P2Y12 Inhibition in Patients Requiring Oral Anticoagulation after Percutaneous Coronary Intervention: The SWAP-AC-2 Study.

BACKGROUND: Among patients treated with a novel oral anticoagulant (NOAC) undergoing percutaneous coronary intervention (PCI), combination therapy with clopidogrel (i.e., known as dual antithrombotic therapy [DAT]) is the treatment of choice. However, there are concerns for individuals with impaired response to clopidogrel. OBJECTIVES: To assess the pharmacodynamic (PD) effects of clopidogrel vs. low-dose ticagrelor in patients with impaired clopidogrel response assessed by the ABCD-GENE score. METHODS: This was a prospective, randomized PD study of NOAC-treated patients undergoing PCI. Patients with an ABCD-GENE score ≥10 (n=39), defined as having impaired clopidogrel response, were randomized to low-dose ticagrelor (n=20; 60 mg/bid) or clopidogrel (n=19; 75 mg/qd). Patients with an ABCD-GENE<10 (n=42) were treated with clopidogrel (75 mg/qd; control cohort). PD assessments at baseline and 30 days post-randomization (trough and peak) were performed to assess P2Y12 signaling [VerifyNow P2Y12 reaction units (PRU), light transmittance aggregometry (LTA), and vasodilator-stimulated phosphoprotein (VASP)]; makers of thrombosis not specific to P2Y12 signaling were also assessed. The primary endpoint was PRU (trough levels) at 30 days. RESULTS: At 30 days, PRU levels were reduced with ticagrelor-based DAT compared with clopidogrel-based DAT at trough (23.0 [3.0-46.0] vs. 154.5 [77.5-183.0]; p<0.001) and peak (6.0 [4.0-14.0] vs. 129.0 [66.0-171.0]; p<0.001). Trough PRU levels in the control arm (104.0 [35.0-167.0]) were higher than ticagrelor-based DAT (p=0.005) and numerically lower than clopidogrel-based DAT (p=0.234). Results were consistent by LTA and VASP. Markers measuring other pathways leading to thrombus formation were largely unaffected. CONCLUSIONS: In NOAC-treated patients undergoing PCI with an ABCD-gene score ≥10, ticagrelor-based DAT using a 60 mg bid regimen reduced platelet P2Y12 reactivity compared to clopidogrel-based DAT.

Sex-based outcomes on unguided de-escalation from ticagrelor to clopidogrel in stabilized patients with acute myocardial infarction undergoing percutaneous coronary intervention: a post-hoc analysis of the TALOS-AMI.

Background: The TALOS-AMI study highlighted the effectiveness of a de-escalation strategy shifting from ticagrelor to clopidogrel 1 month after percutaneous coronary intervention (PCI), resulting in significant reduction in clinical events, primarily attributed to a substantial decrease in bleeding events. Nevertheless, the impact of this strategy on outcomes based on sex remains unclear. Methods: This was a post-hoc analysis of the TALOS-AMI study. At 1 month after PCI, patients who remained adherent to aspirin and ticagrelor without experiencing major adverse events were randomized into either the de-escalation group (clopidogrel plus aspirin) or the active control group (ticagrelor plus aspirin) for an additional 12 months. The primary endpoint encompassed a composite of cardiovascular death, myocardial infarction, stroke, and Bleeding Academic Research Consortium bleeding type 2 or greater at 12 months after randomization. Results: Among the 2,697 patients included in this study, 454 (16.8%) were women. Women, characterized by older age and a higher prevalence of hypertension, diabetes, impaired renal function, and non-ST-segment myocardial infarction, exhibited a lower primary endpoint at 12 months compared to men [adjusted hazards ratio (HR), 0.60; 95% confidence interval (CI), 0.37-0.95; P = 0.03]. Compare to the active control group, the de-escalation group demonstrated a reduced risk of the primary endpoint in both women (adjusted HR, 0.38; 95% CI, 0.15-0.95; P = 0.039) and men (adjusted HR, 0.56; 95% CI, 0.40-0.79; P = 0.001) (interaction P = 0.46). Conclusions: In stabilized patients post-PCI with drug-eluting stents for acute myocardial infarction, the primary endpoint was lower among women compared to men. In this cohort, the benefits of an unguided de-escalation strategy from ticagrelor to clopidogrel were comparable in women and men.

