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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.)

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.

CYP2C19 gene has multiple single nucleotide polymorphism (SNP), which is the major determinant for clopidogrel treatment responses. Therefore, CYP2C19 SNP detection is essential for predicting clopidogrel efficacy. Currently, there is still no quick and effective method for routine detection of common CYP2C19 SNPs in clinical laboratories, which is critically needed prior to clopidogrel treatment. AllGlo™ based quantitative PCR was used to develop a novel genotyping method for CYP2C19 SNP detection, termed CyPAllGlo. The performance of CyPAllGlo was compared with that of the commonly used fluorescence in situ hybridization (FISH) method, and the data was verified by DNA sequencing. CyPallGlo was used to identify CYP2C19 polymorphisms in 363 patients with coronary heart disease. The univariate analysis was used to access the antiplatelet efficacy of clopidogrel in patients. The associations between CYP2C19 polymorphisms and clopidogrel efficacy were analyzed. Using CyPAllGlo to detect CYP2C19*2 and CYP2C19*3 alleles was highly specific and fast. The detection limit was approximately 0.07 µg/µl and 0.7 µg/µl for CYP2C19*2 and CYP2C19*3, respectively. The consistency between FISH and CyPAllGlo were 98.07% for CYP2C19*2 and 99.17% for CYP2C19*3. DNA sequencing showed that the accuracy of CyPAllGlo was 100%. The analysis time for the whole CyPAllGlo procedure was approximately 60 min. Univariate analysis showed that the anticoagulation efficacy of clopidogrel was related to patient age, CYP2C19 genotype, metabolic phenotype, and LDL level. The logistic regression analysis showed that the genotype of CYP2C19 and metabolic phenotype was the two risk factors for clopidogrel antiplatelet ineffectiveness. This novel CyPAllGlo is a rapid and accurate method for detection of CYP2C19 SNP. The specificity and consistency of CyPAllGlo are comparable with that of widely used DNA sequencing. These findings provide valuable rapid method for predicting clopidogrel efficacy, which can be quickly translated to improve personalized precision medicine for coronary heart disease treatment., (© 2024. The Author(s).)

Most proton pump inhibitors (PPIs) inhibit the bioactivation of clopidogrel to its active metabolite. There is controversy concerning whether PPIs alter the effectiveness of clopidogrel in reducing the risk of ischemic stroke (IS). We therefore aimed to examine the risk of IS associated with concomitant use of clopidogrel and omeprazole, a PPI commonly used in clinical settings. We conducted a retrospective cohort study using the National Health Insurance Research Database of Taiwan dated from 2000 to 2013. The study cohorts comprised 407 patients diagnosed with acute coronary syndrome (ACS) and with concomitant use of clopidogrel and omeprazole (the exposed cohort), 814 ACS patients with single use of clopidogrel (the comparison cohort), and 230 ACS patients with concurrent use of clopidogrel and pantoprazole (the reference cohort). The primary outcome was incident IS. The hazard ratios (HRs) and 95% confidence intervals (CIs) derived from the time-dependent Cox regression model were used to assess the association between concomitant use of clopidogrel and omeprazole and the risk of IS. The incidence rate of IS was significantly higher in the exposed cohort (81.67 per 1000 person-years) than in the comparison cohort (57.45 per 1000 person-years), resulting in an adjusted HR of 1.39 (95% CI 1.03-1.74). By contrast, there was no significant difference in the risk of IS between the exposed and reference cohorts (adjusted HR 1.11; 95% CI 0.81-1.52). The present study revealed that patients taking both clopidogrel and omeprazole was associated with an increased risk of IS., (© 2024. The Author(s).)

Stent thrombosis (ST) is a fatal complication after percutaneous coronary intervention (PCI). The association between P2Y12 reaction unit (PRU) level and stent thrombosis occurrence remains unclear. Based on the multicenter, observational PTRG-DES (Platelet function and genoType-Related long-term proGnosis in DES-treated patients) registry of patients with drug-eluting stents (DES) implantation, a total of 11,714 patients with PRU values were analyzed. We sought to identify the predictors of early stent thrombosis (EST) and compared the primary outcome, a composite of cardiac death, myocardial infarction, and revascularization, between EST and non-EST groups. EST, defined as definite ST within 1 month after index PCI, occurred in 51 patients. PRU values were significantly higher in the EST group (263.5 ± 70.8 vs. 217.5 ± 78.7, p < 0.001). In multivariable analysis, PRU ≥ 252 (OR, 5.10; 95% CI 1.58-16.46; p = 0.006) and aspirin reaction unit ≥ 414 (OR 4.85; 95% CI 1.07-21.97; p = 0.040) were independent predictors of EST. The cumulative incidence of primary composite outcome at one year was significantly higher in the EST group (38.2% vs. 3.9%, Log-rank p < 0.001). In patients treated with clopidogrel after successful DES implantation, EST was associated with higher platelet reactivities, and a greater risk of cardiovascular events.Trial Registration: clinicaltrials.gov Identifier: NCT04734028., (© 2024. The Author(s).)

It is believed, but not well established, that renal dysfunction increases the risk of adverse bleeding events associated with dual antiplatelet therapy (DAPT), especially in patients with acute coronary syndrome (ACS). The aim of this study is to estimate the impact of renal function on adverse bleeding events associated with DAPT in patients with ACS. A total of 1,264 ACS patients who received DAPT, clopidogrel (n = 530) or prasugrel (n = 734) in addition to aspirin, were assessed in a multicenter observational study. The relationship between renal function and bleeding event, defined as BARC 3 or 5, was determined using a marginal effect from the logit model and Royston-Parmar model. During an average 313.1 days of the observation period, defined as the duration of DAPT after admission until the implementation of a change in the regimen, bleeding events were observed in 7.4% of patients (n = 94). The estimated curves demonstrated that the probability of bleeding was positive correlated with renal dysfunction (6.0 to 8.6), regardless of the DAPT regimen used. This probability was consistently higher in clopidogrel (7.4 to 10.5) than in prasugrel (4.8 to 0.7). This trend was also shown in maintenance hemodialysis patients (6.7 vs. 10.3). Estimated cumulative incidences among individual stages of renal function were drawn. In conclusion, bleeding events increased with worsening renal function, and prasugrel is safer than clopidogrel as a component of DAPT throughout all levels of renal function, including hemodialysis patients after ACS., (© 2023. The Author(s) under exclusive licence to Japanese Association of Cardiovascular Intervention and Therapeutics.)

Background: Both clopidogrel and atorvastatin metabolism are rooted in hepatic cytochrome p450 activation. There are published reports of atorvastatin interfering with clopidogrel metabolism by inhibiting the activation of clopidogrel. This in turn would decrease the therapeutic effect of clopidogrel potentially resulting in an increase in thrombotic events in patients who are taking both medications. The emergence of viscoelastic assays, such as Thromboelastography with platelet mapping (TEG-PM), has been utilized to identify prothrombotic states and may provide insight into a patient's microvascular coagulation profile. The aim of this prospective, observational study was to delineate the differences in platelet function between patients on clopidogrel alone versus those on clopidogrel and atorvastatin in patients that are undergoing peripheral revascularization., Methods: All patients undergoing revascularization between December 2020 and August 2022 were prospectively evaluated. Patients on clopidogrel and atorvastatin were compared to those on clopidogrel alone. Serial perioperative TEG-PM analysis was performed up to 6 months postoperatively and the platelet function in terms of percent inhibition was evaluated in both groups. Statistical analysis was performed using unpaired t-test to identify differences in platelet function., Results: Over the study period, a total of 182 patients were enrolled. Of this cohort 72 patients met study criteria. 87 samples from the 72 patients were analyzed. 31 (43.05%) patients were on clopidogrel alone and 41 (56.94%) were on clopidogrel and atorvastatin. Patients on clopidogrel alone showed significantly greater platelet inhibition compared to those on clopidogrel and atorvastatin [49.01% vs. 34.54%, P = 0.03]. There was no statistical difference in platelet inhibition between groups in terms of aspirin use alone versus aspirin and atorvastatin., Conclusions: Patients on clopidogrel and atorvastatin showed significantly less platelet inhibition compared to those on clopidogrel alone, supporting the concept that atorvastatin may interfere with the therapeutic effect of clopidogrel. Patients taking atorvastatin may require an alternative antiplatelet therapy regimen that does not include clopidogrel to achieve adequate thromboprophylaxis., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Aims: The role of cilostazol after intracranial or extracranial artery stent implantation is still unclear. Therefore, we designed this trial to explore the efficacy and safety of cilostazol in this particular population., Methods: In this retrospective study, patients were divided into the cilostazol or clopidogrel group by the antiplatelet therapy received after artery stent implantation. The primary efficacy endpoint was ischemic stroke. Bleeding events and other antiplatelet drug-related adverse reactions (ADRs) were also recorded. Neurological function prognosis was evaluated by the modified Rankin Scale (mRS) after discharge., Results: A total of 156 patients were enrolled; 56 underwent intracranial artery stenting, 95 underwent extracranial artery stenting, and 5 underwent intracranial combined with extracranial artery stenting. Any stroke and bleeding events in the hospital of the two groups were comparable (P=0.38, P=0.34, respectively). The incidence of stroke recurrence tended to be lower in the cilostazol group, although not significant (cilostazol vs. clopidogrel, 1.35% vs. 4.88%, P=0.25). There was a significant difference of any bleeding events between the two groups (cilostazol vs. clopidogrel, 5.41% vs. 20.73%, P=0.02). During follow-up, we did not observe an apparent increase of ADRs in the cilostazol group (cilostazol vs. clopidogrel, palpitation 4.05% vs. 2.44%, P=0.58; gastrointestinal discomfort events 8.11% vs. 12.20%, P=0.80). There were no differences between the two groups of neurological function prognosis (P=0.29)., Conclusions: Cilostazol-based dual antiplatelet therapy could be recommended as an effective and safe therapy regimen among patients undergoing intracranial or extracranial artery stent implantation.

