Cost analysis of CYP2C19 genetic testing in percutaneous coronary intervention patients.

CYP2C19 loss of function (LOF) carriers undergoing percutaneous coronary intervention (PCI) have an increased risk of ischemic events when treated with clopidogrel. PCI patients in TAILOR-PCI were randomized to clopidogrel or genotype-guided (GG) therapy in which LOF carriers received ticagrelor and non-carriers clopidogrel. Direct medical costs associated with a GG approach have not been described before. TAILOR-PCI participants for whom direct medical costs were available for the duration from the date of PCI to one-year post PCI were included. Primary cost estimates were obtained from the Mayo Clinic Cost Data Warehouse. There were no differences in direct medical costs between the GG and clopidogrel groups (mean $20,682 versus $19,747, p = 0.11) however total costs were greater in the GG group (mean $21,245 versus $19,891, p = 0.02) which was primarily driven by ticagrelor costs. In conclusion the increased expense of a GG strategy post PCI as compared to clopidogrel for all is primarily driven by the cost of ticagrelor.

Elevated High-Sensitivity C-Reactive Protein Level Enhances the Impact of Lipoprotein(a) on Platelet Reactivity in PCI Patients Treated with Clopidogrel.

BACKGROUND: Recently, the effect of Lipoprotein(a) [Lp(a)] on thrombogenesis has aroused great interest, while inflammation has been reported to modify the Lp(a)-associated risks through an unidentified mechanism. PURPOSE: This study aimed to evaluate the association between platelet reactivity with Lp(a) and high-sensitivity C-reactive protein (hs-CRP) levels in percutaneous intervention (PCI) patients treated with clopidogrel. METHODS: Data were collected from 10,724 consecutive PCI patients throughout the year 2013 in Fuwai Hospital. High on-treatment platelet reactivity (HTPR) and low on-treatment platelet reactivity (LTPR) were defined as thrombelastography (TEG) maximum amplitude of adenosine diphosphate-induced platelet (MAADP) > 47 mm and < 31 mm, respectively. RESULTS: 6615 patients with TEG results were finally enrolled. The mean age was 58.24 ± 10.28 years and 5131 (77.6%) were male. Multivariable logistic regression showed that taking Lp(a) < 30 mg/dL and hs-CRP < 2 mg/L as the reference, isolated Lp(a) elevation [Lp(a) ≥ 30 mg/dL and hs-CRP < 2 mg/L] was not significantly associated with HTPR (P = 0.153) or LTPR (P = 0.312). However, the joint elevation of Lp(a) and hs-CRP [Lp(a) ≥ 30 mg/dL and hs-CRP ≥ 2 mg/L] exhibited enhanced association with both HTPR (OR:1.976, 95% CI 1.677-2.329) and LTPR (OR:0.533, 95% CI 0.454-0.627). CONCLUSIONS: The isolated elevation of Lp(a) level was not an independent indicator for platelet reactivity, yet the concomitant elevation of Lp(a) and hs-CRP levels was significantly associated with increased platelet reactivity. Whether intensified antiplatelet therapy or anti-inflammatory strategies could mitigate the risks in patients presenting combined Lp(a) and hs-CRP elevation requires future investigation.

The polygenic implication of clopidogrel responsiveness: Insights from platelet reactivity analysis and next-generation sequencing.

