Clopidogrel Administration Research Articles

The effect of concurrent clopidogrel and omeprazole administration on clopidogrel metabolism and platelet function in healthy cats.

Some studies in humans show that the concurrent use of clopidogrel and omeprazole decreases plasma clopidogrel active metabolite (CAM) concentrations and clopidogrel antiplatelet effects. Whether this drug interaction occurs in cats is unknown. We hypothesized that administration of clopidogrel with omeprazole would decrease plasma CAM concentrations and decrease clopidogrel antiplatelet effects in healthy cats. Ten domestic cats. In this 2-sequence, 2-period, 2-treatment randomized crossover study, healthy cats were randomly assigned to receive clopidogrel only (18.75 mg PO q24h) or clopidogrel with omeprazole (1 mg/kg PO q12h) for 10 days, followed by a 2-week washout period, and then the opposite treatment for another 10 days. Blood was collected by jugular venipuncture on days 0, 5, and 10. Plasma CAM concentrations were measured using high-performance liquid chromatography-tandem mass spectrometry. Platelet function was evaluated using Plateletworks, Multiplate Analyzer, and Platelet Function Analyzer-100 (PFA-100). Multiplate Analyzer and PFA-100 detected no difference in platelet function between days or treatment groups. Plateletworks detected a significant difference (P < .001) in platelet function from day 0 to 5 and day 0 to 10 in both treatment groups but no difference between treatment groups. Plasma CAM concentrations were significantly lower on day 10 (P < .02) in cats receiving both medications versus clopidogrel only. Concurrent omeprazole and clopidogrel administration was associated with altered pharmacokinetics on day 10, but no difference in pharmacodynamics between the 2 treatment groups. The short-term use of clopidogrel and omeprazole does not seem to alter platelet function significantly.

Comparative Analysis of Ticagrelor and Clopidogrel Effects on Medication Adherence, Adverse Events, and Laboratory Parameters in Iranian Acute Coronary Syndrome Patients Post-PCI

Background: Acute coronary syndrome (ACS) remains a critical health concern, with patient outcomes significantly influenced by the selection of antiplatelet therapy post-percutaneous coronary intervention (PCI). Existing research suggests potential benefits of ticagrelor over clopidogrel in reducing cardiovascular events. However, there is limited comparative data within the Iranian population post-angiography. Objectives: This research aimed to compare laboratory findings, adherence rates, and side effects following the administration of ticagrelor and clopidogrel in ACS patients post-PCI. Methods: A case-control study was conducted to assess the impacts of antiplatelet therapy in 200 ACS patients undergoing PCI at Masih Daneshvari Hospital, Tehran, Iran. Patients were stratified into two groups, matched by age, gender, and type of cardiac disease. One group received clopidogrel, and the other received ticagrelor. Laboratory parameters, including HDL, LDL, and CRP, were evaluated at baseline and two months after treatment initiation. Additionally, adverse effects and medication adherence were assessed to evaluate the safety and efficacy of the two antiplatelet agents. Results: The study enrolled 200 ACS patients post-PCI, with 54% male and 46% female. The age range was 38 to 84 years, with a mean age of 63.07 ± 12.54 years. Of the patients, 76% had non-ST-elevation myocardial infarction (NSTEMI), while 24% had ST-elevation myocardial infarction (STEMI). Among STEMI patients, 56.25% were treated with fibrinolytics, and 43.75% underwent primary PCI. Common adverse events included dyspnea, bleeding, and gastrointestinal symptoms. Both the ticagrelor and clopidogrel groups showed reductions in LDL levels from baseline to the two-month follow-up. Conclusions: Ticagrelor and clopidogrel were both effective in reducing LDL levels after two months of treatment. However, ticagrelor demonstrated a more pronounced decrease in CRP levels, indicating potential anti-inflammatory benefits. These findings provide insight into antiplatelet therapy's role in managing ACS patients post-PCI.

The first in-human study to evaluate the antiplatelet properties of the clopidogrel conjugate DT-678 in acute coronary syndrome patients and healthy volunteers.

DT-678 is a novel antiplatelet prodrug, capable of releasing the antiplatelet active metabolite of clopidogrel (AM) upon exposure to glutathione. In this study, we investigated factors responsible for clopidogrel high on-treatment platelet reactivity (HTPR) in acute coronary syndrome (ACS) patients and evaluated the capacity of DT-678 to overcome HTPR. A total of 300 consecutive ACS patients naive to P2Y12 receptor inhibitors were recruited and genotyped for CYP2C19 alleles. Blood samples were drawn before and after administration of 600-mg clopidogrel. Platelet reactivity index (PRI) and plasma AM concentrations were determined and grouped according to their CYP2C19 genotypes. DT-678 was applied ex vivo to whole blood samples to examine its inhibitory effects. To further examine the antiplatelet effectiveness of DT-678 in vivo, 20 healthy human subjects were recruited in a Phase I clinical trial, and each received a single dose of either 3-mg DT-678 or 75-mg clopidogrel. The pharmacokinetics and pharmacodynamics in different CYP2C19 genotype groups were compared. Statistical analyses revealed that CYP2C19 genotype, body mass index, hyperuricaemia, and baseline PRI were significantly associated with a higher risk of clopidogrel HTPR in ACS patients. The addition of DT-678 ex vivo decreased baseline PRI regardless of CYP2C19 genotypes, overcoming clopidogrel HTPR. This observation was further confirmed in healthy volunteers receiving 3mg of DT-678. These results suggest that DT-678 effectively overcomes clopidogrel HTPR resulting from genetic and/or clinical factors in Chinese ACS patients, demonstrating its potential to improve antiplatelet therapy.