Background: To investigate the risk factors for gastrointestinal bleeding in patients with cerebral infarction after dual antiplatelet therapy., Methods: Cerebral infarction patients who received dual antiplatelet therapy during January 2019 and December 2021 in Nanchang University Affiliated Ganzhou Hospital were included. Patients were divided into a bleeding group and a nonbleeding group. Propensity score matching was used to match the data between the two groups. The risk factors for cerebral infarction with gastrointestinal bleeding after receiving dual antiplatelet therapy were analyzed by conditional logistic regression., Results: There were 2370 cerebral infarction patients who received dual antiplatelet therapy included in the study. There were significant differences between the bleeding group and the nonbleeding group in terms of sex, age, smoking, drinking, hypertension, coronary heart disease, diabetes and peptic ulcer before matching. After matching, 85 patients were included in the bleeding group and nonbleeding group, and there was no significant difference between the two groups in terms of sex, age, smoking, drinking, previous cerebral infarction, hypertension, coronary heart disease, diabetes, gout or peptic ulcer. Conditional logistic regression analysis showed that long-term use of aspirin and severity of cerebral infarction were risk factors for gastrointestinal bleeding in cerebral infarction patients receiving dual antiplatelet therapy, whereas the use of PPI was a protective factor against gastrointestinal bleeding., Conclusions: Long-term use of aspirin and severity of cerebral infarction are risk factors for gastrointestinal bleeding in cerebral infarction patients receiving dual antiplatelet therapy. The use of PPIs could reduce the risk of gastrointestinal bleeding., Competing Interests: Declaration of Competing interest Authors declare no Conflict of Interests for this article., (Copyright © 2023. Published by Elsevier B.V.)

Objective: The aim of this study was to evaluate the use of clopidogrel at the time of carotid endarterectomy (CEA) and its association with postoperative complications., Methods: Single-institution, retrospective review of a prospective database., Results: From 2010 to 2017, CEA was performed in 1066 consecutive patients (median age, 73 years; 66% men). The indications for operation included ≥70% asymptomatic stenosis (458; 43%), prior stroke (314; 29%), and transient cerebral or retinal ischemia (294; 28%). At the time of operation, 509 (48%) patients were taking aspirin alone, 441 (41%) were taking clopidogrel (374 in combination with aspirin, 67 as sole therapy), 83 (8%) were on no documented antiplatelet medication, and 33 (3%) were taking warfarin (with therapeutic international normalized ratio). The likelihood of clopidogrel use at the time of operation was higher for patients with a history of symptomatic carotid disease (P = .002). Over the study period, clopidogrel use increased from 31.9% in 2010 to 56.8% in 2017, which corresponds to an 11% (95% confidence interval, 6%-15%) increase annually. Postoperative strokes occurred in 15 patients (overall incidence, 1.4%), the majority of which were minor (12/15; 80%). Six strokes occurred in patients taking aspirin alone (6/509; 1.2%), two in patients on clopidogrel and aspirin (2/441; 0.5%), two in patients taking clopidogrel alone (2/67; 2.9%), three in patients on no documented antiplatelet medication (3/83; 3.6%), and two in those taking warfarin (one of which was secondary to a fatal intracranial hemorrhage within 30 days of discharge [2/33; 6.1%]). The 30-day mortality rate was 0.03% (3/1066); the risk for the combined endpoint of any stroke, death, or myocardial infarction (MI) was 2.3% (25/1066), and the risk for major stroke, death, or MI was 1.2%. There was no apparent association between clopidogrel use and the incidence of postoperative bleeding (P = .59) or any other postoperative complication (stroke, death, MI, cranial nerve injury; P = .15)., Conclusions: Clopidogrel use in our CEA practice has increased over time and has not been associated with an increased risk of postoperative complications, including bleeding. These data suggest that clopidogrel should not be discontinued prior to CEA and should be considered as part of 'optimal medical therapy' in patients undergoing CEA., (Copyright © 2023 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Background and Purpose: Prophylactic prasugrel for endovascular treatment of intracranial aneurysms has been introduced and increased, but HTPR (high on-treatment platelet reactivity) or LTPR (low on-treatment platelet reactivity) of prasugrel is not uncommon in clinical circumstances. To investigate the predisposing factors of HTPR and LTPR on prasugrel premedication in the neurointerventional field and to determine its clinical implications., Materials and Methods: Between February 2016 and December 2020, 191 patients treated with coil embolization using prophylactic prasugrel in 234 intracranial aneurysms were the final candidates for this study. Patient and aneurysm characteristics, clinical status, and laboratory study values were carefully reviewed retrospectively. We performed risk factor analyses for HTPR and LTPR on prasugrel., Results: Ultimately, 20 patients (10.5%) had HTPR, and 74 patients (38.7%) were categorized as having LTPR. In multivariable analyses, the factors related to HTPR were BMI (adjusted OR 1.21, 95% CI 1.04-1.41, p = 0.01), history of antithrombotics (adjusted OR 3.79, 95% CI 1.39-10.34, p = 0.01), and hematocrit (adjusted OR 0.91, 95% CI 0.84-0.99, p = 0.03). Low BMI was the only risk factor for LTPR (adjusted OR 0.84, 95% CI 0.76-0.94, p = 0.001)., Conclusion: In the neurointerventional field, high BMI and prior use of antithrombotic agents were related to HTPR, and low BMI was associated with LTPR on prophylactic prasugrel. High hematocrit levels decreased the risk of HTPR. When preparing endovascular treatment for intracranial aneurysms, attention to patients with these clinical features is required to address the possibility of ischemic or bleeding complications., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Hong 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: No study has so far evaluated the impact of chronic kidney disease (CKD) on high-on treatment platelet reactivity (HRPR) with ticagrelor and their prognostic consequences, that were therefore the aim of the present study., Methods: Patients on dual antiplatelet therapy with ASA+ticagrelor (90mg/twice a day) after percutaneous coronary revascularization for ACS were scheduled for platelet function assessment 30-90 days post-discharge. The primary study endpoint was defined as the occurrence of major cardiovascular events (a composite of cardiovascular death, recurrent acute coronary syndrome (MI), target vessel revascularization) at the longest available follow-up., Results: We included 396 patients, that were divided according to CKD (eGFR

