Clopidogrel resistance is common in patients undergoing vascular and coronary interventions

Objectives “Clopidogrel resistance,” also defined as heightened platelet reactivity (HPR) while on clopidogrel therapy, may lead to a sub-optimal antiplatelet effect and a potential thrombotic event. There is limited literature addressing the prevalence of HPR in a large cohort of patients receiving either coronary or endovascular interventions. Methods In a large integrated healthcare system, patients with a P2Y12 reaction units (PRU) test were identified. HPR was defined as a PRU ≥ 200 during clopidogrel therapy. Vascular and coronary interventions were identified utilizing CPT codes, HPR prevalence was calculated, and Fischer’s exact test was used to determine significance. Results From an initial cohort of 2,405,957 patients (October 2014 to January 2020), we identified 3301 patients with PRU tests administered. Of these, 1789 tests had a PRU ≥ 200 (HPR overall prevalence, 54%). We then identified 1195 patients who underwent either an endovascular or coronary procedure and had a PRU measurement. This corresponded to 935 coronary and 260 endovascular interventions. In the coronary cohort, the HPR prevalence was 54% (503/935). In the vascular cohort, the HPR prevalence was 53% (137/260); there was no difference between cohorts in HPR prevalence ( p = 0.78). Conclusion “Clopidogrel resistance” or HPR was found to be present in nearly half of patients with cardiovascular disease undergoing intervention. Our data suggest HPR is more common in the cardiovascular patient population than previously appreciated. Evaluating patients for HPR is both inexpensive ($25) and rapid (< 10 min). Future randomized studies are warranted to determine whether HPR has a clinically detectable effect on revascularization outcomes.

Analysis of the Reactivity of Aspirin and Clopidogrel and Its Influencing Factors in Patients with Coronary Heart Disease at High Altitude

Objective. To evaluate the efficacy of dual-antiplatelet treatment (DAPT) in patients with coronary heart disease (CHD) at high altitude by using thrombelastogram (TEG) and to analyze the related biochemical factors affecting drug reactivity. Methods. Totally 118 CHD patients who admitted to the Qinghai People’s Hospital from September 2019 to September 2020 were enrolled in the group. Those people have lived in Qinghai for a long time. Seven days after DAPT, venous blood was collected on an empty stomach in the early morning of the next day; blood routine, coagulation function, and biochemical items were tested. Thrombelastogram (TEG) was used to draw curves to calculate platelet, coagulation and fibrinolysis functions, and drug inhibition rate. Patients were divided into the aspirin resistance (AR) group, clopidogrel resistance (CR) group, dual-antiplatelet drug resistance (DAR) group, and drug-sensitive group according to different inhibition rates. The drug efficacy was analyzed, and the clinical data, biochemical indexes, and TEG parameters of each group were compared to identify the risk factors of drug resistance. Results. Those 118 CHD patients at high altitude were incorporated into the study, ranging from 38 to 84 years of age, including 81 males (68.64%) and 37 females (31.36%). The platelet function and coagulation-fibrinolysis function were detected by TEG, and MATHROMBI, MAADP, and MAAA were higher than the reference range. There were 82 cases (69.49%) of drug resistance, 36 cases (32.53%) of drug sensitivity, 17 cases (14.41%) of AR alone, and 16 cases (12.71%) of CR alone. There was no significant difference in age, gender, BMI, oxygen saturation, TG, GFR, and history of diabetes and hypertension between ACS and CCS groups ( P > 0.05 ). PLT and FIB in the ACS group were higher than those in the CCS group, and the difference was statistically significant ( P < 0.05 ). In addition, MATHROMBIN, MAFIBRIN, E, A, A30, and coagulation composite index were also higher than those in the CCS group, with a statistically significant difference ( P < 0.05 ). Univariate analysis and logistic regression analysis suggested that age, HbA1c, FBG, and diabetes were the main factors of drug resistance. Conclusion. Antiplatelet drugs aspirin and clopidogrel resistance are associated with increased age, elevated HbA1c and FBG, and diabetes. Therefore, it is necessary to take reasonable treatment measures based on the actual situation of patients.

Influence of Genetic Polymorphisms in P2Y12 Receptor Signaling Pathway on Antiplatelet Response to Clopidogrel in Coronary Heart Disease

Backgrounds: Remarkable interindividual variability in clopidogrel response is observed, genetic polymorphisms in P2RY12 and its signal pathway is supposed to affect clopidogrel response in CHD patients. Methods: 539 CHD patients treated with clopidogrel were recruited. The platelet reaction index (PRI) indicated by VASP-P level were detected in 12-24h after clopidogrel loading dose (LD) or within 5-7 days after initiation of maintain dose (MD) clopidogrel. A total of 13 SNPs in relevant genes were genotyped in sample A (239 CHD patients). The SNPs which have significant differences in PRI will be validated in another sample (sample B, 300 CHD patients). Results: CYP2C19*2 increased the risk of clopidogrel resistance significantly. When CYP2C19*2 and CYP2C19*3 were considered, CYP2C19 loss of function (LOF) alleles were associated with more obviously increased the risk of clopidogrel resistance; P2RY12 rs6809699 C>A polymorphism was also associated with increased risk of clopidogrel resistance (AA vs CC: P=0.0398). This difference still existed after stratification by CYP2C19 genotypes. It was also validated in sample B. The association was also still significant even in the case of stratification by CYP2C19 genotypes in all patients (sample A+B). Conclusion: Our data suggest that P2RY12 rs6809699 is associated with clopidogrel resistance in CHD patients. Meanwhile, the rs6809699 AA genotype can increase on-treatment platelet activity independent of CYP2C19 LOF polymorphisms.

