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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., Competing Interests: Disclosures Juan Crestanello reports a relationship with Medtronic Inc that includes: consulting or advisory and with Edwards Lifesciences Corporation that includes: consulting or advisory. The other authors have no conflicts of interest to disclose., (Copyright © 2024 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Introduction: An increasing number of patients attending coronary artery bypass grafting (CABG) receive preoperative antiplatelet drugs (acetylsalicylic acid, clopidogrel, prasugrel, ticagrelor). The optimal assessment of preoperative platelet function is the aim of this study for a shorter surgical timing in patients undergoing elective coronary artery bypass grafting., Methods: This study was performed on patients presenting for first-time isolated CABG on therapy with an P2Y12 receptor blockers loading dose (clopidogrel [300 mg] or prasugrel [60 mg] or ticagrelor [180 mg]) or P2Y12 receptor blockers maintenance therapy at least for five days (clopidogrel [75 mg once daily], prasugrel [10 mg once daily], ticagrelor [90 mg twice daily]). All patients received simultaneously acetylsalicylate acid (100 mg daily). Exclusion criterion was emergency CABG regardless of preoperative antiplatelet and anticoagulant therapy. All patients' data were recorded in an Excel® file and analyzed using RStudio® software., Results: Forty-eight consecutive adult patients presenting for CABG were enrolled. Preoperative thromboelastography-platelet mapping showed platelet resistance to P2Y12 blockers receptor - 25% for clopidogrel (6/24), 33% for ticagrelor (6/18), 33% for prasugrel (2/6), and this data was useful to obtain a shorter CABG waiting time in comparison with current guidelines (2.7 vs. five days for clopidogrel, 2.5 vs. five days for ticagrelor, 3.3 vs. seven days for prasugrel)., Conclusion: Preoperative thromboelastography-platelet mapping is helpful to detect harmful P2Y12 receptor blockers resistance and to minimize CABG waiting time avoiding unnecessary and life-threatening delays.

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., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Competing Interests: M. Galli declares that he has received consulting fees by Terumo, outside the present work. The remaining author reports no conflicts of interest.

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., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Dual antiplatelet therapy (DAPT) is standard treatment for endoluminal stent insertion, and complete resistance to DAPT is rare. A case of in-stent thrombosis occurring 3 hours after stent-assisted coiling of internal carotid artery aneurysm is presented despite compliance with DAPT. Platelet function tests (PFTs) revealed complete clopidogrel and prasugrel resistance., Competing Interests: None declared., (Thieme. All rights reserved.)

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., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Echeverría et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

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., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

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.

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., (© 2024. The Author(s).)

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., Competing Interests: Declaration of competing interest The authors declare they have no conflict of interest., (Copyright © 2024. Published by Elsevier B.V.)

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.

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., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Introduction: In this study, we aimed to investigate the association between gut microbiota and high on-treatment platelet reactivity (HTPR) in patients with acute ischemic stroke (AIS)., Methods: We enrolled a total of 48 AIS patients, including 19 HTPR patients and 29 non-high on-treatment platelet reactivity (NHTPR) patients, along with 10 healthy controls. Clinical and laboratory data, as well as stool samples, were collected from all participants. The composition and function of gut microbiota were assessed using 16S rRNA sequencing. Differences in the gut microbiota between the two groups were analyzed, and a diagnostic model based on the gut microbiota was established using random forest model., Results: HTPR patients exhibited a decreased microbial richness compared to NHTPR patients. Additionally, the relative abundance of unidentified&#95;Clostridia and Ralstonia was lower in HTPR patients. Significant differences in biological functions, such as toxoplasmosis, were observed between the two groups. The combination of Ralstonia, unidentified-Clostridia, Mailhella, Anaerofustis , and Aggregatibacter showed excellent predictive ability for HTPR occurrence (AUC=0.896). When comparing AIS patients with healthy controls, alterations in the microbiota structure were observed in AIS patients, with imbalances in short-chain fatty acid-producing bacteria and pathogenic bacteria. Significant differences in biological functions, such as oxidative phosphorylation, were noted between the two groups. The combination of Alloprevotella, Terrisporobacter, Streptococcus, Proteus , and unidentified&#95;Bacteria exhibited strong predictive power for AIS occurrence (AUC=0.994)., Conclusions: This study is the first to uncover the microbial characteristics of HTPR in AIS patients and demonstrate the predictive potential of specific bacterial combinations for HTPR occurrence., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Lou, Ouyang, Chen, Li, Chen, Zhan, Peng, Du, Zheng, Wen, Xu, Zhao and Zhao.)

Background: Clopidogrel is a widely prescribed prodrug that requires activation via specific pharmacogenes to exert its anti-platelet function. Genetic variations in the genes encoding its transporter, metabolizing enzymes, and target receptor lead to variability in its activation and platelet inhibition and, consequently, its efficacy. This variability increases the risk of secondary cardiovascular events, and therefore, some variations have been utilized as genetic biomarkers when prescribing clopidogrel., Methods: Our study examined clopidogrel-related genes (CYP2C19, ABCB1, PON1, and P2Y12R) in a cohort of 298 healthy Emiratis individuals. The study used whole exome sequencing (WES) data to comprehensively analyze pertinent variations of these genes, including their minor allele frequencies, haplotype distribution, and their resulting phenotypes., Results: Our data shows that approximately 37% (n = 119) of the cohort are likely to benefit from the use of alternative anti-platelet drugs due to their classification as intermediate or poor CYP2C19 metabolizers. Additionally, more than 50% of the studied cohort exhibited variants in ABCB1, PON1, and P2YR12 genes, potentially influencing clopidogrel's transport, enzymatic clearance, and receptor performance., Conclusions: Recognizing these alleles and genotype frequencies may explain the clinical differences in medication response across different ethnicities and predict adverse events. Our findings underscore the need to consider genetic variations in prescribing clopidogrel, with potential implications for implementing personalized anti-platelet therapy among Emiratis based on their genetic profiles., (© 2024. The Author(s).)