The prognostic difference study on the individualized clopidogrel administration in Hmong and Dong patients based on the CYP2C19 gene polymorphism after percutaneous coronary intervention.

This study explored the distribution characteristics of CYP2C19 gene polymorphism among Hmong and Dong patients in the Qiandongnan region of Guizhou province after percutaneous coronary intervention (PCI). The aim was to assess the clinical impact of individualized clopidogrel administration based on CYP2C19 genotypes. A total of 208 patients were classified into ultra-fast, fast, intermediate, and slow metabolic groups. They were randomly assigned to clopidogrel individualized administration (IA) or conventional treatment (CA) groups. Patients were followed for 6 months to evaluate major adverse cardiovascular events (MACE) and adverse reactions. The CYP2C19 genotype distribution was in Hardy-Weinberg equilibrium, showing consistency in the population. While no significant ethnic differences were found in genotype and metabolic distribution, allele distribution varied, with Hmong patients exhibiting a higher proportion of CYP2C19*1 alleles than Dong patients. Following individualized administration, the IA group demonstrated lower incidences of non-fatal myocardial infarction and emergency revascularization compared to the CA group. Bleeding events were higher in the IA group, but the total MACE incidence was lower. No statistical difference in MACE and adverse drug reactions (ADR) was observed in the CA group across metabolic types, but MACE incidence was higher in intermediate and slow metabolic groups. In the IA group, no significant difference in MACE was noted among metabolic types, but ADR incidence varied significantly, particularly in dyspnea. The study highlighted significant CYP2C19 allele distribution differences between Hmong and Dong patients post-PCI in Qiandongnan. Patients with slow metabolic profiles demonstrated higher MACE incidence with conventional clopidogrel dosage, whereas CYP2C19-guided therapy reduced MACE without increasing bleeding risk. These findings supported clinical individualized clopidogrel administration in post-PCI patients in the Qiandongnan region, contributing to rational clopidogrel use.

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

BackgroundWe analyzed The Society of Thoracic Surgeons Database to investigate risks and optimal timing for coronary artery bypass grafting (CABG) after clopidogrel administration. MethodsPatients 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. ResultsAmong 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. ConclusionsCABG 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.

Molecular genomic and epigenomic characteristics related to aspirin and clopidogrel resistance

BackgroundMediators, genomic and epigenomic characteristics involving in metabolism of arachidonic acid by cyclooxygenase (COX) and lipoxygenase (ALOX) and hepatic activation of clopidogrel have been individually suggested as factors associated with resistance against aspirin and clopidogrel. The present multi-center prospective cohort study evaluated whether the mediators, genomic and epigenomic characteristics participating in arachidonic acid metabolism and clopidogrel activation could be factors that improve the prediction of the aspirin and clopidogrel resistance in addition to cardiovascular risks.MethodsWe enrolled 988 patients with transient ischemic attack and ischemic stroke who were evaluated for a recurrence of ischemic stroke to confirm clinical resistance, and measured aspirin (ARU) and P2Y12 reaction units (PRU) using VerifyNow to assess laboratory resistance 12 weeks after aspirin and clopidogrel administration. We investigated whether mediators, genotypes, and promoter methylation of genes involved in COX and ALOX metabolisms and clopidogrel activation could synergistically improve the prediction of ischemic stroke recurrence and the ARU and PRU levels by integrating to the established cardiovascular risk factors.ResultsThe logistic model to predict the recurrence used thromboxane A synthase 1 (TXAS1, rs41708) A/A genotype and ALOX12 promoter methylation as independent variables, and, improved sensitivity of recurrence prediction from 3.4% before to 13.8% after adding the mediators, genomic and epigenomic variables to the cardiovascular risks. The linear model we used to predict the ARU level included leukotriene B4, COX2 (rs20417) C/G and thromboxane A2 receptor (rs1131882) A/A genotypes with the addition of COX1 and ALOX15 promoter methylations as variables. The linear PRU prediction model included G/A and prostaglandin I receptor (rs4987262) G/A genotypes, COX2 and TXAS1 promoter methylation, as well as cytochrome P450 2C19*2 (rs4244285) A/A, G/A, and *3 (rs4986893) A/A genotypes as variables. The linear models for predicting ARU (r = 0.291, R2 = 0.033, p < 0.01) and PRU (r = 0.503, R2 = 0.210, p < 0.001) levels had improved prediction performance after adding the genomic and epigenomic variables to the cardiovascular risks.ConclusionsThis study demonstrates that different mediators, genomic and epigenomic characteristics of arachidonic acid metabolism and clopidogrel activation synergistically improved the prediction of the aspirin and clopidogrel resistance together with the cardiovascular risk factors.Trial registrationURL: https://www.clinicaltrials.gov; Unique identifier: NCT03823274.

