Antiplatelet Activity Of Clopidogrel Research Articles

Prevalence of CYP2C9 and CYP2C19 variants and the impact on clopidogrel efficacy in patients having CYPC19*2 variant.

Human cytochrome p450 enzymes play an important role in the metabolism of various substances. The CYP2C subfamily consists of various important drug-metabolizing enzymes such as CYP2C9 and CYP2C19. The objectives of the study include the determination of the frequency of genetic variants (CYP2C9*2, CYP2C9*3, and CYP2C19*2) of selected enzymes using allele-specific polymerase chain reaction (ASPCR) and its comparison with Indian as well as global past frequencies. We also aimed to study the impact of genetic mutation on clopidogrel efficacy and compare the efficacies between patients with and without CYP2C19*2 genetic variant. In this study, the prevalence of variants CYP2C19*2, CYP2C9*2, and CYP2C9*3, the most popular variants of the respective enzymes, was determined using the ASPCR method. The correlation between the CYP2C19*2 variant and the antiplatelet activity of clopidogrel was studied using platelet aggregation assay (PAA). The determined frequencies of CYP2C19*2, CYP2C9*2, and CYP2C9*3 are 46%, 9%, and 12%. These frequencies are indicative of homozygous as well as heterozygous mutations. Reduced clopidogrel efficacy was observed in patients with a heterozygous mutation of CYP2C19*2 variant. The observed frequencies are not significantly different from that observed in earlier reported studies conducted across India and the world. Antiplatelet activity, as measured using the PAA method, was significantly lesser in patients having the CYP2C19*2 variant. The therapy failure in these patients can lead to serious cardiovascular consequences, and we propose determining the presence of the CYP2C19*2 variant before initiation of clopidogrel therapy.

Reversal of Platelet Inhibition in Patients Receiving Ticagrelor.

Antiplatelet treatment is one of the pillars of contemporary therapy in acute coronary syndromes. It is based on dual antiplatelet therapy (DAPT) consisting of aspirin and a P2Y12 receptor inhibitor. Antiaggregatory treatment reduces ischemic events, but at cost of increased bleeding rates. As a result of irreversible inhibition of platelet P2Y12 receptors, the antiplatelet action of clopidogrel and prasugrel is prolonged for the lifespan of thrombocytes and lasts up to 7 days. The antiaggregatory effect of ticagrelor may persist up to 5 days despite its reversible nature of P2Y12 receptor inhibition. These pharmacodynamic properties may prove problematic in patients requiring immediate reversal of antiplatelet effects due to severe or life-threatening bleeding, or in presence of indications for an urgent surgery. The current review summarizes available knowledge on different strategies of restoring platelet function in patients treated with ticagrelor. Non-specific methods are discussed, including platelet transfusion, human albumin supplementation and hemadsorption. Finally, bentracimab, the first specific antidote for ticagrelor, and in fact against any antiplatelet agent, is described.

Prevalence of CYP2C19 gene mutations in patients with coronary heart disease and its biological activation effect in clopidogrel antiplatelet response