Background: It remains unclear whether clopidogrel is better suited than aspirin as the long-term antiplatelet monotherapy following dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI)., Objectives: This study compared clopidogrel monotherapy following 1 month of DAPT (clopidogrel group) with aspirin monotherapy following 12 months of DAPT (aspirin group) after PCI for 5 years., Methods: STOPDAPT-2 (Short and Optimal Duration of Dual Antiplatelet Therapy 2) is a multicenter, open-label, adjudicator-blinded, randomized clinical trial conducted in Japan. Patients who underwent PCI with cobalt-chromium everolimus-eluting stents were randomized in a 1-to-1 fashion either to clopidogrel or aspirin groups. The primary endpoint was a composite of cardiovascular outcomes (cardiovascular death, myocardial infarction, stroke, or definite stent thrombosis) or major bleeding (TIMI major or minor bleeding)., Results: Among 3,005 study patients (age: 68.6 ± 10.7 years; women: 22.3%; acute coronary syndrome: 38.3%), 2,934 patients (97.6%) completed the 5-year follow-up (adherence to the study drugs at 395 days: 84.7% and 75.9%). The clopidogrel group compared with the aspirin group was noninferior but not superior for the primary endpoint (11.75% and 13.57%, respectively; HR: 0.85; 95% CI: 0.70-1.05; P noninferiority  < 0.001; P superiority  = 0.13), whereas it was superior for the cardiovascular outcomes (8.61% and 11.05%, respectively; HR: 0.77; 95% CI: 0.61-0.97; P = 0.03) and not superior for major bleeding (4.44% and 4.92%, respectively; HR: 0.89; 95% CI: 0.64-1.25; P = 0.51). By the 1-year landmark analysis, clopidogrel was numerically, but not significantly, superior to aspirin for cardiovascular events (6.79% and 8.68%, respectively; HR: 0.77; 95% CI: 0.59-1.01; P = 0.06) without difference in major bleeding (3.99% and 3.32%, respectively; HR: 1.23; 95% CI: 0.84-1.81; P = 0.31)., Conclusions: Clopidogrel might be an attractive alternative to aspirin with a borderline ischemic benefit beyond 1 year after PCI., Competing Interests: Funding Support and Author Disclosures STOPDAPT-2 is funded by Abbott. The funder had no role in the design, data analysis, interpretation, or writing of the report. Dr Watanabe has received personal fees from Abbott; and has received personal fees from Amgen, Pfizer, and Daiichi-Sankyo outside the submitted work. Dr Morimoto has received lecturer’ fees from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi-Sankyo, Japan Lifeline, Kowa, Pfizer, and Tsumura; has received manuscript fees from Bristol Myers Squibb and Pfizer; and has served on the Advisory Board for Novartis and Teijin outside the submitted work. Dr Natsuaki has received honoraria from Abbott Medical Japan, Daiichi-Sankyo, Medtronic, Terumo, Japan Lifeline, Asahi Intecc, Bristol Myers Squibb, Otsuka, Amgen, Sanofi, Takeda, and Bayer. Dr Hibi has received a scholarship donation from Abbott. Dr Kimura has received research grants from Abbott Vascular and Boston Scientific; and serves as an Advisory Board member for Abbott Vascular and Terumo Japan. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

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 (MA ADP ) > 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., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Clopidogrel is an antiplatelet drug widely prescribed to prevent atherothrombotic events in coronary artery disease patients. However, there is evidence to suggest that the effectiveness of clopidogrel varies owing to genetic diversity in CYP2C19. This heterogeneity in South Asians, who are also known to have high risk of cardiac events than other population groups, highlights the importance of investigating CYP2C19 variants to estimate the risk proportion in the groups., Methods: Given the high prevalence and genetic heterogeneity, the population-based case control was conducted in a cohort of 1191 subjects comprising 645 acute coronary syndrome (ACS) cases (unstable angina, ST-elevation myocardial infarction, and non-ST-elevation myocardial infarction) and 546 healthy controls of South Asian Indian origin. The metabolization status of CYP2C19 was assessed using *2, *3 and *17 variants in the stated cohorts to determine the prevalence of metabolization and its association with phenotypes., Results: The results suggest a possible genetic association between studied CYP2C19 polymorphisms and ACS, since there was a higher proportion of intermediate and poor metabolizers present in the studied cohorts. The association analyses revealed that the *2 allele of CYP2C19 confers a significant risk for ACS, while the *17 allele provides protection., Conclusions: These findings contribute to the understanding of CYP2C19 genetic variants and their impact on clopidogrel response in South Asian Indians. Additionally, they underline the significance of assessing CYP2C19 variations in patients receiving clopidogrel therapy in order to improve therapeutic outcomes., (© 2023 John Wiley & Sons, Ltd.)

Objectives: To find out the prevalence of CYP2C19*2 genetic polymorphism in ischaemic heart disease patients, and to determine its relation with clopidogrel resistance in different genotype groups., Methods: The cross-sectional study was conducted from August 2015 to December 2019 at the Army Medical College, National University of Medical Sciences, Rawalpindi, Pakistan, and comprised ischaemic heart disease patients of either gender who were on clopidogrel therapy. CYP2C19*2 genotyping of all the patients was carried out through polymerase chain reaction-restriction fragment length polymorphism. Platelet aggregation analysis was done using a light transmission aggregometer. Data was analysed using SPSS 23., Results: Of the 390 patients, 232(59.5%) were males and 158(40.5%) were females. The overall age range was 16-82 years. Clinical indications of clopidogrel were angina 198(50.8%), myocardial infarction 146(37.4%) and acute coronary syndrome 46(11.8%). CYP2C19*2 genotyping showed that 196(50.24%) patients were homozygous wild type carriers (GG or *1/*1), 159(40.8%) were heterozygous carriers (GA or *1/*2), and 35(9%) were homozygous polymorphic allele carriers (AA or *2/*2). Platelet aggregation studies showed that there were 157(80.1%) clopidogrel responders and 39(19.9%) clopidogrel-resistant patients among GG carriers, 118(74.2%) clopidogrel responders and 41(25.8%) clopidogrel-resistant among GA carriers, and 18(51.4%) clopidogrel responders and 17(48.6%) clopidogrel-resistant among AA carriers (p=0.001). Intergroup mean platelet aggregation was significantly different (p=0.025). Allelic frequency of dominant allele *1 and polymorphic variant allele *2 was 0.706(70.6%) and 0.294(29.4), respectively., Conclusions: Homozygous and heterozygous carriers of CYP2C19 allele *2 was found to have higher prevalence of clopidogrel resistance in the studied population.