Association of CYP2C19 genotypes with postoperative atrial fibrillation after coronary artery bypass surgery.

This cohort study aims to assess the connection between cytochrome P450 family 2 subfamily C member 19 (CYP2C19) genotyping, platelet aggregability following oral clopidogrel administration, and the occurrence of postoperative atrial fibrillation (POAF) after off-pump coronary artery bypass graft (CABG) surgery. From May 2017 to November 2022, a total of 258 patients undergoing elective first-time CABG surgery, receiving 100 mg/day oral aspirin and 75 mg/day oral clopidogrel postoperatively, was included for analysis. These patients were categorized based on CYP2C19 genotyping. Platelet aggregability was assessed serially using multiple-electrode aggregometry before CABG, 1 and 5 days after the procedure, and before discharge. The incidences of POAF were compared using the log-rank test for cumulative risk. CYP2C19 genotyping led to categorization into CYP2C19*1*1 (WT group, n = 123) and CYP2C19*2 or *3 (LOF group, n = 135). Baseline characteristics and operative data showed no significant differences between the two groups. The incidence of POAF after CABG was 42.2% in the LOF group, contrasting with 22.8% in the WT group (hazard risk [HR]: 2.061; 95% confidence interval [CI]: 1.347, 3.153; p = 0.0013). Adenosine diphosphate-stimulated platelet aggregation was notably higher in the LOF group compared to the WT group 5 days after CABG (30.4% ± 6.5% vs. 17.9% ± 4.1%, p < 0.001), remaining a similar higher level at hospital discharge (25.6% ± 6.1% vs. 12.2% ± 3.5%, p < 0.001). The presence of CYP2C19 LOF was linked to a higher incidence of POAF and relatively elevated platelet aggregation after CABG surgery under the same oral clopidogrel regimen.

Platelet reactivity and activated clotting time predict hemorrhagic site complications in patients with chronic coronary syndromes undergoing percutaneous coronary interventions.

Radial access is preferred in patients with chronic coronary syndromes (CCSs) treated with ad hoc percutaneous coronary intervention (PCI). Antithrombotic and antiplatelet treatment before PCI may affect outcomes at vascular access sites. QuikClot Radial is a kaolin-based band that may shorten hemostasis time. Using point-of-care testing, we investigated the effect of antithrombotic and antiplatelet treatment on access-site complications. This prospective observational study included consecutive patients with CCS on chronic aspirin therapy referred for ad hoc PCI. The activated clotting time (ACT), global thrombosis test and VerifyNow P2Y 12 test were done sequentially after unfractionated heparin (UFH) and clopidogrel administration. Patients were monitored for radial artery patency, bleeding and local hematoma until discharge. We enrolled 40 patients [mean age, 68.8 ± 8.8 years; men, 30 (75%)] who received UFH (median dose, 8000 IU; interquartile range, 7000-9000 IU) and clopidogrel (600 mg). All radial arteries remained patent during follow-up. Local bleeding and hematomas were noted in 11 patients (27.5%) each. Patients with bleeding had lower mean platelet activity at 2 h [122.5 ± 51 platelet reactivity units (PRU) vs. 158.7 ± 43 PRU, P = 0.04] and higher ACT (216.9 ± 40 s vs. 184.6 ± 28 s, P = 0.006) than patients without bleeding. An ACT >196 s at 2 h predicted bleeding or hematoma (AUC, 0.72; 95% CI, 0.56-0.85, P = 0.008). Lower platelet activity and higher ACT after PCI were associated with higher bleeding risk at a vascular access site. Point-of-care testing of ACT after the procedure may help identify patients with CCS undergoing PCI who are at higher risk of access-site bleeding.

