Antiplatelet Effect Of Clopidogrel 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.

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.

Influence of Clinically Significant Genes on Antiplatelet Effect of Clopidogrel and Clinical Outcomes in Patients with Acute Coronary Syndrome and Atrial Fibrillation

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.

New Perspectives on Clopidogrel Resistance Systematic Review and Meta-analysis

Background: Clopidogrel resistance can be defined as the failure of clopidogrel to inhibit its target of action. The prevalence of clopidogrel resistance in various studies ranges between 5%–44%. Clopidogrel resistance is a serious scary condition whereby clopidogrel drug is less or not effective for some patients than expected. Hence the present Systematic review was conducted to explore the new perspectives of Clopidogrel and to evaluate the effect of genetic cytochrome CYP2C19 (CYP2C19*2, CYP2C19*3) of the key drug metabolizing enzymes on the response to the anti-platelet effect of clopidogrel. To provide insights into the commentary summarizes the clinical evidence on the pharmacokinetic determinants of clopidogrel efficacy.&#x0D; Material and Method: Systematic review is a type of literature reviews that collects and critically analyzes multiple research studies using methods that are selected before one or more research questions are formulated and then finding and analyzing studies that relate to and answer those questions in a structured methodology.&#x0D; Results: Accumulated information from suggested the presence of high incidence of clopidogrel resistance. Associated with acute coronary syndrome (ACS), Acute myocardial infarction (AMI) and stroke. There was no significant difference in the incidence of resistance according to the type of studies.&#x0D; Conclusion: Accumulated information from previous studies and the present systematic review suggested the presence of high incidence of clopidogrel resistance. This resistance was associated with serious complications such as acute coronary syndrome (ACS), Acute myocardial infarction (AMI) and stroke.

Identify and Assess Drug Interactions with Atorvastatin in Inpatient Care

Background: Atorvastatin is a recent HMG-COA reductase inhibitor used to treat primary hypercholesterolemia, homozygous familial hypercholesterolemia, and mixed dyslipidemias. It is also taken to prevent heart disease, including strokes and heart attacks. In addition, Atorvastatin is used to lower bad cholesterol low-density lipoproteins (LDL) levels, increase good cholesterol high-density lipoprotein (HDL) levels, and lower triglycerides. It works by reducing the amount of cholesterol produced in the body, hence reducing the amount of cholesterol that may build up on the walls of arteries. Atorvastatin is long-acting, has few adverse effects, and is low in price. Nevertheless, it interacts with a wide variety of medications. These interactions may be lead to adverse drug reactions.&#x0D; Objective: The study aims to identify and asset atorvastatin interactions with other medicines at King Abdulaziz Hospital. Also, to prevent atorvastatin interactions in the future.&#x0D; Methods: The retrospective study investigated 280 electronic prescriptions inside the inpatient clinic at King Abdulaziz Hospital in Saudi Arabia between January and April 2021 to identify and asset interactions among atorvastatin and different medications.&#x0D; Results: Most atorvastatin interactions are category C (44.64%) and category B (41.43%). Atorvastatin had the most common interactions with esomeprazole (16.07%), clopidogrel (14.64%), and sitagliptin (12.14%). Atorvastatin had clinical interactions with medications metabolized by the cytochrome P450 3A4 )CYP3A4(. Use of atorvastatin with cyclosporine or clarithromycin increased the risk for atorvastatin toxicities such as myopathy and rhabdomyolysis. In addition, Atorvastatin decreases clopidogrel's antiplatelet effect and increases the risk of skeletal muscle toxicity of daptomycin.&#x0D; Conclusion: The majority of atorvastatin interactions may be avoided by adhering to best practices in clinical care and clinical pharmacology, such as avoiding complicated treatment regimens, utilizing a single pharmacy for all prescriptions, and recognizing patient risk factors. Health care professionals should use drug-drug interaction checkers such as Medscape and Micromedex, as well as a book such as the Handbook of Drug Interactions.