Clopidogrel is widely used worldwide as an antiplatelet therapy in patients with acute coronary disease. Genetic factors influence interindividual variability in response. Some studies have explored the polygenic contributions in the drug response, generating pharmacogenomic risk scores (PgxPRS). Importantly, these factors are less explored in underrepresented populations, such as Latin-American countries. Identifying patients at risk of high-on-treatment platelet reactivity (HTPR) is highly valuable in translational medicine. In this study we used a custom next-generation sequencing (NGS) panel composed of 91 single nucleotide polymorphisms (SNPs) and 28 genes related to clopidogrel metabolism, to analyze 70 patients with platelet reactivity values, assessed through closure time (CT). Our results demonstrated the association of SNPs with HTPR and non-HTPR, revealing the strongest associations with rs2286823 (OR: 5,0; 95% CI: 1,02-24,48; p: 0,03), rs2032582 (OR: 4,41; 95% CI: 1,20-16,12; p: 0,019), and rs1045642 (OR: 3,38; 95% CI: 0,96-11,9; p: 0,05). Bivariate regression analysis demonstrated the significant association of several SNPs with the CT value, a "surrogate" biomarker of clopidogrel response. Exploratory results from the LASSO regression model showed a high discriminatory capacity between HTPR and non-HTPR patients (AUC: 0,955), and the generated PgxPRS demonstrated a significant negative association between the risk score, CT value, and the condition of HTPR and non-HTPR. To our knowledge, our study addresses for the first time the analysis of the polygenic contribution in platelet reactivity using NGS and establishes PgxPRS derived from the LASSO model. Our results demonstrate the polygenic implication of clopidogrel response and offer insights applicable to the translational medicine of antiplatelet therapy in an understudied population.

The effects of CYP2B6 inactivators on the metabolism of ciprofol.

Ciprofol is a novel short-acting intravenous anaesthetic developed in China that is mainly metabolized by cytochrome P450 2B6 (CYP2B6) and uridine diphosphate glucuronosyltransferase 1A9 (UGT1A9). Currently, insufficient evidence is available to support drug‒drug interactions between ciprofol and CYP2B6 inactivators. Here, we established a high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method to assess the concentration of ciprofol and investigated the effects of psoralen and clopidogrel on the metabolism of ciprofol in liver microsomes and rats. In rat and human liver microsomes, the median inhibitory concentration (IC50) values of psoralen were 63.31 µmol·L-1 and 34.05 µmol·L-1, respectively, showing mild inhibitory effects on ciprofol metabolism, whereas the IC50 values of clopidogrel were 6.380 µmol·L-1 and 2.565 µmol·L-1, respectively, with moderate inhibitory effects. SD rats were randomly divided into three groups: psoralen (27 mg·kg-1), clopidogrel (7.5 mg·kg-1), and the same volume of 0.5% carboxy methyl cellulose. After 7 days, all rats were injected with 2.4 mg·kg-1 ciprofol. Compared with the control group, the AUC and MRT values of ciprofol in the psoralen and clopidogrel groups were significantly greater, whereas the CL values were significantly lower. In addition, the durations of loss of righting reflex (LORR) in the psoralen and clopidogrel groups were 16.1% and 23.0% longer than that in the control group, respectively. In conclusion, psoralen and clopidogrel inhibit ciprofol metabolism to different degrees and prolong the duration of LORR in rats.

Ticlopidine protects hepatic ischemia-reperfusion injury via suppressing ferroptosis.

Hepatic ischemia-reperfusion injury (IRI) is a major cause of liver damage during hepatic resection, transplantation, and other surgical procedures, often leading to graft failure and liver dysfunction. Recent studies have identified ferroptosis, a form of regulated cell death characterized by iron-dependent lipid peroxidation, as a key contributor to IRI. In this study, we investigated the protective effects of Ticlopidine, a thienopyridine compound and platelet aggregation inhibitor, on hepatic IRI. Using a C57BL/6J mouse model, we demonstrated that prophylactic Ticlopidine treatment significantly reduced necrotic and fibrotic areas in liver tissues, as well as serum levels of alanine transaminase (ALT) and aspartate aminotransferase (AST). Prussian Blue staining revealed that Ticlopidine pretreatment decreased iron accumulation in hepatic tissues, whereas markers of lipid peroxidation (malondialdehyde and 4-hydroxynonenal) and ferroptosis (PTGS2) were significantly downregulated. Additionally, Ticlopidine ameliorated inflammatory infiltration as indicated by reduced Gr-1 staining. In vitro, Ticlopidine dose-dependently inhibited ferroptosis induced by various inducers in liver cancer cell lines HUH7 and fibrosarcoma cells HT1080. The protective effects involved partial rescue of lipid peroxidation, significant reduction of ferrous iron levels, and strong protection against mitochondrial damage. These findings suggested that Ticlopidine acts as a broad-spectrum ferroptosis inhibitor, offering a promising therapeutic approach for protecting the liver against IRI.