Objective: The purpose of this study was to investigate the effects of CYP2C19 gene mutations on clopidogrel antiplatelet activity in the patients with coronary heart disease treated by percutaneous coronary intervention. Methods: Patients with coronary heart disease, who hospitalized in the Second Affiliated Hospital of Nanchang University from March 2011 to June 2019, and healthy individuals with matching genetic background, gender, and age as controls were included in this study. Basic clinical data were analyzed and blood samples of all research subjects were obtained for extraction of DNA, and Sanger first-generation sequencing method was used to detect CYP2C19 gene mutation from full exon and exon and intron junction. CYP2C19 gene variations in patients with coronary heart disease were compared with the 1000 Genomes Browse database and the sequencing results of healthy controls to determine whether the gene variation was a genetic mutation or a genetic polymorphism. After that, PolyPhen-2 prediction software was used to analyze the harmfulness of gene mutations to predict the effect of mutations on protein function. The same dose of CYP2C19 wild-type plasmid and the CYP2C19 gene mutant plasmids were transfected into human normal liver cells HL-7702. After transfection of 24 h, the expression of CYP2C19 protease in each group was detected. The liver S9 protein was incubated with clopidogrel, acted on platelets to detect the platelet aggregation rate and the activity of human vasodilator-activated phosphoprotein (VASP). Results: A total of 1 493 patients with coronary heart disease (59.36%) were enrolled, the average age was (64.5±10.4) years old, of which 1 129 were male (75.62%). Meanwhile, 1 022 healthy physical examination volunteers (40.64%) were enrolled, and the average age was (64.1±11.0) years old, of which 778 were male (76.13%). A total of 5 gene mutations of CYP2C19 gene were identified in 12 patients (0.80%), namely, 4 known mutations T130K (1 case), M136K (6 cases), N277K (3 cases), V472I (1 case) and one new mutation G27V (1 case), no corresponding gene mutation was found in healthy controls. It was found that T130K and M136K were probably damaging, G27V was possibly damaging, and N277K and V472I were benign mutations. In vitro, we demonstrated that the platelet aggregation rate of the M136K gene mutation group was 24.83% lower than that of the wild type (59.58% vs. 34.75%; P<0.05), and the phosphorylated VASP level was 23.0% higher than that of the wild type (1.0 vs. 1.23; P<0.05). However, the platelet aggregation rate and phosphorylated VASP level were similar between of G27V, T130K, N277K, V472I gene mutation groups and wild type group (P>0.05). Conclusions: In this study, 5 gene mutations are defined in patients with coronary heart disease, namely G27V, T130K, M136K, N277K, V472I. In vitro functional studies show that CYP2C19 gene mutation M136K, as a gain-of-function gene mutation, can enhance the activation of CYP2C19 enzyme on clopidogrel, thereby inhibiting the platelet aggregation rate.

CYP2C19*17 May Increase the Risk of Death Among Patients with an Acute Coronary Syndrome and Non-Valvular Atrial Fibrillation Who Receive Clopidogrel and Rivaroxaban.

IntroductionThe aim of this study is to assess the influence of gene CYP2C19, CYP3A4, CYP3A5 and ABCB1 polymorphisms on clopidogrel antiplatelet activity, rivaroxaban concentration equilibrium, and clinical outcomes among patients with acute coronary syndrome and non-valvular atrial fibrillation.MethodsIn the multicenter prospective registry study of the efficacy and safety of a combined antithrombotic therapy 103 patients with non-valvular atrial fibrillation both undergoing or not a percutaneous coronary intervention were enrolled. The trial assessed the primary outcomes (major bleeding, in-hospital death, cardiovascular death, stroke\ ransient ischaemic attack, death/renal insufficiency) and secondary outcomes (platelet reactivity units (PRU), rivaroxaban concentration).ResultsFor none of the clinical outcomes when combined with other covariates, the carriership of polymorphisms CYP3A5*3 rs776746, CYP2C19*2 rs4244285;*17 rs12248560, ABCB1 3435 C>T, ABCB1 rs4148738 was significant. None of the markers under study (CYP3A5*3 rs776746, CYP2C19*2 rs4244285, *17 rs12248560, ABCB1 3435 C>T, ABCB1 rs4148738) has proven to affect rivaroxaban equilibrium concentration in blood plasma among patients with atrial fibrillation and acute coronary syndrome.ConclusionIn situations of double or triple antithrombotic rivaroxaban and clopidogrel therapy among patients with atrial fibrillation and acute coronary syndrome, the genetic factors associated with bleeding complications risk (CYP2C19*17) may prove to be clinically relevant.

CES1 gene polymorphism effect on the antiplatelet activity of clopidogrel

CES1 gene polymorphism effect on the antiplatelet activity of clopidogrel

Trends in concomitant clopidogrel and proton pump inhibitor treatment among ACS inpatients, 2000-2016.

The US Food and Drug Administration (FDA) issued three safety announcements between January 2009 and October 2010 warning against concomitant use of clopidogrel and proton pump inhibitors (PPIs) due to a potential drug-drug interaction that may attenuate clopidogrel's antiplatelet activity. This primary objective of this study was to examine trends in concomitant clopidogrel/PPI use among acute coronary syndrome (ACS) inpatients in the US between 2000 and 2016, in relation to the FDA safety communications. Adult inpatients with a primary diagnosis of ACS were identified from the Cerner Health Facts® database. The standardized (age, sex, race, and census region) prevalence of clopidogrel use with PPIs was calculated yearly and quarterly. Findings were stratified by PPIs' potential to inhibit clopidogrel's activity and by age. A total of 204,533 inpatients were identified. In 2008, the prevalence of concomitant clopidogrel and PPI treatment was 34.9%, decreasing to 24.4 and 16.4% in 2009 and 2010, respectively, with the decline being similar across age groups. Treatment with inhibiting PPIs (omeprazole and esomeprazole) and clopidogrel has continued to decrease since 2010, with a prevalence of 0.8% in 2016. A similar reduction was not observed with clopidogrel and non-inhibiting PPIs (pantoprazole, lansoprazole, rabeprazole, and dexlansoprazole). During the FDA warning period, the combined treatment with clopidogrel and H2 receptor antagonists, an alternative to PPIs suggested by the FDA, temporarily increased from 7.8% in 2008 to 12.8 and 14.5% in 2009 and 2010, respectively. Findings suggest that clinical practice recommendations made by the FDA were followed. Further research is needed to determine how changes in drug labels and the availability of new drugs may have influenced the observed trends.