Abstract 14311: Gene Guided Antiplatelet Therapy for Acute Coronary Syndrome: An Updated Meta-Analysis

Introduction: Clopidogrel has been the mainstay oral antiplatelet regimen to treat Acute Coronary syndrome (ACS) post percutaneous coronary intervention (PCI) with stents. However, there is marked inter-individual variability due to genetic polymorphisms in the hepatic cytochrome P450 (CYP) 2C19 in the antiplatelet effects of clopidogrel and a reduced response to this drug may be a risk factor for ischemic complications. There has been varied evidence in gene-guided antiplatelet therapy post PCI. An updated meta-analysis was conducted to study the effect of gene-guided antiplatelet therapy in ACS. Methods: A systematic literature review was performed in Embase, PubMed and SCOPUS for all the related articles until May 2021 yielding 180 publications. Nine studies fulfilled inclusion criteria including 8 randomized clinical trials and 1 observational study. The Mantel- Haenszel random-effects model was used to calculate odds ratio (OR) and 95% confidence intervals (CI). Outcomes analyzed were the composite major adverse cardiovascular events (MACE), stent thrombosis, myocardial infarction (MI), bleeding and cardiovascular (CV) death. Results: Gene guided antiplatelet therapy was performed in 7106 patients and conventional therapy in 3970 patients. The MACE events was significantly lower in gene-guided therapy arm (OR = 0.67, 95% CI [0.51 -0.87], P=0.003) driven by lower stent thrombosis (OR=0.47, 95% CI [0.25 -0.88], P=0.02) and lower MI in the gene guided therapy (OR=0.61, 95% CI [0.41 -0.92], P=0.02). The bleeding rates trended to be lower in the gene guided therapy as well (OR = 0.75, 95% CI [0.54-1.02], P=0.07). There is no significance difference in CV death. (OR=0.57, 95% CI [0.21-1.55]) Conclusions: Genotype guided antiplatelet therapy in ACS has lower adverse cardiovascular outcomes driven by lower stent thrombosis and MI with lower bleeding trends as well.

Clopidogrel-herb Interactions: A Pharmacokinetic and Pharmacodynamic Assessment in a Rat Model.

Herbs usually contain a mixture of biologically active constituents, which can interact with numerous prescribed drugs and alter their safety profiles. The current investigation was aimed to evaluate the effect of commonly used herbal products including black seed (Nigella sativa), garden cress (Lepidium sativum), and fenugreek (Trigonella foenum-graecum) on the pharmacokinetics and pharmacodynamics of clopidogrel using a Wistar rat model. A GC-MS analysis revealed the presence of several phytoconstitutents (polyphenols) in the extracts of black seed, garden cress, and fenugreek. These polyphenols have the potential to interfere with clopidogrel effect. Plasma concentrations of clopidogrel were measured at different time points in the absence and presence of the concurrent use of tested herbal products and the pharmacokinetic parameters were calculated. Bleeding time was measured in various groups as a measure of the antiplatelet effect of clopidogrel. Area under the plasma concentration-time curves (AUC0-∞) of clopidogrel were 35.53 ±0.89 μg/ml*h (p<0.05), 26.01 ±0.90 μg/ml*h (p>0.05) and 32.80 ±2.51 μg/ml*h (p<0.05) in the black seed, garden cress and fenugreek group, respectively, compared with that of the control group (27.02 ±0.42 μg/ml*h). Treatment with black seed also caused an increase in clopidogrel Cmax by 31.52% (p<0.05) and with fenugreek by 21.42% (p<0.05); Cmax, did not changed with garden cress treatment (6.48 ±0.15 μg/ml versus 6.12 ±0.21 μg/ml, p>0.05). The pharmacodynamic evaluation of the antiplatelet effect of clopidogrel in the presence of herbal products treatment showed a significant prolongation in the bleeding time from a control baseline by ~22-26%, and by added ~8-12% in reference to clopidogrel therapeutic effect (p<0.05). The concurrent use of black seed, fenugreek, or garden cress can alter the pharmacokinetics and pharmacodynamics of clopidogrel to varying degrees due to the presence of various bioactive polyphenols. This is probably due to changes in drug disposition and its antiplatelet action. Further confirmation can determine the clinical relevance of these observations and identify the exact constituents responsible for such activities.

Platelet-fibrin clot strength measured by thromboelastography could predict hypercoagulability and antiplatelet effects in patients after percutaneous coronary intervention.

