Pharmacokinetic/Pharmacodynamic Assessment of the Structural Refinement of Clopidogrel Focusing on the Balance between Bioactivation and Deactivation.

The delicate balance between ischemic and bleeding risks is a critical factor in antiplatelet therapy administration. Clopidogrel and prasugrel, belonging to the thienopyridine class of antiplatelet drugs, are known for their variability in individual responsiveness and high incidence of bleeding events, respectively. The present study is centered on the development and assessment of a range of deuterated thienopyridine derivatives, leveraging insights from structure-pharmacokinetic relationships of clopidogrel and prasugrel. Our approaches were grounded in the molecular framework of clopidogrel and incorporated the C2-pharmacophore design from prasugrel. The selection of ester or carbamate substituents at the C2-position facilitated the generation of the 2-oxointermediate through hydrolysis, akin to prasugrel, thereby bypassing the issue of CYP2C19 dependency. The bulky C2-pharmacophore in our approach distinguishes itself from prasugrel's acetyloxy substituent by exhibiting a moderated hydrolysis rate, resulting in a more gradual formation of the active metabolite. Excessive and rapid release of the active metabolite, believed to be linked with an elevated risk of bleeding, is thus mitigated. Our proposed structural modification retains the hydrolysis-sensitive methyl ester of clopidogrel but substitutes it with a deuterated methyl group, shown to effectively reduce metabolic deactivation. Three promising compounds demonstrated a pharmacokinetic profile similar to that of clopidogrel at four times the dose, while also augmenting its antiplatelet activity. SIGNIFICANCE STATEMENT: Inspired by the structure-pharmacokinetic relationship of clopidogrel and prasugrel, a range of clopidogrel derivatives were designed, synthesized, and assessed. Among them, three promising compounds have been identified, striking a delicate balance between efficacy and safety for antiplatelet therapy. Additionally, the ozagrel prodrug conjugate was discovered to exert a synergistic therapeutic effect alongside clopidogrel.

Pharmacogenomics in Asian Subpopulations and Impacts on Commonly Prescribed Medications.

Asians as a group comprise > 60% the world's population. There is an incredible amount of diversity in Asian and admixed populations that has not been addressed in a pharmacogenetic context. The known pharmacogenetic differences in Asian subgroups generally represent previously known variants that are present at much lower or higher frequencies in Asians compared with other populations. In this review we summarize the main drugs and known genes that appear to have differences in their pharmacogenetic properties in certain Asian populations. Evidence-based guidelines and summary statistics from the US Food and Drug Administration and the Clinical Pharmacogenetics Implementation Consortium were analyzed for ethnic differences in outcomes. Implicated drugs included commonly prescribed drugs such as warfarin, clopidogrel, carbamazepine, and allopurinol. The majority of these associations are due to Asians more commonly being poor metabolizers of cytochrome P450 (CYP) 2C19 and carriers of the human leukocyte antigen (HLA)-B*15:02 allele. The relative risk increase was shown to vary between genes and drugs, but could be > 100-fold higher in Asians. Specifically, there was a 172-fold increased risk of Stevens-Johnson syndrome and toxic epidermal necrolysis with carbamazepine use among HLA-B*15:02 carriers. The effects ranged from relatively benign reactions such as reduced drug efficacy to severe cutaneous skin reactions. These reactions are severe and prevalent enough to warrant pharmacogenetic testing and appropriate changes in dose and medication choice for at-risk populations. Further studies should be done on Asian cohorts to more fully understand pharmacogenetic variants in these populations and to clarify how such differences may influence drug response.

Economic Evaluations of CYP2C19 Genotype-Guided Antiplatelet Therapy Compared to the Universal Use of Antiplatelets in Patients With Acute Coronary Syndrome: A Systematic Review.

