% confidence interval (CI) 1.456-5.748; p = 0.002], mutant homozygous genotype (OR 4.741; 95% CI 1.828-12.298; p = 0.001), and high HCY levels (OR 1.209; 95% CI 1.072-1.362; p = 0.002) were significantly associated with clopidogrel resistance. According to our results, carrying the CYP2C19*2/*3 allele and high HCY levels are independent risk factors for clopidogrel resistance after clopidogrel therapy in patients with AIS. These two factors should be considered prior to clopidogrel administration.

Gene polymorphisms of insulin secretion signaling pathway associated with clopidogrel resistance in Han Chinese population.

BackgroundDue to the loss of responsiveness to insulin, diabetes mellitus (DM) patients develop increased platelet reactivity and reduced response to antiplatelet agents. Nevertheless, the relationship between the single‐nucleotide polymorphisms (SNP) of the signal pathway gene of insulin secretion and the effect of clopidogrel is elusive.MethodsBlood samples were collected from patients administered with dual‐antiplatelet therapy (clopidogrel, 75 mg, once daily and aspirin, 100 mg, once daily) after 5 days and completed test within 4 h. The VerifyNow P2Y12 assay was used to measure the platelet functions, and the results were expressed as a P2Y12 reaction unit (PRU). Notably, the selected SNPs were analyzed to demonstrate the functionality of genetic variants.ResultsAnalysis of the study population showed that old age, lower plasma albumin (ALB) level, higher creatinine (CREA) level, higher uric acid (UA) level, lower platelet (PLT) count, and lower plateletcrit (PCT) potentially increased the risk of clopidogrel resistance. In a single‐nucleotide polymorphism rs6056209 of the PCLB1 gene, the AG genotype was a risk factor for clopidogrel resistance (p < 0.05, OR = 1.574). Similarly, the CC and AG genotype in GNAS rs7121 and CCKAR rs1800857 were protective factors (p < 0.05, OR = 0.094; p <0.05, OR = 0.491). TT was a protective factor in rs10814274 of the CREB3 gene (p < 0.05, OR = 0.444). In the RAPGEF4 gene polymorphism rs17746510, TG was the protective genotype, and the TT genotype was a risk factor for clopidogrel resistance. GCG rs5645 was confirmed; there was a relationship between genotypes containing A or G and clopidogrel resistance.ConclusionSingle‐nucleotide polymorphisms of insulin secretion signaling pathway genes trigger clopidogrel resistance.

Genetic Polymorphisms of ABCB1 Gene in Patients Having Resistance to Clopidogrel

Objectives: We sought to study the genetic polymorphisms of ABCB1 gene in post percutaneous coronary intervention (PCI) patients with clopidogrel resistance. Background: Dual antiplatelet therapy (DAPT) is a guideline mandated therapy for patients who undergo PCI. However there exists interindividual variability in drug response to the antiplatelet agents leading to recurrent thrombotic events. Genetic polymorphisms of ABCB1 gene are one among the causes of this interindividual variability. Methods: It is a single center prospective trial and includes221 patients who underwent PCI and were given clopidogrel as a part of DAPT. Platelet reactivity was assessed by grading of platelet activity index (PAI) and considered as high on treatment platelet reactivity (HTPR), i.e., clopidogrel resistance if PAI > 5. Genetic analysis for ABCB1 C-T polymorphism was done by polymerase chain reaction (PCR) and single strand confirmation polymorphism (SSCP) analysis. Results: Amongst 221 patients, 37 (16.7%) patients had ABCB1 C-T polymorphisms. The mean PAI value in these patients was 5.1 ± 3.0, while it was 3.5 ± 2.5 in those patients without ABCB1 C-T polymorphisms (p = 0.004). Compared to patients without HTPR, the occurrence of primary endpoints was not significantly increased in patients with HTPR except for stent thrombosis which was significantly high in patients with HTPR. HTPR was also associated with ABCB1 C-T polymorphisms (p = 0.04), but these polymorphisms did not predict the clinical outcome. Conclusions: There was significant prevalence of ABCB1 C-T polymorphisms in patients with HTPR. However it was not an independent risk factor for clopidogrel resistance and also it did not influence adverse cardiovascular outcomes.

Antiplatelet drug resistance is associated with early neurological deterioration in acute minor ischemic stroke in the Chinese population.