Clopidogrel combined with aspirin is widely used in coronary artery disease (CAD) patients, while some patients exhibit high platelet activity when receiving the combined treatment. Current environmental and genetic factors could only explain part of the variability in clopidogrel efficacy. Human platelets harbor abundant miRNAs which might affect clopidogrel efficacy by regulating the expression of key proteins in the clopidogrel antiplatelet signaling pathway. This study aimed to investigate the association between platelet miRNA levels and clopidogrel efficacy. Here we recruited 508 CAD patients who underwent clopidogrel antiplatelet therapy and determined the platelet reactivity index (PRI) to evaluate antiplatelet reactivity responses to clopidogrel. Subsequently, 22 patients with extreme clopidogrel response were selected for platelet small RNA sequencing. Another 41 CAD patients taking clopidogrel were collected to verify the differentially expressed candidate miRNAs. We found the metabolic types of the CYP2C19 enzyme (based on CYP2C19 * 2 and  * 3 polymorphisms) could significantly affect the PRI of CAD patients with or without percutaneous coronary intervention (PCI) in Chinese. A total of 43 miRNAs were differentially expressed in the platelets from the 22 extreme clopidogrel response samples, and 109 miRNAs were differentially expressed in the 13 CYP2C19 extensive metabolizers with extreme clopidogrel response. Platelet miR-199a-5p levels were correlated negatively with PRI after clopidogrel therapy. Studies in cultured cells revealed that miR-199a-5p inhibited the expression of VASP, a key effector protein downstream of the P2Y 12 receptor. In conclusion, we found the expression of VASP could be inhibited by miR-199a-5p, and decreased platelet miR-199a-5p was associated with high on-clopidogrel platelet reactivity in CAD patients.

Purpose: To assess the antiplatelet effect of cilostazol clinically, we compared the effects of cilostazol in combination with clopidogrel on various platelet function tests., Methods: We recruited patients with ischemic stroke at high risk of recurrence who were treated with clopidogrel alone within 180 days after stroke onset. Subjects underwent baseline platelet function tests, and were then randomly assigned to receive dual antiplatelet therapy (DAPT) comprising clopidogrel and cilostazol or clopidogrel monotherapy (SAPT). After 6 months, platelet function was measured again and compared to that at baseline in each group, and the rate of change was compared between groups., Results: Thirty-four patients were enrolled, but 4 patients were excluded for various reasons. In total, 30 subjects (13 in DAPT and 17 in SAPT group) were analyzed. Adenosine diphosphate- and collagen-induced aggregation, VerifyNow P2Y 12 reaction units, vasodilator-stimulated phosphoprotein (platelet reactivity index: PRI) and plasma p-selectin concentration were significantly lower (P = 0.004, 0.042, 0.049, 0.003 and 0.006 respectively), while VerifyNow % inhibition was significantly higher at 6 months compared to baseline (P = 0.003) in the DAPT group only. Comparison of the rate of change in each parameter from baseline to 6 months showed that while PRI decreased at a greater rate (P = 0.012), VerifyNow % inhibition increased at a greater rate (P = 0.003) in the DAPT group than the SAPT group., Conclusions: The inhibitory effects of adjunctive cilostazol added to clopidogrel on platelet function differed by type of platelet function test. VerifyNow % inhibition and PRI were more inhibited than the other platelet function tests., Trial Registration: CSPS.com substudy in TWMU (UMIN000026672), registered on April 1, 2017. This study was performed as a substudy of CSPS.com (UMIN000012180, registered on October 31, 2013) and was retrospectively registered., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Clopidogrel is an inhibitor of the P2Y12 platelet receptor but testing to demonstrate a drug effect is controversial since there are often discordant results between different tests methods., Methods: Samples from patients taking clopidogrel prior to intracranial flow-diversion procedures were tested using light transmission aggregometry (LTA), whole blood impedance aggregometry (WBIA) and the VerifyNow device (VND). Samples were classified as concordant if all test results were either responsive (inhibition) or resistant. Discordant results were separated using the VND into those with a responsive versus a resistant test result., Results: Samples from 96 patients were studied. Concordance for all three tests was seen in 53/96 (55%) of samples, of which 41 (43%) were responsive and 12 (12%) were resistant. Discordance was observed in 43 samples (45%), 37 (28%) of which were caused by responsive VND and either a resistant WBIA or LTA and 6 (7%) of which were caused by a resistant VND but a responsive test result using either WBIA or LTA. These two discordant groups differed in both platelet count and hematocrit, but no such difference was present between the two concordant groups., Conclusion: Discordance in P2Y12 inhibition testing may be partly explained by sample platelet count and hematocrit., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background The ADAPTABLE (Aspirin Dosing: A Patient-Centric Trial Assessing Benefits and Long-Term Effectiveness) was a large, pragmatic, randomized controlled trial that found no difference between high- versus low-dose aspirin for secondary prevention of atherosclerotic cardiovascular disease. Whether concomitant P2Y12 inhibitor therapy modifies the effect of aspirin dose on clinical events remains unclear. Methods and Results Participants in ADAPTABLE were stratified according to baseline use of clopidogrel or prasugrel (P2Y12 group). The primary effectiveness end point was a composite of death, myocardial infarction, or stroke; and the primary safety end point was major bleeding requiring blood transfusions. We used multivariable Cox regression to compare the relative effectiveness and safety of aspirin dose within P2Y12 and non-P2Y12 groups. Of 13 815 (91.6%) participants with available data, 3051 (22.1%) were receiving clopidogrel (2849 [93.4%]) or prasugrel (203 [6.7%]) at baseline. P2Y12 inhibitor use was associated with higher risk of the primary effectiveness end point (10.86% versus 6.31%; adjusted hazard ratio [HR], 1.40 [95% CI, 1.22-1.62]) but was not associated with bleeding (0.95% versus 0.53%; adjusted HR, 1.42 [95% CI, 0.91-2.22]). We found no interaction in the relative effectiveness and safety of high- versus low-dose aspirin by P2Y12 inhibitor use. Overall, dose switching or discontinuation was more common in the high-dose compared with low-dose aspirin group, but the pattern was not modified by P2Y12 inhibitor use. Conclusions In this prespecified analysis of ADAPTABLE, we found that the relative effectiveness and safety of high- versus low-dose aspirin was not modified by baseline P2Y12 inhibitor use. Registration https://www.clinical.trials.gov. Unique identifier: NCT02697916.