Platelet reactivity and clinical outcomes in patients using CYP3A4-metabolized statins with clopidogrel in percutaneous coronary intervention.

Statins are primarily metabolized by cytochrome P450 3A4 (CYP3A4), which reduces clopidogrel to its active metabolite. Recent studies suggest that CYP3A4-metabolized statins attenuate clopidogrel's anti-aggregatory effect on platelets. We aimed to assess the impact of concomitant CYP3A4-metabolized statin and clopidogrel use on antiplatelet activity and clinical outcomes in patients undergoing percutaneous coronary intervention (PCI). We enrolled 1187 patients from the HOST-ASSURE trial with platelet reactivity unit (PRU) values at both baseline and 1 month. Patients were assigned to the CYP3A4-metabolized statin group (group A, n=725) or non-CYP3A4-metabolized statin group (group B, n=462) according to type of statin used. Co-primary outcomes were the differences between PRU at baseline and 1 month and the composite of cardiovascular death, recurrent myocardial infarction, stent thrombosis, revascularization, and cerebrovascular accident. We found that follow-up PRU values did not change in group A and decreased significantly in group B (mean difference: -15±79, p<0.001) in both the crude and matched cohorts. Patients with a high PRU value at baseline, irrespective of statin type, had a significant reduction in mean PRU difference (group A, -62±78, p<0.001; group B, -59±69, p<0.001) in both the crude and matched cohorts. The composite of clinical events did not differ between groups in either cohort. CYP3A4-metabolized statins slightly inhibit the antiplatelet activity of clopidogrel during dual antiplatelet therapy. However, they do not inhibit clopidogrel's antiplatelet effect in patients with high platelet reactivity or increase clinical events in patients following PCI.

Simultaneous subacute coronary artery stent thrombosis in a carrier of two CYP2C19 loss–of function polymorphisms (*2/*3)

Simultaneous subacute coronary artery stent thrombosis in a carrier of two CYP2C19 loss–of function polymorphisms (*2/*3)

Cytochrome P450 CYP 2C19*2 Associated with Adverse 1-Year Cardiovascular Events in Patients with Acute Coronary Syndrome.

BackgroundThe cytochrome P450 (CYP450) 2C19 681 genotypes affect the antiplatelet activity of clopidogrel. We investigated the correlation of CYP 2C19 681G > A mutation with clopidogrel resistance (CR). Additionally, we studied the effect of CR on clinical prognosis of patients with acute coronary syndrome (ACS).MethodsOne hundred ten ACS patients undergoing percutaneous coronary intervention, who were followed-up for 1 year, were included in the study. The patients were co-administered aspirin 100 mg/d and clopidogrel 75mg/d following a loading dose of 300 mg. CR was assessed on the basis of polymorphism observed in the CYP2C19 subgroup.ResultsPatients in GG genotype group exhibited greater inhibition of platelet aggregation than patients in GA and AA genotype groups (16.2 ± 10.1%; 10.2 ± 9.9%; 8.0 ± 5.9%, respectively, p < 0.01). CYP2C19 681GG genotype group was associated with lower CR than CYP2C19 681A allele (GA + AA) group (9/59 vs. (12+5)/51; p = 0.009). Over a follow-up of 12 months, the incidence of recurrent angina, acute myocardial infarction, and intra-stent thrombosis in CYP2C19 681 GG carriers was significantly lower than that in CYP2C19 681A allele (GA + AA) group (2/59 vs. 8/51, 1/59 vs. 6/51, 0 vs. 4/51, respectively, p < 0.05).ConclusionCYP 2C19*2 is associated with reduced clopidogrel antiplatelet activity and might be an important marker for poor prognosis of ACS.