Effect of Preoperative Clopidogrel on Outcomes of Isolated Coronary Artery Bypass Graft: An STS National Database Analysis.

BACKGROUND: We analyzed The Society of Thoracic Surgeons Database to investigate risks and optimal timing for coronary artery bypass grafting (CABG) after clopidogrel administration. METHODS: Patients were categorized based on clopidogrel use within 5 days and further stratified by days from the last dose (0 to 5 days). Controls were patients who did not receive clopidogrel within 5 days of surgery. The primary outcome was operative mortality, and secondary outcomes included mediastinal reexploration for bleeding and blood product use. RESULTS: Among 148,317 isolated CABG, 19,553 patients (13.2%) received clopidogrel within 5 days. Minimal differences in operative mortality (2.8% vs 2.1%, P < .001), but higher rates of mediastinal reexploration (3.5% vs 2.1%, P < .001) and blood product utilization (72.7% vs 56.8%, P < .001) were observed in the clopidogrel group. The adjusted odds ratio of operative mortality peaked on the day of clopidogrel administration but was comparable to controls thereafter. The odds of reexploration were highest on day 0, decreasing gradually to a plateau after day 3. Patients who underwent operations on day 3 after clopidogrel administration had similar odds of operative mortality and mediastinal reexploration for bleeding and shorter total and preoperative lengths of stay but higher blood product use compared with day 5. CONCLUSIONS: CABG within 5 days from clopidogrel is associated with a modest increase in operative mortality and reexploration for bleeding and a substantial increase in blood product use. Risks decreased with increasing time from discontinuation, plateauing after 3 days from clopidogrel. CABG at 3 days yields comparable outcomes as 5 days, reducing the waiting period.

Analysis of the effect of CYP2C19 gene properties on the anti-platelet aggregation of clopidogrel after carotid artery stenting under network pharmacology.

Antiplatelet therapy is an important factor influencing the postterm patency rate of carotid artery stenting (CAS). Clopidogrel is a platelet aggregation inhibitor mediated by the adenosine diphosphate receptor and is affected by CYP2C19 gene polymorphisms in vivo. When the CYP2C19 gene has a nonfunctional mutation, the activity of the encoded enzyme will be weakened or lost, which directly affects the metabolism of clopidogrel and ultimately weakens its antiplatelet aggregation ability. Therefore, based on network pharmacology, analyzing the influence of CYP2C19 gene polymorphisms on the antiplatelet therapeutic effect of clopidogrel after CAS is highly important for the formulation of individualized clinical drug regimens. The effect of the CYP2C19 gene polymorphism on the antiplatelet aggregation of clopidogrel after CAS was analyzed based on network pharmacology. A total of 100 patients with ischemic cerebrovascular disease who were confirmed by the neurology department and required CAS treatment were studied. CYP2C19 genotyping was performed on all patients via a gene chip. All patients were classified into the wild-type (WT) group (*1/*1), heterozygous mutation (HTM) group (CYP2C19*1/*2, CYP2C19*1/*3), and homozygous mutation (HMM) group (CYP2C19*2/*2, CYP2C19*2/*3, and CYP2C19*3/*3). High-performance liquid chromatography (HPLC) with tandem mass spectrometry (MS/MS) was used to detect the blood concentration of clopidogrel and the plasma clopidogrel clearance (CL) rate in different groups of patients before and after clopidogrel treatment. The platelet aggregation rate of patients with different genotypes was measured by turbidimetry. The incidences of clopidogrel resistance (CR) and stent thrombosis in different groups after three months of treatment were analyzed. The results showed that among the different CYP2C19 genotypes, patients from the HTM group accounted for the most patients, while patients from the HTM group accounted for the least patients. Similarly, the clopidogrel CL of patients in the HMM group was lower than that of patients in the WT group and HTM group (P < 0.01). The platelet inhibition rate of patients in the HMM group was evidently inferior to that of patients in the WT group and HTM group (P < 0.01). The incidence of CR and stent thrombosis in the WT group was notably lower than that in the HTM and HMM groups (P < 0.01). These results indicate that the CYP2C19 gene can affect CR occurrence and stent thrombosis after CAS by influencing clopidogrel metabolism and platelet count.