BACKGROUND AND OBJECTIVES: Clopidogrel is widely used after the percutaneous coronary intervention (PCI) in patients with acute coronary syndrome (ACS) and requires activation by cytochrome P450 (CYP), primarily CYP2C19. Patients with CYP2C19 loss-of-function alleles are at increased risk of major adverse cardiovascular events, while more expensive novel antiplatelet agents (ticagrelor and prasugrel) are unaffected by the CYP2C19 mutations. This systematic review aims to answer the question about whether overall evidence supports the genotype-guided selection of antiplatelet therapy as a cost-effective strategy in post-PCI ACS. METHODS: A systematic literature search of PubMed, EMBASE, EconLit, and PharmGKB was done to identify all the economic evaluations related to genotype-guided therapy compared to the universal use of antiplatelets in ACS patients. Quality of Health Economic Studies tool was used for quality assessment. RESULTS: The search identified 13 articles, where genotype-guided treatment was compared to universal clopidogrel, ticagrelor, and/or prasugrel. Six studies showed that genotype-guided therapy was cost-effective compared to universal clopidogrel, while 5 studies showed that it was dominant. One study specified that genotype-guided with ticagrelor is cost-effective only in both CYP2C19 intermediate and poor metabolizers. Genotype-guided therapy was dominant when compared to universal prasugrel, ticagrelor, or both in 5, 1, and 3 studies, respectively. Only 2 studies reported that universal ticagrelor was cost-effective compared to genotype-guided treatment. All the included articles had good quality. CONCLUSION: Based on current economic evaluations in the literature, implementing CYP2C19 genotype-guided therapy is a cost-effective approach in guiding the selection of medication in patients with ACS undergoing PCI.

Efficacy and Safety of Clopidogrel, Prasugrel and Ticagrelor in ACS Patients Treated with PCI: A Propensity Score Analysis of the RENAMI and BleeMACS Registries.

INTRODUCTION: Real-life data comparing clopidogrel, prasugrel, and ticagrelor for unselected patients undergoing percutaneous coronary intervention (PCI) for acute coronary syndrome (ACS) are lacking, as are data for the temporal distribution of ischemic and bleeding risks. METHODS: A total of 19,825 patients were enrolled from the RENAMI and BleeMACS registries. Both were multicenter, retrospective, observational registries including the data and outcomes of consecutive patients with ACS who underwent primary PCI and were discharged with dual antiplatelet therapy (DAPT). We evaluated the long-term outcome stratified by the different antiplatelet agents. RESULTS: A total of 14,105 patients (71.2%) were treated with clopidogrel, 2364 patients (11.9%) with prasugrel and 3356 patients (16.9%) with ticagrelor. After propensity score matching, at 1 year, prasugrel reduced the incidence of net adverse clinical events (NACE; a composite endpoint of all-cause death, myocardial infarction [MI] and Bleeding Academic Research Consortium [BARC] 3-5 bleeding) (4.2% vs.7.6%, p = 0.002) and of major adverse cardiovascular events (MACE; a composite endpoint of death and MI) compared with clopidogrel (2.6% vs. 5.2%, p = 0.007). Ticagrelor decreased rates of MACE compared with clopidogrel (2.7% vs. 6.2%, p < 0.001), but not of NACE (6.6% vs. 8.7%, p = 0.07). Ticagrelor presented similar performance in terms of MACE compared with prasugrel (2.8% vs. 2.4%, p = 0.56), with a trend towards a reduction in MI (0.2% vs. 0.4%, p = 0.56), but with higher risk of BARC 3-5 bleedings (3.8% vs. 1.7%, p = 0.04). In the daily risk analysis, clopidogrel presented a binomial distribution with a peak of ischemic risk at 3 months, which decreased towards bleedings; prasugrel had a constant equivalence between opposite risks; and ticagrelor constantly reduced recurrent MIs despite higher risk of BARC 3-5 events. CONCLUSION: In real life, ticagrelor is more effective in reducing ischemic events during the first year after ACS, despite an increased risk of major bleedings, while prasugrel assures a better balance between ischemic and bleeding recurrent events.

Projected Cost-Effectiveness for 2 Gene-Drug Pairs Using a Multigene Panel for Patients Undergoing Percutaneous Coronary Intervention.