Bleeding After Dental Extraction in Patients Undergoing Percutaneous Coronary Intervention During Uninterrupted Single and Dual Antiplatelet Therapy.

Purpose: This study aimed to assess bleeding risk after exodontia in patients with recent percutaneous coronary intervention during uninterrupted single or dual antiplatelet therapy. Study design: A total of 100 patients who had a history of percutaneous stent insertion during the past year candidate for extraction of teeth were included in the study. Fifty patients took aspirin 100mg (monotherapy group), and 50 patients took a combination of aspirin 100mg and clopidogrel 75mg (dual therapy group). After exodontia, the bleeding status was categorized as "complete hemostasis," "persistent bleeding," and "delayed bleeding." Personal data, underlying diseases, number of teeth and roots extracted, and type of procedure required for exodontia were statistically analyzed. Results: No significant difference was observed in the status of bleeding between the two groups regarding sex, age, underlying diseases, number of teeth and roots extracted, and type of procedure (p > 0.05). 39/50 (78%) of monotherapy patients and 32/50 (64%) of dual therapy patients achieved complete hemostasis. Persistent bleeding was noted in 11/50 (22%) of monotherapy participants, and 14/50 (28%) of dual therapy patients. Only 4/50 (8%) of dual therapy patients experienced delayed bleeding. However, these differences were not significant (p = 0.08). All persistent and delayed bleeding was easily controlled via local measures. Conclusion: Simple or complicated extraction of multiple teeth can be performed safely during the first year after percutaneous coronary intervention without interruption of antiplatelet therapy.

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 vs clopidogrel when coadministered with bivalirudin in patients with acute coronary syndrome undergoing percutaneous coronary intervention.

Background: The optimal perioperative antithrombotic strategy for patients with acute coronary syndrome (ACS) during percutaneous coronary intervention (PCI) remains controversial. Objectives: To determine the safety and effectiveness of bivalirudin plus ticagrelor vs bivalirudin plus clopidogrel in patients with ACS undergoing PCI in the real world. Methods: Between March 2016 and March 2019, 7234 patients with ACS who had undergone PCI, received bivalirudin periprocedurally, and were prescribed ticagrelor or clopidogrel were enrolled in a single-center, all-comer, modern, retrospective cohort study. Incidence rates of 12-month ischemia (cardiac death, myocardial infarction, or stroke), all-cause death, Bleeding Academic Research Consortium (BARC) type 2,3,5 bleeding, and BARC type 3,5 bleeding were compared between different groups. Results: In total, 4960 patients received bivalirudin plus clopidogrel and 2274 patients received bivalirudin plus ticagrelor. Compared with bivalirudin plus clopidogrel, bivalirudin plus ticagrelor was associated with lower ischemic events (1.74% vs 2.84%; relative risk, 0.61; 95% CI, 0.41-0.91; P = .02) and stroke (0.05% vs 1.01%, P < .001) within 12 months after PCI without excessive risk of bleeding (BARC type 2,3,5 bleeding: 4.49% vs 3.76%, P = .22; BARC type 3,5 bleeding: 2.84% vs 2.02%, P = .08). The beneficial effects of bivalirudin plus ticagrelor were consistent among subgroups. Conclusion: As an initial treatment strategy, bivalirudin plus ticagrelor could reduce the 12-month risk of ischemic events compared with bivalirudin plus clopidogrel significantly without increasing the bleeding risk in ACS patients undergoing PCI.

Safety of Clopidogrel vs. Ticagrelor in Dual Antiplatelet Therapy Regimens for High-Bleeding Risk Acute Coronary Syndrome Patients: A Comprehensive Meta-analysis of Adverse Outcomes.