Evaluation of risk factors affecting the lifespan and efficiency of dialysis accesses installed in dialysis patients referees to Ahvaz therapeutic centers in a two-year cohort study

Introduction: It is crucial in order to provide optimal hemodialysis to patients with end-stage renal disease (ESRD) to establish venous access with the least amount of complications. Objectives: In this study, we examined the risk factors that affect the efficiency and longevity of dialysis access for patients receiving dialysis in Ahvaz medical centers. Patients and Methods: In our retrospective study, 180 hemodialysis patients were referred to the Golestan educational and medical center in Ahvaz, Iran. An arteriovenous fistula (AVF) or catheter was conducted to provide them with vascular access. Detailed demographic information about the patient was collected, including age, gender, height, weight, body mass index (BMI), cause of ESRD, duration of renal failure, duration of dialysis, and comorbidities. There were instances of access inefficiency as a result of infection, stenosis, closure, thrombosis, bleeding, and pseudoaneurysms. The data was analyzed using Mann-Whitney U, t test, and chi-square tests with SPSS version 22. Statistics were considered significant at a P value of 0.05. Results: The mean age of the patients was 50.08 ± 12.213 years, and the mean BMI was 27.90 ± 9.112 kg/m2 . Among dialysis patients, there was a significant relationship between male gender, clopidogrel administration, diabetes history, hypertension and access failure. It is estimated that 36.7% of vascular access failures are caused by thrombosis, while 32.8% are due to access stenosis or closure. Conclusion: Our study showed that male gender, clopidogrel administration, and a history of diabetes and hypertension were risk factors affecting dialysis access quality and efficiency. According to our study, it may be possible to develop a more appropriate approach for determining the type and location of dialysis access.

Antiplatelet Agents Inhibit Platelet Adhesion and Aggregation on Glass Surface Under Physiological Flow Conditions: Toward a Microfluidic Platelet Functional Assay Without Additional Adhesion Protein Modification.

As the pathogenesis of arterial thrombosis often includes platelet adhesion and aggregation, antiplatelet agents are commonly used to prevent thromboembolic events. Here, a new microfluidic method without additional adhesion protein modification was developed to quantify the inhibitory effect of antiplatelet drugs on the adhesion and aggregation behavior of platelets on glass surfaces under physiological flow conditions. Polydimethylsiloxane-glass microfluidic chips were fabricated by soft photolithography. Blood samples from healthy volunteers or patients before and after taking antiplatelet drugs flowed through the microchannels at wall shear rates of 300 and 1500 second -1 , respectively. The time to reach 2.5% platelet aggregation surface coverage (Ti), surface coverage (A 150s ), and mean fluorescence intensity (F 150s ) were used as quantitative indicators. Aspirin (80 μM) prolonged Ti and reduced F 150s . Alprostadil, ticagrelor, eptifibatide, and tirofiban prolonged Ti and reduced A 150s and F 150s in a concentration-dependent manner, whereas high concentrations of alprostadil did not completely inhibit platelet aggregation. Aspirin combined with ticagrelor synergistically inhibited platelet adhesion and aggregation; GPIb-IX-von Willebrand factor inhibitors partially inhibited platelet aggregation, and the inhibition was more pronounced at 1500 than at 300 second -1 . Patient administration of aspirin or (and) clopidogrel inhibited platelet adhesion and aggregation on the glass surface under flow conditions. This technology is capable of distinguishing the pharmacological effects of various antiplatelet drugs on inhibition of platelet adhesion aggregation on glass surface under physiological flow conditions, which providing a new way to develop microfluidic platelet function detection method without additional adhesive protein modification for determining the inhibitory effects of antiplatelet drugs in the clinical setting.

Interplay among proton pump inhibitors, platelet reactivity and CYP2C19 genotyping in clopidogrel-treated patients after drug-eluting stent implantation

Abstract Background Several published data suggested that concomitant use of clopidogrel and proton pump inhibitors (PPIs) is associated with reduced antiplatelet efficacy of clopidogrel and increased adverse clinical outcomes. We sought to evaluate the interplay between PPI and clopidogrel on platelet reactivity and long-term clinical outcomes in patients after percutaneous coronary intervention (PCI) with drug-eluting stent (DES) implantation. Methods The PTRG-DES (Platelet function and genoType-Related long-term proGnosis in DES-treated patients) registry is a multi-center, real-world registry of patients who underwent PCI with DES and received dual antiplatelet therapy of aspirin and clopidogrel in South Korea. Patients prescribed with PPI were compared to those without the use of PPI (the control group). The primary outcome was a composite of all-cause death, myocardial infarction, stent thrombosis, and stroke at 5 years. Secondary outcomes included cardiac death, major bleeding, and gastrointestinal bleeding. Adjusted outcomes were compared after 1:2 propensity score (PS) matching analysis. Results Among 13,160 patients, 2235 (17.0%) were prescribed with concomitant PPI at the time of clopidogrel loading. Average age was 64.4 years, 67.2% were men, and 35.1% had diabetes. The PPI group demonstrated a higher on-treatment P2Y12 reaction unit than the control group (p&amp;lt;0.001). The 5-year cumulative incidence of the composite primary outcome was higher in the PPI group (12.1% vs. 9.8%, log-rank p&amp;lt;0.001). After PS matching, the primary outcome was similar between the two groups (12.9% vs. 12.1%, log-rank p=0.24). However, the PPI group with CYP2C19 poor metabolizers showed an increased adjusted risk of the primary outcome (hazard ratio 2.69, p&amp;lt;0.001). Conclusions PPI use in patients with clopidogrel administration after DES implantation was associated with increased platelet reactivity, but similar cardiovascular outcomes in real-world practice. Physicians should be careful when administering PPI with clopidogrel in patients with CYP2C19 poor metabolizers.Distribution of P2Y12 reaction unitCumulative Incidence of outcomes