Objective Despite aggressive therapeutic interventions during the acute phase of branch atheromatous disease (BAD)-type cerebral infarction, many patients, even those with a mild condition at the onset, experience neurological deterioration after hospitalization and develop serious deficits. We compared the therapeutic efficacy of multiple antithrombotic therapies for BAD between patients who received a clopidogrel loading dose (loading group; LG) and those without loading (non-loading group; NLG). Patients Between January 2019 and May 2022, patients with BAD-type cerebral infarction in the lenticulostriate artery admitted within 24 h of the onset were recruited. This study included 95 consecutive patients who received combination argatroban and dual antiplatelet therapy (aspirin and clopidogrel). Methods Patients were classified into the LG and NLG according to whether or not a loading dose of clopidogrel (300 mg) had been administered on admission. Changes in neurological severity [National Institutes of Health Stroke Scale (NIHSS) score] during the acute phase were retrospectively evaluated. Results There were 34 (36%) and 61 (64%) patients in the LG and NLG, respectively. On admission, the median NIHSS score was similar between the groups [LG: 2.5 (2-4) vs. NLG: 3 (2-4), p=0.771]. At 48 h following admission, the median NIHSS scores were 1 (0.25-4), and 2 (1-5) in the LG and NLG, respectively (p=0.045). Early neurological deterioration (END; defined as worsening of the NIHSS score by ≥4 points at 48 h after admission) occurred in 3% of LG and 20% of NLG patients (p=0.028). Conclusion Administration of a clopidogrel loading dose with combination antithrombotic therapy for BAD reduced END.

Objectives: To compare the effectiveness of aspirin-clopidogrel dual antiplatelet therapy (DAPT) with aspirin or clopidogrel antiplatelet monotherapy (AM) in patients with ischemic stroke., Methods: It was a single-center, retrospective cross-sectional study of medical records of ischemic stroke patients admitted at King Abdulaziz University Hospital between January 2015 and October 2019. The primary endpoints were ischemic stroke recurrence, rehospitalization, and all-cause mortality between DAPT and AM. Kaplan-Meier and Cox proportional hazard analyses were employed in univariate and multivariate time-to-event analyses., Results: The median time to recurrence of ischemic stroke was 15.0 months (95% confidence interval [CI], 8.586-23.01) for DAPT and 20.4 months (95% CI, 9.872-30.928) for the AM. The median survival time until all-cause mortality was 8.0 months (95% CI, 2.893-13.107) for DAPT and 14.1 months (95% CI, 8.173-19.97) for the AM. No statistically significant reductions in the instantaneous risks of recurrence (hazard ratio [HR], 1.27; 95% CI, 0.59-2.72; p =0.54), re-hospitalization (HR, 0.95; 95% CI, 0.59-1.48; p = 0.77), and mortality (HR, 1.04; 95% CI, 0.48-2.26; p =0.92) were found between the DAPT and AM groups., Conclusion: The DAPT was not superior to AM in reducing recurrence and mortality events in patients with ischemic stroke. Rehospitalization due to the sequelae of the composite of stroke, angina, and myocardial infarction was higher in the DAPT group., (Copyright: © Neurosciences.)

Background and Purpose: Light transmission aggregometry (LTA) and CYP2C19 genotype analysis are commonly used to evaluate the antiplatelet effects of clopidogrel during the interventional treatment of intracranial aneurysms. The aim of this study was to determine which test can predict ischaemic events during these treatments., Methods: Patient demographic information, imaging data, laboratory data and ischaemic complications were recorded. LTA and CYP2C19 genotype results were compared, and multiple linear regression was performed to examine factors related to platelet reactivity. Multivariate regression analysis was performed to determine whether LTA and CYP2C19 could predict ischaemic complications and to identify other clinical risk factors. Receiver operating characteristic curve analysis was conducted to calculate the cut-off value for predicting ischaemic complications. A subgroup analysis was also performed for different CYP2C19 genotype metabolisers, as well as for patients with flow diverters and traditional stents., Results: A total of 379 patients were included, of which 22 developed ischaemic events. Maximum platelet aggregation induced by ADP (ADP-MPA) could predict ischaemic events (p<0.001; area under the curve, 0.752 (95% CI 0.663 to 0.842)), and its cut-off value was 41.5%. ADP-MPA (p=0.001) and hypertension duration >10 years (p=0.022) were independent risk factors for ischaemic events, while the CYP2C19 genotype was not associated with ischaemic events. In the subgroup analysis, ADP-MPA could predict ischaemic events in fast metabolisers (p=0.004) and intermediate metabolisers (p=0.003). The cut-off value for ischaemic events was lower in patients with flow diverters (ADP-MPA=36.4%) than in patients with traditional stents (ADP-MPA=42.9%)., Conclusions: ADP-MPA can predict ischaemic complications during endovascular treatment of intracranial aneurysms. Patients with flow diverters require stronger antiplatelet medication than patients with traditional stents., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Obese patients exhibit an overall increased platelet reactivity and a reduced sensitivity to antiplatelet therapy. The aim of this study is to evaluate the platelet reactivity measured by impedance aggregometry in overweight and obese patients and chronic coronary syndrome (CCS) that were treated with dual antiplatelet therapy (DAPT)., Methods: Platelet aggregation was assessed by impedance aggregometry in patients with CCS receiving DAPT (aspirin plus clopidogrel). We compared the platelet reactivity in patients with a normal weight versus overweight or obese patients. Furthermore, the correlation between the body mass index (BMI) and adenosine diphosphate- (ADP-) or thrombin receptor-activating peptide- (TRAP-) dependent platelet aggregation was analyzed., Results: 64 patients were included in the study of which 35.9% were patients with normal weight. A higher ADP- and TRAP-dependent platelet reactivity was observed in overweight and obese patients (ADP: median 27 units (U) [IQR 13-39.5] vs. 7 U [6-15], p < 0.001 and TRAP: 97 U [73-118.5] vs. 85 U [36-103], p = 0.035). Significant positive correlations were observed between agonist-induced platelet reactivity and BMI., Conclusion: Despite the use of DAPT, a higher platelet reactivity was found in overweight and obese patients with CCS. If these patients will benefit from treatment with more potent platelet inhibitors, it needs to be evaluated in future clinical trials., (© 2022. The Author(s).)