Mo1156 Predictors for Elevation in Serum Gastrin Following Proton Pump Inhibitor Treatment

Background: It has been suggested that proton pump inhibitors (especially omeprazole and esomeprazole) may reduce the effectiveness of clopidogrel's anti-platelet activity possibly reflecting inhibition of Cytochrome P450 (CYP) 2C19, a hepatic iso-enzyme responsible for conversion of the agent from pro-drug to its active moiety. Whether differences exist between PPIs types on reduction in platelet inhibition during simultaneous PPI and clopidogrel therapy however remains uncertain. The aim of this study was to compare the effects of different PPIs on clopidogrel-mediated platelet inhibition using platelet aggregometry. Methods: 53 patients (29 men, mean age 79±10yrs) concurrently treated with clopidogrel and PPIs were identified. 57%were receiving pantoprazole, 19% omeprazole, 15% esomeprazole, 6% rabeprazole, and 3% lansoprazole. Platelet reactivity was determined on 5ml fresh blood using the Accumetrics VerifyNow® assay system. Results were expressed as P2Y12 platelet reactivity units (PRU) with a value of >235 units indicating suboptimal inhibition of clopidogrel-mediated anti-platelet activity.[i] PRU values were compared for different PPIs using Student's t-test. The prevalence of sub-optimal platelet inhibition was compared with Fisher's exact test. Results: The PRU was >235 in 13 of 53 patients (25%). Of these, 4 were receiving pantoprazole (13% of total patients taking pantoprazole), 4 esomeprazole (4/8, 50%), and the remaining 5 patients omeprazole (5/10, 50%). PRU values in the 5 patients receiving lansoprazole or rabeprazole were 235 compared to patients treated with pantoprazole, lansoprazole or rabeprazole (p<0.05). The mean PRU in subjects <80 years was 152.2±16.15 versus 200.0±11.93 in subjects who were aged over 80 (p= 0.0183). Conclusion: Patients receiving a combination of clopidogrel with either esomeprazole or omeprazole have a higher incidence of suboptimal inhibition of clopidogrelmediated platelet activity when compared to other PPIs. Monitoring of platelet function should be considered in patients at high risk of cardiovascular events who receive concurrent clopidogrel and PPI therapy. [i] M.J. Price et al. Prognostic significance of post-clopidogrel platelet reactivity assessed by a point-of-care assay on thrombotic events after drug-eluting stent implantation., European Heat Journal (2008) 29, 992-1000.

Mo1155 Differential Effects Between Proton Pump Inhibitors on Clopidogrel-Mediated Anti-Platelet Inhibition

Background: It has been suggested that proton pump inhibitors (especially omeprazole and esomeprazole) may reduce the effectiveness of clopidogrel's anti-platelet activity possibly reflecting inhibition of Cytochrome P450 (CYP) 2C19, a hepatic iso-enzyme responsible for conversion of the agent from pro-drug to its active moiety. Whether differences exist between PPIs types on reduction in platelet inhibition during simultaneous PPI and clopidogrel therapy however remains uncertain. The aim of this study was to compare the effects of different PPIs on clopidogrel-mediated platelet inhibition using platelet aggregometry. Methods: 53 patients (29 men, mean age 79±10yrs) concurrently treated with clopidogrel and PPIs were identified. 57%were receiving pantoprazole, 19% omeprazole, 15% esomeprazole, 6% rabeprazole, and 3% lansoprazole. Platelet reactivity was determined on 5ml fresh blood using the Accumetrics VerifyNow® assay system. Results were expressed as P2Y12 platelet reactivity units (PRU) with a value of >235 units indicating suboptimal inhibition of clopidogrel-mediated anti-platelet activity.[i] PRU values were compared for different PPIs using Student's t-test. The prevalence of sub-optimal platelet inhibition was compared with Fisher's exact test. Results: The PRU was >235 in 13 of 53 patients (25%). Of these, 4 were receiving pantoprazole (13% of total patients taking pantoprazole), 4 esomeprazole (4/8, 50%), and the remaining 5 patients omeprazole (5/10, 50%). PRU values in the 5 patients receiving lansoprazole or rabeprazole were 235 compared to patients treated with pantoprazole, lansoprazole or rabeprazole (p<0.05). The mean PRU in subjects <80 years was 152.2±16.15 versus 200.0±11.93 in subjects who were aged over 80 (p= 0.0183). Conclusion: Patients receiving a combination of clopidogrel with either esomeprazole or omeprazole have a higher incidence of suboptimal inhibition of clopidogrelmediated platelet activity when compared to other PPIs. Monitoring of platelet function should be considered in patients at high risk of cardiovascular events who receive concurrent clopidogrel and PPI therapy. [i] M.J. Price et al. Prognostic significance of post-clopidogrel platelet reactivity assessed by a point-of-care assay on thrombotic events after drug-eluting stent implantation., European Heat Journal (2008) 29, 992-1000.