How much protection does clopidogrel provide to cats with hypertrophic cardiomyopathy?

Cats with hypertrophic cardiomyopathy (HCM) have a risk of developing aortic thromboembolism (ATE). Clopidogrel reduces the risk of redeveloping ATE and delays recurrence of ATE in cats that have experienced an ATE episode. Consequently, cardiologists have recommended administering clopidogrel to cats as a primary preventative, suggesting that all cats with severe HCM be administered clopidogrel. However, clopidogrel is unpalatable in its manufactured format, making such administration problematic for many clients. Therefore, estimating the potential benefit of administration might help clinicians determine on a case-by-case basis the need to treat cats with clopidogrel. Relatively simple statistical analyses of currently available data, along with certain assumptions and extrapolations, allow such an estimation of benefit in terms of relative and absolute risk reduction conferred by clopidogrel. Using this approach, and provided certain assumptions are true, clopidogrel likely confers a reduction in risk of ATE in cats with moderate to severe HCM of approximately 3% to 4%. Given the difficulty of administering clopidogrel to cats, clinicians should weigh these relatively small potential benefits against the potential harms (difficulty of administration) and not necessarily insist that clients administer clopidogrel.

Is CYP2C Haplotype Relevant for Efficacy and Bleeding Risk in Clopidogrel-Treated Patients?

A recently discovered haplotype-CYP2C:TG-determines the ultrarapid metabolism of several CYP2C19 substrates. The platelet inhibitor clopidogrel requires CYP2C19-mediated activation: the risk of ischemic events is increased in patients with a poor (PM) or intermediate (IM) CYP2C19 metabolizer phenotype (vs. normal, NM; rapid, RM; or ultrarapid, UM). We investigated whether the CYP2C:TG haplotype affected efficacy/bleeding risk in clopidogrel-treated patients. Adults (n = 283) treated with clopidogrel over 3-6 months were classified by CYP2C19 phenotype based on the CYP2C19*2*17 genotype, and based on the CYP2C19/CYP2C cluster genotype, and regarding carriage of the CYP2:TG haplotype, and were balanced on a number of covariates across the levels of phenotypes/haplotype carriage. Overall, 45 (15.9%) patients experienced ischemic events, and 49 (17.3%) experienced bleedings. By either classification, the incidence of ischemic events was similarly numerically higher in PM/IM patients (21.6%, 21.8%, respectively) than in mutually similar NM, RM, and UM patients (13.2-14.8%), whereas the incidence of bleeding events was numerically lower (13.1% vs. 16.6-20.5%). The incidence of ischemic events was similar in CYP2C:TG carries and non-carries (14.1% vs. 16.1%), whereas the incidence of bleedings appeared mildly lower in the former (14.9% vs. 20.1%). We observed no signal to suggest a major effect of the CYP2C19/CYP2C cluster genotype or CYP2C:TG haplotype on the clinical efficacy/safety of clopidogrel.

Association of clopidogrel resistance and ABCD-GENE score with long-term clinical prognosis in patients with ischemic stroke or TIA.