INTRODUCTION: Patients of acute coronary syndrome (ACS) at a high-bleeding risk (HBR) often require dual antiplatelet therapy (DAPT) to reduce the risk of recurrent cardiovascular events. Clopidogrel and ticagrelor are the most commonly used antiplatelet agents in DAPT regimens. However, the safety profiles of these drugs in ACS patients at HBR remain a subject of ongoing debate. AIM: To investigate any difference between the safety of clopidogrel and ticagrelor used as a part of DAPT regimen in ACS patients at HBR. METHODS: A systematic search on PubMed, Cochrane Library, and Google Scholar was conducted to identify experimental and observational studies published up to the knowledge cutoff date in September 2023. Studies comparing the safety of clopidogrel and ticagrelor in ACS patients at HBR were included for analysis. The primary outcomes assessed were major bleeding events, stroke, and myocardial infarction (MI), while secondary outcomes included all-cause mortality, major adverse cardiac and cerebrovascular events (MACCE), and net adverse clinical and cerebral events (NACCE). RESULTS: We included a total of 8 observational studies in our meta-analysis. The pooled analysis revealed a statistically significant increase in the risk of MI (pooled RR = 1.43; 95% CI 1.12-1.83; P = 0.005) in the patients using clopidogrel. There were no statistically significant differences in major bleeding events (pooled RR = 0.94; 95% CI 0.82-1.09; P = 0.44), stroke (pooled RR = 1.36; 95% CI 0.86-2.14; P = 0.18), all-cause mortality (pooled RR = 1.17; 95% CI 0.97-1.41; P = 0.10), MACCE (pooled RR = 1.07; 95% CI 0.76-1.50; P = 0.69) and NACCE (pooled RR = 0.95; 95% CI 0.66-1.37; P = 0.78) between the two groups. Subgroup analyses based on region were performed. CONCLUSION: Both drugs are generally safe for treating ACS patients with HBR at baseline, although a higher risk of MI was observed with the use of clopidogrel. Nevertheless, drug choice should factor in regional variations, patient-specific characteristics, cost, accessibility, and potential drug interactions.

Investigation of smoking on the antiplatelet response to clopidogrel: Unravelling the smoker's paradox.

The intricate relationship between smoking and the effects of the antiplatelet drug clopidogrel has been termed the "smoker's paradox". This paradox details the enhanced efficacy of clopidogrel in smokers compared to non-smokers. This review begins with an exploration of the proposed mechanisms of the smoker's paradox, particularly drawing attention to the induction of cytochrome P450 (CYP) isoenzymes via tobacco smoke, specifically the enzymes CYP1A2 and CYP2C19. Moreover, an investigation of the effects of genetic variability on the smoker's paradox was undertaken from both clinical and molecular perspectives, delving into the effects of ethnicity and genetic polymorphisms. The intriguing role of CYP1A2 genotypes and the response to clopidogrel in smoking and non-smoking populations was examined conferring insight into the individuality rather than universality of the smoker's paradox. CYP1A2 induction is hypothesised to elucidate the potency of smoking in exerting a counteracting effect in those taking clopidogrel who possess CYP2C19 loss of function polymorphisms. Furthermore, we assess the comparative efficacies of clopidogrel and other antiplatelet agents, namely prasugrel and ticagrelor. Studies indicated that prasugrel and ticagrelor provided a more consistent effect and further reduced platelet reactivity compared to clopidogrel within both smoking and non-smoking populations. Personalised dosing was another focus of the review considering patient comorbidities, genetic makeup, and smoking status with the objective of improving the antiplatelet response of those taking clopidogrel. In summation, this review provides insight into multiple areas of research concerning clopidogrel and the smoker's paradox taking into account proposed mechanisms, genetics, other antiplatelet agents, and personalised dosing.

Comparative effectiveness and safety of ticagrelor and clopidogrel in patients with or without chronic liver disease: a nationwide cohort study.