Background: Crushed formulations of specific antiplatelet agents produce earlier and stronger platelet inhibition. We studied the platelet inhibitory effect of crushed clopidogrel in patients with acute coronary syndrome (ACS) and its relative efficacy compared with integral clopidogrel, crushed and integral ticagrelor., Objectives: We aimed to compare the platelet inhibitory effect of crushed and integral formulations of clopidogrel and ticagrelor in patients with acute coronary syndrome (ACS)., Methods: Overall, 142 patients with suspected ACS were randomly assigned to receive crushed or integral formulations of clopidogrel or ticagrelor. Platelet inhibition at baseline and 1 and 8 h was assessed using the VerifyNow assay. High on-treatment platelet reactivity (HTPR) ≥ 235 P2Y 12  reaction units (PRUs) 1 h after the medication loading dose was also determined., Results: The PRU and percentage inhibition median (interquartile range) at 1 h for the different formulations were as follows: crushed clopidogrel: 196.50 (155.50, 246.50), 9.36 (- 1.79, 25.10); integral clopidogrel: 189.50 (159.00, 214.00), 2.32 (- 2.67, 19.89); crushed ticagrelor: 59.00 (10.00, 96.00), 75.53 (49.12, 95.18); and integral ticagrelor: 126.50 (50.00, 168.00), 40.56 (25.59, 78.69). There was no significant difference in PRU or percentage platelet inhibition between the crushed and integral formulations of clopidogrel (p = 0.990, p = 0.479); both formulations of ticagrelor were superior to the clopidogrel formulations (p < 0.05). On paired comparison, crushed ticagrelor showed robust early inhibition of platelets compared with the integral formulation (p = 0.03). Crushed clopidogrel exhibited the maximal HTPR of 34.3%, but was < 3% for both formulations of ticagrelor., Conclusions: The platelet inhibitory effect of crushed clopidogrel is not superior to integral preparation in patients with ACS. Crushed ticagrelor produced maximal platelet inhibition acutely. HTPR rates in ACS are similar and very low with both formulations of ticagrelor, and maximal with crushed clopidogrel. Clinical Trials Registry of India identifier number CTRI/2020/06/025647., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: Credible diagnostic stratification remains a challenge for coronary artery disease patients with clopidogrel resistance after percutaneous coronary intervention. Tongue diagnostic parameters-based diagnostic signatures might predict clopidogrel resistance., Methods: Clinical and tongue diagnostic parameters data were obtained from coronary artery disease patients with clopidogrel resistance after percutaneous coronary intervention patients and then analyzed. Tongue diagnostic parameters-based diagnostic signatures were developed through univariate and multivariate logistic regression analysis. The diagnostic prediction was assessed using a receiver operating characteristic curve., Results: A total of 101 patients were consecutively identified. Then, tongue diagnostic parameters were identified as significantly associated with clopidogrel resistance diagnosis and were combined with risk factors to develop a model. The receiver operating characteristic curve analysis showed that tongue diagnostic parameters-based diagnostic signatures performed well in diagnosing clopidogrel resistance with an area under the receiver operating characteristic curve value of 0.819., Conclusions: This study identified a novel tongue diagnostic parameters-based diagnostic signature to reliably distinguish clopidogrel resistance diagnosis in coronary artery disease patients undergoing percutaneous coronary intervention. Further larger, multicenter prospective studies are desired to validate this model., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background No large-scale study has compared the clinical impact of triple antiplatelet therapy (TAPT: aspirin, clopidogrel, and cilostazol) and dual antiplatelet therapy (DAPT) on adverse limb events in patients with diabetes after endovascular therapy (EVT) for peripheral artery disease. Thus, we investigate the effect of cilostazol added to a DAPT on the clinical outcomes after EVT in patients with diabetes using a nationwide, multicenter, real-world registry. Methods and Results A total of 990 patients with diabetes who underwent EVT were enrolled from the retrospective cohorts of a Korean multicenter EVT registry and were divided according to the antiplatelet regimen (TAPT [n=350; 35.4%] versus DAPT [n=640; 64.6%]). After propensity score matching based on clinical characteristics, a total of 350 pairs were compared for clinical outcomes. The primary end points were major adverse limb events, a composite of major amputation, minor amputation, and reintervention. For the matched study groups, the lesion length was 125.4±102.0 mm, and severe calcification was observed in 47.4%. The technical success rate (96.9% versus 94.0%; P =0.102) and the complication rate (6.9% versus 6.6%; P >0.999) were similar between the TAPT and DAPT groups. At 2-year follow-up, the incidence of major adverse limb events (16.6% versus 19.4%; P =0.260) did not differ between the 2 groups. However, the TAPT group showed less minor amputation than the DAPT group (2.0% versus 6.3%; P =0.004). In multivariate analysis, TAPT was an independent predictor of minor amputation (adjusted hazard ratio, 0.354 [95% CI, 0.158-0.794]; P =0.012). Conclusions In patients with diabetes undergoing EVT for peripheral artery disease, TAPT did not decrease the incidence of major adverse limb events but may be associated with a decreased risk of minor amputation.