BACKGROUND: For patients undergoing percutaneous coronary intervention, gene-drug associations exist relevant to first-line treatment options-antiplatelet agent, clopidogrel, and pain medication, tramadol. Knowledge of genotype information may allow for avoidance of adverse drug events during critical clinical windows. OBJECTIVE: This evaluation estimated cost-effectiveness associated with a multi-gene panel pre-emptively testing two genes providing CYP2C19 genotype-guided strategy for antiplatelet therapy, with CYP2D6 genotype-guided pain management, compared to single gene test for CYP2C19 with random assignment for pain treatment, and to no testing (empiric clopidogrel with random assignment for pain treatment). METHODS: Decision analysis modeling was used to project costs from a payer perspective and patient quality-adjusted life years (QALYs) from the three strategies. The model captured composite risks of major adverse cardiovascular events and pain therapy-related adverse drug events and associated utility estimates. We conducted sensitivity analyses to assess influential input parameters. RESULTS: Over 15 months, multi-gene testing was least costly and yielded more QALYs compared to both single gene and no testing; total incremental costs were $1646 lower with incremental gains of 0.04 QALYs for multi-gene compared with single gene and $11 368 lower with 0.17 QALY gains compared to no test. Base case analyses revealed multi gene was dominant compared to both single gene and no test, as it demonstrated cost savings with increased QALYs. CONCLUSIONS: For these patients, a multi-gene-guided strategy yields a favorable incremental cost-effectiveness ratio compared to the other two treatment strategies. Pre-emptively ascertaining additional gene-drug pair information can inform clinical and economic decision-making at the point of care.

A pharmacokinetic assessment of optimal dosing, preparation, and chronotherapy of aspirin in pregnancy.

BACKGROUND: The benefit of aspirin in preventing preeclampsia is well established; however, studies over the years have demonstrated variability in outcomes with its use. Potential contributing factors to this variation in efficacy include dosing, time of dosing, and preparation of aspirin. OBJECTIVE: We aimed to compare the difference in pharmacokinetics of aspirin, through its major active metabolite, salicylic acid, in pregnant women and nonpregnant women, and to examine the effect of dose (100 mg vs 150 mg), preparation (enteric coated vs non-enteric-coated), and chronotherapy of aspirin (morning vs evening) between the 2 groups. MATERIALS AND METHODS: Twelve high-risk pregnant women and 3 nonpregnant women were enrolled in this study. Pregnant women were in 1 of 4 groups (100 mg enteric coated, 100 mg non-enteric-coated, 150 mg non-enteric-coated morning dosing, and 150 mg non-enteric-coated evening dosing), whereas nonpregnant women undertook each of the 4 dosing schedules with at least a 30-day washout period. Blood samples were collected at baseline (before ingestion) and at 1, 2, 4, 6, 12, and 24 hours after ingestion of aspirin. Plasma obtained was analyzed for salicylic acid levels by means of liquid chromatography-mass spectrometry. Pharmacokinetic values of area under the curve from time point 0 to 24 hours point of maximum concentration, time of maximum concentration, volume of distribution, clearance, and elimination half-life were analyzed for statistical significance with SPSS v25 software. RESULTS: Pregnant women had a 40% ± 4% reduction in area under the curve from time point 0 to 24 hours (P < .01) and 29% ± 3% reduction in point of maximum concentration (P < .01) with a 44% ± 8% increase in clearance (P < .01) in comparison to that in nonpregnant women when 100 mg aspirin was administered. The reduction in the area under the curve from time point 0 to 24 hours, however, was minimized with the use of 150 mg aspirin in pregnant women, with which the area under the curve from time point 0 to 24 hours was closer to that achieved with the use of 100 mg aspirin in nonpregnant women. There was a 4-hour delay (P < .01) in the time of maximum concentration, a 47% ± 3% reduction in point of maximum concentration (P < .01) and a 48% ± 1% increase in volume of distribution (P < .01) with the use of 100 mg enteric-coated aspirin compared to non-enteric-coated aspirin, with no difference in the overall area under the curve. There was no difference in the pharmacokinetics of aspirin between morning and evening dosing. CONCLUSION: There is a reduction in the total drug metabolite concentration of aspirin in pregnancy, and therefore a dose adjustment is potentially required in pregnant women. This is likely due to the altered pharmacokinetics of aspirin in pregnancy, with an increase in clearance. There was no difference in the total drug metabolite concentration of aspirin between enteric-coated and non-enteric-coated aspirin and between morning and evening dosing of aspirin. Further pharmacodynamic and clinical studies are required to examine the clinical relevance of these pharmacokinetic findings.

Defibrotide: An Oligonucleotide for Sinusoidal Obstruction Syndrome.