BACKGROUND: Clopidogrel resistance (CR) is associated with adverse clinical outcomes in acute ischemic stroke or transient ischemic attack (TIA) patients. However, whether CR affects the long-term clinical prognosis remains to be clarified. The ABCD-GENE score is a novel risk model that identifies CR in cardiovascular disease patients; its diagnostic ability and application in ischemic stroke or TIA remain to be studied. This study aimed to investigate the diagnostic ability of the ABCD-GENE score for CR and analyze the relationship between CR and long-term clinical prognosis in patients with ischemic stroke or TIA. METHODS: From January 2018 to January 2021, 251 ischemic stroke or TIA patients who were treated with clopidogrel for more than three months after onset and maintained the medication until the follow-up time were enrolled, and platelet reactivity was detected by thromboelastography. CYP2C19 gene analysis was performed. Adverse clinical outcomes were recorded from 3months after onset. The median follow-up time was 878days. RESULTS: The prevalence of CR was 33.9%. The proportion of CYP2C19 loss-of-function carriers was 62.2%. The ABCD-GENE score≥10 was independently associated with CR (OR=1.82, 95% CI: 1.02-3.24, P=0.041), and the C-statistic value of the score (as a binary and integer variable) on CR was 0.58 and 0.63, respectively. The risk of long-term adverse clinical outcomes was not significantly different between CR and clopidogrel sensitive groups (12.94% vs. 11.44%, HR=1.22, 95% CI: 0.57-2.62, P=0.603). A similar result was observed between ABCD-GENE score≥10 and ABCD-GENE score<10 groups (10.38% vs. 12.64%, HR=1.19, 95% CI: 0.55-2.60, P=0.666). CONCLUSIONS: In ischemic stroke or TIA patients, the ABCD-GENE score could identify the risk of CR. CR was not associated with long-term adverse clinical outcomes.

Development and assessment of immediate-release tablets containing clopidogrel bisulphate & aspirin-strategy for optimizing the combination formulation.

The main goal of the study was to improve the compliance and convenience of patients by designing and development of an immediate release (IR) fixed-dose combination (Clopidogrel bisulphate and Aspirin) tablets. The proposed combination product utilizes Clopidogrel to protect the moisture-sensitive aspirin component, enhancing its stability against atmospheric conditions. Response-surface approach (Design Expert vs. 13) was used to generate this IR tablet by calculating the right composition of independent variables such as Microcrystalline cellulose 102, pregelatinized starch and Hydroxypropyl cellulose. 32 factorial design was used to estimate the effects of these independent variables on the responses of dependent variables (disintegration & friability) and constructed a total of nine (9) formulations. Pre and Post formulation, quality control parameters were investigated as per pharmacopeia. A systematic approach was used for the optimization process and a prototype checkpoint batch (CPB) based on the better contrast of independent variables was prepared. In vitro analysis of formulations was carried out to estimate the responses. Friability was found in the range of 0.088-1.076%w/w, except F1 = 1.076 all are within limits (NMT 1.0%). Disintegration time was recorded 7.3 ± 1.20 as lower and 24.5 ± 1.63 min was the highest. The release of drugs from their dosage form was fast and rapid, for clopidogrel after 15min was 70.42-96.82% with SD ± 8.71 and aspirin was 69.88-91.49% in 15 min with SD ± 6.41, all the tablets were released more than 80% in 20 min. The stability outcomes of CPB tablets after 15 days of stress study (60 ± 2°C and 75 ± 5%) indicated good compatibility and stability of APIs with excipients. It was concluded that the direct compression method can be preferred to prepare a combination product with cost-effectiveness. It was also concluded that the proposed methodology could increase Aspirin's stability and allow for an aqueous coating system to finish the product with a film coating. By using Design Expert software, the best composition of the formulation can be selected and optimized in a short period of time with minimum trial and errors. The results also demonstrated that the use of a fixed-dose combination tablet instead of the individual is expected to be more convenient to patients and thus improves patient compliance and decreases the occurrence of adverse effects and side effects.

Clopidogrel induced reduction in neutrophil count: An overlooked beneficial effect?

Complement-stimulated neutrophils are able to adhere to the endothelium and damage endothelial cells both in vitro and in vivo. These blood cells participate in the early stages, growth and complications of atherosclerotic plaques. Recent findings, based on mendelian randomization analysis, support the concept that high neutrophil counts are a causal risk factor for ischemic heart disease and myocardial infarction . Clopidogrel decreases leukocyte count and inflammatory markers in patients with acute coronary syndromes; this off-target effect, which is independent of the antiplatelet action, may help explaining secondary prevention data showing a superiority of clopidogrel over aspirin in reducing new cardiovascular events.