To evaluate the prevalence and risk factors of antiplatelet drug resistance and its association with early neurological deterioration (END) and recurrent ischemic stroke (RIS) in patients with acute minor stroke. Antiplatelet drug resistance was assessed by platelet aggregation assay in 426 patients with minor stroke who were receiving combined treatment of aspirin and clopidogrel. All patients were followed up for 90days. The primary endpoint of the study was END within 10days after admission. The secondary endpoints included RIS, myocardial infarction and death during 90days of treatment. The safety endpoints were intracerebral or extracranial hemorrhagic events. Cox proportional hazard regression analysis was performed to determine the risk factors for the primary endpoint and secondary endpoints. Among the 426 patients, 24.4% exhibited aspirin resistance, 35.9% exhibited clopidogrel resistance, and 19.2% displayed concomitant aspirin and clopidogrel resistance. In multivariate analysis, diabetes mellitus and high level of low density lipoprotein-cholesterol were independent risk factors for aspirin resistance, while diabetes mellitus was the only independent risk factor for clopidogrel resistance. END was observed in 93 (21.8%) patients. Diabetes mellitus, high fasting blood glucose level, and concomitant aspirin and clopidogrel resistance were independent risk factors for END. RIS was observed in 40 (9.4%) patients. Diabetes mellitus, hypertension, and concomitant aspirin and clopidogrel resistance were independent risk factors for RIS. Antiplatelet drug resistance is common in acute minor ischemic stroke patients and is associated with END and RIS after acute minor ischemic stroke in the Chinese population. http://www.chictr.org/ . Unique Identifier: ChiCTR-OCH-14004724.

Associations of CYP3A4, NR1I2, CYP2C19 and P2RY12 polymorphisms with clopidogrel resistance in Chinese patients with ischemic stroke.

There is a high incidence of the antiplatelet drug clopidogrel resistance (CR) in Asian populations. Because clopidogrel is a prodrug, polymorphisms of genes encoding the enzymes involved in its biotransformation may be the primary influential factors. The goal of this study was to investigate the associations of polymorphisms of CYP3A4, NR1I2, CYP2C19 and P2RY12 genes with CR in Chinese patients with ischemic stroke. A total of 191 patients with ischemic stroke were enrolled. The patients were treated with clopidogrel for at least 5 days. Platelet function was measured by light transmission aggregometry. The SNPs NR1I2 (rs13059232), CYP3A4(*)1G (rs2242480), CYP2C19(*)2 (rs4244285) and P2RY12 (rs2046934) were genotyped. The CR rate in this population was 36%. The CYP2C19(*)2 variant was a risk factor for CR ((*)2/(*)2+wt/(*)2 vs wt/wt, OR: 2.366, 95% CI: 1.180-4.741, P=0.014), whereas the CYP3A4(*)1G variant had a protective effect on CR ((*)1/(*)1 vs (*)1G/(*)1G+(*)1/(*)1G, OR: 2.360, 95% CI: 1.247-4.468, P=0.008). The NR1I2 (rs13059232) polymorphism was moderately associated with CR (CC vs TT+TC, OR: 0.533, 95% CI: 0.286-0.991, P=0.046). The C allele in P2RY12 (rs2046934) was predicted to be a protective factor for CR (CC+TC vs 0.407, 95% CI: 0.191-0.867, P=0.018). In addition, an association was found between hypertension and CR (P=0.022). The individuals with both the CYP2C19(*)2 allele and hypertension are at high risk of CR during anti-thrombosis therapy. The CYP3A4(*)1G allele, P2RY12 (rs2046934) C allele and NR1I2 (rs13059232) CC genotype may be protective factors for CR. The associated SNPs studied may be useful to predict clopidogrel resistance in Chinese patients with ischemic stroke.

Clopidogrel resistance response in patients with coronary artery disease and metabolic syndrome: the role of hyperglycemia and obesity.