Purpose: Insulin resistance and β-cell dysfunction are fundamental defects contributing to type 2 diabetes development. Prior studies indicated that insulin resistance may be correlated with low responsiveness to clopidogrel. This study aimed to investigate the effects of β-cell function on clopidogrel-induced platelet P2Y12 inhibition and the clinical outcomes of nondiabetic patients undergoing elective percutaneous coronary intervention (PCI)., Methods: Patients scheduled to undergo elective PCI and receive clopidogrel in addition to aspirin were recruited for this study. Homeostatic model assessment 2 of β-cell function (HOMA2-β%) was used to classify participants into quartiles. Thromboelastography (TEG) was used to calculate the quantitative platelet inhibition rate to assess clopidogrel-induced antiplatelet reactivity. The clinical outcome was major adverse cardiovascular and cerebrovascular events (MACCEs)., Results: Of the 784 participants evaluated, 21.3% of them (169 of 784) had low responsiveness to clopidogrel. According to multivariate linear regression analysis, the first quartile of HOMA2-β% (19.9-78.1), indicating greater β-cell dysfunction, was independently associated with low responsiveness to clopidogrel compared with the fourth quartile (126.8-326.2) after adjustment for potential covariates [odds ratio 2.140, 95% confidence interval (CI) (1.336 to 3.570), P = 0.038]. In addition, at one year, the first quartile of HOMA2-β% was associated with an increased risk of 1-year MACCE occurrence compared with the fourth quartile [adjusted hazard ratio 4.989, 95% CI (1.571 to 15.845), P = 0.006]., Conclusion: Increased β-cell dysfunction, indicated by a low HOMA2-β%, was associated with low responsiveness to clopidogrel and an increased risk of one-year MACCEs in nondiabetic patients undergoing elective PCI., (© 2021. Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Although there is a growing body of evidence that CYP2C19 genotyping can be beneficial when considering treatment with clopidogrel after percutaneous coronary intervention (PCI), whether a genotype-guided strategy can be generally adopted in routine practice remains unclear among East Asians., Objectives: This study sought to investigate long-term outcomes of patients undergoing clopidogrel-based antiplatelet therapy after drug-eluting stent (DES) implantation according to CYP2C19 genotypes., Methods: From the nationwide multicenter PTRG-DES (Platelet function and genoType-Related long-term proGnosis in DES-treated patients) consortium, patients who underwent CYP2C19 genotyping were selected and classified according to CYP2C19 loss-of-function allele: rapid metabolizers (RMs) or normal metabolizers (NMs) vs intermediate metabolizers (IMs) or poor metabolizers (PMs). The primary outcome was a composite of cardiac death, myocardial infarction, and stent thrombosis at 5 years after the index procedure., Results: Of 8,163 patients with CYP2C19 genotyping, 56.7% presented with acute coronary syndrome. There were 3,098 (37.9%) in the RM or NM group, 3,906 (47.9%) in the IM group, and 1,159 (14.2%) in the PM group. IMs or PMs were associated with an increased risk of 5-year primary outcome compared with RMs or NMs (HR adj : 1.42; 95% CI: 1.01-1.98; P = 0.041), and the effect was more pronounced in the first year (HR adj : 1.67; 95% CI: 1.10-2.55; P = 0.016). The prognostic implication of being an IM and PM was significant in acute coronary syndrome patients (HR adj : 1.88; 95% CI: 1.20-2.93; P = 0.005) but not in those with stable angina (HR adj : 0.92; 95% CI: 0.54-1.55; P = 0.751) (interaction P = 0.028)., Conclusions: Among East Asians with clopidogrel-based antiplatelet therapy after DES implantation, CYP2C19 genotyping could stratify patients who were likely to have an increased risk of atherothrombotic events. (Platelet Function and genoType-Related Long-term progGosis in DES-treated Patients: A Consortium From Multi-centered Registries [PTRG-DES]; NCT04734028)., Competing Interests: Funding Support and Author Disclosures The study was sponsored by the Platelet-Thrombosis Research Group under the Korean Society of Intervention Cardiology. Dr Jeong has received honoraria for lectures from AstraZeneca, Daiichi Sankyo, Sanofi, Han-mi Pharmaceuticals, and Yuhan Pharmaceuticals; and research grants or support from Yuhan Pharmaceuticals and U&I Corporation. Dr Joo has received honoraria for lectures from AstraZeneca, Hanmi, Samjin, Dong-A, HK inno. N Pharmaceuticals, and DIO Medical Ltd. Dr Song has received honoraria for lectures from AstraZeneca, Daiichi Sankyo, Sanofi, Bayer Korea, and Samjin Pharmaceutical. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Clopidogrel resistance is a well-described phenomenon that has been linked to adverse cardiovascular events in patients with coronary artery disease. The impact of clopidogrel resistance in patient outcomes after vascular and endovascular surgery is not well-established., Methods: Using preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines, a literature review with the medical subject headings (MeSH) terms "(clopidogrel resistance) and (vascular)", "(clopidogrel resistance) and (vascular surgery)", "(clopidogrel resistance) and (endovascular)", and "(clopidogrel resistance) and (endovascular surgery)" was performed in PubMed and Cochrane databases, to identify all peer-reviewed studies performed on clopidogrel resistance in vascular and endovascular surgery. Studies written in the English language from inception to 2022 were included. Case reports, studies with limited information, nonhuman studies, and studies not pertaining to vascular or endovascular surgery were excluded from analysis. Each study was independently reviewed by 2 qualified researchers to assess eligibility., Results: Of the 691 studies identified through the MeSH strategy, 16 studies met the inclusion criteria and were reviewed and summarized. These studies focused on extracranial cerebrovascular disease (n = 5) and peripheral arterial disease (PAD, n = 11), encompassing a total of 1,716 patients. The prevalence of clopidogrel resistance ranged from 0% to 83.3%, depending on the diagnostic assay and cutoff values used. In cerebrovascular disease, clopidogrel resistance may be associated with cerebral embolization, ischemic neurologic events, and vascular-related mortality. In PAD, clopidogrel resistance has been linked to recurrent stent thrombosis, target lesion revascularization, amputation-free survival, and all-cause mortality., Conclusions: This systematic review provides an up-to-date summary of clopidogrel resistance in vascular and endovascular surgery. The impact of clopidogrel resistance remains incompletely investigated, and future studies are needed to clarify the role of resistance testing in patients with vascular disease., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Thrombotic thrombocytopenic purpura (TTP) is a rare variant of thrombotic microangiopathy. We report a case of TTP in a Nigerian chronic kidney disease (CKD) patient who was previously on clopidogrel. The features of TTP resolved soon after clopidogrel was withdrawn. Clopidogrel is a cardio-protective anti-platelet drug used in CKD patients at risk of dyspepsia. However, its potential to cause TTP should be recognized and considered in acute kidney injury (AKI) patients previously on clopidogrel., (© 2023 Ndulue CN et al.)

Background: The effect of multiple mutations in CYP2C19 , PON1 and ABCB1 genes on the effectiveness and safety of dual antiplatelet therapy after percutaneous coronary intervention remains unclear. Methods: In total, 263 Chinese Han patients were enrolled in this study. Platelet aggregation rates and thrombosis risk were used to compare clopidogrel responses and outcomes in patients with different numbers of genetic mutations. Results: Our study demonstrated that 74% of the patients carried more than two genetic mutations. High platelet aggregation rates were associated with genetic mutations in patients receiving clopidogrel and aspirin after percutaneous coronary intervention. Genetic mutations were closely related to the recurrence of thrombotic events, but not bleeding. The number of genes that become dysfunctional in patients is directly correlated with the risk of recurrent thrombosis. Conclusion: Compared with CYP2C19 alone or the platelet aggregation rate, it is more helpful to predict clinical outcomes by considering the polymorphisms of all three genes.

