Antiplatelet Effect Of Clopidogrel Research Articles

Impact of the proton pump inhibitors and CYP2C19*2 polymorphism on platelet response to clopidogrel as assessed by four platelet function assays

Previous studies suggested a possible negative interference of proton pump inhibitors (PPIs) on clopidogrel's antiplatelet effect because of the competitive inhibition of the CYP 2C19 isoenzyme. Moreover, carriers of the loss-of-function allele of CYP2C19 polymorphism (CYP2C19*2) display significantly lower responses to clopidogrel. In this study, we investigated the association between CYP2C19*2 genotype, PPI intake and clopidogrel resistance in patients with coronary artery disease (CAD) and their effect on clinical outcome. We recruited 95 patients with CAD receiving chronic clopidogrel therapy in combination with aspirin. Platelet reactivity was simultaneously assessed by INNOVANCE PFA-100 P2Y, ADP-induced light transmission aggregometry (LTA), flow-cytometric vasodilator-stimulated phosphoprotein (VASP)-phosphorylation assay and multiple electrode aggregometry (Multiplate). Cardiovascular outcomes were recorded during 1-year follow-up period. Only platelet reactivity assessed by measuring platelet phosphorylated-VASP demonstrated a significant higher platelet reactivity in carriers of CYP2C19*2 (p=0.023). The other methods displayed higher - but not statistically significant - platelet reactivity in patients carrying the CYP2C19*2 variant as compared with non-carriers. Patients on PPIs demonstrated almost similar suppression of platelet reactivity in comparison with those not treated with PPIs by all platelet function assays. In logistic regression analysis none of the platelet function assays measurements were related with clinical outcomes. Similarly neither CYP2C19*2 genetic variant nor PPI treatment were associated with adverse clinical events. PPI co-administration did not influence clopidogrel's antiplatelet effect on laboratory testing by all platelet function assays used. On the contrary, patients carrying CYP2C19*2 genotype had significantly higher residual platelet reactivity as estimated by VASP-phosphorylation assay.

P2Y12 receptor gene polymorphism and antiplatelet effect of clopidogrel in patients with coronary artery disease after coronary stenting

Platelets have a central role in the pathophysiology of thrombosis. Adenosine diphosphate (ADP) plays a pivotal role as an agonist of platelet activation. Genetic polymorphisms of the P2Y12 ADP receptor might influence the activation of this receptor by ADP or the response of patients to platelet inhibitors. The present study was conducted on a total number of 80 participants, 40 patients were diagnosed with acute coronary syndrome and 40 sex and aged-matched healthy volunteers were included as controls. Platelet aggregation was assessed (before and 1 week after clopidogrel administration) and genotyping of the T744C genetic polymorphism of P2Y12 receptor gene was carried out using the restriction fragment length polymorphism polymerase chain reaction (PCR-RFLP) method. Platelet aggregation of the patients had a range of 54-183% before clopidogrel administration and had a range of 4-113% after its administration. Genotyping of the candidate gene revealed that 72.5% of the patients had a wild allele (TT), whereas 27.5% had a C allele (heterozygous CT, homozygous CC). On the contrary, 97.5% of controls had a wild allele (TT), whereas 2.5% had a C allele (heterozygous CT, homozygous CC). Our study elicited an association between the T744C polymorphism of the P2Y12 ADP receptor gene and platelet reactivity. Carrying the C allele at this position is associated with an increased platelet activation response to ADP.

CYP2C19 Genetic Polymorphism, Rabeprazole and Esomeprazole Have no Effect on the Antiplatelet Action of Clopidogrel

The aim of this study is to investigate the effect of CYP2C19 polymorphism and cotherapy with rabeprazole or esomeprazole on the antiplatelet effect of clopidogrel. Patients receiving clopidogrel 75 mg ± rabeprazole or esomeprazole underwent genotyping for CYP2C19*2 and CYP2C19*3, and vasodilator-stimulated phosphoprotein testing to measure platelet reactivity index (PRI). Two hundred thirty-nine consecutive patients were enrolled as follows: 92 clopidogrel (C group), 94 clopidogrel + rabeprazole (CR), and 53 clopidogrel + esomeprazole (CE). Forty-five patients had loss of function (LOF) polymorphism (43 heterozygous; 2 homozygous mutant for CYP2C19*2). The mean PRI was 20.7% ± 21.9% in the C group, 19.1% ± 20.9% in the CR group, and 24.5% ± 22.9% in the CE group (P = NS). 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, and CE, respectively (P = NS). HPR was similar in rapid metabolizers between groups. On multivariate logistic regression, neither CYP2C19 LOF alleles nor proton pump inhibitor cotherapy were associated with HPR. The use of proton pump inhibitors was indicated in 30.6% of recipients. As a conclusion, CYP2C19*2 LOF allele and the use of esomeprazole or rabeprazole have no effect on the action of clopidogrel.