BackgroundDespite the proven benefits of clopidogrel combined aspirin therapy for coronary artery disease (CAD), CAD patients with metabolic syndrome (MS) still tend to have coronary thrombotic events. We aimed to investigate the influence of metabolic risk factors on the efficacy of clopidogrel treatment in patients with CAD undergoing percutaneous coronary intervention (PCI).MethodsCohorts of 168 MS and 168 non-MS subjects with CAD identified by coronary angiography (CAG) were enrolled in our study. MS was defined by modified Adult Treatment Panel III criteria. All subjects had taken 100 mg aspirin and 75 mg clopidogrel daily for more than 1 month, and administered loading doses of 600 mg clopidogrel and 300 mg aspirin before PCI. Blood samples were taken 24 h after the loading doses of clopidogrel and aspirin. Platelet aggregation was measured using light transmittance aggregometry (LTA) and thrombelastography (TEG). Clopidogrel resistance was defined as more than 50% adenosine diphosphate (ADP) induced platelet aggregation as measured by TEG.ResultsPlatelet aggregation inhibition rate by ADP was significantly lower in patients with MS as measured both by TEG (55% ± 31% vs. 68% ± 32%; P < 0.001) and LTA (29% ± 23% vs. 42% ± 29%; P < 0.001). In the multivariate analysis, elderly [OR (95% CI): 1.483 (1.047–6.248); P = 0.002], obesity [OR (95% CI): 3.608 (1.241–10.488); P = 0.018], high fasting plasma glucose level [OR (95% CI): 2.717 (1.176–6.277); P = 0.019] and hyperuricemia [OR (95% CI): 2.583 (1.095–6.094); P = 0.030] were all statistically risk factors for clopidogrel resistance. CAD patients with diabetes and obesity were more likely to have clopidogrel resistance than the CAD patients without diabetes and obesity [75% (61/81) vs. 43% (67/156); P < 0.001].ConclusionsCAD patients with MS appeared to have poorer antiplatelet response to clopidogrel compared to those without MS. Obesity, diabetes and hyperuricemia were all significantly associated with clopidogrel resistance.

Antiplatelet resistance and the role of associated variables in stable patients treated with stenting.

IntroductionNowadays, clopidogrel and acetylsalicylic acid (ASA) have become routinely applied therapies in percutaneous coronary interventions (PCI) with stenting.AimNumerous variables can interfere with antiplatelet responsiveness, so we aimed to investigate the role of different variables associated with ASA or clopidogrel resistance in stable coronary artery disease.Material and methodsA total of 207 patients undergoing elective PCI were included in the analysis. All patients received a loading dose of clopidogrel and ASA during PCI procedure and followed by dual antiplatelet therapy. Clopidogrel and ASA resistance were measured by impedance aggregometry method.ResultsOf the patients, 19.8% had clopidogrel resistance, 18.8% had ASA resistance, 9.2% had both clopidogrel and ASA resistance, and 71.5% were responsive to both drugs. In multivariate analysis, platelet count, angiotensin receptor blocker (ARB) use, and ASA resistance were independent variables associated with clopidogrel resistance, and clopidogrel resistance was the only variable associated with ASA resistance. In differentiating whether clopidogrel resistance exists or not, optimum ASA aggregometry response cut-off values were specified, and in differentiating whether ASA resistance exists or not, optimum clopidogrel aggregometry response cut-off values were specified.ConclusionsIn this study, there was a higher incidence of low responsiveness to ASA when there was a low response to clopidogrel, and vice versa. Angiotensin receptor blocker use, platelet count, and ASA resistance were independent variables associated with clopidogrel resistance. Clopidogrel resistance was the only independent variable associated with ASA resistance. Angiotensin receptor blocker use seems to an independent risk factor for clopidogrel resistance in this study, but this result needs to be verified in other studies.

Clopidogrel use in end-stage kidney disease.

Clopidogrel irreversibly binds to the P2Y12 platelet receptor and acts as a potent inhibitor of platelet activation and aggregation. It is currently recommended for the prevention of cardiovascular events in patients with acute coronary syndromes, recent ischemic stroke, and peripheral arterial disease. Clopidogrel is a prodrug requiring hepatic conversion into its active metabolite. In the general population, genetic polymorphisms in the CYP2C19 gene interfering with hepatic conversion and the ABCB1 gene interfering with gut absorption of clopidogrel, account for the large interindividual response to clopidogrel and clopidogrel resistance. Chronic kidney disease (CKD) and ESKD are independent risk factors for clopidogrel resistance; 50-80% of patients with ESKD have high on-treatment residual platelet reactivity when treated with clopidogrel. This may partially explain the abysmal outcomes for patients with kidney disease post coronary intervention. Several assays are used to determine residual on-treatment platelet reactivity; however, their use in tailoring the suitability of clopidogrel treatment in patients with ESKD is unclear. Although clopidogrel decreased cardiovascular events in the general population after acute coronary syndromes and percutaneous intervention in the CURE and CREDO trials, a reanalysis of these studies in patients with CKD (eGFR <60ml/minute) showed either a reduced or no benefit from clopidogrel treatment. ESKD patients were not represented in these two large trials; this is true for most of the trials that established clopidogrel as an integral part of the therapeutic armamentarium for cardiovascular disease. Furthermore, clopidogrel has been associated with an increased risk of death, death from bleeding, and hospitalization for bleeding in patients with ESKD. In conclusion, current evidence suggests that ESKD patients may not derive the same benefits from clopidogrel therapy as the general population and this therapy may be associated with harm. Properly designed observational studies and randomized controlled trials are needed to establish the role of clopidogrel in patients with ESKD, the use of platelet assays to tailor therapy, and the role of other antiplatelet agents such as prasugrel or ticagrelor in patients who exhibit high on-treatment residual platelet reactivity.

