Background: Antiplatelet resistance is one factor that contributes to stroke recurrence among patients with noncardioembolic ischemic strokes. Objectives: This paper aims to describe the prevalence of aspirin and clopidogrel resistance, along with frequency of statin, NSAID and proton pump inhibitor use among our cohort of stroke patients. Method. This is a single-center cross-sectional review that included all adult patients with recurrent noncardioembolic ischemic stroke admitted in a tertiary hospital between January 2019 and June 2023. Results: A total of 1,374 patients were admitted for ischemic stroke from January 2019 to June 2023. Among these, 155 (11.28%) were recurrent noncardioembolic ischemic strokes. Prevalence of aspirin and clopidogrel resistance were 25% and 32.7%, respectively. Clinical profiles of those in the resistant group were comparable with those in the nonresistant group. None of the patients taking aspirin had concomitant use of nonsteroidal antiinflammatory drugs. Only 2 of the patients who were resistant to clopidogrel were on proton pump inhibitors. More than half of the patients both in the resistant and the nonresistant groups were on statin. The study had a small sample size and hence it was not enough to establish causal relationship between factors and antiplatelet resistance. Conclusion More patients were resistant to clopidogrel than to aspirin. Further studies with a bigger sample size are recommended to explore factors that contribute to antiplatelet resistance in Filipino patients.
Aspirin ; Clopidogrel ; Ischemic Stroke ; Tertiary Care Centers

INTRODUCTION

While a 600 mg loading dose (LD) of clopidogrel has demonstrated superior inhibition of platelet function compared to 300 mg LD, the clinical evidence supporting this superiority is limited. The debate centers on whether higher clopidogrel LD regimen in percutaneous coronary intervention (PCI) outperforms the standard 300 mg LD, with potential benefits being more pronounced in higher-risk patients. Balancing enhanced platelet inhibition to reduce ischemic events against the associated risk of increased bleeding remains a critical consideration in determining the optimal loading dose of clopidogrel for patients with ischemic heart disease.

A systematic literature search for randomized clinical trials (RCTs) was performed comparing 600 mg with 300 mg LD of clopidogrel using PubMed, MEDLINE, Embase, Cochrane, Clinicaltrials.gov and HerdinPH. Studies included those between 2010 and 2023 involving human subjects. The primary efficacy endpoint was a 1-month rate of major adverse cardiac event (MACE) and the primary safety outcome was bleeding adverse effects.

Nine RCTs involving 29,827 patients were included in the efficacy analysis. Mean duration of follow-up was 30 days. Only eight studies were eligible for safety analysis. Compared with standard LD clopidogrel, high LD significantly reduced the incidence of overall MACE (OR: 0.82, 95% CI: 0.74-0.91, p = 0.0002), nonfatal myocardial infarction (OR: 0.56; 95% CI: 0.32-0.99, p = 0.15) and target vessel revascularization (OR: 0.63; 95% CI: 0.41-0.95, p = 0.03), without significant difference in terms of cardiac death (OR: 0.89; 95% CI: 0.76-1.04, p = 0.15) and stroke (OR: 0.92; 95% CI: 0.67-1.26, p = 0.61). However, major bleeding risk was higher in the 600 mg LD (1.9%; 261/13288) compared with 300 mg LD (2.4%; 328/13242) [OR: 1.27; 95% CI: 1.08-1.49, p = 0.005] without significant difference in minor bleeding (OR: 1.05; 95% CI: 0.94-1.17, p = 0.35).

The administration of 600 mg clopidogrel LD reduces the overall risk of MACE with associated increased risk of major bleeding.

Clopidogrel is the cornerstone of antiplatelet therapy, but there are ethnic and individual differences in the suppression of platelets. Some patients regularly taking drugs still cannot prevent the recurrence of cardio- and cerebrovascular thrombosis, thereby manifest low drug reactivity, i.e., clopidogrel resistance. Genetic polymorphism is the main reason for individual difference. Genetic testing has been used for evaluating the efficacy of antiplatelet therapy, adjusting therapeutic plan, and predicting the risk of cardio- and cerebrovascular thromboembolic events by determining the genetic polymorphisms related with antiplatelet drugs. This article provides a review for the status quo and countermeasure of clopidogrel resistance predicted by gene testing.
Blood Platelets ; Clopidogrel ; Drug Resistance ; Genetic Testing ; Humans ; Platelet Aggregation Inhibitors ; Ticlopidine