CYP2C19 Polymorphisms and Antiplatelet Effects of Clopidogrel in Acute Ischemic Stroke in China

Little research regarding genotypes and clopidogrel response related to acute ischemic stroke has been published. This study was conducted to investigate whether the polymorphisms of receptors or enzymes involved in the metabolic process of clopidogrel affect clopidogrel response and prognosis related to acute stroke. A total of 259 patients with acute ischemic stroke were enrolled in this study; all received follow-up evaluations 3 and 6 months after clopidogrel treatment. CYP2C19, CYP3A4, and P2Y12 were screened. The adenosine diphosphate-induced platelet aggregation test, the National Institutes of Health Stroke Scale (NIHSS), and the modified Rankin Scale (mRS) were used, and blood vascular events were evaluated. The difference before and after clopidogrel treatment on adenosine diphosphate-induced platelet aggregation was significantly smaller in patients carrying 1 or 2 CYP2C19 loss-of-function alleles (*2, *3) compared with patients carrying none. Patients with none had better outcomes than patients with CYP2C19 loss-of-function alleles, as demonstrated by NIHSS and mRS scores at 3 and 6 months after treatment. Regression analysis showed that CYP2C19 was an independent predictor of clopidogrel resistance. CYP2C19 genotypes had significant impact on clopidogrel response and prognosis of patients with stroke. Clinical Trial Registration Information- URL: http://www.chictr.org/. Unique Identifier: ChiCTR-OCH-12002681.

Introduction of new oral antiplatelet drugs in myocardial infarction hospital network: initial experience

New oral antiplatelet drugs (prasugrel, ticagrelor) are recommended in the current European Society of Cardiology guidelines for the management of patients presenting with ST-segment elevation myocardial infarction (STEMI) [1]. However, in many STEMI hospital networks administration of a 600-mg clopidogrel loading dose before or during transfer to cathlab (including in ambulance administration) is a standard of care, since this strategy has been implemented for many years. Early administration of the drug may enhance antiplatelet effects of clopidogrel at the time of primary percutaneous coronary intervention (PCI), in comparison to the administration in the cathlab. On the other hand, the response to clopidogrel in patients with STEMI, especially in patients with hemodynamic compromise is impaired. Prasugrel and ticagrelor are more potent antiplatelet drugs, with faster and more profound antiplatelet effect. These agents are preferred over clopidogrel, if not contraindicated, in patients with STEMI since both are superior in comparison to clopidogrel in terms of the reduction of ischemic events [2, 3]. However, introduction of prasugrel and ticagrelor may need to change STEMI network logistics since those new drugs are predominantly administered in the cathlab, but not in ambulances or in non-PCI centers before transportation [4]. In our high-volume primary PCI center, early (before transfer to cathlab) administration of acetylsalicylic acid, unfractionated heparin and a 600-mg clopidogrel loading dose has been a well-established standard of treatment from many years. In-cathlab administration of antiplatelet drugs was a rare strategy so it was necessary to reorganize STEMI network for new antiplatelet drugs introduction in daily practice. An observational, prospective registry was designed to describe the implementation of new oral antiplatelet drugs in our network. First 100 consecutive STEMI patients (no exclusion criteria) admitted to our center after introduction of prasugrel and ticagrelor were enrolled. Registry was focused on antiplatelet therapy including type of drug, moment of administration, time from administration to PCI. Data on reason for the administration of clopidogrel instead of new drugs was also collected. Additionally, platelet aggregation inhibition was assessed at the time of PCI (guide wire introduction) with Plateletworks Aggregation Kits (Helena Laboratories, Beaumont, TX, USA) [5]. The registry analyzed the current clinical practice and did not modify patients diagnostics and treatment. A total of 100 consecutive STEMI patients entered the registry. Clinical characteristics of patient population are presented in Table 1. Registry represents real life STEMI population including elderly patients and patients in cardiogenic shock. Acetylsalicylic acid was administered before transfer to cathlab in all patients. New oral antiplatelet drugs were given after cathlab admission before or during coronary angiography only in 15 out of 100 patients (13 patients treated with a 60-mg prasugrel loading dose; 2 patients treated with a 180-mg ticagrelor loading dose). In the remaining 85 patients a 600-mg clopidogrel loading T. Rakowski (&) A. Dziewierz Z. Siudak P. Kleczynski J. S. Dubiel Second Department of Cardiology, Jagiellonian University Medical College, Kopernika 17 Street, 31-501 Krakow, Poland e-mail: mcrakows@cyfronet.pl