Paraoxonase-1 Deficiency does not Influence Clopidogrel Antiplatelet Function in Mice

Abstract Background: Clopidogrel is an antiplatelet agent used in the treatment of vascular diseases. It requires in vivo bio activation linked to the cytochrome P450. Several studies reported that paraoxonase-1 (PON1) was a crucial enzyme in clopidogrel activation, and that patients carrying a variant of the PON1192 gene polymorphism have a high risk of thrombosis. However, these reports were not confirmed by subsequent results. The present study was aimed at investigating whether PON1 deficiency affects the biological action of clopidogrel in mice. Methods: PON1-deficient mice (n = 50) and wild type animals (n = 50) received different treatments for 3 days: a) clopidogrel, b) aspirin, c) cilostazol, d) clopidogrel + aspirin, and e) clopidogrel + aspirin + cilostazol. Blood was collected for the Platelet Function Analysis (PFA-100). Results: The different anticoagulant treatments resulted in higher aggregation times in all the mice, compared to the internal PFA control; demonstrating the anti-platelet effect of these compounds. We did not observe any significant alterations on the PFA assay in PON1-deficient mice, relative to wild type animals. Conclusion: PON1 deficiency does not influence the antiplatelet action of clopidogrel in mice, and supports the proposition that this enzyme is not involved in clopidogrel bio activation.

Antiplatelet Effect of Clopidogrel Can Be Reduced by Calcium-Channel Blockers

PurposeClopidogrel is metabolized by the hepatic cytochrome P450 (CYP) system into its active thiol metabolite. CYP3A4 is involved in the metabolism of both clopidogrel and dihydropyridine calcium channel blockers (CCBs). A few reports have suggested an inhibitory interaction between CCBs and clopidogrel. Accordingly, the aim of this study was to determine the effect of CCBs on the antiplatelet activity of clopidogrel by serial P2Y12 reaction unit (PRU) measurements.Materials and MethodsWe assessed changes in antiplatelet activity in patients receiving both clopidogrel and CCBs for at least 2 months prior to enrollment in the study. The antiplatelet activity of clopidogrel was measured by VerifyNow P2Y12 assay in the same patient while medicated with CCBs and at 8 weeks after discontinuation of CCBs. After discontinuation of the CCBs, angiotensin receptor blockers were newly administered to the patients or dosed up for control of blood pressure.ResultsThirty patients finished this study. PRU significantly decreased after discontinuation of CCBs (238.1±74.1 vs. 215.0±69.3; p=0.001). Of the 11 patients with high post-treatment platelet reactivity to clopidogrel (PRU≥275), PRU decreased in nine patients, decreasing below the cut-off value in seven of these nine patients after 8 weeks. Decrease in PRU was not related to CYP2C19 genotype.ConclusionCCBs inhibit the antiplatelet activity of clopidogrel.

CYP2C19 Genetic Polymorphism, Rabeprazole and Esomeprazole Have No Effect on the Anti-Platelet Action of Clopidogrel