The Dynamic Effect of Non-CYP3A4-Metabolized and CYP3A4-Metabolized Statins on Clopidogrel Resistance in Patients With Cerebral Infarction

Objective: To explore the treatment effect of statins used together with clopidogrel on cerebral infarction (CI).Methods: One hundred and thirty non-clopidogrel resistant patients were divided into a dynamic clopidogrel resistant (DCR) group and a continuous Non clopidogrel resistance (NCR) group. Patients were randomly assigned to AC group (atorvastatin 40 mg/d + clopidogrel, 51 patients) and RC group (rosuvastatin 20 mg/d + clopidogrel, 47 patients). The patient’s platelet aggregation rate (PAR) was measured on visit 0 (baseline), visit 1 (1 week after clopidogrel alone treatment), and visits 2 to 4 (one, three, and 6 months after clopidogrel plus statins treatment). The platelet reactivity index (PRI) was assessed on visits 0, 2, and 4, and clopidogrel thiol metabolite (H4) levels was measured on visits 2 and 4. DNA sequencing was used to determine CYP3A4, CYP2C9, and CYP2C19 genotypes in all patients.Results: PAR, PRI, and H4 levels, DCR ratio, and the genotype frequencies of CYP2C9*3εC, CYP2C19*2εA, and CYP2C19*3εA of both groups were similar (p &gt; 0.05). CYP2C19εA *2 and *3 were independent risk factors for DCR (p &lt; 0.05).Conclusion: Clopidogrel combined with atorvastatin does not affect platelet inhibition and does not increase the incidence of DCR. The incidence of DCR in the Chinese population is high and is related to CYP2C19εA.

Platelet miR-107 Participates in Clopidogrel Resistance after PCI Treatment by Regulating P2Y12

<b><i>Introduction:</i></b> High platelet reactivity (HPR) caused by clopidogrel tolerance is an adverse reaction of acute coronary syndrome (ACS) patients who receive clopidogrel antiplatelet therapy after percutaneous coronary intervention (PCI) surgery. Platelet microRNA (miRNA) is related to platelet reactivity. This study explored the mechanism of platelet miRNA in regulating platelet reactivity. <b><i>Methods:</i></b> We recruited 50 ACS/PCI patients and divided them into the HPR group (P2Y12 reaction units [PRU] ≥300) and the LPR group (PRU &#x3c; 170) according to the PRU through the VerifyNow P2Y12 assay. P2Y12-related miRNAs were screened by TargetScan, miRWalk, and Gene Expression Omnibus. The expressions of P2Y12 and miRNAs in the HPR group and the LPR group were determined by quantitative reverse transcription polymerase chain reaction (qRT-PCR). Pearson correlation analysis was used to determine the correlation between P2Y12 and miRNAs. The interactions between P2Y12 and miR-107 were predicted by TargetScan and verified by dual-luciferase reporter assay. The regulation of miR-107 mimic or inhibitor on P2Y12 expression was detected by qRT-PCR and Western blot. <b><i>Results:</i></b> There were 22 patients in the LPR group and 28 patients in the HPR group. PY212 was highly expressed in the HPR group compared with the LPR group. We screened the P2Y12-related miRNAs (miR-145-5p, miR-4701-3p, miR-107, and miR-15b-5p), but only miR-107 and miR-15b-5p expressions were downregulated in the HPR group and were negatively correlated with PY212 expression. P2Y12 was the target gene of miR-107. PY212 expression was inhibited by miR-107 overexpression but suppressed by miR-107 silencing. <b><i>Conclusion:</i></b> Platelet miR-107 participated in clopidogrel resistance in ACS/PCI patients by regulating P2Y12 expression.

Clopidogrel Resistance in Patients With Stroke Recurrence Under Single or Dual Antiplatelet Treatment

Background: The factors associated with clopidogrel resistance in patients with stroke recurrence receiving single or dual antiplatelet treatment (SAPT or DAPT) may differ. This study compared the high on-treatment platelet reactivities (HPRs) and the factors associated with clopidogrel resistance in recurrent ischemic stroke patients receiving clopidogrel or aspirin and clopidogrel.Methods: We enrolled and allocated 275 recurrent ischemic stroke patients to the clopidogrel and DAPT groups and compared their demographics, conventional risk factors, and P2Y12 reaction units (PRUs). Clopidogrel resistance was categorized as PRU higher than 275. We performed a multivariate logistic regression analysis to determine the factors underlying clopidogrel resistance during SAPT and DAPT.Results: In total, 145 (52.7%) and 130 (47.3%) patients received clopidogrel and DAPT, respectively at recurrence. The risk factors of the two groups were not significantly different, except that coronary artery disease was more frequent in the DAPT group. The PRU was higher (255 ± 91 vs. 221 ± 84; p = 0.002) and clopidogrel resistance was more frequent (45.5 vs. 31.5%; p = 0.018) in the SAPT than in the DAPT group. Hyperlipidemia was associated with clopidogrel resistance during SAPT, and smoking (Odds ratio = 0.426, 95% confidence interval 0.210–0.861; p = 0.018) had a protective effect against clopidogrel resistance. For those receiving DAPT, old age, female, low hemoglobin A1c level, and high ARU were associated with clopidogrel resistance.Conclusions: HPR and clopidogrel resistance were more frequent in recurrent ischemic stroke patients receiving clopidogrel than in those receiving DAPT. Smoking was independently associated with less clopidogrel resistance among those receiving clopidogrel SAPT but not in those receiving DAPT.