It has been estimated that nearly one-fifth post-percutaneous coronary intervention (PCI) patients treated with clopidogrel continued to have recurrent thrombotic events, which implied the limitation of "one-size-fits all" strategy for antiplatelet therapy. From July 2017 to April 2019, patients with acute coronary syndrome [ACS, including unstable angina (UA), non-ST segment elevation myocardial infraction (NSTEMI), and ST segment elevation myocardial infraction (STEMI)] or old myocardial infarction (OMI), or patients without coronary heart disease (non-CAD) were retrospectively enrolled in this study. For CAD patients undergoing PCI, standard dual antiplatelet therapy (100 mg aspirin and 75 mg clopidogrel) was prescribed. After administration of dual antiplatelet agents for at least 5 days, whole blood samples were collected and platelet function was tested using thrombelastography (TEG). Thrombin-induced platelet-fibrin clot strength (MAthrombin) and ADPinduced platelet-fibrin clot strength (MAADP) were measured to assess the hypercoagulability and antiplatelet effects. A total of 571 patients, including 479 ACS patients, 21 OMI patients and 71 non-CAD patients were enrolled. Highest level of MAthrombin was detected in STEMI patients, while lowest MAthrombin level was observed in non-CAD patients (P1 <0.05 for OMI vs. non-CAD; P2 <0.001 for ACS vs. non-CAD; P3<0.05 among ACS). Higher MAADP was also observed in STEMI and NSTEMI patients compared with UA patients (P<0.001). When MAADP was divided into trisections (MAADP <31; 31-47; >47 mm), a considerable portion of 41.8% ACS patients were in the first trisection (MAADP <31 mm), containing 50.4% of UA patients, 35.7% of NSTEMI patients and 26.5% of STEMI patients, with significant difference being observed between UA patients and other ACS patients (P<0.05 for NSTEMI vs. UA; P<0.001 for STEMI vs. UA). Meanwhile, 27.6% of NSTEMI and 31.0% of STEMI patients were in the third trisection (MAADP >47 mm), which was significantly higher than that of UA patients (12.7%) (P<0.001 for NSTEMI or STEMI vs. UA). Considering various degrees of hypercoagulability and antiplatelet effects of clopidogrel among OMI and ACS patients post-PCI. More attention should be paid to personalized antiplatelet therapy according to individual's effects of P2Y12 receptor inhibitors.

The potential interaction of statins and clopidogrel in patients undergoing percutaneous coronary intervention

Clopidogrel is widely used for patients with acute coronary syndrome. It is a pro-drug that requires bioactivation by several cytochrome P450 (CYP) enzymes, mainly CYP3A4, CYP2C9, and CYP2C19 enzymes. Lipophilic statins such as atorvastatin are used concomitantly with clopidogrel due to their beneficial effects on morbidity and mortality in the arena of cardiovascular diseases. However, lipophilic statins are eliminated by CYP3A4 and undergo the same metabolic pathway of clopidogrel. Hence, statins may compete with clopidogrel for CYP3A4 enzyme resulting in diminishing the anti-platelet effect of clopidogrel. We aimed to study the impact of concomitant statin therapy on clopidogrel efficacy in patients undergoing percutaneous coronary intervention (PCI) evaluate the clinical relevance of potential clopidogrel and statins interaction and association between use of statins and risk of future adverse cardiac events. A cross-sectional retrospective cohort study was conducted on 50 patients attending Prince Sultan Cardiac Center for follow-up after PCI. All patients discharged on clopidogrel, aspirin, and atorvastatin were later divided into two groups according to the occurrence of MACEs. Statistical analysis was performed by Statistical Package for the Social Science (SPSS; V. 21.0). This study was on adult and geriatric males (72%)and female (28%). More than half of them exhibited major adverse cardiac events (MACEs), of which 48% exhibited it after 4 to 6 months from PCI indexing followed by 1 to 3 months (34%), and the least after 7 to 9 months. A significant association arises between gender and MACEs (P=0.042). Moreover, the average age was significantly higher in patients who experience MACEs compared to others (62.7 vs. 55.4, P=0.037). Regarding comorbidities, hypertension increased in patients with MACEs (73.1%) compared to those without MACEs (45.8%). The average duration of taking clopidogrel was significantly shorter in patients with MACEs compared to those who did not (3.42 vs. 5.54 months, P&lt;0.001). According to the findings of this study, atorvastatin affects clopidogrel efficacy in patients undergoing PCI.