BACKGROUND: Although the effectiveness and safety of ticagrelor versus clopidogrel may differ in patients with chronic liver disease, there is a scarcity of evidence comparing ticagrelor and clopidogrel in patients with chronic liver disease. We aimed to evaluate the risk of major adverse cardiovascular events (MACE) and major bleeding associated with ticagrelor versus clopidogrel in patients undergoing percutaneous coronary intervention (PCI) due to acute coronary syndrome by chronic liver disease status. METHODS: Using the Korean healthcare database, we included adult patients who underwent PCI and initiated ticagrelor or clopidogrel treatment within 7 days of an acute coronary syndrome diagnosis. Patients were divided into two mutually exclusive groups: patients with chronic liver disease and patients without chronic liver disease. Within each group, the hazard ratios (HRs) with 95% confidence intervals (CIs) of MACE and major bleeding associated with ticagrelor versus clopidogrel were calculated using a Cox proportional hazards model within a 1:1 propensity score (PS) matched cohort. RESULTS: The final cohort included 14,261 and 148,535 patients with and without chronic liver disease, respectively. After PS matching, the risk of MACE (with chronic liver disease, HR: 1.01, 95% CI: 0.91-1.13; without chronic liver disease, HR: 1.02, 95% CI: 0.98-1.05; P for homogeneity: 0.865) and major bleeding (with chronic liver disease, HR: 1.07, 95% CI: 0.71-1.61; without chronic liver disease, HR: 1.32, 95% CI: 1.15-1.53; P for homogeneity: 0.342) for ticagrelor versus clopidogrel do not vary with chronic liver disease status. CONCLUSIONS: Among acute coronary syndrome patients undergoing PCI, the use of ticagrelor versus clopidogrel was associated with a similar risk of MACE and an increased risk of major bleeding, but these risks did not vary with chronic liver disease status.

Ticagrelor, but Not Clopidogrel, Attenuates Hepatic Steatosis in a Model of Metabolic Dysfunction-Associated Steatotic Liver Disease.

BACKGROUND: Previous studies have suggested that platelets are associated with inflammation and steatosis and may play an important role in liver health. Therefore, we evaluated whether antiplatelet agents can improve metabolic disorder-related fatty liver disease (MASLD). METHODS: The mice used in the study were fed a high-fat-diet (HFD) and were stratified through liver biopsy at 18 weeks. A total of 22 mice with NAFLD activity scores (NAS) ≥ 4 were randomly divided into three groups (HFD-only, clopidogrel (CLO; 35 mg/kg/day), ticagrelor (TIC; 40 mg/kg/day) group). And then, they were fed a feed mixed with the respective drug for 15 weeks. Blood and tissue samples were collected and used in the study. RESULTS: The TIC group showed a significantly lower degree of NAS and steatosis than the HFD group (p = 0.0047), but no effect on the CLO group was observed. Hepatic lipogenesis markers' (SREBP1c, FAS, SCD1, and DGAT2) expression and endoplasmic reticulum (ER) stress markers (CHOP, Xbp1, and GRP78) only reduced significantly in the TIC treatment group. Inflammation genes (MCP1 and TNF-α) also decreased significantly in the TIC group, but not in the CLO group. Nile red staining intensity and hepatic lipogenesis markers were reduced significantly in HepG2 cells following TIC treatment. CONCLUSION: Ticagrelor attenuated NAS and hepatic steatosis in a MASLD mice model by attenuating lipogenesis and inflammation, but not in the CLO group.

Effectiveness of Clopidogrel vs Alternative P2Y12 Inhibitors Based on the ABCD-GENE Score.