This article reviews the available published data on optimizing clopidogrel and aspirin therapy using translational and integrative medicine. Translational and evidence-based medical studies show that the CYP2C19 gene mutation (CYP2C19*2 and CYP2C19*3) could affect > 50% of the Chinese population, and that this mutation is closely associated with clopidogrel resistance and an increased risk of major adverse cardiovascular events, particularly stent thrombosis in patients following percutaneous coronary intervention (PCI). Adjusted-dose warfarin and aspirin reduce stroke in patients with atrial fibrillation (AF), and warfarin is substantially more efficacious than aspirin. However, a poor compliance is a big problem in warfarin use especially in China. The genetic variants of vitamin K expoxide reductase might account for the universally lower warfarin dosage used in Chinese population. The available evidence indicates that the integrating mainstream treatments (e.g., clopidogrel, CYP2C19 genotyping) and non-mainstream medicines [e.g., Chinese medicines, Naoxintong Capsule (, NXT)] to treat CYP2C19 gene mutation patients following PCI can be effective. Aspirin combined NXT and the adjusted-dose warfarin was equally effective in elderly patients with non-valvular AF in prevention of ischemic stroke.
Aspirin ; therapeutic use ; Clopidogrel ; therapeutic use ; Humans ; Integrative Medicine ; Translational Medical Research

Objective To explore the risk factors of clopidogrel resistance (CR) in the elderly patients with atherosclerotic cardiovascular disease and to provide evidence for the antiplatelet therapy. Methods A total of 223 elderly patients (≥80 years old) with atherosclerotic cardiovascular disease treated in the Department of Geriatrics in the Peking University People's Hospital from January 18,2013 to November 30,2019 and meeting the inclusion criteria were enrolled in this study.The clinical data and laboratory test results were collected,including clinical disease,drug use,physical examination,complete blood cell analysis,biochemical indicators,and thromboelastogram (TEG).The rate of platelet inhibition induced by adenosine diphosphate was calculated according to the TEG.We assigned the patients into a CR group (n=84) and a control group (n=139) to analyze the incidence and influence factors of CR in the elderly patients with atherosclerotic cardiovascular disease. Results The incidence of CR was 37.7% in the elderly patients with atherosclerotic cardiovascular disease.The CR group had lower hemoglobin (t=3.533,P=0.001) and higher hypertension prevalence rate (χ²=6.581,P=0.006),proportion of multiple drugs (χ²=3.332,P=0.048),body mass index (BMI) (t=-2.181,P=0.030),total cholesterol (t=-2.264,P=0.025),triglycerides (Z=-2.937,P=0.003),low-density lipoprotein cholesterol (LDL-C) (t=-2.347,P=0.020),and proportion of women (χ²=5.562,P=0.014) than the control group.The results of multivariate Logistic regression showed that hemoglobin (OR=0.962,P<0.001),BMI (OR=1.154,P=0.003),and LDL-C (OR=1.688,P=0.018) were the factors influencing CR in the elderly patients with atherosclerotic cardiovascular disease. Conclusion Hemoglobin,BMI,and LDL-C may be independent factors associated with the occurrence of CR in the elderly patients with atherosclerotic cardiovascular disease.
Aged ; Aged, 80 and over ; Female ; Humans ; Atherosclerosis ; Cardiovascular Diseases ; Cholesterol, LDL ; Clopidogrel/therapeutic use* ; Risk Factors

To explore differential expression of long non-coding RNA (lncRNA) in patients with coronary artery disease plus clopidogrel resistance.
 Methods: Patients underwent percutaneous coronary intervention (PCI) and treated with clopidogrel were recruited, and their clinical data and blood samples were collected. Patients were divided into a clopidogrel sensitive group and a clopidogrel resistance group according to platelet aggregation rate. lncRNA microarray and real-time RT-PCR were performed in 5 and 34 patients in each group, respectively.
 Results: lncRNA microarray showed that 11 lncRNAs in peripheral leukocytes were up-regulated and 8 lncRNAs were down-regulated in clopidogrel resistant group. Real-time PCR indicated that two lncRNAs (NONHSAT083775.2 and NONHSAT107804.2) in leukocytes were up-regulated and one lncRNA (NONHSAT133455.2) was down-regulated in the clopidogrel resistant group compared with the clopidogrel sensitive group, consistent with the results of lncRNA microarray.
 Conclusion: Clopidogrel resistance is associated with the up-regulation of lncRNA NONHSAT083775.2 and NONHSAT107804.2 and the down-regulation of NONHSAT133455.2.
Clopidogrel ; Coronary Artery Disease ; genetics ; Humans ; Percutaneous Coronary Intervention ; Platelet Aggregation ; Platelet Aggregation Inhibitors ; RNA, Long Noncoding