Decreased Platelet Inhibition by Thienopyridines in Hyperuricemia

PurposeHyperuricemia carries an increased risk of atherothrombotic events in acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI). This may at least in part be due to inadequate P2Y12 inhibition. The aim of this study was to prospectively investigate the potential association between hyperuricemia and decreased platelet inhibition by P2Y12 antagonists.MethodsLevels of uric acid as well as on-treatment residual platelet reactivity in response to adenosine diphosphate (ADP) were assessed in 301 clopidogrel-treated patients undergoing elective angioplasty and stenting, and in 206 prasugrel- (n = 118) or ticagrelor-treated (n = 88) ACS patients following acute PCI. Cut-off values for high on-treatment residual ADP-inducible platelet reactivity (HRPR) were based on previous studies showing an association of test results with clinical outcomes.ResultsHyperuricemia was significantly associated with increased on-treatment residual ADP-inducible platelet reactivity in clopidogrel- and prasugrel-treated patients in univariate analyses and after adjustment for differences in patient characteristics by multivariate regression analyses. In contrast, ticagrelor-treated patients without and with hyperuricemia showed similar levels of on-treatment residual platelet reactivity to ADP. HRPR occurred more frequently in clopidogrel- and prasugrel-treated patients with hyperuricemia than in those with normal uric acid levels. In contrast, hyperuricemic patients receiving ticagrelor did not have a higher risk of HRPR compared with those with normal uric acid levels.ConclusionHyperuricemia is associated with decreased platelet inhibition by thienopyridines but a normal response to ticagrelor. It remains to be established if lowering uric acid increases the antiplatelet effects of clopidogrel and prasugrel in hyperuricemic patients with HRPR.

The effect of single and dual antiplatelet therapy on the activity of pro-inflammatory cytokines in patients with coronary artery disease and obstructive sleep apnea

Aim. To study the activity of pro-inflammatory cytokines in patients with coronary artery disease (CAD) associated with obstructive sleep apnea (OSA), depending on the type of antiplatelet therapy. Material and methods . The study included 148 patients with stable CAD, 30% (n=44) of whom had mild OSA, 10% (n=14) — moderate and severe OSA. There were 60% (n=90) of patients without OSA. Pro-inflammatory activity of cytokines was assessed by the level of interleukins (IL): IL- 1β, IL-6, IL-10. Results. Using dual antiplatelet therapy, there were no differences in aggregation activity of platelets (spontaneous and induced by 0,1 pM ADP) in patients with and without OSA. This indicates the synergism and potentiation of the antiplatelet effect of clopidogrel and acetylsalicylic acid (ASA). Patients with moderate and severe OSA and stable CAD had higher levels of IL- 1β and IL-6 compared with patients without OSA. Antiplatelet therapy, especially dual one, had an anti-inflammatory effect, which was reflected in lower values of pro-inflammatory IL both in patients with and without OSA. Conclusion. Patients with moderate and severe OSA and stable CAD had higher levels of pro-inflammatory IL (IL- 1β, IL-6) compared with patients without OSA. The combined use of clopidogrel and ASA potentiates antiplatelet and anti-inflammatory effects. This is reflected in lower values of pro-inflammatory IL and lower aggregation activity of platelets in patients with stable CAD, regardless of OSA.

Clopidogrel response in ischemic stroke patients: Is polymorphism or gender more important? Results of the CRISP study

Clopidogrel (CLP) is a second generation thienopyridine drug commonly used in secondary prevention of ischemic stroke (IS). Its antiplatelet response maybe variable due to genetic and non-genetic factors. Adipokines may affect platelet aggregation through ADP mediated platelet signalling. However, the combined effect of CYP genetic variants and adipokines on antiplatelet response of clopidogrel is unclear. Patients of IS/Transient ischemic attack (TIAs) within 3 months were prospectively screened following clopidogrel treatment. Major exclusions were cardioembolic and non atherosclerotic strokes. Antiplatelet effect of clopidogrel along with adipokine (Leptin and adiponectin) levels and genotyping of CYP, P2Y12 gene were investigated. Rare genetic variants were confirmed by DNA sequencing. 204 patients with ischemic stroke/TIAs were screened and 163 were recruited. 85 (52.1%) patients were poor responders to clopidogrel. Antiplatelet response to clopidogrel was weaker in females [Median 8.0 (IQR: 3.0–14.0)] compared to males [Median 5.0 (IQR: 2.0–10.0)]. In female subgroup analysis, association was found among high leptin levels and PPI (+) usage in poor responders. None of the genetic variants (CYP2C19*2,*3,*4*, CYP2C9*3, CYP2B6 and P2Y12) were found to influence the antiplatelet effects (p > 0.05). On multivariable logistic regression, a poor clopidogrel response was associated with female gender (Adjusted OR 2.55, 95% CI: 1.05–6.18) and PPI usage (Adjusted OR 2.42, 95% CI: 1.09–5.34). Despite a high prevalence of clopidogrel resistance in the North Indian stroke patients, female gender rather than genetic polymorphisms of CYP and P2Y12 genes may influence its antiplatelet effect. Further research may ascertain the role of gender on clopidogrel response.