Platelet reactivity and activated clotting time predict haemorrhagic site complications in patients with chronic coronary syndromes undergoing percutaneous coronary intervention

Abstract Background/Introduction Same-day discharge has become a standard of care for patients with chronic coronary syndromes (CCS) treated with ad hoc percutaneous coronary interventions (PCI). QuickClot Radial kaolin-based haemostatic device may shorten haemostasis time and reduce the incidence of vascular site complications. Besides unfractionated heparin (UFH) and aspirin (ASA), an ad hoc procedure demands a loading dose of clopidogrel. Dynamic changes in platelets and thrombotic activity may influence the outcomes at vascular sites. Rapid "point-of-care" testing measures the effects of anticoagulation but the optimal threshold during and after PCI still requires further research. Purpose We investigated the effect of a standard dose of UFH and a loading dose of clopidogrel measured with point-of-care devices: Hemochron activated clotting time device (ACT), VerifyNow P2Y12 test on on-site outcomes. Methods We conducted a prospective, observational study of consecutive patients with CCS who qualified for ad hoc PCI. Patients were on chronic ASA therapy, received 100 IU/kg UFH, and a 600 mg loading dose of clopidogrel. ACT was measured before and 10 min, 2 h, and 6 h after the administration of UFH and clopidogrel, respectively, and the VerifyNow P2Y12 test measured after 2 and 6 h. A QuickClot haemostatic pad with gradually released compression for up to 2 h was used in all patients. Ultrasonographic assessment of artery diameter and patency was performed before and 6 h after the procedure. Bleeding (BARC criteria) or local haematoma (EASY scale) were observed regularly until hospital discharge. Results Forty patients were enrolled in the study. The mean±SD age was 68.8±8.8 years, 30 (75%) patients were men, 13 (35%) had diabetes, 38 (95%) hypertension, 16 (40%) previous myocardial infarction, and 15 (37,5%) were active smokers. Patients received a median [interquartile range (IQR)] 8000 [7000-9000] IU of UFH and 600 mg of clopidogrel. All of the radial arteries remained patent during observation; local bleeding (BARC 2) was observed in 11 (27,5%) and haematomas (EASY 1 and 2) in 11 (27,5%) patients. Patients with bleeding had lower platelet activity measured with platelet reactivity units (PRU) after 2 h (122.5± 51 vs 158.7± 43, p= 0.04) and higher ACT (s) (216.9 ±40 vs. 184.6±28 s, p=0.006). An ACT &amp;gt;196 s, measured 2 h after the procedure, predicted the occurrence of bleeding or haematoma (AUC 0.72; 95%CI 0.56-0.85, p=0.008). Conclusion Lower platelet activity and higher ACT after PCI were associated with higher risk of haemorrhagic site complications. "Point-of-care" measures post PCI in CCS patients may be clinically applicable.

Assessing the hypolipidemic and gastro-liver protective activity of herbal combination with emphasis on PPI amid selected multiple antihypertensive drug combination in experimental animal models.

Peptic ulcer (PU) and hypertension are chronic diseases affecting up to 10% and 30% of the adult population worldwide. Most of these patients will require treatment with a combination of antihypertensive medicines, which have adverse effects on the body's different organs. This study specifically focused on antihypertensive multi-drug induced PU disease and disturbance of liver function. During a 14-day oral administration of antihypertensive drugs, Cilnidipine (1 mg/kg), Rosuvastatin (1 mg/kg), Bisoprolol (0.52 mg/kg), and Clopidogrel (7.81 mg/kg) were observed for their effects on the stomach lining and liver function in Wister albino rats. This study aimed to assess the potential of an herbal combination of (BO) + (BA) + (ZO) 0.26 mg/kg body weight (b.w.) Powder and water mixture on the ulcer, lipid profile, and liver function for 14 days in the treatment of the indomethacin-induced gastric ulcers in rats at doses of 30 mg/kg b.w. for three days. Esomeprazole (20 mg/kg b.w.) is used as a standard reference to evaluate antiulcer activity in rat models. The experiment suggests that the gastroprotective effect of the herbal combination can be attributed to its reducing effect on the peptic and the Serum Glutamic Pyruvic Transaminase (SGPT) levels and within the normal range of 34.67 ± 0.88 IU/L. The results for Total Cholesterol (TC), Triglyceride (TG), High-density lipoprotein (HDL) and Low-density lipoprotein (LDL) of the herbal combination were 52 ± 9.81495 (mg/dl), 70 ± 12.12435 (mg/dl), 23.33 ± 6.06446 (mg/dl), 14.5 ± 1.32790 (mg/dl), respectively, where the standard group (atorvastatin) 5 mg/kg TC, TG, HDL and LDL were 69.77 ± 9.92 (mg/dl), 47.7 ± 10.35 (mg/dl), 33.43 ± 5.70 (mg/dl), 26.8 ± 3.70 (mg/dl), and control group total cholesterol, triglyceride, HDL and LDL were 68.67 ± 2.20 (mg/dl), 124.07 ± 2.94 (mg/dl), 49.14 ± 1.05 (mg/dl), 54.11 ± 1.15 (mg/dl). CThis investigation reported that antihypertensive drugs did not produce gastrointestinal (GI) toxicity, and the morphological structure of the organ was not changed. So, it could be concluded that the herbal combination used in this experiment has a promising role in controlling lipid profile, liver function, and antiulcer effects. Moreover, multiple drug therapy for hypertension does not cause any harm to the stomach. Further investigations might be carried out on a larger scale to make these statements more valid.