OBJECTIVE: To study the clinical effect and safety of clopidogrel combined with aspirin in antithrombotic therapy for children with Kawasaki disease (KD) complicated by coronary artery aneurysm (CAA). METHODS: A total of 77 KD children who were diagnosed with multiple small/medium-sized CAAs by echocardiography between January 2013 and June 2018 were enrolled. They were randomly divided into observation group with 38 children (treated with clopidogrel and aspirin) and control group with 39 children (treated with low-molecular-weight heparin and aspirin). All children were followed up regularly, and the first 3 months of the course of the disease was the observation period. The children were observed in terms of the change of the coronary artery and the incidence of complications. RESULTS: At month 3 of follow-up, among the children in the observation group, 6 had normal coronary artery, 11 had coronary artery retraction, 19 had stable coronary artery, and 2 progressed to giant coronary aneurysm; among the children in the control group, 7 had normal coronary artery, 12 had coronary artery retraction, 19 had stable coronary artery, and 1 progressed to giant coronary aneurysm; there was no significant difference in the change of the coronary artery between the two groups (P>0.05). There were 2 cases of epistaxis and 6 cases of skin ecchymosis in the observation group, and 1 case of epistaxis and 7 cases of petechiae and ecchymosis at the injection site in the control group, and no other serious bleeding events were observed in either group. CONCLUSIONS Clopidogrel combined with low-dose aspirin is safe and effective in antithrombotic therapy for children with KD complicated by CAA.
Aspirin ; therapeutic use ; Child ; Clopidogrel ; Coronary Aneurysm ; drug therapy ; etiology ; Coronary Vessels ; Fibrinolytic Agents ; Humans ; Mucocutaneous Lymph Node Syndrome ; complications

BACKGROUND: Geriatric hip fracture patients receiving clopidogrel are a surgical challenge. In China, most of these patients undergo delayed surgical treatment after clopidogrel withdrawal for at least 5 to 7 days. However, delayed surgery is associated with increased complications and mortality in the older adults. This retrospective paralleled comparison study investigated the safety of early surgery for geriatric hip fracture patients within 5 days of clopidogrel withdrawal. METHODS: Acute hip fracture patients (≥65 years) who were hospitalized in the orthogeriatric co-management ward of Beijing Jishuitan Hospital between November 2016 and April 2018 were retrospectively reviewed. Sixty patients taking clopidogrel before injury and discontinued <5 days before surgery constituted the clopidogrel group. The control group constituted 60 patients not taking antiplatelet or anticoagulant drugs and matched 1:1 with the clopidogrel group for sex, fracture type, operative procedure, and time from injury to operation (±10 h). The primary outcome was perioperative blood loss and the secondary outcomes were transfusion requirement, complications, and mortality. The Student's t test or Wilcoxon signed rank sum test was used for continuous variables and the Chi-square test was used for categorical variables. RESULTS: Age, body mass index, American Society of Anesthesiologists score, and percentage undergoing general anesthesia were comparable between the groups (P > 0.050). The percentages of patients with coronary heart disease (61.7% vs. 18.3%; P < 0.001) and cerebrovascular disease (45.0% vs. 15.0%; P < 0.010) were significantly higher in the clopidogrel vs. control groups, respectively. The median clopidogrel discontinuation time before operation was 73.0 (range: 3.0-120.0) h. There was no significant difference in the estimated perioperative blood loss between the clopidogrel group (median: 745 mL) and control group (median: 772 mL) (P = 0.866). The intra-operative transfusion rate was higher in the clopidogrel group (22/60, 36.7%) than that in the control group (12/60, 20.0%) (P < 0.050). However, there was no significant difference in the blood transfusion rate during the entire perioperative period (26/60, 43.3% vs. 20/60, 33.3%; clopidogrel group vs. control group, respectively; P > 0.050). There was no significant difference in perioperative complications, and 30-day and 1-year mortality rates between the groups. CONCLUSIONS Early hip fracture surgery is safe for elderly patients within 5 days of clopidogrel withdrawal, without increased perioperative blood loss, transfusion requirement, complications, and mortality compared with patients not taking antiplatelet drugs.
Aged ; Case-Control Studies ; Clopidogrel/therapeutic use* ; Hip Fractures/surgery* ; Humans ; Platelet Aggregation Inhibitors/adverse effects* ; Retrospective Studies ; Ticlopidine/adverse effects*