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

Background: No study has compared pharmacologic properties of ticagrelor and clopidogrel in non-dialysis patients with stage 4-5 chronic kidney disease (CKD)., Methods: We conducted a double-blind RCT to compare effects of ticagrelor and clopidogrel in 48 CKD, with the primary outcome of ADP-induced platelet aggregation (WBPA) after 2 weeks of DAPT. In a parallel arm, we compared effects of 2 weeks of ticagrelor plus aspirin on mean changes in WBPA and markers of thromboinflammation among non-CKD controls (n = 26) with that of CKD in the ticagrelor-arm., Results: Average age of CKD was 53.7 years, with 62% women, 54% African American, and 42% with stage 5 CKD. Ticagrelor generated statistically lower WBPA values post treatment [median 0 Ω (IQR 0, 2)] vs. clopidogrel [median 0 Ω (IQR 0, 5)] (P = 0.002); percent inhibition of WBPA was greater (87 ± 22% vs. 63 ± 50%; P = 0.04; and plasma IL-6 levels were much lower (8.42 ± 1.73 pg/ml vs. 18.48 ± 26.56 pg/ml; P = 0.04). No differences in mean changes in WBPA between CKD-ticagrelor and control groups were observed. Ticagrelor- DAPT reduced levels of IL-1α and IL-1β in CKD-ticagrelor and control groups, attenuated lowering of TNFα and TRAIL levels in CKD-ticagrelor (vs controls), and had global changes in correlation between various cytokines in a subgroup of CKD-ticagrelor subjects not on statins (n = 10). Peak/trough levels of ticagrelor/metabolite were not different between CKD-ticagrelor and control groups., Conclusions: We report significant differences in platelet aggregation and anti-inflammatory properties between ticagrelor- and clopidogrel-based DAPT in non-dialysis people with stage 4-5 CKD. These notable inflammatory responses suggest ticagrelor-based DAPT might lower inflammatory burden of asymptomatic patients with stage 4 or 5 CKD. (clinicaltrials.gov # NCT03649711)., 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 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: There are few studies on the relationship between the occurrence of clopidogrel-related high residual platelet reactivity (HRPR) and estimated glomerular filtration rate (eGFR) at admission in patients with ischemic stroke. The aim of this study was to investigate the possible relationship between the two., Methods: Patients who were hospitalized and diagnosed with acute ischemic stroke were recruited from July 1, 2017, to June 30, 2018, at Shanghai TCM-Integrated Hospital. Renal function was measured within 24 h of enrollment and eGFR was calculated. Patients were tested for platelet reactivity using the VerifyNow system after 7 days of antiplatelet therapy with clopidogrel 75 mg/d alone, and patients with P2Y12 reaction unit values ≥230 were diagnosed with HRPR. The association between HRPR and eGFR was analyzed., Results: A total of 274 patients were enrolled in the study, of whom 91 (33.21%) had HRPR. Multivariate logistic regression analysis suggested that an increased risk of HRPR was independently associated with female sex and reduced eGFR (female sex: OR = 2.24, 95% CI: 1.26-3.99, p = 0.006; mild chronic kidney disease [CKD]: OR = 2.95, 95% CI: 1.47-5.93, p = 0.002; moderate CKD: OR = 3.07, 95% CI: 1.08-8.75, p = 0.04)., Conclusion: Decreased eGFR is an independent risk factor for the occurrence of HRPR in patients with ischemic stroke., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Background: Clopidogrel activity is influenced by cytochrome P450 (CYP450). CYP2C19 polymorphisms vary by ethnicity and region., Objective: The aim of the study is to assess the effect of genetic polymorphisms in CYP2C19*2 and *3 and clinical and demographic factors on major adverse cardiovascular events (MACE) in Kazak patients following percutaneous coronary intervention (PCI)., Methods: 397 patients with PCI treated with clopidogrel and aspirin for at least 12 months were enrolled and outcomes within 1 year were recorded. Approximately 2 ml of peripheral venous blood samples were used for genotype detection. Multivariable logistic regression analyses were performed to identify factors associated with MACE., Results: 95 patients (23.9%) suffered MACE during the period. Logistic regression analysis revealed CYP2C19*2 carriers (odds ratio [OR]: 2.431, 95% [confidence interval] CI: 1.136- 5.275, P = 0.027) and poor metabolizers (OR: 2.128, 95% CI: 0.899-4.82, P = 0.043) to be significantly associated with MACE., Conclusion: The CYP2C19*2 allele variants and poor metabolizers were found to be associated with MACE in a clopidogrel-treated Kazak population with acute coronary syndrome following PCI., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Objective: The POPular AGE trial showed that clopidogrel significantly reduced bleeding risk compared with ticagrelor without any signs of an increase in thrombotic events. The aim of this analysis was to estimate the long-term cost-effectiveness of clopidogrel compared with ticagrelor in these patients aged 70 years or older with non-ST-elevation acute coronary syndrome (NSTE-ACS)., Methods and Results: A 1-year decision tree based on the POPular AGE trial in combination with a lifelong Markov model was developed to compare clopidogrel with ticagrelor in terms of clinical outcomes, costs, and quality-adjusted life years (QALYs) in elderly patients (above 70 year) with NSTE-ACS. Cost-effectiveness was assessed from a Dutch healthcare system perspective. Events rates and utility data observed in the POPular AGE trial were combined with lifetime projections to evaluate costs and effects for a fictional cohort of 1000 patients. Treatment with clopidogrel instead of ticagrelor led to a cost saving of €1484 575 (€1485 per patient) and a decrease of 10.96 QALYs (0.011 QALY per patient) in the fictional cohort. In an alternative base case with equal distribution over health states in the first year, treatment with clopidogrel led to an increase in QALYs. In all scenario analyses, treatment with clopidogrel was cost-saving., Conclusion: Clopidogrel is a cost-saving alternative to ticagrelor in elderly patients after NSTE-ACS, though regarding overall cost-effectiveness clopidogrel was not superior to ticagrelor, as it resulted in a small negative effect on QALYs. However, based on the results of the alternative base case and clinical outcomes of the POPular AGE trial, clopidogrel could be a reasonable alternative to ticagrelor for elderly NSTE-ACS patients with a higher bleeding risk., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Purpose: Due to shared hepatic metabolism, concomitant medication with a proton pump inhibitor (PPI) and clopidogrel might reduce the effectiveness of clopidogrel in the prevention of cardiovascular events after percutaneous coronary intervention (PCI). We aimed to examine the risk of major cardiovascular events after PCI comparing patients who used clopidogrel together with PPI with those who used clopidogrel alone., Methods: This Swedish nationwide cohort study included patients who received clopidogrel after primary PCI in 2005-2019. Patients were followed for up to 12 months after PCI. Data were retrieved from the Swedish Prescribed Drug Registry, Patient Registry, Cancer Registry, and Cause of Death Registry. Multivariable Cox regression provided hazard ratios (HRs) with 95% confidence intervals (CIs) for cardiovascular events comparing PPI users (exposed) with non-users of PPI (non-exposed). The HRs were adjusted for sex, age, comorbidity, calendar period, obesity, diabetes, anti-diabetic medication, tobacco-related diseases, hypertension, and congestive heart failure., Results: The cohort included 99,836 patients who received clopidogrel after primary PCI. Among these, 35,772 (35.8%) received concomitant PPI. Compared to non-users, PPI users had increased adjusted HRs of all study outcomes, i.e., the main outcome myocardial infarction (HR = 1.23, 95% CI 1.15-1.32) and the secondary outcomes coronary heart disease (HR = 1.28, 95% CI 1.24-1.33), stroke (HR = 1.21, 95% CI 1.05-1.40), and death due to coronary heart disease (HR = 1.52, 95% CI 1.37-1.69). The results were similar in analyses including both primary and secondary PCIs., Conclusions: In patients who receive clopidogrel after PCI, concomitant use of PPI seems to increase the risk of major cardiovascular events., (© 2021. The Author(s).)

Introduction: Clopidogrel is the only antiplatelet agent whose activity is significantly affected by CYP2C19 polymorphism., Areas Covered: This review has summarized the available evidence on the clinically significant association between CYP2C19 polymorphism and clopidogrel-based therapy; reviewed the current recommendations for clinical use of CYP2C19 genotype test results in patients on clopidogrel treatment; and discussed possible pitfalls of routine application, and future perspectives of antiplatelets pharmacogenetics., Expert Opinion: The available body of evidence, reflected in several meta-analyses and high-quality clinical practice guidelines, shows that the presence of CYP2C19 LOF alleles, especially CYP2C19*2 , correlates with impaired activation of clopidogrel and variable platelet inhibition, followed by minimal or no antiplatelet effect, and higher risk of treatment failure. In combination with other known risk factors, CYP2C19 genetic testing could be very valuable in predicting low clopidogrel efficacy. At the same time, it could be very successful in selecting patients who will most probably benefit from the clopidogrel-based therapy, thus decreasing the pool of those who might need more expensive and otherwise riskier antiplatelet alternatives.