Background: Excess mortality remains the cornerstone concern despite dual antiplatelet therapy (DAPT) after acute coronary syndrome. Some data suggest that shorter periods than 12 months of DAPT diminish bleeding risks yet still provide adequate vascular protection and improving survival. However, the precise timing of deaths after acute coronary syndrome has not been mapped in many studies. This knowledge may be critical for defining optimal treatment duration., Methods: Access was gained to the data set for the Platelet Inhibition and Outcomes (PLATO) trial, which was issued by the Food and Drug Administration, in which post hoc analyses of timing of death events during DAPT (with either aspirin/ticagrelor or aspirin/clopidogrel) were performed. All-cause individual deaths were counted and plotted over time from day 1 to day 365 after the index event., Results: Among 18,624 enrollees, 938 total deaths were reported to the Food and Drug Administration in PLATO. After exclusion of deceased patients with missing dates, randomization errors, and deaths beyond 1 year of follow-up, 913 fatalities (509 after clopidogrel and 404 after ticagrelor) were analyzed. The PLATO records did not indicate where exactly deaths occurred making impossible to triage in the hospital versus outpatient fatalities. Most frequent deaths occurred within the Day 1 (n = 41); Day 2 (n = 48); and Day 3 (n = 33) and overall during the first week (n = 202; 22.1%) after the index acute coronary syndrome, with a gradual decline after Day 10 and Day 60, reaching background counts after Day 220., Conclusion: Focusing on mortality reduction, this large data set may support a shorter than 12 months' duration of DAPT., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: After treatment, high residual platelet reactivity (HRPR) is considered as an essential risk factor for recurrent ischemic events., Aim: To evaluate the impact of fibrinogen on HRPR after implantation of emergency drug-eluting stents (DES) in patients treated with aspirin and clopidogrel or ticagrelor due to ST-elevation myocardial infarction (STEMI) and to explore the predictive values of HRPR and fibrinogen for adverse ischemic events at 12 months., Method: This single-center prospective observational study analyzed patients with STEMI who underwent primary percutaneous coronary intervention (PCI) with second-generation DES implantation from January 2017 to December 2018. Platelet reactivity was measured by thromboelastography (TEG) at 60-72 h after primary PCI. HRPR was defined as the adenosine diphosphate-induced maximum amplitude (MA ADP ) > 47 mm., Results: A total of 919 patients were analyzed, of which 512 (55.8%) received aspirin and clopidogrel and 406 (44.2%) received aspirin and ticagrelor. Elevated fibrinogen levels were associated with an increased prevalence of HRPR (P < 0.001). High fibrinogen (quartile IV, ≥ 410 mg/dL) was an independent risk factor for HRPR after multivariate regression (odds ratio 6.556, 95% confidence interval [CI]: 3.200-13.431, P < 0.001). When analyzed by Kaplan-Meier survival curves, the combination of high fibrinogen and HRPR was strongly predictive for ischemic major adverse cardiac events at 12 months compared to the group without HRPR and with low fibrinogen (hazard ratio 9.681, 95% CI: 4.467-20.98, log-rank P < 0.001). Similar results were confirmed in subgroups according to different dual antiplatelet therapies., Conclusion: A combination of high fibrinogen and HRPR may identify recurrent adverse ischemic events over 12 months. Ticagrelor exhibited more potent platelet inhibition and a better prognosis than clopidogrel., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background and Purpose: High-on-treatment platelet reactivity (HTPR) has been established as a predictor of major adverse cardiovascular events (MACE) in patients undergoing percutaneous coronary interventions on dual antiplatelet therapy (DAPT), but no data are available on its predictive value in patients on DAPT after carotid artery stenting (CAS). We aimed to evaluate the possible association between HTPR in patients on aspirin plus clopidogrel therapy after CAS and subsequent MACE., Methods: All consecutive patients treated with CAS in a single institution were enrolled in a prospective clinical study. HTPR was evaluated with 5 different laboratory assays carried out just before CAS. MACE incidence (cerebral ischemia, myocardial infarction, stent thrombosis, acute limb ischemia and vascular death) was evaluated at 30 days and thereafter at yearly visits., Results: A total of 300 patients were enrolled in the study, and eight were then excluded because blood samples resulted unsuitable for the laboratory testing or CAS aborted for technical problems. Median follow-up was 5.8 years and during this period 47 MACE occurred. HTPR detected by multiplate electronic aggregometry (MEA) and the VASP phosphorylation assay (VASP) were associated with a significantly enhanced risk of MACE (p = 0.048 and p = 0.038, respectively). However, HTPR to three tests (HTPR3) was more strongly predictive of increased risk of a vascular event at follow up (p = 0.005) at bivariate analysis and also at Cox regression multivariate analysis (p = 0.002)., Conclusions: HTPR to three different assays (mainly to VASP + PFA P2Y+ VerifyNow) in patients on DAPT after CAS has predictive value for subsequent MACE. Prospective studies to assess whether platelet function testing-guided antiplatelet therapy is superior to standard DAPT in patient undergoing CAS should be considered., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objective: Routine antiplatelet responsiveness testing for patients undergoing carotid artery stenting procedures is not performed at most endovascular centers and remains a topic of controversy within the neurointerventional community. The objective of this study was to determine if nonresponsiveness to acetylsalicylic acid or clopidogrel was associated with the development of symptomatic thromboembolic events in patients undergoing carotid stenting procedures., Methods: A prospective study was conducted at the Foothills Medical Centre in Calgary, Alberta, Canada, from August 2019 to July 2021. Patients undergoing carotid artery stenting procedures and who were receiving dual antiplatelet therapy were enrolled in the study. Responsiveness to the antiplatelet medications was determined through whole blood impedance aggregometry. The primary outcome was development of a symptomatic thromboembolic event within 90 days after the procedure. The treating physicians were blinded to the aggregometry results for the duration of the study., Results: One hundred two procedures were performed in 100 patients. Eight thromboembolic events (8%) occurred during the study. Age (p = 0.03) and nonresponsiveness to clopidogrel (p = 0.003) were associated with the development of thromboembolic events. The multivariable model showed that clopidogrel nonresponsiveness was independently associated with the development of a thromboembolic event (adjusted OR 6.14, 95% CI 1.25-30.11, p = 0.03)., Conclusions: This study demonstrated that patients who were identified as clopidogrel nonresponders, using whole blood impedance aggregometry, were at an increased risk of developing thromboembolic events. Larger studies are needed to assess the utility of routine platelet function testing prior to carotid artery stenting procedures.