OBJECTIVE: To review the efficacy and safety of defibrotide as well as its pharmacology, mechanism of action, pharmacokinetics (PK), drug-drug interactions, dosing, cost considerations, and place in therapy. DATA SOURCES: A PubMed search was performed through August 2017 using the terms defibrotide, oligonucleotide, hepatic veno-occlusive disease (VOD), sinusoidal obstruction syndrome (SOS), and hematopoietic cell transplantation (HCT). Other data sources were from references of identified studies, review articles, and conference abstracts plus manufacturer product labeling and website, the Food and Drug Administration website, and clinicaltrials.gov. STUDY SELECTION AND DATA EXTRACTION: English-language trials that examined defibrotide's pharmacodynamics, mechanism, PK, efficacy, safety, dosing, and cost-effectiveness were included. DATA SYNTHESIS: Trials have confirmed the safety and efficacy of defibrotide for treatment of VOD/SOS in adult and pediatric HCT patients, with complete response rates and day +100 overall survival rates ranging from 25.5% to 76% and 35% to 64%, respectively. The British Committee for Standards in Haematology/British Society for Blood and Marrow Transplantation Guidelines recommend defibrotide prophylaxis in pediatric and adult HCT patients with risk factors for VOD/SOS; however, its prophylactic use in the United States is controversial. Although there are efficacy data to support this strategy, cost-effectiveness data have not shown it to be cost-effective. Defibrotide has manageable toxicities, with low rates of grade 3 to 4 adverse effects. CONCLUSIONS: Defibrotide is the first medication approved in the United States for the treatment of adults and children with hepatic VOD/SOS, with renal or pulmonary dysfunction following HCT. Data evaluating defibrotide for VOD/SOS prevention are conflicting and have not shown cost-effectiveness.

Comparative pharmacodynamic effects of two clopidogrel formulations under steady-state conditions in healthy Thai volunteers
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OBJECTIVE: Clopidogrel is a commonly used antiplatelet aggregation agent. Compared with the reference clopidogrel product, most commercially available generic clopidogrel products contain different crystalline forms of clopidogrel. This study was aimed to compare the pharmacodynamics of a commonly used generic clopidogrel product in Thailand with the reference clopidogrel product under steady state conditions. METHODS: A multiple-dose, randomized 2-way crossover study was conducted in 32 healthy male Thai volunteers. The subjects were assigned to receive 75 mg once daily of the test or the reference product for 7 days with a 2-week wash out period. Blood samples were collected on days 1, 5, 6, and 7 prior to drug administration and at 1, 2, 3, 4, 8, 12, and 24 hours after the last dose administered. The antiplatelet aggregation effects of clopidogrel were determined by using two different ex-vivo platelet aggregation tests including the whole blood impedance assay (WBA) and the VerifyNow® P2Y12 assay. Both pharmacodynamic parameters, the maximal antiplatelet effect (Emax) and the areas under the antiplatelet effect-time curve (AUEC0-24h), were calculated. RESULTS: Neither the mean values of Emax (90.70 ± 15.15 vs. 89.50 ± 10.71% inhibition) nor of AUEC0-24h (1,892.84 ± 657.22 vs. 1,853.58 ± 673.95% inhibition × h) under steady-state conditions obtained using the WBA method of these two clopidogrel products were significantly different. The results obtained using the VerifyNow® P2Y12 assay were consistent with those of the WBA assay. CONCLUSION: This study clearly demonstrated that ex-vivo antiplatelet aggregation effect under steady-state conditions of the test product was not significantly different from the reference product.
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Identifying clinically relevant sources of variability: The clopidogrel challenge.

High interindividual variability in clinical outcomes following clopidogrel's standard dosing regimen continues to be a challenge even two decades after its approval. CYP2C19 polymorphisms, obesity, older age, diabetes, and drug-drug interactions have been identified as risk factors for adverse events and treatment failure. We conducted a mechanism-based pharmacokinetic/pharmacodynamic analysis, where we integrated knowledge on in vitro enzyme kinetic, physiological, genetic, and demographic information to characterize changes in platelet reactivity from baseline following clopidogrel antiplatelet therapy. When considering the combined impact of these covariates, our analysis results indicate that higher maintenance doses are required for CYP2C19 intermediate metabolizers and poor metabolizers compared to extensive metabolizers and that respective maintenance doses have to be further increased for obese subjects for each of these CYP2C19 phenotypes. In addition, interindividual differences in the fraction absorbed and the CES1 activity were identified as sources of interindividual differences in clopidogrel's active metabolite concentrations and, thus, platelet reactivity.