Clopidogrel Resistance in a Murine Model of Diet-Induced Obesity Is Mediated by the Interleukin-1 Receptor and Overcome With DT-678.

Clopidogrel is a commonly used P2Y12 inhibitor to treat and prevent arterial thrombotic events. Clopidogrel is a prodrug that requires bioactivation by CYP (cytochrome P450) enzymes to exert antiplatelet activity. Diabetes mellitus is associated with an increased risk of ischemic events, and impaired ability to generate the active metabolite (AM) from clopidogrel. The objective of this study is to identify the mechanism of clopidogrel resistance in a murine model of diet-induced obesity (DIO). Approach and Results: C57BL/6J mice and IL-1R-/- mice were given high-fat diet for 10 weeks to generate a murine model of diet-induced obesity. Platelet aggregation and carotid arterial thrombosis were assessed in response to clopidogrel treatment. Wild-type DIO mice exhibited resistance to antiplatelet and antithrombotic effects of clopidogrel that was associated with reduced hepatic expression of CYP genes and reduced generation of the AM. IL (Interleukin)-1 receptor-deficient DIO (IL1R-/- DIO) mice showed no resistance to clopidogrel. Lack of resistance was accompanied by increased exposure of the clopidogrel AM. This resistance was also absent when wild-type DIO mice were treated with the conjugate of the clopidogrel AM, DT-678. These findings indicate that antiplatelet effects of clopidogrel may be impaired in the setting of diabetes mellitus due to reduced prodrug bioactivation related to IL-1 receptor signaling. Therapeutic targeting of P2Y12 in patients with diabetes mellitus using the conjugate of clopidogrel AM may lead to improved outcomes.

Effects of clopidogrel and prednisone on platelet function in healthy dogs

BackgroundGlucocorticoids cause hypercoagulability, but it is unknown if they counteract clopidogrel's antiplatelet effects.Hypothesis/ObjectivesDetermine the effects of clopidogrel and prednisone on platelet function.AnimalsTwenty‐four healthy dogs.MethodsDouble‐blinded, placebo‐controlled randomized trial. Platelet function was evaluated using a platelet function analyzer and impedance aggregometry (days 0, 14, and 28) for dogs treated with placebo, clopidogrel (2‐3 mg/kg/d), prednisone (2 mg/kg/d), or prednisone with clopidogrel PO for 28 days. Results were categorized as nonresponder versus responder (platelet function analyzer), and inadequate, ideal, or excessive response (aggregometry). Results were compared using mixed model, split‐plot repeated measures analysis of variance and generalized estimating equation proportional odds models. P < .05 was considered significant.ResultsClosure times differed by treatment (F [3, 20] = 10.5; P < .001), time (F [2, 40] = 14.3; P < .001), and treatment‐by‐time (F [6, 40] = 3.4; P = .01). Area under the curve (AUC) differed by treatment (F [3, 20] = 19.6; P < .001), time (F [2, 40] = 35.4; P < .001), and treatment‐by‐time (F [6, 40] = 13.5; P < .001). Based on closure times, 5/6 dogs each in the clopidogrel and prednisone/clopidogrel groups were responders. All dogs in the prednisone/clopidogrel group were overcontrolled based on AUC (days 14 and 28), whereas 5/6 (day 14) and 2/6 (day 28) dogs treated with clopidogrel were overcontrolled. Compared to clopidogrel, dogs receiving prednisone/clopidogrel were 11 times (P = .03) more likely to have an excessive response.Conclusions and Clinical ImportanceAdministration of clopidogrel/prednisone increases platelet dysfunction in healthy dogs.

Impact of genetic variants of selected cytochrome P450 isoenzymes on pharmacokinetics and pharmacodynamics of clopidogrel in patients co-treated with atorvastatin or rosuvastatin.