Risk factors for clopidogrel resistance in patients with ischemic cerebral infarction and the correlation with ABCB1 gene rs1045642 polymorphism.

The aim of the present study was to examine clopidogrel resistance (CR) in patients with ischemic cerebral infarction and its potential association with a single nucleotide polymorphism (SNP; rs1045642) in the ABCB1 gene. Patients with ischemic cerebral infarction received clopidogrel (75 mg/day) for 7 days and were then subjected to a turbidimetric assay to determine platelet aggregation. Patients were then divided into a CR group and a clopidogrel-sensitive (CS) group. Demographic and clinical data between the two groups were compared. Multivariate logistic regression analysis was performed to determine independent risk factors of CR. PCR products were sequenced to assess ABCB1 rs1045642 SNP genotype and allele frequencies in each group. In total, 303 patients were enrolled in the study; this included 51 CR cases (16.83%) and 252 CS cases (83.17%). Several parameters, including hypertension, diabetes, calcium channel blocker (CCB), β-receptor blocking agent and proton pump inhibitor use, and creatinine, fasting blood glucose, homocysteine (HCY), high-sensitivity C-reactive protein (hs-CRP) and triglyceride levels were significantly higher in the CR group than in the CS group. Diabetes, hs-CRP-increased use of CCBs, and use of β-blockers were found to be independent risk factors for CR. However, ABCB1 gene rs1045642 polymorphism was not found to be an independent risk factor for CR. In conclusion, CR in ischemic stroke patients is associated with several independent risk factors, including diabetes, hs-CRP-increased use of CCBs, and use of β-blockers. However, ABCB1 gene rs1045642 polymorphism has no correlation with CR.

Association between clopidogrel resistance and polymorphism of platelet adenosine diphosphate receptor in patients with coronary atherosclerotic disease

To investigate the relation of clopidogrel resistance to polymorphism of adenosine diphosphate receptor (P2Y12). Three hundred and seventy patients with coronary atherosclerotic heart disease, who were admitted in hospital from May 2011 to November 2012 and underwent percutaneous coronary intervention, were enrolled in the study. All patients received antiplatelet therapy (oral aspirin 100 mg per night and clopidogrel 75 mg per day for >7 d). The gene polymorphisms of C34T and G52T P2Y12 receptor were detected by using DNA sequencing technique. The relationship of gene polymorphism with the incidence of clopidogrel resistance and clinical outcomes were analyzed. Among 370 patients, clopidogrel resistance developed in 100 cases, including 36 males (36%) and 64 females (64%). In the C34T locus, 212 cases were of CC genotype and 158 were of CT+TT genotype; the incidence of clopidogrel resistance in CC genotype was significantly lower than that in CT+TT genotype (P<0.05). In the G52T locus, 218 cases were of GG genotype and 152 cases were of GT+TT genotype; the incidence of clopidogrel resistance in GT+TT genotype were significantly higher than that in GG genotype (P<0.05). After 1-year follow-up, patients with CC genotype had lower incidence of angina recurrence than patients with CT+TT genotype did (13.2% vs 19.6%, Χ2=4.956, P<0.05), and patients with GG genotype had lower incidence of emergency revascularization, angina, and cardiovascular composite endpoint events than patients with GT+TT genotype did (Χ2=4.135,6.823,5.916, Ps<0.05). T-34, -52 mutations on P2Y12 receptor gene may be a risk factor for clopidogrel resistance and adverse cardiovascular events.

Drug interaction with anti-mycobacterial treatment as a cause of clopidogrel resistance

The case is reported of a patient presenting with recurrent acute myocardial infarction due to stent thrombosis resulting from possible clopidogrel resistance caused by interaction between clopidogrel and anti-tuberculosis drugs....