Background: Antithrombotic regimen in patients on oral anticoagulation (OAC) post-percutaneous coronary intervention (PCI) is challenging. At least, one antiplatelet agent in combination with OAC is recommended after PCI for 6-12 months. Clopidogrel is used most frequently in this setting. However, data comparing P2Y12 inhibition with clopidogrel versus cyclooxygenase inhibition by acetylsalicylic acid (ASA, aspirin) is missing. It is well known that the antiplatelet effects of ASA and clopidogrel are frequently impaired (high on-treatment platelet reactivity [HTPR]). In this pilot investigation, we compared the antiplatelet effects of clopidogrel versus ASA., Methods: In this retrospective single-center database analysis, we investigated platelet reactivity by light transmission aggregometry in patients under different antiplatelet regimes. Results were presented as maximum of aggregation (MoA). HTPR to ASA and to clopidogrel were assessed., Results: 755 patients were enrolled. 677 were on ASA, 521 were on clopidogrel, and 198 had OAC. Overall mean age was 73 ± 13.4 years, and 458 (60.7%) were male. HTPR to ASA occurred in 94/677 patients (13.9%), and mean arachidonic acid-induced MoA was 14.15 ± 19.04%. HTPR to clopidogrel occurred in 241/521 patients (46.3%), and mean adenosine diphosphate-induced MoA was 50.06 ± 20.42%. HTPR to clopidogrel was significantly more frequent than HTPR to ASA; single antiplatelet therapy (SAPT)-mono ASA: 27/199 (13.6%) versus mono clopidogrel: 6/18 (33.3%); p = 0.037; SAPT with OAC-OAC with ASA: 8/35 (22.9%) versus OAC with clopidogrel: 27/60 (45%); p = 0.046. Same difference in HTPR contingency could be shown in subgroups of dual antiplatelet therapy and ASA + clopidogrel + OAC therapy., Conclusion: Impaired pharmacodynamic response to clopidogrel was more frequent as HTPR to ASA. Hence, ASA should be tested in combination with OAC post-PCI., (© 2022 The Author(s). Published by S. Karger AG, Basel.)

Pharmacogenomics has long lacked dedicated studies in African Americans, resulting in a lack of indepth data in this populations. The ACCOuNT consortium has collected a cohort of 167 African American patients on steady state clopidogrel with the goal of discovering population specific variation that may contribute to the response of this anti-platelet agent. Here we analyze the role of both global and local ancestry on the clinical phenotypes of P2Y12 reaction units (PRU) and high on-treatment platelet reactivity (HTPR) in this cohort. We found that local ancestry at the TSS of three genes, IRS-1, ABCB1 and KDR were nominally associated with PRU, and local ancestry-adjusted SNP association identified variants in ITGA2 associated to increased PRU. These finding help to explain the variability in drug response seen in African Americans, especially as few studies on genes outside of CYP2C19 has been conducted in this population.

In the late 1990s, the antithrombotic antiplatelet agent, clopidogrel, a P2Y12 inhibitor, was introduced. Around the same time, there was an increase in a number of new methods to measure platelet function (e.g., PFA-100 in 1995), and this has continued. It became evident that not all patients responded to clopidogrel in the same way and that some patients had a relative "resistance" to therapy, termed "high on-treatment platelet reactivity." This then led to some publications to advocate platelet function testing being used for patients on antiplatelet therapy. Platelet function testing was also suggested for use in patients awaiting cardiac surgery after stopping their antiplatelet therapy as a way of balancing thrombotic risk pre-surgery and bleeding risk perioperatively. This chapter will discuss some of the commonly used platelet function tests used in these settings, particularly those that are sometimes referred to as point-of-care tests or that require minimal laboratory sample manipulation. The latest guidance and recommendations for platelet function testing will be discussed following several clinical trials looking at the usefulness of platelet function testing in these clinical settings., (© 2023. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Background and Objectives: Dual antiplatelet therapy (DAPT) is essential in the treatment of patients with acute coronary syndrome (ACS). The objective of this study was to evaluate the effectiveness of antiplatelet medication in our practice and to investigate the factors that influence it. Materials and Methods: A prospective cohort observational study was conducted, in which 193 patients with ACS were enrolled. The patients were stented in the catheterization laboratory between May 2019 and October 2020, before and during the COVID-19 pandemic, and were receiving DAPT. Their platelet functions were tested using a Multiplate Analyzer. In addition to this, clinical data, demographics, laboratory tests, and cardiovascular risk factors were also analyzed. Results: 43.46% of the patients treated with aspirin were found to be resistant to it. This phenomenon was more common in men (48.17% vs. 31.48%, p = 0.036), and it was associated with being under the age of 50 (OR: 2.08; 95% CI: 1.11-3.90) and weighing over 70 kg (OR: 3.00; 95% CI: 1.21-7.40). Most of the patients treated with clopidogrel were in the optimal treatment window, while about half of the patients treated with ticagrelor had an exaggerated pharmacological response. Among the laboratory parameters, leukocytosis and platelet count were found to be determinants of platelet reactivity for both the aspirin and ticagrelor treatments. Conclusions: Many patients treated with antiplatelet agents are outside of the treatment window. The results obtained showed that low doses of gastro-resistant aspirin tablets are ineffective, and their efficacy can be influenced by various clinical and laboratory factors. Patients receiving ticagrelor have significantly reduced platelet reactivity, influenced only by certain laboratory indicators. The pandemic significantly influenced the results of the platelet aggregation tests only in patients treated with clopidogrel.

What Is Known and Objectives: Bleeding is the most common adverse reaction to aspirin and can lead to drug discontinuation or even be life-threatening in the secondary prevention of stroke or transient ischemic attack. The aim of this study was to evaluate risk factors for bleeding adverse reaction of aspirin in ischemic stroke or transient ischemic attack., Methods: This retrospective analysis included patients treated with aspirin (100 mg) as a secondary prevention for ischemic stroke or transient ischemic attack. The bleeding events that occurred during the first year were collected, including gastrointestinal, skin, nasal cavity, gum, and urinary tract bleeding events. Then, univariate and multivariate logistic regression analyses were used to identify independent factors associated with bleeding events of aspirin., Results and Discussion: A total of 578 patients were enrolled in this study, and 58 patients developed bleeding during the first year of secondary prevention. Body weight and combination with selective serotonin reuptake inhibitors were found to be significant risk factors for overall bleeding (p = 0.025 and 0.012). Body weight below 60 kg was a risk factor for overall bleeding and gastrointestinal bleeding events., What Is New and Conclusion: Patients weighing less than 60 kg were at increased risk of bleeding with 100 mg aspirin for secondary prevention of cerebral infarction transient ischemic attack., (© 2022 John Wiley & Sons Ltd.)