PHARMACOLOGICAL ASSESSMENT OF HISPIDULIN - A NATURAL BIOACTIVE FLAVONE.

Hispidulin is well-known natural bioactive flavone on behalf of its pharmacological aspects. This review contains data on isolation, synthetic methodology, pharmacokinetics and bioactivities of hispidulin. The article provides a critical assessment of present knowledge about hispidulin with some clear conclusions, perspectives and directions for future research in potential applications.

Assessment of bleeding risk in patients with coronary artery disease on dual antiplatelet therapy. A systematic review.

Patients with coronary artery disease are usually treated with dual antiplatelet therapy (DAPT) after percutaneous coronary intervention. Patients on DAPT are at risk of both ischaemic and bleeding events. Although side-lined for a long time, real-life studies have shown that both the incidence and the associated morbidity and mortality of out-of-hospital bleeding are high. This indicates that prevention of (post-interventional) bleeding is as important as prevention of ischaemia. For this purpose it is crucial to reliably identify patients with a high bleeding risk. In order to postulate an algorithm, which could help identifying these patients, we performed a systematic review to determine the value of previously proposed prognostic modalities for bleeding. We searched and appraised the following tools: platelet function tests, genetic tests, bleeding scores and questionnaires and haemostatic tests. Most studies indicated that low on-treatment platelet reactivity (LTPR), as measured by several platelet function tests, and the carriage of CYP2C19*17 allele were independent risk factors for bleeding. A bleeding score also proved to be helpful in identifying patients at risk. No studies on haemostatic tests were retrieved. Several patient characteristics were also identified as independent predictors of bleeding, such as older age, female sex and renal failure. Combining these risk factors we propose an algorithm that would hypothetically facilitate identification of those patients at highest risk, warranting prevention measures for bleeding. This could be a starting point for further research concerning the topic.

Assessement of the pharmacokinetics, tissue distribution and excretion studies of a novel antiplatelet agent S007-867, following administration to rats.

S007-867 is a promising novel antiplatelet agent with better efficacy and lesser bleeding risk than existing agents. The present study investigated the absorption, tissue distribution, and excretion of S007-867 in rat model for further advancement of the molecule. A simple and robust ultra fast liquid chromatography-tandem mass spectrometry (UFLC-MS/MS) bioanalytical method was used to determine S007-867 in various matrices. Following oral administration, the compound was quickly dispersed in the various tissues and peak concentration levels were achieved within 0.5-1 h. Overall, exposure of drug, i.e., AUC in different tissues was found in the order of small intestine > liver > heart > spleen > lungs > kidney > brain. The total recoveries of the S007-867 within 96 h were 3.36% in urine and faeces. This might be due to a first-pass effect by the liver and intestine as most of the drug was eliminated in metabolite form. These findings provide a crucial information about further development of S007-867 as antithrombotic agent. Copyright © 2015 John Wiley & Sons, Ltd.

Assessment of efficacy of single dose acetylsalicylic acid over a 24-hour period.

OBJECTIVE: Acetylsalicylic acid (ASA) has a half-life of less than 30 minutes in the human body. This study aimed to test whether the effects of a single dose of ASA wane over a 24-hour period due to the daily release of new reactive blood platelets into the bloodstream. METHODS: The study included 30 patients (10 female and 20 male, mean age: 62.8±9.0). Each took a single dose of 300 mg enteric coated ASA orally. Platelet aggregation was determined using VerifyNow® Aspirin kits immediately prior to intake, and at 12 and 24 hours following intake. Laboratory parameters such as serum CRP and CBC were also examined before ASA intake. Patients were included irrespective of routine ASA and/or clopidogrel use. RESULTS: Aspirin reaction unit (ARU) values were lower than 550 at 24 hours after drug intake in 26 (86.7%) patients. Values lower than 550 indicate therapeutic range of ASA on platelet function. Two (6.7%) patients were found to be responsive to ASA at 12 hours after intake, but unresponsive at 24 hours. Aspirin resistance was found in another 2 (6.7%) patients. CONCLUSION: Although ASA was found to be effective on platelet inhibition over a 24-hour period in most of the patients, there was a considerable number who were resistant to ASA, and who had developed unresponsiveness to ASA by the end of 24 hours. There is evidence in the literature regarding the clinical importance of ASA resistance, but the importance of loss ASA's effectiveness during a day warrants further studies.