BACKGROUND: An ABCD-GENE (age, body mass index, chronic kidney disease, diabetes, and CYP2C19 genetic variants) score ≥10 predicts reduced clopidogrel effectiveness, but its association with response to alternative therapy remains unclear. OBJECTIVES: The aim of this study was to evaluate the association between ABCD-GENE score and the effectiveness of clopidogrel vs alternative P2Y12 inhibitor (prasugrel or ticagrelor) therapy after percutaneous coronary intervention (PCI). METHODS: A total of 4,335 patients who underwent PCI, CYP2C19 genotyping, and P2Y12 inhibitor treatment were included. The primary outcome was major atherothrombotic events (MAE) within 1 year after PCI. Cox regression was performed to assess event risk in clopidogrel-treated (reference) vs alternatively treated patients, with stabilized inverse probability weights derived from exposure propensity scores after stratifying by ABCD-GENE score and further by CYP2C19 loss-of-function (LOF) genotype. RESULTS: Among patients with scores <10 (n = 3,200), MAE was not different with alternative therapy vs clopidogrel (weighted HR: 0.89; 95% CI: 0.65-1.22; P = 0.475). The risk for MAE also did not significantly differ by treatment among patients with scores ≥10 (n = 1,135; weighted HR: 0.75; 95% CI: 0.51-1.11; P = 0.155). Among CYP2C19 LOF allele carriers, MAE risk appeared lower with alternative therapy in both the group with scores <10 (weighted HR: 0.50; 95% CI: 0.25-1.01; P = 0.052) and the group with scores ≥10 (weighted HR: 0.48; 95% CI: 0.29-0.80; P = 0.004), while there was no difference in the group with scores <10 and no LOF alleles (weighted HR: 1.03; 95% CI: 0.70-1.51; P = 0.885). CONCLUSIONS: These data support the use of alternative therapy over clopidogrel in CYP2C19 LOF allele carriers after PCI, regardless of ABCD-GENE score, while clopidogrel is as effective as alternative therapy in non-LOF patients with scores <10.

Ticagrelor versus clopidogrel in dual antiplatelet therapy after minor stroke or transient ischemic attack: an updated network meta-analysis.

BACKGROUND: Dual antiplatelet therapy (DAPT) with clopidogrel plus aspirin is a well-established practice after a minor stroke or transient ischemic attack (TIA). However, ticagrelor plus aspirin may be an alternative. AIMS: We systematically searched PubMed, Embase, and Cochrane Central from inception to January 2024. We included randomized controlled trials (RCTs) enrolling adults with acute minor stroke or TIA within 72 hours of the onset of the symptoms. RESULTS: A total of 8 RCTs were included in our meta-analysis. Ticagrelor plus aspirin (RR, 0.70; 95% CrI 0.52, 0.91) and clopidogrel plus aspirin (RR, 0.79; 95% CrI 0.64, 0.98) were superior to aspirin in preventing stroke recurrence in overall analysis. Excluding studies with dual antiplatelet up to 90 days, ticagrelor plus aspirin was the only strategy that maintained superiority compared with aspirin regarding stroke recurrence (RR, 0.70; 95% CrI 0.51, 0.95) and ischemic stroke (RR, 0.68; 95% CrI 0.47, 0.94). There was no significant difference between treatment groups regarding hemorrhagic stroke, functional disability, and mortality. CONCLUSIONS: DAPTs were superior to aspirin in preventing recurrence or ischemic stroke. Although no significant difference was observed between DAPTs, ticagrelor plus aspirin may be related to worse major bleeding results, including intracranial bleeding. Ticagrelor plus aspirin is a considerable option for patients after a minor stroke or TIA.

The Association between CYP2C19 Genetic Polymorphism and Prognosis in Patients Receiving Endovascular Therapy.