The ABCD-GENE score was constructed to identify patients with high platelet reactivity (HPR) after 30 days of clopidogrel treatment. In our study, 1297 eligible patients with acute coronary syndrome (ACS) were included, and 44 (3.4%) major adverse cardiovascular events (MACEs) occurred during the 12-month clopidogrel treatment. The score with a cutoff of ≥ 10 was independently associated with the risk of 5-day HPR (adjusted HR: 1.73, 95% CI: 1.09-2.74, P = 0.020) and MACEs (adjusted HR: 2.25, 95% CI: 1.19-4.25, P = 0.013). The risk of MACEs increased when the multivariable model with the score (≥ 10) plus 5-day HPR was used (adjusted HR: 4.37, 95% CI: 1.90-10.10, P = 0.001). The c-statistic for MACEs was 0.60 when using the score threshold of ≥ 10 and 0.63 when using the model with the score plus 5-day HPR. As a simple tool, the ABCD-GENE score could identify clopidogrel-treated Chinese patients with ACS who are at increased risk of MACEs. The addition of 5-day HPR could slightly improve the diagnostic ability of the score., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

CYP2C19 catalyzes the bioactivation of the antiplatelet prodrug clopidogrel, and CYP2C19 genotype impacts clopidogrel active metabolite formation. CYP2C19 intermediate and poor metabolizers who receive clopidogrel experience reduced platelet inhibition and increased risk for major adverse cardiovascular and cerebrovascular events. This guideline is an update to the 2013 Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for the use of clopidogrel based on CYP2C19 genotype and includes expanded indications for CYP2C19 genotype-guided antiplatelet therapy, increased strength of recommendation for CYP2C19 intermediate metabolizers, updated CYP2C19 genotype to phenotype translation, and evidence from an expanded literature review (updates at www.cpicpgx.org)., (© 2022 The Authors. Clinical Pharmacology & Therapeutics © 2022 American Society for Clinical Pharmacology and Therapeutics.)

Purpose of Review: The benefit of using antiplatelet monotherapy in acute ischemic stroke and secondary stroke prevention is well established. In the last few years, several large randomized trials showed that the use of short-term dual antiplatelet therapy in particular stroke subtypes may reduce the risk of recurrent ischemic events. The aim of this article is to provide a critical analysis of the current evidence and recommendations for the use of antiplatelet agents for stroke prevention., Recent Findings: Long-term therapy with aspirin, clopidogrel, or aspirin plus extended-release dipyridamole is recommended for secondary stroke prevention in patients with noncardioembolic ischemic stroke. Short-term dual antiplatelet therapy with aspirin and clopidogrel is superior to antiplatelet monotherapy in secondary stroke prevention when used in patients with mild noncardioembolic stroke or high-risk transient ischemic attack. Dual therapy, however, is associated with an increased risk of major bleeding, particularly when the treatment is extended for greater than 30 days. Similarly, aspirin plus ticagrelor is superior to aspirin monotherapy for the prevention of recurrent ischemic stroke, although this combination is associated with a higher risk of hemorrhagic complications when compared to other dual antiplatelet regimens. Among patients who carry CYP2C19 genetic polymorphisms associated with a slow bioactivation of clopidogrel, short-term treatment with aspirin plus ticagrelor is superior to aspirin plus clopidogrel for the reduction of recurrent stroke; however, the use of ticagrelor is associated with a higher risk of any bleeding. In patients with symptomatic intracranial stenosis, aggressive medical management in addition to dual antiplatelet therapy up to 90 days is recommended. Antiplatelet therapy has an essential role in the management of ischemic stroke. The specific antiplatelet regimen should be individualized based on the stroke characteristics, time from symptom onset, and patient-specific predisposition to develop hemorrhagic complications., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: Clopidogrel resistance (CR) is mostly caused by interindividual variability of the platelet inhibition of clopidogrel, which may induce cardiovascular events. The aim of this research was to evaluate whether DNAm levels of CREB5 (cg01534253) are involved in CR among acute coronary syndrome (ACS) patients treated with clopidogrel., Methods: 72 patients(36 CR and 36 non-CR) who underwent ACS were included in this study. The VerifyNow P2Y12 assay was selected to evaluate residual platelet reactivity, and bisulfite pyrosequencing methods was used to examine DNA methylation levels on cg01534253. Secondly, CREB5 mRNA expression was analyzed via quantitative real-time PCR. Last, we employed logistic regression to test the interaction between genetic factors of CREB5 methylation and multiple clinical variables in CR patients., Results: Subunit analysis indicated that for patients whose HbA1c levels were ≥6.5% or whose GLU levels were ≥7 mmol/L, lower methylation of cg01534253 indicated a poorer clopidogrel response. In addition, CREB5 mRNA expression was increased in CR patients with GLU levels ≥7 mmol/L. Moreover, regression analysis indicated that the values of albumin and uric acid were correlated with the incidence of CR., Conclusions: Our findings were likely to provide fresh understanding for the new mechanism of platelet inhibition failure and promote individualized antiplatelet therapy., (© 2022 The Authors. Journal of Clinical Laboratory Analysis published by Wiley Periodicals LLC.)

Background and Purpose: To investigate the associations of perioperative P2Y12 reaction units (PRU) measured using VerifyNow with ischemic and bleeding events, and to determine the PRU threshold in the setting of elective neuro-endovascular treatment (EVT) for intracranial/extracranial vascular disease in patients taking aspirin and clopidogrel., Methods: Of the patients undergoing elective neuro-EVT while taking aspirin and clopidogrel, those taking both antiplatelet agents for 7 days or more and whose PRU and aspirin reaction units (ARU) were measured were included. The primary and safety outcomes were defined as symptomatic ischemic and major bleeding events within 30 days after EVT., Results: A total of 197 patients were available for the analyses. Higher PRU was associated with symptomatic ischemic events on multivariable logistic analysis (odds ratio per 10 increase 1.14 [95% confidence interval 1.03-1.27], p=0.011). Receiver operating characteristic curve analysis showed that PRU ≥212 was the threshold to predict symptomatic ischemic events (area under the curve=0.73; sensitivity, 62.5%; specificity, 82.0%). Lower PRU was also associated with major bleeding events (odds ratio per 10 increase 0.87 [0.78-0.96], p=0.004), and the threshold to predict major bleeding events was PRU ≤46 (area under the curve=0.76; sensitivity, 70.0%; specificity, 87.2%) CONCLUSIONS: The PRU value was associated with symptomatic ischemic and major bleeding events after elective neuro-EVT in patients taking aspirin and clopidogrel. PRU ≥212 and PRU ≤46 appeared to be the threshold values to predict symptomatic ischemic and major bleeding events, respectively., Competing Interests: Declaration of Competing Interest None declared., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background Insulin receptor substrate-1 ( IRS-1 ) rs956115 is associated with vascular risk in patients with coronary artery disease and concomitant diabetes. CYP2C19*2 (rs4244285) modulates clopidogrel response and predicts the outcome of coronary artery disease. This study was designed to explore the association between IRS-1 , CYP2C19*2 genotypes, platelet reactivity, and 1-year outcome in patients with coronary artery disease undergoing percutaneous coronary intervention. Methods and Results Genotyping was performed using an improved multiplex ligation detection reaction technique. Platelet aggregation was assessed by light transmission aggregometry. Major adverse cardiovascular events were defined as a composite of cardiovascular death, myocardial infarction, and ischemic stroke. A total of 2213 consecutive patients were screened and 1614 were recruited. At 1 month, patients with IRS-1 CG genotype had significantly lower levels of ADP-induced platelet aggregation compared with patients with CC homozygotes. Patients with IRS-1 CG or GG genotype had a 2.09-fold higher risk of major adverse cardiovascular events compared with those with CC homozygotes (95% CI, 1.04-4.19; P =0.0376). By comparison, patients with CYP2C19*2 GA or AA genotype had higher ADP-induced platelet aggregation compared with patients with GG homozygotes. Although there was no significant difference in risk of major adverse cardiovascular events between patients with GA/AA and GG genotypes, patients with GA genotype had a 2.19-fold higher risk than those with GG homozygotes (95% CI, 1.13-4.24; P =0.0200). No interaction between IRS-1 and CYP2C19*2 genotypes was observed. Conclusions In patients following percutaneous coronary intervention, IRS-1 GG/CG and CYP2C19*2 GA genotypes were associated with 2.09- and 2.19-fold increased cardiovascular risk, respectively, at 1-year follow-up. The association between IRS-1 genotypes and major adverse cardiovascular events appeared to be independent of known clinical predictors. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01968499.