Circulation: Cardiovascular Interventions Editors’ Picks

<i>Circulation: Cardiovascular Interventions</i> Editors’ Picks

First experience of a bioresorbable vascular scaffold implantation in left main stenosis

[1] Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, et al. Variability in individual responsiveness to clopidogrel clinical implications, management, and future perspectives. J Am Coll Cardiol 2007;49:1505–16. [2] Matetzky S, Shenkman B, Guetta V, et al. Clopidogrel resistance is associated with increased risk of recurrent atherothrombotic events in patients with acute myocardial infarction. Circulation 2004;109:3171–5. [3] Cuisset T, Frere C, Quilici J, et al. High post-treatment platelet reactivity identified low-responders to dual antiplatelet therapy at increased risk of recurrent cardiovascular events after stenting for acute coronary syndrome. J Thromb Haemost 2006;4:542–9. [4] Buonamici P, Marcucci R, Migliorini A, et al. Impact of platelet reactivity after clopidogrel administration on drug-eluting stent thrombosis. J Am Coll Cardiol 2007;49:2312–7. [5] Cuisset T, Cayla G, Frere C, et al. Predictive value of post-treatment platelet reactivity for occurrence of post-discharge bleeding after non-ST elevation acute coronary syndrome. Shifting from antiplatelet resistance to bleeding risk assessment? EuroIntervention 2009;5:325–9. [6] Sibbing D, Schulz S, Braun S, et al. Antiplatelet effects of clopidogrel and bleeding in patients undergoing coronary stent placement. J Thromb Haemost 2010;8:250–6. [7] Campo G, Parrinello G, Ferraresi P, et al. Prospective evaluation of on-clopidogrel platelet reactivity over time in patients treated with percutaneous coronary intervention relationship with gene polymorphisms and clinical outcome. J Am Coll Cardiol 2011;57:2474–83. [8] Cuisset T, Quilici J, LoosveldM, et al. Comparison between initial and chronic response to clopidogrel therapy after coronary stenting for acute coronary syndrome and influence on clinical outcomes. Am Heart J 2012;164(3):327–33. [9] Alexopoulos D, Dimitropoulos G, Davlouros P, et al. Prasugrel overcomes high onclopidogrel platelet reactivity post-stentingmore effectively than high-dose (150-mg) clopidogrel: the importance of CYP2C19*2 genotyping. JACC Cardiovasc Interv 2011;4:403–10.

High on-treatment platelet reactivity - why should we be concerned?

High on-treatment platelet reactivity - why should we be concerned?

High on-treatment platelet reactivity (HPR): What does it mean, and does it matter?