Ticagrelor downregulates the expression of proatherogenic and proinflammatory miR125-b compared to clopidogrel: A randomized, controlled trial.

BACKGROUND: Platelet P2Y12 antagonist ticagrelor reduces cardiovascular mortality after acute myocardial infarction (AMI) compared to clopidogrel, but the underlying mechanism is unknown. Because activated platelets release proatherogenic and proinflammatory microRNAs, including miR-125a, miR-125b and miR-223, we hypothesized that the expression of these miRNAs is lower on ticagrelor, compared to clopidogrel. OBJECTIVES: We compared miR-125a, miR-125b and miR-223 expression in plasma of patients after AMI treated with ticagrelor or clopidogrel. METHODS: After percutaneous coronary intervention on acetylsalicylic acid and clopidogrel, 60 patients with first AMI were randomized to switch to ticagrelor or to continue with clopidogrel. Plasma expression of miR-223, miR-125a-5p, miR-125b was measured using quantitative polymerase chain reaction at baseline and after 72 h and 6 months of treatment with ticagrelor or clopidogrel in patients and one in 30 healthy volunteers. Multiple electrode aggregometry using ADP test was used to determine platelet reactivity in response to P2Y12 inhibitors. RESULTS: Expression of miR-125b was higher in patients with AMI 72 h and 6 months, compared to healthy volunteers (p = 0.001), whereas expression of miR-125a-5p and miR-223 were comparable. In patients randomized to ticagrelor, expression of miR-125b decreased at 72 h (p = 0.007) and increased back to baseline at 6 months (p = 0.005). Expression of miR-125a-5p and miR-223 was not affected by the switch from clopidogrel to ticagrelor. CONCLUSIONS: Ticagrelor treatment leads to lower plasma expression of miR-125b after AMI, compared to clopidogrel. Higher expression of miR-125b might explain recurrent thrombotic events and worse clinical outcomes in patients treated with clopidogrel, compared to ticagrelor.

Time interval of esomeprazole and dual antiplatelet therapy in patients with cardiocerebrovascular diseases.

Dual antiplatelet therapy (DAPT) with the combination of clopidogrel and aspirin is recommended for preventing secondary ischemic events in patients with acute coronary syndrome (ACS) or acute ischemic stroke (AIS). Proton pump inhibitors (PPIs) are suggested as preventive treatment for these patients. Due to clopidogrel-PPI interactions, separating their administration might be considered. However, a paucity of studies has been conducted to investigate the outcome differences between concurrent and interval-based use in ACS and AIS patients. Our study aimed to evaluate clinical outcomes based on administration timing. This study included patients with ACS or AIS onset or recurrence of within the last month. Patients who were expected to receive DAPT for at least 6 months and who were currently taking or planning to take esomeprazole were included. Patients were divided into Group 1 (interval administration group, IA group) and Group 2 (concurrent administration group, CA group) according to the interval between esomeprazole and DAPT administration. The time interval was based on 12 hours. The primary outcome was the occurrence of major adverse cardiocerebrovascular events (MACCEs), and safety outcomes were defined as major bleeding, minor bleeding and gastrointestinal bleeding and intracranial hemorrhage. A total of 3600 patients completed this study. The proportions of patients in the 2 groups were as follows: CA group, 99% (n = 3489) and IA group, 1% (n = 111). The primary outcome occurred in 0.9% of patients in the IA group and 1.8% of patients in the CA group (P = .51). There was no significant distinction in the overall bleeding risk of the CA group compared to that of the IA group (2.75% in the CA group and 2.70% in the IA group). Additionally, there was no significant difference observed between the 2 groups for safety outcomes. This multicenter, prospective, observational study that enrolled patients with ACS or AIS demonstrated that there was no significant difference in the occurrence of MACCEs and bleeding issues within 6 months according to the medication administration interval. The majority of patients with DAPT were taking PPIs simultaneously in real-world practice.