In this study, we reported a young male patient with acute chest pain who was diagnosed as myocardial infarction. The regular medication was performed following coronary intervention. Under such condition, this patient had 3 times myocardial infarction within a half month. The laboratory results showed that there might be a state of hypercoagulability. Aspirin combined with clopidogrel and other treatment were administrated. Meanwhile, the examination demonstrated that there was aspirin-resistant in the patient. The antiplatelet drug and extended anticoagulation therapy were carried out. There was no further myocardial infarction, and no coronary arteries stenosis was found in the re-examination angiography. Aspirin resistance and hypercoagulability should be considered when patients occurred the repeated myocardial infarction after regular medication and coronary intervention. Replacement of the antiplatelet treatment or combination with anticoagulant therapy is necessary in similar patient to avoid the sever consequence.
Aspirin/therapeutic use* ; Clopidogrel/therapeutic use* ; Drug Therapy, Combination ; Humans ; Male ; Myocardial Infarction/drug therapy* ; Percutaneous Coronary Intervention ; Platelet Aggregation Inhibitors/therapeutic use* ; Thrombophilia/drug therapy* ; Treatment Outcome

Objective: To investigate the effects of clopidogrel resistence and CYP2C19 genotype on the clinical prognosis of acute coronary syndrome(ACS) patients undergoing percutaneous coronary intervention(PCI). Methods: This study was a retrospective cohort study. ACS patients who underwent PCI in Beijing Anzhen Hospital from October 2015 to January 2017 were recruited. The inhibition rate of adenosine diphosphate(ADP) was monitored by thromboelastography. All of these patients were divided into clopidogrel resistance and non-resistance group according to the monitoring results. CYP2C19 genotype was detected by TaqMan probe-based real-time quantitative PCR. Patients were divided into slow, medium and fast metabolic group, according to the CYP2C19 genotype. After 12 months of follow-up, the end points included all-cause death, cardiac death, angina, myocardial infarction, stent thrombosis, ischemic stroke and hemorrhage were collected. Combined thrombotic events were defined as a composite of angina, myocardial infarction, stent thrombosis and ischemic stroke. The differences of the incidence of clinical events between groups were compared. Cox regression was used to analyze the effects of clopidogrel resistance and CYP2C19 genotype on the combined thrombotic events, cardiac death and hemorrhage. Results: A total of 1 696 patients were included, and the age was (59.4±9.6) years, with 1 280(75.5%) males. There were 471 cases(27.8%) in clopidogrel resistance group, and 1 225 cases(72.2%) in clopidogrel non-resistance group. There were 218 patients(12.9%) were in slow metabolic group, 668(39.4%) in medium metabolic group, and 810 (47.8%) in fast metabolic group. The median follow-up time was 13.3 months, and 131 cases were lost to follow-up, with a loss follow-up rate of 7.7%. Compared with the clopidogrel non-resistance group, the clopidogrel resistance group had a higher incidence of myocardial infarction(7.6%(36/471) vs. 5.1%(62/1 225), P=0.041), a lower incidence of hemorrhage (13.2%(62/471) vs. 17.9%(219/1 225), P=0.020) and minor hemorrhage(11.5%(54/471) vs. 15.8% (194/1 225), P=0.022). There were no statistically significant difference in all-cause death, cardiac death, angina, stent thrombosis, ischemic stroke and severe bleeding between clopidogrel resistance and non-resistance group(all P>0.05). There was no statistically significant difference in the incidence of endpoint events among different CYP2C19 genotypes (all P>0.05). Cox regression analysis showed that clopidogrel resistance was an independent factor of combined thrombotic events (OR=2.334, 95%CI 1.215-4.443, P=0.016) and bleeding events (OR=0.481, 95%CI 0.174-0.901, P=0.023). While CYP2C19 genotype was not independent factor for combined thrombotic events, cardiac death and hemorrhage (all P>0.05). Conclusion: For ACS patients after PCI, clopidogrel resistance can increase the risk of combined thrombotic events, but also reduce the risk of bleeding; while CYP2C19 genotype is not an independent factor for clinical prognosis.
Acute Coronary Syndrome/genetics* ; Clopidogrel/therapeutic use* ; Cytochrome P-450 CYP2C19/genetics* ; Genotype ; Humans ; Male ; Percutaneous Coronary Intervention ; Platelet Aggregation Inhibitors/therapeutic use* ; Prognosis ; Retrospective Studies ; Treatment Outcome