2013; 109: 347-355. In this issue of Thrombosis and Haemostasis, Saucedo et al. (1) demonstrate that the prevalence of high on-treatment platelet reactivity was decreased after changing clopidogrel to prasugrel. It is perhaps appealing that the patients with adverse “high on-treatment platelet reactivity (HPR)” with clopidogrel was reduced when switched to prasugrel. From a scientific point of view, the meaning of “HPR” is still unclear. This uncertainty is derived from an arguably confusing clinical development history of the thienopyridine-type antiplatelet agents (ticlopidine, clopidogrel, and prasugrel). Indeed, the use of these agents was greatly expanded based on the clinical experience, rather than on their mechanistic understanding. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE)was published in 1996 (2). However, the precise mechanism of antiplatelet action exerted by clopidogrel was clarified only after cloning the target ADP receptor of P2Y12 in 2001 (3). Moreover, the extent of P2Y12 ADP receptor blockade by active metabolite of clopidogrel in an individual patient, which should be a real bio-marker for this drug, has been measured in a very limited number of studies only (4). Nonetheless, some uncertainty remains about how much percentage of P2Y12 receptor should be blocked to achieve appropriate antithrombotic effects in individual patients. Obviously, the goal is not to achieve 100% inhibition of P2Y12 because P2Y12 deficiency manifests as a bleeding disorder (5). Perhaps some focus should be on the drugs per se. Both clopidogrel and prasugrel are pro-drugs. The chemical structure of active metabolite(s) of clopidogrel was detected in 2002 (6). Since the active metabolite(s) of clopidogrel are very labile in character with a reactive thiol function, it is most likely that the majority of produced active metabolite(s) easily binds to P2Y12 receptors on platelets circulating in liver, where it is produced (▶ Figure 1A) Thus, plasma concentrations of active metabolite(s) per se would not necessarily be good pharmaco-dynamic marker(s) for the antiplatelet effects of clopidogrel (8). Thus, the extent of P2Y12 receptor blockage, once achieved in the liver circulation, would be the same in platelet circulating in peripheral blood.

Inhibiteurs de la pompe à protons et clopidogrel (Plavix®) : une liaison dangereuse ?

Proton pump inhibitors (PPI) and antiplatelet agents, especially aspirin and clopidogrel, are among the most prescribed medications worldwide. Their co-administration is justified by the increased risk of gastrointestinal bleeding related to the antiplatelet therapy. The issue of the interaction between PPI and clopidogrel has been raised with the emergence of the concept of “high on-clopidogrel platelet reactivity” (or “clopidogrel resistance”) together with the discovery of the role of CYP2C19 isoform in the pharmacokinetics of those two medications. Indeed, CYP2C19 is involved in the conversion of the clopidogrel pro-drug into its active metabolite and is involved in the metabolisation of PPI into inactive metabolites, acting as substrates/inhibitors of CYP2C19. Despite their heterogeneity, most pharmacodynamic studies have shown a decreased clopidogrel antiplatelet effect when associated to PPI, especially those with the highest CYP2C19 inhibiting activity (omeprazole, lansoprazole, rabeprazole). On the other hand, clinical studies are inconclusive. Retrospective studies have shown an increased risk of major cardiovascular events or mortality when clopidogrel and PPI are associated in comparison with clopidogrel alone, particularly in the patients with the higher cardiovascular risk. However, the two prospective randomized studies published so far did not find any interaction and confirmed the benefit of PPI on the gastrointestinal bleeding. As a conclusion, as the clinical studies are not conclusive, the French health authorities have recently removed the alert about this interaction. PPI and clopidogrel can thus be co-prescribed.

Effect of the CYP2C19*2 and *3 genotypes, ABCB1 C3435T and PON1 Q192R alleles on the pharmacodynamics and adverse clinical events of clopidogrel in Chinese people after percutaneous coronary intervention

Chinese people are more frequent carriers of cytochrome P450 2C19 (CYP2C19) loss-of-function alleles than Caucasians. The effect of the ATP-binding cassette, sub-family B, member 1 (ABCB1), and paraoxonase 1 (PON1) variants on platelet reactivity and clinical outcomes of clopidogrel treatment has not yet been reported in Chinese patients after percutaneous coronary intervention. The aim of this study was to investigate the effect of the CYP2C19, ABCB1, and PON1 variants on clopidogrel pharmacodynamics and clinical outcomes in these patients. Six hundred and seventy patients after percutaneous coronary intervention were enrolled in a single-center registry. The antiplatelet effect of clopidogrel was assessed by thromboelastography, and the CYP2C19, ABCB1, and PON1 genotypes were detected by the ligase detection reaction. Primary clinical endpoints included cardiovascular death, nonfatal myocardial infarction, target vessel revascularization, and stent thrombosis. The secondary clinical endpoints were thrombolysis in myocardial infarction bleeding. The follow-up period was 12 months. The frequency of the CYP2C19 loss-of-function alleles was relatively high (57.3 %). The risk of a low response to clopidogrel and composite ischemic events increased with the number of CYP2C19 loss-of-function alleles. However, there were not significant differences in clopidogrel pharmacodynamics and clinical outcomes across the ABCB1 and PON1 genotype groups; bleeding was not significantly different across the CYP2C19, ABCB1, and PON1 genotype groups. The CYP2C19 loss-of-function alleles had a gene dose effect on the pharmacodynamics and composite ischemic events of clopidogrel in our study population. Neither the ABCB1 nor the PON1 genotype significantly influenced the antiplatelet effect and clinical outcomes of clopidogrel in these patients.