Purpose: To investigate the effect of CYP2C19 genetic polymorphism and concomitant use of rabeprazole or esomeprazole on the anti-platelet effect of clopidogrel in vitro. Methods: Patients receiving a stable dose of clopidogrel 75 mg with or without rabeprazole or esomeprazole for > 2 weeks were recruited. Genotyping for CYP2C19 and VASP testing using flow cytometry to measure platelet reactivity index (PRI) were performed. A detailed questionnaire regarding the indication and duration of use of clopidogrel and PPI therapy was completed on all patients including a detailed concomitant drug history. Results: 239 consecutive patients (176M and 63F; mean age = 67.1±12.0) were enrolled after informed consent. 92 patients were on clopidogrel without concomitant PPI therapy (C group), 94 were on clopidogrel + rabeprazole (CR group), and 53 on clopidogrel + esomeprazole (CE group). The mean number of concomitant medications in addition to clopidogrel was 5.7± 3.0. The main indications for clopidogrel were cardiac, neurologic, and peripheral vascular disease (71.5, 25.5, and 2.5% respectively) and the mean duration of clopidogrel therapy was 33.1 ± 40.4 months. The indications for PPI use were considered appropriate in 30.6% of users. On CYP2C19 genotyping, 194 patients did not have loss of function polymorphism (LOF) while 45 had LOF (43 heterozygous and 2 homozygous mutant for CYP2C19*2).The mean PRI was 20.7±21.9% in the clopidogrel group, 19.1±20.9% in the CR group, and 24.5±22.9% in the CE group (p=0.386). High-on-treatment Platelet Reactivity (HPR) defined as PRI>50%, was observed in 12 (13.0%), 13 (13.8%), and 10 (18.9%) patients on C, CR, CE, respectively (p=0.608). A PRI of >30% was noted in 23 (25.0%), 22 (23.4%), and 20 (37.7%) patients on C, CR, CE respectively (p=0.144). In participants with no LOF alleles (194/239 or 81.2% of study population), a PRI>30% was noted in 21.9%, 22.1% and 38.6% of the C, CR and CE groups patients respectively (p=0.085) (p-value of 0.052 between the C and CE groups and p-value of 0.051 between the CR and CE groups). On multivariate logistic regression, neither the presence of CYP2C19 LOF alleles nor the use of esomeprazole or rabeprazole were associated with HPR. Conclusion: 14.4% of individuals on clopidogrel monotherapy have an unsatisfactory in vitro platelet inhibition independent of CYP2C19 polymorphism. Neither CYP2C19 LOF alleles, nor esomeprazole nor rabeprazole had a significant effect on the anti-platelet action of clopidogrel in vitro, although there was a trend for a relatively reduced platelet inhibition with esomeprazole compared to rabeprazole users or non-PPI users in patients without CYP2C19 LOF mutations.

Genetic polymorphisms of CYP2C19 influences the response to clopidogrel in ischemic heart disease patients in the South Indian Tamilian population

The antiplatelet activity of clopidogrel is variable among patients suffering from ischemic heart disease. Variation in the cytochrome P450 2C19 (CYP2C19) gene coding for the CYP2C19 enzyme is one of the major determinants of this variable response to clopidogrel. The activity of the CYP2C19 enzyme, which plays a role in the conversion of the prodrug clopidogrel to its active metabolite, is genetically influenced by polymorphisms in its gene. The aim of our study was to evaluate the association of CYP2C19 polymorphisms and the antiplatelet effect of clopidogrel in the South Indian Tamilian population. Genotyping and platelet aggregation results of 149 ischemic heart disease patients on clopidogrel maintenance therapy (75 mg daily dose) were analyzed in this study. CYP2C19 polymorphisms were genotyped by the PCR-restriction fragment length polymorphism method. We measured residual platelet activities in these patients on clopidogrel therapy in terms of impedance (expressed as ohms). The study subjects were divided into two metabolizer phenotype groups [group 1: poor/intermediate metabolizers (PM/IM); group 2: extensive/ultra-rapid metabolizers (EM/URM)] based on CYP2C19 genotype, and the residual platelet activities were compared. Higher values of impedance denote increased residual platelet activity. Poor/intermediate metabolizers had significantly higher impedance values than EM/URM [(median; range) 4.0; 0-13 vs. 2.0; 0-11, respectively; p = 0.04]. These higher impedance values denote higher residual platelet activities among the carriers of loss-of-function alleles (CYP2C19*2,*3) than among non-carriers. However, residual platelet activities were lower among the carriers of the gain-of-function allele (CYP2C19*17) than among non-carriers, although this difference was not significant. Patients with CYP2C19 (*2 or *3) genetic polymorphisms had higher residual platelet activities and were associated with a reduced antiplatelet response to clopidogrel. As the South Indian Tamilian population is characterized with higher frequencies of these genetic polymorphisms, our findings mandate further studies aimed at initiating genome-based personalized antiplatelet therapy.