Evaluation of thrombin generation in dogs administered clopidogrel.

The antiplatelet effect of clopidogrel can vary between patients. A modified thromboelastography (TEG) protocol (TEG-Platelet Mapping assay® [TEG-PM]) can be used for clopidogrel monitoring but is not widely available. Thrombin generation (TG) assays could offer a novel alternative. The main objective of this pilot study was to assess TG assay variables (lag time, peak, endogenous thrombin potential [ETP]) in dogs before and after 7 days of clopidogrel administration and compare with TEG-PM variables (maximum amplitude [MA]-ADP and percentage (%) inhibition). Six healthy mix-breed dogs were enrolled in this pilot study. Blood samples for platelet count, TG assays, and TEG-PM were obtained at two time points, corresponding to baseline, and after 7 days of clopidogrel administration (mean 2.3 +/- 0.3 mg/kg PO q24 hours). Data were then compared with a Student's t-test. There was no significant change in TG assay variables performed on platelet poor plasma after 7 days of clopidogrel administration: lag time (Day 1: 1.8 +/- 0.2 min, Day 7: 1.8 +/- 0.2 min, p = 0.42); peak (Day 1: 76 +/- 7 nM, Day 7: 72 +/- 10 nM, p = 0.49); and ETP (Day 1: 399 +/- 27 nM*min, Day 7: 392 +/- 32 nM*min; p = 0.49). There were significant changes in TEG MA-ADP (Day 1: 19 +/- 8 mm, Day 7: 9 +/- 6 mm, p = 0.04) and % inhibition (Day 1: 58 +/- 27, Day 7: 99 +/- 0.3, p = 0.02). Clopidogrel administration did not lead to changes in TG assay variables performed on platelet poor plasma samples, despite concomitant changes in TEG-PM variables consistent with platelet inhibition. Based on this pilot study, thrombin generation performed on platelet poor plasma may not be a useful antiplatelet monitoring tool in dogs.

Thrombus architecture is influenced by the antiplatelet loading treatment in patients with acute myocardial infarction

BackgroundIntracoronary thrombus formation is a main cause of acute myocardial infarction triggered by platelet activation. However, there are no data on the impact of different treatment strategies with antiplatelet agents before percutaneous coronary intervention (PCI) on histological characteristics of thrombus formation. ObjectiveIn this study, we investigate the impact of preinterventional administration of the P2Y12-inhibitors clopidogrel and prasugrel on thrombus composition, highlighting significant changes associated with the antiplatelet pre-treatment. MethodsWe prospectively enrolled 104 consecutive patients with ST-segment elevation myocardial infarction (STEMI) undergoing immediate PCI and thrombus aspiration by immunohistochemical staining along with RNA-sequencing employing Nanostring analysis. Fifty-two patients were treated with either prasugrel loading (60 mg) or clopidogrel loading (600 mg) prior to PCI, respectively. ResultsIn Patients with STEMI, intracoronary thrombus architecture was significantly altered between patients pre-treated with prasugrel when compared to clopidogrel. Fibrin content of thrombi was significantly decreased (41.8 % versus 66.7 %, p = 0.009) after pre-treatment with prasugrel compared to clopidogrel. Furthermore, levels of MPO positive cells in intracoronary thrombi were significantly decreased in patients with prasugrel pre-treatment (90.5 versus 201.1, p = 0.014) indicating an association of antiplatelet pre-treatment and the inflammatory responses during thrombus formation. Most strikingly, we observed significant differences among both pre-treatment groups regarding altered RNA expression and signaling pathways of thrombo-inflammatory processes within the thrombotic material, which were independently associated with antiplatelet strategies. ConclusionsOur study elucidates the impact of antiplatelet pre-treatment on thrombus remodeling and architecture, thereby lowering the risk of recurrent adverse cardiovascular events in prasugrel-treated patients.

Role of circadian clock in the chronoefficacy and chronotoxicity of clopidogrel.