Impaired antiplatelet effect of clopidogrel (CLP) can result from drug-drug interactions and genetic polymorphisms of drug-metabolizing enzymes. The aim of the study was to evaluate the effect of genetic polymorphisms of ABCB1 and the selected cytochrome P450 isoenzymes on the pharmacodynamics and pharmacokinetics of CLP and its metabolites in patients co-treated with atorvastatin or rosuvastatin. The study involved 50 patients after coronary angiography/angioplasty treated with CLP and atorvastatin (n= 25) or rosuvastatin (n= 25) for at least 6months. Plasma concentrations of CLP, diastereoisomers of thiol metabolite (inactive H3 and active H4), and inactive CLP carboxylic acid metabolite were measured by UPLC-MS/MS method. Identification of the CYP2C19*2, CYP2C19*17, CYP3A4*1G, CYP1A2*1F, and ABCB1 C3435T genetic polymorphisms was performed by PCR-RFLP, while platelet reactivity units (PRU) were tested using the VerifyNow P2Y12 assay. There were significant differences in the pharmacokinetic parameters of the H4 active metabolite of CLP in the atorvastatin and rosuvastatin group divided according to their CYP2C19 genotype. There were no significant associations between CYP3A4, CYP1A2, and ABCB1 genotypes and pharmacokinetic parameters in either statin groups. In the multivariate analysis, CYP2C19*2 genotype and non-genetic factors including BMI, age, and diabetes significantly affected platelet reactivity in the studied groups of patients (P< 0.01). In the atorvastatin group, CYP2C19*2, CYP3A4*1G, and ABCB1 C3435T TT genotypes were independent determinants of PRU values (P< 0.01). The CYP2C19*2 allele is the primary determinant of the exposition to the H4 active metabolite of clopidogrel and platelet reactivity in patients co-treated with atorvastatin or rosuvastatin.

Antiaggregation effect of clopidogrel in coronary heart disease patients using omeprazole.

Background Antiplatelet agents used in coronary heart disease (CHD) cause gastrointestinal side effects. Omeprazole can prevent and cure these antiplatelet side effects. Clopidogrel combined with aspirin increases the risk of gastrointestinal tract ulcers and bleeding. This research studied the effect of omeprazole on the antiplatelet effect of clopidogrel. Methods CHD patients using clopidogrel and aspirin receive omeprazole 20 mg in a single dose for 10 days. Platelet antiaggregation point for clopidogrel was measured using VerifyNow P2Y12. The cutoff points used were: low on treatment platelet reactivity (LPR) <85 P2Y12 reaction unit (PRU), normal on treatment platelet reactivity (NPR) 85-208 PRU, and high on treatment platelet reactivity (HPR) >208 PRU. Results Using the paired t-test PRU points pre- and post-omeprazole were 154 ± 85.89 PRU and 169.4 ± 56.15 PRU, respectively. The PRU points were consistent or decreased from the previous PRU points below the HPR cutoff (p: 0.215; >0.05). Before omeprazole use, five patients were categorized as NPR, two patients as LPR, and three patients as HPR. After omeprazole use, two patients, each from HPR and NPR category had a PRU point >208; the rest showed results below the HPR point. Conclusions In this study the PRU points of clopidogrel after omeprazole use showed a PRU <208. The hypothesis that omeprazole may reduce the antiaggregation effect of clopidogrel as shown by the increase in PRU above the cutoff points >208 PRU (HPR) was not proven.

Effectiveness and Safety of Clopidogrel Co-administered With Statins and Proton Pump Inhibitors: A Korean National Health Insurance Database Study.

Simultaneous competition for cytochrome P450 (CYP) 2C19 and CYP3A4 might diminish clopidogrel's antiplatelet effect by impacting its metabolic activation. This pharmacoepidemiologic study investigated whether proton pump inhibitors (PPIs) and CYP3A4-metabolized statins individually and jointly increase thrombotic events by attenuating clopidogrel's effectiveness. From Korean nationwide claims data (2007-2015), we selected 59,233 patients who initiated clopidogrel and statins after coronary stenting and compared thrombotic risks by PPI or CYP3A4-metabolized statin use or both. PPIs were associated with increased thrombotic risks (hazard ratio (HR) 1.27, 95% confidence interval (CI) 1.12-1.45), unlike CYP3A4-metabolized statins (HR 1.03, 95% CI 0.98-1.07). PPIs with high CYP2C19-inhibitory potential were more relevant than those with low potential (HR 1.28, 95% CI 1.02-1.61). Joint effects of PPIs and CYP3A4-metabolized statins were nonsignificant (relative excess risk due to interaction -0.14, 95% CI -0.34 to 0.07). Concurrent PPIs were associated with increased thrombotic risks in patients receiving clopidogrel and statins; CYP3A4-metabolized statins did not exacerbate PPI-associated risks.