Purpose: Oral antiplatelet therapy is routinely used to prevent adverse cardiovascular events in patients with peripheral artery disease (PAD). Several laboratory tests are available to quantify the degree of platelet inhibition following antiplatelet therapy. This article aims to provide a review of the literature surrounding platelet functional testing in patients with PAD receiving oral P2Y12 inhibitors and to offer guidance to clinicians for the use and interpretation of these tests., Summary: A literature search of PubMed and the Web of Science Core Collection database was conducted. All studies that performed platelet function testing and reported clinical outcomes in patients with PAD were included. Evaluation of the data suggests that, among the available testing strategies, the VerifyNow platelet reactivity unit (PRU) test is the most widely used. Despite numerous investigations attempting to define a laboratory threshold indicating suboptimal response to antiplatelet therapy, controversy exists about which PRU value best correlates with cardiovascular outcomes (ie, mortality, stent thrombosis, etc). In the PAD literature, the most commonly used PRU thresholds are 208 or higher and 235 or higher. Nonetheless, adjusting antiplatelet regimens based on suboptimal P2Y12 reactivity values has yet to be proven useful in reducing the incidence of adverse cardiovascular outcomes. This review examines platelet function testing in patients with PAD and discusses the interpretation and application of these tests when monitoring the safety and efficacy of P2Y12 inhibitors., Conclusion: Although platelet functional tests may be simple to use, clinical trials thus far have failed to show benefit from therapy adjustments based on test results. Clinicians should be cautioned against relying on this test result alone and should instead consider a combination of laboratory, clinical, and patient-specific factors when adjusting P2Y12 inhibitor therapy in clinical practice., (© American Society of Health-System Pharmacists 2022. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background The objective of the study was to assess the cost-effectiveness of cilostazol (a selective phosphodiesterase 3 inhibitor) added to aspirin or clopidogrel for secondary stroke prevention in patients with noncardioembolic stroke. Methods and Results A Markov model decision tree was used to examine lifetime costs and quality-adjusted life years (QALYs) of patients with noncardioembolic stroke treated with either aspirin or clopidogrel or with additional cilostazol 100 mg twice daily. Cohorts were followed until all patients died from competing risks or ischemic or hemorrhagic stroke. Probabilistic sensitivity analysis using Monte Carlo simulation was used to model 10 000 cohorts of 10 000 patients. The addition of cilostazol to aspirin or clopidogrel is strongly cost saving. In all 10 000 simulations, the cilostazol strategy resulted in lower health care costs compared with aspirin or clopidogrel alone (mean $13 488 cost savings per patient; SD, $8087) and resulted in higher QALYs (mean, 0.585 more QALYs per patient lifetime; SD, 0.290). This result remained robust across a variety of sensitivity analyses, varying cost inputs, and treatment effects. At a willingness-to-pay threshold of $50 000/QALY, average net monetary benefit from the addition of cilostazol was $42 743 per patient over their lifetime. Conclusions Based on the best available data, the addition of cilostazol to aspirin or clopidogrel for secondary prevention following noncardioembolic stroke results in significantly reduced health care costs and a gain in lifetime QALYs.

Objectives: Genetic variation has been considered a major contributor to the high variability in the response to dual antiplatelet therapy in patients with acute ischemic stroke or transient ischemic attack. Recently, incidences of ischemic stroke are increasing rapidly in China. We aimed to evaluate the influence of potential determinants on the response of antiplatelet therapy and adverse events in Chinese ischemic stroke patients receiving clopidogrel-aspirin treatment., Methods: Based on the clopidogrel drug response pathway and the coagulation and anticoagulation function, we systematically selected 34 genetic polymorphisms in 12 candidate genes. Three hundred and eight patients were divided into 2 groups according to their degree of inhibition of platelet aggregation. Multivariate analysis was then performed to assess the influence of demographic, clinical and genetic factors on platelet reactivity in Chinese ischemic stroke patients., Results: We found that polymorphisms in CYP2C19 and F2R genes were still significantly associated with platelet reactivity in Chinese ischemic stroke patients (P = 0.037 and 0.015). The newly identified rs168753 in F2R gene may influence the efficacy to clopidogrel-aspirin therapy for ischemic stroke patients. We also found that ischemic stroke patients with low level of inhibition of platelet aggregation had higher risk of recurrent ischemic events (P = 0.001)., Conclusions: Together, these results emphasized the necessity of genotype-directed antiplatelet therapy and facilitated to minimize adverse ischemic events., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Clopidogrel, an antiplatelet drug, is frequently prescribed to patients diagnosed with ischemic diseases such as those suffering from acute coronary syndromes or ischemic stroke. Despite the drug being effective in majority of the patients, some still experience ischemic events early in the treatment which might be due to poor platelet inhibition. This study aims to investigate the association of cytochrome P450 2C19 (CYP2C19) loss-of-function polymorphisms, haplotypes as well as a wide range of clinical and demographic variables with platelet aggregation phenotypes to clopidogrel in a Pakistani cohort. The study comprised of a total of 120 patients diagnosed with cardiovascular diseases and were treated with clopidogrel. Antiplatelet response to clopidogrel was monitored by Helena AggRAM (HL-2-1785P) and patients with maximal platelet aggregation more than 50% were categorized as low responders and those with less than 50% as high responders. Our results show that 56.6% of patients were homozygous for the CYP2C19 wild-type allele, 38.3% of patients possessed one copy of the CYP2C19*2 allele and 5% of patients possessed both CYP2C19*2 alleles. No CYP2C19*3 allele was found in our patient cohort. There was no statistically significant difference between the high and low responder groups to clopidogrel in terms of extensive, intermediate and poor metabolizer genotypes. However, haplotype (H1), leukocyte count, random blood glucose, and history of diabetes mellitus was associated with the antiplatelet response to clopidogrel. The prevalence of clopidogrel resistance in our population was in line with that reported for other regional and global populations., (© 2022. The Author(s).)

Objective: Clopidogrel is a common antiplatelet used as secondary prevention of ischemic stroke, known to have better efficacy than aspirin, with a equivalent safety profile. However, clopidogrel resistance is not uncommon but has not been widely studied in Asia. This study will further assess clopidogrel resistance and its risk factors., Materials and Methods: A cross-sectional study was conducted at Rumah Sakit Universitas, Indonesia, and Rumah Sakit Cipto Mangunkusumo, Indonesia in 2020-2021. All patients had had at least one episode of ischemic stroke. Clopidogrel resistance was assessed using a VerifyNow assay., Results: 57 subjects were enrolled in this study. We found 15.8% of subjects were clopidogrel resistant. Gender was significantly associated with clopidogrel resistance, with males having 80% lower clopidogrel resistance (OR 0.2 (95% CI 0.022 - 0.638); P=0.006). Meanwhile, smoking was not associated with clopidogrel responsiveness (P=0.051). We found no association between haemoglobin, blood glucose, HbA1c, cholesterol, liver enzymes, serum urea concentration or creatinine levels and clopidogrel resistance., Conclusion: Clopidogrel remains an effective treatment to prevent recurrent ischemic stroke in Indonesia. Further studies are needed to assess gene polymorphism and clopidogrel resistance, which may explain the findings of this study., (Copyright © 2022 by Academy of Sciences and Arts of Bosnia and Herzegovina.)