The role of circadian locomotor output cycles kaput (CLOCK) in regulating drug chronoefficacy and chronotoxicity remains elusive. Here, we aimed to uncover the impact of CLOCK and dosing time on clopidogrel efficacy and toxicity. The antiplatelet effect, toxicity and pharmacokinetics experiments were conducted with Clock-/- mice and wild-type mice, after gavage administration of clopidogrel at different circadian time points. The expression levels of drug-metabolizing enzymes were determined by quantitative polymerase chain reaction (qPCR) and western blotting. Transcriptional gene regulation was investigated using luciferase reporter and chromatin immunoprecipitation assays. The antiplatelet effect and toxicity of clopidogrel in wild-type mice showed a dosing time-dependent variation. Clock ablation reduced the antiplatelet effect of clopidogrel, but increased clopidogrel-induced hepatotoxicity, with attenuated rhythms of clopidogrel active metabolite (Clop-AM) and clopidogrel, respectively. We found that Clock regulated the diurnal variation of Clop-AM formation by modulating the rhythmic expression of CYP1A2 and CYP3A1, and altered clopidogrel chronopharmacokinetics by regulation of CES1D expression. Mechanistic studies revealed that CLOCK activated Cyp1a2 and Ces1d transcription by directly binding to the enhancer box (E-box) elements in their promoters, and promoted Cyp3a11 transcription through enhancing the transactivation activity of albumin D-site-binding protein (DBP) and thyrotroph embryonic factor (TEF). CLOCK regulates the diurnal rhythmicity in clopidogrel efficacy and toxicity through regulation of CYP1A2, CYP3A11 and CES1D expression. These findings may contribute to optimizing dosing schedules for clopidogrel and may deepen understanding of the circadian clock and chronopharmacology.

The effects of P2Y12 adenosine receptors' inhibitors on central and peripheral chemoreflexes.

Introduction: The most common side effect of ticagrelor is dyspnea, which leads to premature withdrawal of this life-saving medication in 6.5% of patients. Increased chemoreceptors' sensitivity was suggested as a possible pathophysiological explanation of this phenomenon; however, the link between oversensitization of peripheral and/or central chemosensory areas and ticagrelor intake has not been conclusively proved. Methods: We measured peripheral chemoreceptors' sensitivity using hypoxic ventilatory response (HVR), central chemoreceptors' sensitivity using hypercapnic hyperoxic ventilatory response (HCVR), and dyspnea severity before and 4 ± 1 weeks following ticagrelor initiation in 11 subjects with chronic coronary syndrome undergoing percutaneous coronary intervention (PCI). The same tests were performed in 11 age-, sex-, and BMI-matched patients treated with clopidogrel. The study is registered at ClinicalTrials.com at NCT05080478. Results: Ticagrelor significantly increased both HVR (0.52 ± 0.46 vs. 0.84 ± 0.69 L min-1%-1; p < 0.01) and HCVR (1.05 ± 0.64 vs. 1.75 ± 1.04Lmin-1mmHg-1; p < 0.01). The absolute change in HVR correlated with the change in HCVR. Clopidogrel administration did not significantly influence HVR (0.63 ± 0.32 vs. 0.58 ± 0.33 L min-1%-1; p = 0.53) and HCVR (1.22 ± 0.67 vs. 1.2 ± 0.64Lmin-1mmHg-1; p = 0.79). Drug-related dyspnea was reported by three subjects in the ticagrelor group and by none in the clopidogrel group. These patients were characterized by either high baseline HVR and HCVR or excessive increase in HVR following ticagrelor initiation. Discussion: Ticagrelor, contrary to clopidogrel, sensitizes both peripheral and central facets of chemodetection. Two potential mechanisms of ticagrelor-induced dyspnea have been identified: 1) high baseline HVR and HCVR or 2) excessive increase in HVR or HVR and HCVR. Whether other patterns of changes in chemosensitivities play a role in the pathogenesis of this phenomenon needs to be further investigated.

Impact of Cyp2c19 Allele 17 Mutase on Clopidogrel Hyper-Responsiveness in Indonesian Patients with Ischemic Stroke

BACKGROUND: Ischemic stroke dominated up to 76% of the 101.5 million stroke cases globally. One of the treatments for stroke is secondary prevention by administering antiplatelet. Clopidogrel is an add-on antiplatelet to the dual antiplatelet therapy (DAPT) regimen. In its metabolism, clopidogrel can show the nature of resistance and bleeding risk. Studies on resistance have been widely put forward but not with the bleeding. The study of the bleeding risk to Asian races focused only on East Asian races. AIM: The objective of the study is to determine the bleeding risk in the Indonesian population and the correlation with the polymorphism of CYP2C19 allele 17. METHODS: There were 112 participants in this study. About 45.5% showed a normal response to clopidogrel, but 40.2% had a bleeding risk. All participants (100.0%) had mutations in CYP2C19 allele 17, with 47.3% being intermediate metabolizers. RESULTS: The bleeding risk was significantly correlated with clopidogrel (p: 0.02). The Indonesian population has a high bleeding risk from the clopidogrel administration. CONCLUSION: Compared to DAPT administration, clopidogrel can be a monotherapy for secondary stroke prevention.