Background: Potentially substantial impacts on the prognosis have been observed in individuals undergoing endovascular treatment due to cytochrome P450 2c19 (CYP2C19) polymorphism. In an attempt to improve prognosis and lower the recurrence rate, this study investigated the CYP2C19 polymorphism in acute ischemic stroke patients. Materials and Methods: A retrospective analysis was performed on 292 patients with cerebral infarction who had acute endovascular recanalization at the Department of Neurology of Chongqing Hospital of Traditional Chinese Medicine between May 2017 and 2019. The patients were categorized into rapid-, medium-, and slow-metabolism groups based on CYP2C19 gene polymorphism, and their prognosis was monitored. In addition, the prognosis of 188 patients selectively receiving carotid artery stenting at a selected time was also observed. Results: Among the 292 cerebral infarction cases receiving acute endovascular recanalization, the patients in the CYP2C19 rapid-metabolism group regularly took clopidogrel and aspirin combined with antiplatelet therapy and suffered from reoccurrence of apoplexy and cerebral hemorrhage; the 90-day good prognosis had a statistical difference (P < 0.05, prognostic assessment includes hospitalization and 6 months after discharge) and the other adverse events had no statistical difference (including mortality). The 188 patients selectively receiving carotid artery stenting had a recurrence of apoplexy, cerebral hemorrhage, and restenosis rate with a statistical difference (P < 0.05), and the other adverse events had no statistical difference. Conclusions: In conclusion, the findings of the current study indicate that irrespective of whether patients are undergoing selective carotid artery stenting or acute endovascular recanalization, those with rapid CYP2C19 metabolism have a significantly lower likelihood of experiencing adverse prognostic events compared to those with intermediate and slow metabolism. Furthermore, this group also has a more favorable prognosis than the other two groups.

Comparison of clopidogrel and ticagrelor in treating acute coronary syndrome undergoing PCI: A systematic review and meta-analysis.

Objective: The study aims to evaluate and compare the efficacy and safety between ticagrelor and clopidogrel in acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI). Methods: We searched MEDLINE (via PubMed), Cochrane, Embase, and the Cochrane library databases for eligible citations (the last search was up to December 2021). Subgroup analyses were performed based on region, study design, dose, and single-center/multicenter. Meta regressions were conducted to explore the source of heterogeneity. A sensitivity analysis was conducted to assess the robustness of the results. Funnel plots and Egger's test were preformed to test publication bias of the meta-analysis. Results: A total of 29 studies were included, totaling 165,981 patients. Ticagrelor reduced the overall incidence rate of major adverse cardiovascular events (MACEs) (HR 0.74; 95% CI, 0.62, 0.89; P = 0.001; I2 = 88.3%, P < 0.001) and all-cause mortality (HR 0.85; 95% CI, 0.75, 0.97; P = 0.019; I2 = 39.7%, P = 0.052) compared with clopidogrel. However, there was a higher risk of major bleeding (HR 1.21; 95% CI, 1.02,1.44; P = 0.026, I2 = 59.3%, P = 0.012) and all bleeding (HR 1.42; 95% CI, 1.24, 1.62; P < 0.001, I2 = 76.4%, P < 0.001) with ticagrelor compared to clopidogrel. The stability of the results was demonstrated by sensitivity analysis. Furthermore, subgroup analyses and meta-regression revealed that the heterogeneity in the study may stem from factors such as whether it was conducted in a single-center or multicenter setting, as well as the geographical region. Conclusion: Ticagrelor has demonstrated superior efficacy compared to clopidogrel in ACS patients undergoing PCI, particularly in Asia and Europe. Nevertheless, it is crucial to acknowledge that the utilization of ticagrelor is linked to a heightened risk of bleeding. To provide guidance for clinical decision-making regarding the use of ticagrelor, future multicenter randomized trials that are relevant and encompass longer follow-up periods are necessary. The category of the manuscript a meta-analysis: PROSPERO registration number CRD42021274198.

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

OBJECTIVE: Clopidogrel 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 METHODS: In 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. RESULTS: In 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). CONCLUSIONS: The 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.

Development of a routine bedside CYP2C19 genotype assessment program for antiplatelet therapy guidance in a community hospital catheterization laboratory.