Impact of hemodialysis on efficacies of the antiplatelet agents in coronary artery disease patients complicated with end-stage renal disease.

It is controversial whether hemodialysis affects the efficacy of the antiplatelet agents. We aimed to investigate the impact of hemodialysis on efficacies of the antiplatelet agents in coronary artery disease (CAD) patients complicated with end-stage renal disease (ESRD). 86 CAD patients complicated with ESRD requiring hemodialysis were consecutively enrolled. After 5-day treatment with aspirin and clopidogrel or ticagrelor, the platelet aggregations induced by arachidonic acid (PLAA) or adenosine diphosphate (PLADP), and the P2Y12 reaction unit (PRU) were measured before and after hemodialysis. The propensity matching score method was adopted to generate a control group with normal renal function from 2439 CAD patients. In patients taking aspirin, the PLAA remained unchanged after hemodialysis. In patients taking clopidogrel, the PLADP (37.26 ± 17.04 vs. 31.77 ± 16.09, p = 0.029) and corresponding clopidogrel resistance (CR) rate (23 [48.9%] vs. 14 [29.8%], p = 0.022) significantly decreased after hemodialysis, though PRU remained unchanged. Subgroup analysis indicated that PLADP significantly decreased while using polysulfone membrane (36.8 ± 17.9 vs. 31.1 ± 14.5, p = 0.024). In patients taking ticagrelor, PLADP, and PRU remained unchanged after hemodialysis. ESRD patients had higher incidences of aspirin resistance (AR) and CR compared to those with normal renal function (AR: 16.1% vs. 0%, p = 0.001; CR: 48.4% vs. 24.8%, p = 0.024). Hemodialysis does not have negative effect on the efficacies of aspirin, clopidogrel and ticagrelor in ESRD patients with CAD. ESRD patients have higher incidences of AR and CR compared with those with normal renal function.Trial registration ClinicalTrials.gov Identifier: NCT03330223, first registered January 4, 2018.

The effects of CYP2C19 genotype polymorphism and clopidogrel resistance on ischemic event occurrence in patients with peripheral arterial disease undergoing revascularization: A prospective cohort study.

INTRODUCTION: Peripheral arterial disease (PAD) affects approximately 236 million people worldwide. Therefore, this study aimed to investigate the relationship between CYP2C19 genotype polymorphisms and clopidogrel resistance (CR) following revascularization in patients with PAD. MATERIALS AND METHODS: In total, 345 patients who underwent PAD revascularization were monitored for five years and risk factors for ischemic events were identified. Platelet reactivity and CYP2C19 genotypes were measured, and patients were classified as normal, intermediate, or poor metabolizers based on their genotypes. The study endpoint was defined as an ischemic event, that encompassed major adverse cardiovascular or limb events, or all-cause death. RESULTS: In this study, ischemic events following PAD revascularization were associated with patient age, prior minor amputation, the Rutherford category before revascularization, indications for revascularization, index ankle-branchial index before revascularization, CYP2C19 phenotypes, and CR. Intermediate and poor metabolism, the Rutherford category before revascularization, and CR were independent risk factors for ischemic events in patients after PAD revascularization. Similarly, intermediate and poor metabolism, the Rutherford category before revascularization, and CR were independent risk factors for ischemic events in patients with PAD after revascularization within five years. Intermediate and poor metabolizers had a higher platelet reactivity and risk of CR than normal metabolizers. However, poor metabolizers had a higher platelet reactivity and risk of CR than intermediate metabolizers. Furthermore, the hazard ratio for ischemic events increased with platelet reactivity. This effect was more prevalent in intermediate and poor metabolizers than in normal metabolizers. CONCLUSIONS: Ischemic events in patients after PAD revascularization were affected by independent risk factors. Decreased clopidogrel metabolism increased the platelet reactivity and CR in patients after PAD revascularization. Furthermore, high platelet reactivity was associated with an increased risk of ischemic events in patients with intermediate and poor metabolism.