Background: Inflammation increases the risk of thrombosis in coronary artery disease (CAD) patients and affects the antiplatelet efficacy of clopidogrel. C1q interacts with platelets to activate platelets and induce thrombosis by participating in and regulating the inflammatory response. Whether C1q affects adenosine diphosphate (ADP)-induced platelet reactivity during clopidogrel therapy was unclear and our study aimed to explore the issue., Method: We enrolled 1,334 CAD patients receiving clopidogrel therapy and evaluated the association between C1q level and high residual platelet reactivity (HRPR) using logistic regression and restricted cubic spline (RCS). HRPR was defined as ADP-induced maximum amplitude (MA ADP ) > 47 mm plus ADP-induced platelet aggregation (ADP i ) < 50%., Results: A total of 516 patients (38.7%) performed HRPR. The frequency of HRPR increases with the increase in C1q level (26.3%, 38.4%, 43.2%, and 46.7% for the 1st to 4th quartile of C1q). The result of multivariate logistic regression demonstrated elevated C1q as an independent predictor for HRPR (2 nd quartile: OR = 1.722, 95% CI 1.215-2.440; 3 rd quartile: OR = 2.015, 95% CI 1.413-2.874; 4 th quartile: OR = 2.362, 95% CI 1.631-3.421, compared to the 1st quartile). RCS depicted the nonlinear relationship between C1q and HRPR risk ( p for non-linear < 0.05)., Conclusion: The current research is the first to explore the association of C1q and ADP-induced platelet reactivity and to demonstrate elevated C1q as an independent risk factor for HRPR in CAD patients during clopidogrel therapy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zhao, Ma, Huang, Sun, Han, Yang and Zhou.)

Background: The impact of 1-month dual antiplatelet therapy (DAPT) followed by aspirin monotherapy according to clinical presentation has not been elucidated., Aims: This study aimed to compare the impact of 1-month DAPT followed by aspirin monotherapy after polymer-free drug-coated stent (PF-DCS) implantation (1-month DAPT after PF-DCS) vs 6-12-month DAPT followed by aspirin monotherapy after biodegradable polymer drug-eluting stent (BP-DES) implantation (6-12-month DAPT after BP-DES) according to clinical presentation., Methods: This is a post hoc analysis of the One-Month DAPT trial. The primary outcome was the composite of major adverse cardiac and cerebrovascular events (MACCE; a composite of cardiac death, non-fatal myocardial infarction, target vessel revascularisation, and stroke) and major bleeding., Results: Among 1,828 patients with stable coronary artery disease (CAD), 1-month DAPT after PF-DCS resulted in lower rates of the primary outcome than 6-12-month DAPT after BP-DES (3.9% vs 6.5%; hazard ratio [HR] 0.59, 95% confidence interval [CI]: 0.39-0.90; p=0.012). However, among 1,192 patients with acute coronary syndrome (ACS), the rates of the primary outcome were not significantly different between the two therapy groups (5.6% vs 3.6%; HR 1.57, 95% CI: 0.91-2.70; p=0.102) and a significant interaction was observed between therapy and clinical presentation regarding the primary outcome (P int =0.005). A significant interaction was observed in MACCE (P int =0.016), but not in major bleeding (P int =0.276)., Conclusions: In patients undergoing drug-eluting stent implantation for non-complex lesions, the benefits of 1-month DAPT followed by aspirin monotherapy for a composite of ischaemic and bleeding outcomes were found in patients with stable CAD, but not in those with ACS., Clinicaltrials: gov: NCT02513810.

BACKGROUND This study aimed to investigate the optimum time to reintroduce the original antiplatelet drugs after upper gastrointestinal hemorrhage in patients as secondary prevention for cardiovascular and cerebrovascular diseases. MATERIAL AND METHODS After the upper gastrointestinal bleeding stopped, patients were randomly divided according to the oral antiplatelet drugs administered. The aspirin group was further divided into 3-day and 7-day aspirin groups. The patients who took aspirin and clopidogrel were randomly divided into 3 groups: 0-day aspirin+3-day clopidogrel; 0-day aspirin+7-day clopidogrel; and 3-day aspirin+7-day clopidogrel. The recovery time, rebleeding rate, incidence of cardiovascular and cerebrovascular events, and death were observed. RESULTS The 3-day aspirin group had more rebleeding, reduced risk of cardiovascular and cerebrovascular events, and a similar mortality rate compared to the other groups. In the aspirin+clopidogrel group, the 0-day aspirin+3-day clopidogrel group had the highest rebleeding rate and the lowest risk of cardiovascular and cerebrovascular events. The 3-day aspirin+7-day clopidogrel group had the highest risk of cardiovascular and cerebrovascular events and increased hospitalization time. The risk of rebleeding and cardiovascular and cerebrovascular events was lower in the 0-day aspirin+7-day clopidogrel group, and the overall mortality rate was the lowest in this group. CONCLUSIONS In patients receiving only aspirin, this drug should be reintroduced as soon as possible after peptic ulcer hemorrhage. Aspirin and clopidogrel are dual antiplatelet drugs used for the secondary prevention of cardiovascular diseases. In patients under dual-drug therapy, aspirin should not be stopped, while clopidogrel should be restarted in about 7 days.

Evidence assessing potential diurnal variations of platelet reactivity in patients on clopidogrel treated with elective percutaneous coronary intervention (PCI) for chronic coronary syndrome (CCS) are currently lacking. We prospectively enrolled 15 patients affected by stable coronary artery disease (CAD) previously treated with elective PCI and on clopidogrel for at least 8 days (administered at 8 a.m.). A significant heterogeneity in diurnal levels of ADP-dependent platelet aggregation was found (p = 0.0004), with a peak of platelet reactivity occurring at the 6 a.m. assessment, which resulted significantly increased compared to the afternoon (6 p.m.) evaluation (255 ± 66 vs 184 ± 67, p = 0.002). In addition, at the early-morning evaluation a considerably high proportion of patients with high platelet reactivity (53.3%) were observed. In conclusion, clopidogrel-induced platelet inhibition in patients with CCS after elective PCI follows a circadian rhythm, thus suggesting that a consistent and durable antiplatelet inhibition is often failed with standard clopidogrel administration at morning., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)