Genotype based personalized antiplatelet therapy in the setting of percutaneous coronary intervention (PCI) has been studied in clinical trials. Despite the demonstrated risk associated with CYP2C19 loss-of-function (LoF) carriage in clopidogrel-treated PCI patients, real-world implementation of genotyping for PCI has been low. The goal of the current study was to provide CYP2C19 genotype information to the interventionalist prior to the completion of the catheterization to facilitate immediate personalized antiplatelet therapy. Routine personalization of P2Y12 inhibitor therapy for PCI in a community hospital cardiac catheterization laboratory by POC genotyping with the SpartanRx system was first offered in February 2017. A best practice advisory (BPA) based on the Clinical Pharmacogenetics Implementation Consortium Guideline for CYP2C19 genotype and clopidogrel therapy was placed in the electronic health record prescription medication ordering system. By December 2019, 1,052 patients had CYP2C19 genotype testing, 429 patients underwent PCI with genotype guided antiplatelet therapy, and 250 patients underwent PCI without genotype testing and received antiplatelet therapy at the discretion of the treating physician. BPA compliance was 93. 87% of LoF allele carriers were prescribed ticagrelor or prasugrel whereas 96% of non-LoF allele carriers were prescribed clopidogrel. The genotyping results were available within 1 h and made immediately available for decision making by the interventional cardiologist. POC CYP2C19 genotyping is feasible in a community hospital catheterization laboratory and is associated with high rate of best practice compliance.Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT03040622.

METTL3-mediated methylation of CYP2C19 mRNA may aggravate clopidogrel resistance in ischemic stroke patients.

Background: N6-methyladenosine (m6A) is the most frequently occurring interior modification in eukaryotic messenger RNA (mRNA), and abnormal mRNA modifications can affect many biological processes. However, m6A's effect on the metabolism of antiplatelet drugs for the prevention of ischemic stroke (IS) remains largely unclear. Methods: We analyzed the m6A enzymes and m6A methylation in peripheral blood samples of IS patients with/without clopidogrel resistance (CR), and the peripheral blood and liver of rat models with/without CR. We also compared the effect of m6A methylation on the expression of the drug-metabolizing enzymes (CYP2C19 and CYP2C6v1) in CR and non-CR samples. Results: Methyltransferase-like 3 (METTL3), an m6A enzyme, was highly expressed in the peripheral blood of patients with CR, and in both the peripheral blood and liver of rats with CR. This enzyme targets CYP2C19 or CYP2C6v1 mRNA through m6A methylation, resulting in low expression of CYP2C19 or CYP2C6v1 mRNA. Consequently, this leads to decreased clopidogrel metabolism and CR. Conclusion: The METTL3-mediated methylation of CYP2C19 mRNA may aggravate CR in IS patients.

Clopidogrel versus newer P2Y12 inhibitors in the dual antiplatelet therapy for stent-assisted coil embolization of intracranial aneurysms: A meta-analysis.

INTRODUCTION: Stent-assisted coil embolization (SACE) for cerebral aneurysms requires dual antiplatelet therapy (DAPT), commonly clopidogrel plus aspirin is preferable to ticagrelor or prasugrel plus aspirin. However, there are few studies assessing the safety of the association of ticagrelor or prasugrel plus aspirin. OBJECTIVES: Compare the safety of newer P2Y12 inhibitors with clopidogrel in patients that underwent a SACE for cerebral aneurysms. METHODS: In accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines, we searched PubMed and Embase for studies comparing newer P2Y12 inhibitors with clopidogrel in patients undergoing DAPT for SACE. Outcomes were total number of complications, number of hemorrhagic complications, and number of thromboembolic complications both intraoperative and follow-up. A random effects model was used to calculate odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS: We included 1026 patients from six studies. Newer P2Y12 inhibitors were used in 562 (54,77%) patients. There were no significant differences between groups in total number of complications (OR 0.80; 95% CI 0.32, 1.99; p < 0.01; I2 = 78%), in intraoperative hemorrhagic complications (OR 0.66; 95% CI 0.09, 4.71; p = 0.68; I2 = 0%), follow-up hemorrhagic complications (OR 1.23; 95% CI 0.70, 2.15; p = 0.49; I2 = 0%), intraoperative thromboembolic complications (OR 0.43; 95% CI 0.14, 1.35; p = 0.25; I2 = 24%), and in follow-up thromboembolic complications (OR 0.89; 95% CI 0.33, 2.39; p = 0.03; I2 = 59%). CONCLUSION: In patients who underwent a SACE, newer P2Y12 inhibitors showed no differences in intraoperative and follow-up complications compared with clopidogrel.