Bringing pharmacogenetics to the bedside

Dear Editor, The study ‘Genetic polymorphisms of CYP2C19 influences the response to clopidogrel in ischemic heart disease patients in the South Indian Tamilian population’ by K. Subraja and colleagues [1] brings to attention the effect of genetic polymorphisms on the antiplatelet effect of clopidogrel. The authors suggest that further studies on genome-based personalized antiplatelet therapy are required. However, a major barrier to conducting such a study and the integration of antiplatelet therapy pharmacogenetics into clinical care has been the lack of a point of care (POC) genetic test. Recently, a prospective, randomized, proof of concept trial published in The Lancet demonstrated that a POC genetic test after percutaneous coronary intervention (PCI) could be effectively performed at the bedside [2]. The bedside POC test used in the study analyzed buccal swab DNA samples and provided results within 60 min. Most importantly, all tests were performed by clinical trial nurses who received a 30-min training session but had no prior laboratory training. It is often argued that platelet function testing could be used alone instead of genetic testing. Although platelet function testing has the advantage of covering other non-genetic variables affecting response to antiplatelet therapy, its utility in the acute setting is limited. Patients presenting to the hospital with acute coronary syndrome can have wide fluctuations in platelet reactivity. Factors affecting the results of the platelet function assay test include timing of when the test is performed, loading dose and type of antiplatelet medications administered. The platelet function assay should also not be performed in patients who have been administered Aggrastat® or Integrilin® within 2 days or ReoPro® within 2 weeks. Early platelet function testing in the acute phase frequently results in the incorrect labeling of patients as “non-responders” to clopidogrel. In the GRAVITAS trial [3], 38 % of poor-responder patients randomized to a standard clopidogrel regimen became responders at 1 month compared to platelet reactivity measured 12– 24 h after PCI. Therefore, platelet function testing-based antiplatelet therapy is not optimal for use in the hospital setting before discharge. In contrast, genotype test results are not affected by either the dose of clopidogrel or timing of genotype testing. The best approach for guiding antiplatelet therapy may be a hybrid one where patients found to be nonresponders undergo genetic testing to confirm the presence of loss of functional alleles. Patients confirmed to have non-functional alleles could then be switched to prasugrel or ticagrelor. This would result in more costeffective care and prevent the unnecessary exposure of patients to stronger antiplatelet medications and subsequent adverse events.

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.

CYTOCHROME P450 2C19 POLYMORPHISM AND PLATELET AGGREGATION IN CLOPIDOGREL-TREATED PATIENTS AMONG MALAYSIAN MULTIETHNIC POPULATION

ObjectivesCytochrome P450 2C19 (CYP2C19) *2 (681G>A; rs4244285) and CYP2C19*3 (636G>A; rs4986893) null alleles are responsible for the phenotypes of poor CYP2C19 enzyme function, hence adversely affecting the ability of clopidogrel...

Clinical Significance of the Clopidogrel–Proton Pump Inhibitor Interaction After Peripheral Endovascular Intervention for Claudication