Abstract: The aim of this study was to investigate the association between CYP2C19 gene polymorphisms and the risk of cardiovascular events in the early stage and subsequent period after percutaneous coronary intervention (PCI) among patients who received clopidogrel. Between October 2015 and January 2017, CYP2C19 genotyped patients who were treated with clopidogrel after PCI were enrolled in this study. Included patients were categorized as non-loss-of-function metabolizers, intermediate metabolizers, and poor metabolizers based on CYP2C19 genotype. The primary outcome was a composite of any-cause mortality, nonfatal myocardial infarction, nonfatal ischemic stroke, and stent thrombosis occurring during exposure to clopidogrel. The rates of clinical outcome events were compared between CYP2C19 phenotypes. Landmark analyses were processed at 90 days and 1 year post-PCI. Of 1341 patients, 161 (12.0%) had 2 copies of loss-of-function (LOF) alleles, 621(46.3%) had one LOF allele, and 559 (41.7%) had no LOF allele. At the 3-month follow-up, the primary outcome events were more frequent in carriers of 2 LOF alleles (5.6%) than in noncarriers (1.8%) [adjusted hazard ratio (HR) 2.944, 95% confidence interval, 1.184-7.321, P = 0.020). A similar finding was observed among in patients with acute coronary syndrome indications at the index PCI (adjusted HR 3.046, 95% confidence interval, 1.237-7.501, P = 0.015). These differences did not persist within the subsequent 9 months of follow-up, among either all comers or subjects with acute coronary syndrome. In conclusion, these data demonstrate a higher risk for ischemic events in patients with 2 CYP2C19 LOF alleles who are prescribed clopidogrel, seen at 3 months after PCI, that is not sustained for 12 months., Competing Interests: The authors reports no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Patients undergoing coronary artery bypass graft (CABG) surgery or carotid endarterectomy (CEA) continue antiplatelet therapy perioperatively, which may increase bleeding risk. We aimed to investigate whether Rotational thromboelastometry (ROTEM ® ) platelet, a newly marketed platelet function analysis, would detect antiplatelet therapy in CABG and CEA patients; whether detection of reduced platelet function was associated with increased bleeding; and whether ex vivo desmopressin increased platelet function. We included 20 CABG patients continuing aspirin and 20 CEA patients continuing clopidogrel ( n  = 1) or clopidogrel and aspirin ( n  = 19). Platelet function was analyzed with ROTEM ® platelet and light transmission aggregometry (LTA). According to the lower reference limit, ROTEM ® platelet managed to detect aspirin, but clopidogrel detection was inadequate compared to LTA. Using a previously published cut-off for bleeding risk, 6 (30%) patients receiving aspirin and 4 (21%) patients receiving both clopidogrel and aspirin demonstrated platelet function below this cut-off. One of the four CEA patients below the cut-off died from intracerebral hemorrhage postoperatively. CABG patients below ( n  = 6) and above ( n  = 14) the cut-off did not differ in chest tube output (median [range]: 373 ml [250-900] vs . 368 ml [195-820]). Ex vivo addition of desmopressin did not increase platelet function. In conclusion, ROTEM ® platelet does reveal aspirin treatment whereas clopidogrel treatment is most often overlooked. Due to low bleeding in the study population, it was not possible to conclude on the association with bleeding risk.

Competing Interests: The authors report no conflicts of interest.

Introduction: The interindividual variability of the antiplatelet effect of clopidogrel is determined by multiple clinical and genetic factors. A lot of genotype-oriented studies have concentrated on the impact of CYP2C19 gene polymorphisms on platelet aggregation in patients receiving clopidogrel. However, the influence of this polymorphism may be only 12-20%, so other genetic markers should also be investigated. The aim of this work was to study the impact of carriage of CES1, PON1, ABCG2, CYP4F2, CYP3A4, IGTB3, P2Y12, PEAR1, and B4GALT2 polymorphisms on antiplatelet effect of clopidogrel and clinical outcomes in patients with acute coronary syndrome (ACS) and atrial fibrillation (AF)., Methods: 103 patients who underwent ACS with or without percutaneous coronary intervention and concomitant nonvalvular AF were included in an open multicenter prospective study to assess efficacy and safety of combined antithrombotic therapy. The study assessed the frequency of different primary clinical outcomes (incidence of major bleeding, hospital mortality, cardiovascular mortality, stroke and transient ischemic attacks (TIAs), renal mortality) and secondary outcomes (resistance to therapy - high residual platelet reactivity, excessive platelet suppression). Residual platelet reactivity was examined using the VerifyNow system (Accumetrics, Latham, NY, USA)., Results: None of the studied genetic markers had no statistically significant effect on the antiaggregant response to clopidogrel in patients with ACS and AF. However, CYP4F2 C(Val433Met) T, PEAR1 rs41273215 C>T were statistically significantly associated with an increased frequency of bleeding on antithrombotic therapy. B4GALT2 rs1061781 was statistically significantly associated with increased frequency of strokes and TIA., Conclusion: In our study, we determined that carriers of CYP4F2 gene polymorphisms C(Val433Met)T, PEAR1 rs41273215 C>T (CT+TT) were associated with lower safety of antithrombotic therapy in patients with ACS and AF. And, the B4GALT2 rs1061781 gene polymorphism was associated with a greater risk of insufficient efficacy of the therapy. The data obtained in our study may improve the understanding of the effect of less studied genetic markers on the efficacy and safety of antithrombotic therapy in patients with ACS and AF., (© 2022 S. Karger AG, Basel.)

Background: Data are conflicting on whether proton pump inhibitors (PPIs) diminish the efficacy of clopidogrel. We investigated individual PPIs and adverse cardiovascular events in postpercutaneous coronary intervention (PCI) patients on dual antiplatelet therapy with clopidogrel., Methods: We searched Ovid-MEDLINE, EMBASE, and Cochrane from inception to March 2020 to identify studies that evaluated the efficacy and safety of clopidogrel added PPIs versus clopidogrel only in post-PCI patient. We extracted data from 28 studies for major adverse cardiovascular endpoints (MACE), myocardial infarction (MI), cardiovascular death, and gastrointestinal bleeding. Risk ratios (RR) and hazard ratios (HR) were pooled separately., Results: Data were extracted on 131,412 patients from the 28 studies included. Concomitant use of PPI with clopidogrel was associated with increased risk of MACE (RR 1.30; 95% confidence interval [CI] 1.15-1.48; P < .001) and MI (RR 1.43; 95% CI 1.25-1.64; P < .001). Random-effects meta-analyses with individual PPIs demonstrated an increased risk of MACE in those taking pantoprazole (RR 1.31; 95% CI 1.07-1.61, P = .01) or lansoprazole (RR 1.35; 95% CI 1.19-1.54, P < .0001) compared with patients not on PPIs. Likewise, in adjusted analyses, the pooled HR of adjusted events for MACEs showed that the increased risk of MACEs was similar for 4 classes of PPIs but not for rabeprazole (HR: 1.32; 95% CI 0.69-2.53, P = .40)., Conclusion: The post-PCI patients on dual antiplatelet therapy with clopidogrel in the PPI group were associated with higher risk of MACE and MI. Although the results for rabeprazole were not robust, it was the only PPI that did not yield a significantly increased risk of MACE., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background Efficacy of clopidogrel may be diminished due to either co-administration of proton pump inhibitors or carrying CYP2C19 loss-of-function alleles. However, patients may be at greater risk of major adverse cardiovascular events if taking clopidogrel together with proton pump inhibitors and also inherited the CYP2C19 loss-of-function alleles which may cause further reduction of clopidogrel efficacy. This is due to the cumulative effects of drug-drug interactions and drug-gene interactions collectively referred to as multifactorial drug-gene interactions. Aim of the review The aim of this analysis was to estimate aggregated risk of major adverse cardiovascular events for either coronary heart disease or stroke patients with multifactorial drug-gene interactions versus clopidogrel alone with or without drug-gene interactions. Methods Literatures were searched using different resources based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Meta-analysis was performed using RevMan software following either fixed/random effects model based on the levels of heterogeneity. A p value < 0.05 (2-sided) was considered statistically significant. Results In total, five studies consisting 8,802 patients of coronary artery diseases or stroke were included in this meta-analysis in which 3,767 were prescribed clopidogrel alone, 1,931 were concomitantly taking clopidogrel and PPIs, 2,146 were carrying CYP2C19 loss-of-function alleles and 958 were taking both clopidogrel and proton pump inhibitors while also carrying CYP2C19 loss-of-function alleles. It was found that patients with multifactorial drug-gene interactions were associated with significantly increased risk of major adverse cardiovascular events compared to those taking clopidogrel alone without CYP2C19 loss-of-function alleles (12% vs. 5.8%; RR 1.73; 95% CI 1.12-2.67; p = 0.01). Patients with multifactorial drug-gene interactions were also associated with significantly increased risk of major adverse cardiovascular events compared to drug-gene interactions (RR 1.63; 95% CI 1.31-2.03; p < 0.0001). Patients taking clopidogrel with proton pump inhibitors were also associated with 35% significantly increased risk of major adverse cardiovascular events compared to those taking only clopidogrel (RR 1.35; 95% CI 1.11-1.65; p = 0.003). Conclusion Patients inheriting CYP2C19 loss-of-function alleles have significantly increased risk of major adverse cardiovascular events when taking clopidogrel and proton pump inhibitors concurrently., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