Effects of thienopyridine class antiplatelets on bleeding outcomes following robot-assisted radical prostatectomy.

This study aimed to assess the effects of thienopyridine-class antiplatelet agents (including ticlopidine, clopidogrel, and prasugrel) on bleeding complications in patients who underwent robot-assisted radical prostatectomy. This cohort study used a database for robot-assisted radical prostatectomy at 23 tertiary centers nationwide between 2011 and 2022. Patients who received thienopyridines (thienopyridine group) were compared with those who received aspirin monotherapy (aspirin group). The primary outcome was the incidence of bleeding complications. High-grade complications were defined as Clavien-Dindo grade III or higher. The risks of these outcomes were evaluated using inverse probability of treatment weighted regression models. The study results demonstrated that thienopyridine therapy was associated with a higher risk of overall bleeding complications (OR: 3.62, 95%CI 1.54-8.49). The increased risks of the thienopyridine group were detected for low-grade bleeding complications (OR: 3.20, 95%CI 1.23-8.30) but not for high-grade bleeding complications (OR: 5.23, 95%CI 0.78-34.9). The increased risk of bleeding complications was not observed when thienopyridine was discontinued (OR: 2.52, 95%CI 0.83-7.70); however, it became apparent when it was continued perioperatively (OR: 4.35, 95%CI 1.14-16.61). In conclusion, thienopyridine increased the incidence of bleeding complications, particularly low-grade bleeding complications, following robot-assisted radical prostatectomy. These bleeding effects emerged when thienopyridine was continued perioperatively.

Impact of Platelet Hyperreactivity and Diabetes Mellitus on Ischemic Stroke Recurrence: A Single-Center Cohort Clinical Study.

Purpose: Ischemic stroke recurrence (ISR) is prevented by inhibiting platelet function. To investigate the impact of high on-treatment platelet reactivity (HTPR) assessed by thromboelastography (TEG) and its risk factors on ISR in individuals who have experienced acute ischemic stroke (AIS) receiving dual anti-platelet therapy (DAPT). Patients and Methods: At the end of follow-up, a total of 264 patients who met the criteria were enrolled in this cohort study. The primary endpoint event was a recurrence of ischemic stroke within 90 days of onset. Results: The ISR rate was 7.2% (19/264). The recurrence rate in the HTPR group was 15.1% (8/53), which was significantly higher than the 5.2% (11/211) in the non-HTPR group (p = 0.013), and the type 2 diabetes mellitus (T2DM) group (12.5%, 10/80) was also significantly higher compared to the non-T2DM group (4.9%, 9/184) (p = 0.028). T2DM was an isolated risk factor for HTPR (adjusted OR = 3.06, 95% CI 1.57-5.98, P = 0.001). Kaplan-Meier plots showed that the cumulative risk (CR) of ISR was statistically different in the HTPR and T2DM groups compared to the non-HTPR group (log-rank P = 0.009) and the non-T2DM group (log-rank P = 0.026), respectively. The HTPR and T2DM groups had greater hazard ratios (HR) of ISR than the non-HTPR (adjusted HR = 2.78, 95% CI 1.06-7.32, P = 0.038) and non-T2DM (adjusted HR = 2.64, 95% CI 1.01-6.92, P = 0.049) groups. Conclusion: Both HTPR and T2DM are linked to ISR. Platelet Inhibition Rate (PIR) of TEG can early identify patients who are at high risk for having another ischemic stroke in patients undergoing DAPT, and this study may offer more evidence in favor of clinically personalized treatment and secondary prevention tactics.

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.