Despite numerous studies in the cardiology literature, the clinical impact of proton pump inhibitor (PPI) administration on the antiplatelet effect of clopidogrel remains controversial. The objective of this study is to evaluate the effects of concurrent PPI and clopidogrel administration on outcomes after percutaneous transluminal angioplasty and stenting (PTA&S) of the superficial femoral artery (SFA) for claudication. Retrospective review of a prospectively maintained database (2004-2010) identified patients undergoing PTA&S of the SFA for lifestyle-limiting claudication (Rutherford Class III). Statistical analysis included univariate comparison (Wilcoxon, chi-square) of demographics, lesion characteristics, complication rates, and outcome measures. Patency comparisons were made with Cox-PH multivariable models and Kaplan-Meier survival analysis. Totally, 109 limbs were treated in 103 patients. All were prescribed clopidogrel for 1 month; concurrent PPI use (+PPI) was identified after 42 (38.5%) interventions. There were no statistically significant differences in demographics, comorbidity prevalence, lesion length, degree of stenosis, or runoff associated with PPI use. There were no cases of early thrombosis in either group. There were more instances of patency loss (28 [50%] vs 21 [42%]; P = .40) in patients with +PPI, and a trend toward reduced primary patency that did not achieve statistical significance (P = .5). By multivariate analysis only TransAtlantic Inter-Society Consensus (TASC) D lesions were independent predictors of primary (hazards ratio [HR] = 4.366; [95% confidence interval (CI): 1.291-14.764; P = .018) and assisted patency loss (HR = 6.815 [1.181-39.327]; P = .032). The clinical significance of the clopidogrel-PPI interaction is a controversial topic that has been the subject of numerous studies in the cardiology literature. This is the first report to examine this medication interaction after peripheral intervention. While there is no apparent association between PPI coadministration with clopidogrel in this series, the high prevalence of PPI use among patients prescribed clopidogrel following peripheral intervention warrants ongoing attention to this purported medication interaction.

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 inhibitor omeprazole on the antiplatelet effect of clopidogrel in individuals with various CYP2C19*2 genotypes

To investigate the impact of omeprazole on platelet response to clopidogrel and the effect of polymorphisms of CYP2C19 on the antiplatelet effect of clopidogrel. Platelet aggregation (PA) was assessed before 300 mg aspirin plus 300 mg loading dose of clopidogrel and after 300 mg aspirin plus 75 mg maintenance dose of clopidogrel 7 days later in 414 patients with acute coronary syndrome who have undergone percutaneous coronary intervention (PCI). Thereafter, gastric mucosal protective drugs were given (omeprazolem 20 mg, n=224 or cimetidine 800 mg, n=190). Fourteen days later, PA was measured again. Genotypes of CYP2C19*2 were analyzed with polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). After taken aspirin and clopidogrel, PA has decreased significantly in both groups. Compared with cimetidine, omeprazole had no significant impact on PA on 7 and 21 days post PCI. Compared with homozygotes or heterozygotes for the wild-type CYP2C19*2, patients with CYP2C19*2 AA genotype had significantly higher PA on 7 and 21 days post PCI (P<0.05). No attenuating effect on platelet response to clopidogrel has been observed for Omeprazole. The variant of CYP2C19*2 AA genotype is significantly associated with attenuated response to clopidogrel.

Pantoprazole significantly interferes with antiplatelet effect of clopidogrel: Results of a pilot randomized trial

BackgroundThe CYP2C19*2 polymorphism is significantly associated with residual platelet reactivity (RPR) and maybe a major confounding factor in studies evaluating pharmacological interactions with clopidogrel. ObjectivesWe sought to evaluate the influence of a proton pump inhibitor (PPI), pantoprazole, indicated as relatively less influent than other PPIs, on the antiplatelet effect of clopidogrel, considering a stratification of the population for the presence of cytochrome 2C19*2 polymorphism. Methods105 patients with ST elevation myocardial infarction (STEMI), treated with percutaneous coronary angioplasty (PCI) and who received dual antiplatelet therapy, were randomized between pantoprazole (n=54) or ranitidine (n=51). RPR was evaluated by Platelet Function Analyzer-100 (PFA-100) with collagen-epinephrine (CEPI) and collagene-ADP (CADP) cartridges and by light transmitted aggregometry with 10μM adenosin diphosphate (ADP) and 1mM arachidonic acid (AA), on 5 (T0) and 30 (T1) days after PCI. ResultsDemographic, clinical and procedural data and the prevalence of CYP2C19*2 polymorphism were similar between the two groups. Not statistically differences were observed for CEPI-CT and for the maximal aggregation (MA) values with AA stimulus at both times. We observed a significant increase in MA values with ADP in PPI group at T0 (p=0.01) and T1 (p=0.03). At the multiple regression analysis PPI use remained significantly associated with ADP-MA both at T0 (p=0.05) and T1 (p=0.03). ConclusionsThis is the first documentation in a randomized trial, after correction for the bias of CYP2C19*2 polymorphism, that pantoprazole increases the ADP-MA in patients treated with dual antiplatelet therapy.