Antiplatelet effects of aspirin and clopidogrel after left atrial appendage (LAA) occluder implantation

BackgroundThe optimal antithrombotic strategy after interventional left atrial appendage closure (LAAC) is controversial. Dual antiplatelet therapy with aspirin and clopidogrel is the most frequently used regiment. However, pharmacodynamic response to antiplatelet medication differs significantly between individuals. Therefore, we aimed to analyse pharmacodynamic response to aspirin and clopidogrel after LAAC. MethodsIn this study, we included 129 patients undergoing interventional LAAC. Primary end point was pharmacodynamic response to antiplatelet medication. Platelet reactivity was measured by light transmittance aggregometry and vasodilator stimulated protein phosphorylation assay. Secondary endpoints were TIMI bleeding events and MACCE during hospital course and one-year follow-up. ResultsInsufficient pharmacodynamic response (high on-treatment platelet reactivity — HTPR) to clopidogrel occurred in 67 patients (52%); HTPR to aspirin in 15 patients (12%); low on-treatment platelet reactivity — LTPR — to clopidogrel in 13 patients (10%). No occluder thrombosis or stroke occurred during one year follow-up. Pharmacodynamic response to antiplatelet medication was not associated with MACCE. However, the incidence of TIMI minor bleeding was increased in patients with LTPR to clopidogrel. ConclusionsImpaired clopidogrel antiplatelet effects were very frequent in patients after LAAC. No stroke or occluder thrombosis occurred. Patients with LTPR to clopidogrel showed more minor bleeding events. Therefore, this hypothesis generating pilot study raises the question if clopidogrel early after LAAC is needed. This question should be addressed in large scale trials.

Systematic review with meta-analysis: risk of adverse cardiovascular events with proton pump inhibitors independent of clopidogrel.

Clopidogrel's anti-platelet effects may be attenuated by a pharmacokinetic interaction with co-prescribed proton pump inhibitors, which inhibit oxidative pathways that convert clopidogrel into its active metabolites. Despite this, the impact of PPIs on cardiovascular risk in the absence of clopidogrel is not well defined. To report on a systematic review and meta-analysis of the association between PPIs and cardiovascular risk, independent of clopidogrel. The databases of MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Scopus, Web of Science, and ClinicalTrials.gov were systematically searched in October 2017. The primary outcome was association between PPI monotherapy and any adverse cardiovascular event. The secondary outcome was association between proton pump inhibitor monotherapy and acute myocardial infarction. Studies were excluded if they reported or did not adjust for concomitant anti-platelet therapy or involved participants aged less than 18years. A total of 22 studies were included in the systematic review. Data from 16 studies were included in the meta-analysis (involving 447408 participants). Of these, eight were randomised controlled trials, seven were observational studies and one was a retrospective analysis of a randomised controlled trial. An increased risk of any adverse cardiovascular event with PPI monotherapy was observed using pooled data from observational studies (risk ratio 1.25, 95% CI 1.11-1.42, I2 81%, P<0.001), but not from randomised controlled trials (risk ratio 0.89, 95% CI 0.34-2.33, I2 0%, P=0.85). There is no clear evidence of an association between PPI monotherapy and increased cardiovascular risk.

Clinical outcomes of CYP2C19 genotype-guided antiplatelet therapy: existing evidence and future directions.

It is well established that theCYP2C19nonfunctional *2 and *3 polymorphisms impair the bioactivation and antiplatelet effects of clopidogrel, and increase the risk of adverse cardiovascular events following percutaneous coronary intervention. In contrast,CYP2C19genotype does not impact clinical response to prasugrel or ticagrelor. Recent studies have evaluated the impact ofCYP2C19genotype-guided selection of antiplatelet therapy on clinical outcomes and begun to close some of the gaps in knowledge and uncertainty that have impeded widespread clinical implementation of this precision medicine approach. This review will critically evaluate recent data and offer new insight into the potential clinical utility of genotype-guided antiplatelet therapy in the context of current clinical practice guidelines.