Ten-year trends in sex differences in cardiovascular risk factors, in-hospital management, and outcomes of ischemic stroke in China: Analyses of a nationwide serial cross-sectional survey from 2005 to 2015.

Women with stroke differ from men in terms of risk factors, treatment, and outcomes. However, previous inconsistent results in China hampered the development of tailored sex-specific strategies for ischemic stroke management. We performed a nationwide serial cross-sectional survey to obtain national-level estimates to assess the 10-year trends in sex differences in cardiovascular risk factors, in-hospital management, and outcomes in China from 2005 to 2015. We used a two-stage random sampling design, economic-geographical region-stratified random sampling for hospitals first and then systematic sampling for patients, to obtain a nationally representative sample of ischemic strokes in China in 2005, 2010, and 2015. We extracted data on clinical characteristics, management measures (diagnostic tests, interventions, and secondary prevention treatments), in-hospital outcomes (all-cause in-hospital mortality, discharge against medical advice [DAMA], and a composite outcome of in-hospital death and DAMA), and comorbidities. We applied weights proportional to the inverse sampling fraction of hospitals within each stratum and the inverse sampling fraction of patients within each hospital. A total of 26,900 ischemic stroke admissions were analyzed. Compared to men, women had a much lower prevalence of current smokers and a slightly higher prevalence of hypertension, diabetes, dyslipidemia, and atrial fibrillation at admission. Prevalence differences between sex in these cardiovascular risk factors were stable except for atrial fibrillation (decreased from 3.7% [95% CI: 1.8% to 5.7%] to 1.3% [95% CI: 0.5% to 2.0%]) and current smoker (increased from -18.0 [95% CI: -20.2% to -15.9%] to -25.6% [95% CI: -26.6% to -24.6%]). From 2005 to 2015, in-hospital management and outcomes were improved both for women and men, and sex differences in cerebrovascular assessment, cervical vessels assessment, and transthoracic echocardiography/transesophageal echocardiography were improved as well. However, women increased more slowly than men in the administration of clopidogrel (from 0.3% [95% CI: -0.9% to 1.4%) to -7.3% [95% CI: -8.7% to -6.0%]) and aspirin plus clopidogrel (0.3% [95% CI: -5.0% to 1.1%] to -5.0% [95% CI: -6.2% to -3.9%]). Compared to men, women patients with ischemic stroke had a steadily higher prevalence of cardiovascular risk factors, a slower increase rate in the administration of key secondary prevention drugs, and comparable in-hospital outcomes. More effort should be paid to the treatment and control of cardiovascular risk factors and also to the prescription of antiplatelets at discharge for women.

Abstract Number ‐ 140: Transcranial Doppler Emboli Monitoring for Stroke Prevention after Flow Diversion: A Single Center Experience

Introduction Following the favorable clinical and radiographical results of flow diversion, its use has continually expanded for the treatment of complex intracranial aneurysms. The high metal surface of flow diverters (FD) increases the risk of thromboembolic complications. Current emboli monitoring data after FD placement is limited. Transcranial doppler (TCD) offers a non‐invasive evaluation of microembolic signals and might be a valuable tool to prevent ischemic complications. We evaluated the rate of embolic signals and their management after FD implantation. Methods We performed a retrospective, single‐center evaluation of adult patients who underwent a FD procedure with the Pipeline Embolization Device (PED) for unruptured intracranial aneurysms between 2012 and 2016. Covariates included patient demographics, comorbidities, aneurysm characteristics, procedure characteristics, and post‐procedure TCD emboli monitoring (immediate and &gt;12 hours post‐operative). TCD emboli signals were classified as positive (&lt; 15 microembolic signals) and strongly positive (&gt;15 signals). The primary outcome was the rate of symptomatic stroke at 2 and 12 weeks in these patients. Results 105 patients with 132 aneurysms were analyzed. Mean age was 59.7 years, and 78% were females. Mean aneurysm size was 7.8 ± 6.4 mm. Most of them were located in the paraclinoid region (40%). Two PEDs were implanted in 12 (11%) cases and adjunctive coiling was performed in 15 (14%) cases. Microemboli were detected in 11.4% of cases (12/105 patients) after PED deployment. In 5/12 patients, the emboli resolved upon repeat testing with no intervention. In 6/12 patients, further heparinization, additional clopidogrel administration, or change in antiplatelet agents were needed. These treatments reduced the microembolic events. In 1 patient who was clopidogrel‐resistant and a ticagrelor super‐responder, mechanical thrombectomy was necessary due to acute in‐stent thrombosis. There were no symptomatic strokes at 2 and 12 weeks. Conclusions TCD emboli monitoring can be a powerful non‐invasive tool for the early identification and prevention of thromboembolic events after FD implantation. Early detection of microembolic signals offers the possibility to modify postoperative management, avoid silent emboli, and potentially avoid symptomatic strokes.