Response to Letters Regarding Article, “Platelet Reactivity and Cardiovascular Outcomes After Percutaneous Coronary Intervention: A Time-Dependent Analysis of the Gauging Responsiveness With a VerifyNow P2Y12 Assay: Impact on Thrombosis and Safety (GRAVITAS) Trial”

We thank Dr Nezami and colleagues for their interest in our study. As they note, statin therapy has been associated with improved clinical outcomes after percutaneous coronary intervention. Although an early observational study suggested an interaction between atorvastatin and the antiplatelet effect of clopidogrel in the acute phase of treatment, presumably due to shared metabolism via the CYP3A4 pathway, this does not occur during maintenance clopidogrel therapy and was not confirmed in subsequent randomized pharmacodynamic studies. In addition, clinical outcome studies have failed to identify a clear impact of statins on the ability of clopidogrel to reduce recurrent ischemic events.1 In order to address the questions of Dr Nezami and colleagues about our trial, we assessed the effect of statin use in GRAVITAS by incorporating this covariate into our time-dependent multivariate regression model.2 Statin use was not associated with clinical outcome at 60 days (adjusted hazard ratio [HR] 0.89, 95% confidence interval [CI], 0.27–3.02) or 6 months (adjusted HR 0.86. 95% CI, 0.39–1.91), nor did it affect the relationship between on-treatment reactivity <208 PRU and outcome at either time point (adjusted HR 0.23, 95% CI, 0.05–0.98, P =0.047 at 60 days and adjusted HR 0.54, 95% CI: 0.28–1.04, P …

Abstract 2383: The Antiplatelet Effect Of Clopidogrel Is Associated With CYP2C19 *2 And *3 Polymorphism But Not With Pon-1 Q192R Polymorphism In Japanese Patients Undergoing neurointervention

Background Patients with cervical carotid or intracranial stenting are routinely premedicated with antithrombotic agents, clopidogrel and aspirin (ASA). A recent study has showed paraoxonase-1 (PON-1) Q192R genotypes impacts on antiplatlet effect of clopidogrel rather than CYP2C19 mutation. We investigate the influence of CYP2C19 *2, *3, and PON-1 Q192R genotypes on antiplatelet effect of clopidogrel in Japanese patients scheduled for neurointervention such as extracranial carotid artery stenting, intracranial artery stenting, or coil embolization of the cerebral aneurysm. Method A total of 102 consecutive patients scheduled for neurointervention and treated with ASA and clopidogrel were enrolled. Genotyping of three single-nucleotide polymorphisms (SNPs) defining the two major CYP2C19 alleles *2, *3 and PON-1 Q192R was performed with the use of TaqMan® SNP Genotyping Assays (Applied Biosystems, CA) from stored DNA. Antiplatlet effect of clopidogrel was assessed by VerifyNow P2Y12 assay. Result The frequencies of CYP2C19 *1/*1, *1/*2, *1/*3, *2/*2, *2/*3, and *3/*3 were 28 (27.5%), 39 (38.2%), 13 (12.7%), 9 (8.8%), 11 (10.8%), and 2 (2.0%), respectively. On the basis of CYP2C19 genotype, 28 patients (27.5%) were classified as an extensive metabolizer (EM), 52 (51.0%) as an intermediate metabolizer (IM) and 22 (21.6%) as a poor metabolizer (PM). The proportion of patients harboring CYP2C19 loss of function SNPs is 72.5%. The frequencies of PON-1 QQ192, QR192, and RR192 were 8 (7.8%), 52 (51.0%), and 42 (41.2%), respectively. P2Y12 reaction unit (PRU) in the VerifyNow P2Y12 assay was significantly higher in patients with CYP2C19 loss of function SNPs than those without (253.6±100.2 vs. 161.3±85.5, P&lt;0.001). However, the PRU in patients with QR192 or RR192 were not significantly different from those with QQ192 ( 227.0±128.1 vs. 228.8±103.0, P=0.973). Conclusion: In Japanese patients undergoing neurointervention, antiplatlet effect of clopidogrel was associated with CYP2C19 genotype *2and *3 but not with PON-1 Q192R genotype.