Impact of proton pump inhibitors or famotidine on the antiplatelet actions during dual-antiplatelet therapy in Japanese patients

It has been reported that the antiplatelet action becomes attenuated when a proton pump inhibitor is used in combination with clopidogrel. The effect of an antacid causing platelet aggregation during the administration of clopidogrel was investigated. The subjects consisted of 265 patients with coronary artery disease. Platelet aggregation function testing (light transmittance aggregometry) was conducted while aspirin and clopidogrel 75mg were taken orally and the minimum concentration of aggregation induction platelet aggregation threshold index was measured. The ADP-PATI, measured with ADP as the inducing substance, was compared and investigated according to the type of concomitantly used antacid. The results of the ADP-PATI were: control group: 3.47±0.95μM (N=67), famotidine group: 3.80±0.52μM (N=32), rabeprazole group: 3.43±0.93μM (N=87), lansoprazole group: 3.28±1.04μM (N=63) and omeprazole group: 3.33±0.81μM (N=16). No statistically significant difference was observed regarding the ADP-PATI of respective groups compared to the control group. The concomitant use of famotidine, rabeprazole, lansoprazole, and omeprazole did not affect the antiplatelet action of clopidogrel in Japanese patients.

Differential inhibitory effects of proton pump inhibitors on the metabolism and antiplatelet activities of clopidogrel and prasugrel

The interaction between proton pump inhibitors (PPIs) and clopidogrel/prasugrel was investigated. The IC50 values of omeprazole, esomeprazole, lansoprazole, pantoprazole and rabeprazole on the metabolic ratios of 2-oxo-clopidogrel/clopidogrel, H4 (the active metabolite of clopidogrel)/2-oxo-clopidogrel and R-138727 (the active metabolite of prasugrel)/prasugrel thiolactone in human liver microsomes were determined. The antiplatelet activities of clopidogrel and prasugrel were measured with or without PPIs. As a result, most PPIs (except for pantoprazole) inhibited the formation of 2-oxo-clopidogrel with IC50 values of 20-32 μm and inhibited the formation of H4 with IC50 values of 6-20 μm. PPIs inhibited the formation of R-138727 with IC50 values of 9-25 μm. Among the tested PPIs, omeprazole exhibited the highest inhibitory potency on the formation of H4. Omeprazole, esomeprazole and rabeprazole exhibited the highest inhibitory potencies on the formation of R-138727. For platelet aggregation, omeprazole and lansoprazole show higher inhibitory effects on the antiplatelet activity of clopidogrel. On the other hand, omeprazole, esomeprazole and rabeprazole significantly decreased the antiplatelet activity of prasugrel thiolactone. These data indicate that PPIs differ in their effects of inhibiting the metabolism and antiplatelet activities of clopidogrel and prasugrel.

An insight into the Interaction between Clopidogrel and Proton Pump Inhibitors

Platelet activation and aggregation have been established as pivotal elements in the pathogenesis of atherosclerotic and ischemic diseases, including acute coronary syndromes. The difficulty of achieving optimal platelet inhibition remains a major constraint following dual-antiplatelet therapy, which can lead to a diminished response following initiation of clopidogrel therapy. Though the absolute mechanisms underlying clopidogrel resistance are controversial, a variety of responsible factors are recognized. Clopidogrel, being a prodrug, requires conversion to an active metabolite for its activity. This metabolism involves various cytochrome P450 (CYP) enzymes at different steps, and it is hypothesized that competitive inhibition of CYPs may contribute to clopidogrel resistance. Proton pump inhibitors (PPIs) are competitive inhibitors of CYPs that can attenuate the antiplatelet activity of clopidogrel, and this can lead to clopidogrel resistance. Available data from different clinical studies have postulated the possibility of a drug-drug interaction between clopidogrel and PPIs. PPIs differ somewhat in their pharmacokinetic properties like bioavaibility and affinity for CYP2C19. However it is not clear whether the proposed drug interaction of PPI with clopidogrel is same with all PPIs (i.e., a class effect) or it is limited to a subset of PPIs (i.e., a drug effect). This interaction needs further assessment with well designed prospective clinical trials, before any change in clinical practice should be considered. In this review, we attempt to evaluate the available evidence exploring drug interactions with PPIs as the underlying mechanism for the reduced antiplatelet effect of clopidogrel.

Genotype Testing for Clopidogrel Responsiveness May Not Predict Events

Variation in individual response to clopidogrel's antiplatelet activity is, in part, governed by genetic variation in the CYP2C19 activating enzyme. To

The Effect of CYP2C19 Genetic Polymorphisms and the Concomitant Use of Rabeprazole or Esomeprazole on the Anti-Platelet Action of Clopidogrel

The Effect of CYP2C19 Genetic Polymorphisms and the Concomitant Use of Rabeprazole or Esomeprazole on the Anti-Platelet Action of Clopidogrel