There is limited data about the bleeding complication of antiplatelet therapy after coronary artery bypass graft (CABG) operations focused on diabetic patients. Herein, we aimed to evaluate the effects of aspirin and clopidogrel monotherapies on postoperative bleeding in these patients. A total of 165 diabetic patients who underwent isolated off-pump beating heart coronary artery bypass (OPCAB) operation were evaluated, 84 patients were included in this retrospective study. Patients were divided into groups according to the type of antiplatelet regime. Chest tube drainage amounts and the amount of blood product transfusions were evaluated. Acetylsalicylic acid (ASA) - group included 42 aspirin monotherapy and Clopidogrel - group included 42 clopidogrel monotherapy patients after propensity matching. The mean drainage amount in ASA - group was 670.24 ± 185.46 mL, in Clopidogrel - group was 921.43 ± 167.53 mL ( p < 0.001). More packed red blood cell (PRBC) and fresh frozen plasma (FFP) units were needed in the Clopidogrel - group than in the ASA - group (2.05 ± 1.13 vs. 0.83 ± 0.93 units of PRBC, and 1.90 ± 0.58 vs. 1.05 ± 0.58 units of FFP, respectively, p < 0.001). In conclusion, clopidogrel had a stronger effect on bleeding in diabetic patients than aspirin after OPCAB surgery., Competing Interests: The authors declare no conflict of interest., (© 2021 The Author(s). Published by IMR Press.)

Background: Geriatric hip fracture patients receiving clopidogrel are a surgical challenge. In China, most of these patients undergo delayed surgical treatment after clopidogrel withdrawal for at least 5 to 7 days. However, delayed surgery is associated with increased complications and mortality in the older adults. This retrospective paralleled comparison study investigated the safety of early surgery for geriatric hip fracture patients within 5 days of clopidogrel withdrawal., Methods: Acute hip fracture patients (≥65 years) who were hospitalized in the orthogeriatric co-management ward of Beijing Jishuitan Hospital between November 2016 and April 2018 were retrospectively reviewed. Sixty patients taking clopidogrel before injury and discontinued <5 days before surgery constituted the clopidogrel group. The control group constituted 60 patients not taking antiplatelet or anticoagulant drugs and matched 1:1 with the clopidogrel group for sex, fracture type, operative procedure, and time from injury to operation (±10 h). The primary outcome was perioperative blood loss and the secondary outcomes were transfusion requirement, complications, and mortality. The Student's t test or Wilcoxon signed rank sum test was used for continuous variables and the Chi-square test was used for categorical variables., Results: Age, body mass index, American Society of Anesthesiologists score, and percentage undergoing general anesthesia were comparable between the groups (P > 0.050). The percentages of patients with coronary heart disease (61.7% vs. 18.3%; P < 0.001) and cerebrovascular disease (45.0% vs. 15.0%; P < 0.010) were significantly higher in the clopidogrel vs. control groups, respectively. The median clopidogrel discontinuation time before operation was 73.0 (range: 3.0-120.0) h. There was no significant difference in the estimated perioperative blood loss between the clopidogrel group (median: 745 mL) and control group (median: 772 mL) (P = 0.866). The intra-operative transfusion rate was higher in the clopidogrel group (22/60, 36.7%) than that in the control group (12/60, 20.0%) (P < 0.050). However, there was no significant difference in the blood transfusion rate during the entire perioperative period (26/60, 43.3% vs. 20/60, 33.3%; clopidogrel group vs. control group, respectively; P > 0.050). There was no significant difference in perioperative complications, and 30-day and 1-year mortality rates between the groups., Conclusions: Early hip fracture surgery is safe for elderly patients within 5 days of clopidogrel withdrawal, without increased perioperative blood loss, transfusion requirement, complications, and mortality compared with patients not taking antiplatelet drugs., (Copyright © 2021 The Chinese Medical Association, produced by Wolters Kluwer, Inc. under the CC-BY-NC-ND license.)

Background: Current guidelines recommend administering dual antiplatelet therapy (DAPT) for 12 months to patients with acute coronary syndromes (ACS) and without contraindications after drug-eluting stent (DES) implantation. A recent study reported that 3 months of DAPT followed by ticagrelor monotherapy is effective and safe in ACS patients undergoing DES implantation compared with the standard duration of DAPT. However, it is unclear whether antiplatelet monotherapy with ticagrelor alone versus ticagrelor plus aspirin reduces the incidence of clinically relevant bleeding without increasing the risk of major adverse cardiovascular and cerebrovascular events (MACCEs) in ACS patients undergoing percutaneous coronary intervention (PCI) with DES implantation guided by either intravascular ultrasound (IVUS) or angiography who have completed a 1-month course of DAPT with aspirin plus ticagrelor., Methods: The IVUS-ACS and ULTIMATE-DAPT is a prospective, multicenter, randomized, controlled trial designed to determine (1) whether IVUS-guided versus angiography-guided DES implantation in patients with ACS reduces the risk of target vessel failure (TVF) at 12 months and (2) whether ticagrelor alone versus ticagrelor plus aspirin reduces the risk of clinically relevant bleeding without increasing the risk of MACCE 1-12 months after the index PCI in ACS patients undergoing DES implantation guided by either IVUS or angiography. This study will enroll 3486 ACS patients eligible for DES implantation, as confirmed by angiographic studies. The patients who meet the inclusion criteria and none of the exclusion criteria will be randomly assigned in a 1:1 fashion to the IVUS- or angiography-guided group (first randomization). All enrolled patients will complete a 1-month course of DAPT with aspirin plus ticagrelor after the index PCI. Patients with no MACCEs or major bleeding (≥Bleeding Academic Research Consortium (BARC) 3b) within 30 days will be randomized in a 1:1 fashion to either the ticagrelor plus matching placebo (SAPT)group or ticagrelor plus aspirin (DAPT)group for an additional 11 months (second randomization). The primary endpoint of the IVUS-ACS trial is TVF at 12 months, including cardiac death, target vessel myocardial infarction (TVMI), or clinically driven target vessel revascularization (CD-TVR). The primary superiority endpoint of the ULTIMATE-DAPT trial is clinically relevant bleeding, defined as BARC Types 2, 3, or 5 bleeding, and the primary non-inferiority endpoint of the ULTIMATE-DAPT trial is MACCE, defined as cardiac death, myocardial infarction, ischemic stroke, CD-TVR, or definite stent thrombosis occurring 1-12 months in the second randomized population., Conclusion: The IVUS-ACS and ULTIMATE-DAPT trial is designed to test the efficacy and safety of 2 different antiplatelet strategies in ACS patients undergoing PCI with DES implantation guided by either IVUS or angiography. This study will provide novel insights into the optimal DAPT duration in ACS patients undergoing PCI and provide evidence on the clinical benefits of IVUS-guided PCI in ACS patients., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Chronic kidney disease (CKD) is a common comorbidity in patients with acute coronary syndrome (ACS) and may potentially influence platelet function., Hypothesis: We explored the influence of renal function on platelet reactivity to investigate whether high residual platelet reactivity (HRPR) is associated with cardiovascular events., Methods: ACS patients treated with aspirin and clopidogrel were prospectively enrolled. Patients were categorized into two groups on the basis of baseline estimated glomerular filtration rate (eGFR): non-CKD (eGFR ≥60 mL/min/1.73 m 2 ) and CKD (eGFR <60 mL/min/1.73 m 2 ). Platelet function was measured by thromboelastography ≥5 days after maintenance dual antiplatelet therapy. Major adverse clinical events (MACEs) were collected at 1 year after discharge., Results: There were 282 non-CKD patients and 212 CKD patients. A significant difference in median MA ADP value was observed between the two groups (15.0 mm vs. 31.3 mm, p < .001). HRPR was more prevalent in the CKD group than the non-CKD group (27.4% vs 9.6%, p < .001). At 1-year follow-up, the incidence of MACEs was significantly higher for those with both CKD and HRPR compared with those with either CKD or HRPR (37.9% vs. 18.5%, p < .001). The relationship between HRPR and MACEs was consistent across CKD strata without evidence of interaction. Adding platelet reactivity to eGFR improved the model with area under the curve increasing from 0.703 to 0.734., Conclusion: In patients with ACS, the risk of HRPR increased with declining eGFR. Both CKD and HRPR were associated with MACEs at 1-year follow-up., (© 2021 The Authors. Clinical Cardiology published by Wiley Periodicals LLC.)