Population pharmacokinetics and safety of eptifibatide in healthy Chinese volunteers and simulations on the dose regimens approved for a Western population.

OBJECTIVE: This study was designed to evaluate the pharmacokinetics (PK) and safety of eptifibatide in healthy Chinese volunteers and provide information for the further study in the Chinese population. METHODS: 30 healthy volunteers (15 male) were enrolled in the study and divided into three dose groups (45 µg x kg⁻¹, 90 µg x kg⁻¹, and 180 µg x kg⁻¹). Plasma and urine samples were drawn after one single-bolus administration and measured by LC-MS/MS. The plasma and urine data were analyzed simultaneously by the population approach using the NONMEM software and evaluated by the visual predicted check (VPC) and bootstraping. The PK profiles of dose regimens approved for a Western population in the Chinese population were simulated. RESULTS: A two-compartment model adequately described the PK profiles of eptifibatide. The clearance (CL) and the distribution volume (V1) of the central compartment were 0.128 L x h⁻¹ x kg⁻¹ and 0.175 L x kg⁻¹, respectively. The clearance (Q) and V2of the peripheral compartment were 0.0988 L x h⁻¹ x kg⁻¹ and 0.147 L x kg⁻¹, respectively. The elimination fraction from plasma to urine (F0) was 17.2%. No covariates were found to have a significant effect. Inter-individual variabilites were all within 33.9%. The VPC plots and bootstrap results indicated good precision and prediction of the model. The simulations of the approved regimens in the Chinese population showed much lower steady-state concentrations than the target concentration obtained from the Western clinical trials. No severe safety events were found in this study. CONCLUSIONS: The PK model of eptifibatide was established and could provide PK information for further studies in the Chinese population.

[Effect of original and generic clopidogrel on prognosis in relation to different gene polymorphisms].

AIM: To analyze the influence of clinical and pharmacogenetic factors on the risk of resistance to original or generic clopidogrel and that of cardiovascular events (CVE) during 12 months of follow-up. SUBJECTS AND METHODS: Two hundred and fifty patients admitted to Moscow hospitals in October 2011 to September 2012 were examined. All the patients received clopidogrel. During their stay at hospital, venous blood samples were collected twice (before and 7-10 days after continuous clopidogrel intake). Platelet function was determined by optical aggregometry. A less than 10% reduction in platelet aggregation was taken as a resistance criterion. In addition, CYP2C9 and CYP2C19 gene polymorphisms were investigated. RESULTS: Whether original or generic clopidogrel is used, the level of baseline or post-7-day ADP-induced platelet aggregation (ADP aggregation) fails to affect the risk of its resistance. Evaluation of ADP-induced platelet aggregation in patients with different CYP2C9 and CYP2C19 gene polymorphisms during the administration of original or generic clopidogrel also showed no significant differences in its resistance. During the 12-month follow-up, CVE significantly less frequently occurred as a result of the intake of original versus generic clopidogrel. CONCLUSION: The use of original clopidogrel does not affect the risk of resistance to antiplatelet drugs, but it is associated with the lower incidence of CVE during a year.

[Comparative assessment of antiaggregant efficacy of acetylsalicylic acid and clopidogrel in peripheral atherosclerosis].

Presented in the article are the results of studying antiaggregate activity of acetylsalicylic acid and clopidogrel in a total of 36 patients suffering from various-severity chronic arterial insufficiency of lower limbs on the background of atherosclerosis obliterans. The study was conducted prior to treatment for correct selection of a particular antiplatelet agent. The obtained results showed that clopidogrel was not always more efficient than acetylsalicylic acid, since there is individual sensitivity of each patients to a particular antiplatelet agent. Therefore, an individual approach is necessary to conservative therapy of arterial insufficiency of lower limbs. For some patients it is preferable to administer clopidogrel, for others - acetylsalicylic acid. In a series of cases combined treatment is justified, while some patients having low sensitivity to both acetylsalicylic acid and clopidogrel require careful selection of alternative agents influencing other thrombocyte receptors.

Routine assessment of on-clopidogrel platelet reactivity and gene polymorphisms in predicting clinical outcome following drug-eluting stent implantation in patients with stable coronary artery disease.

OBJECTIVES: This study sought to assess the usefulness of clopidogrel-pathway genotyping and on-treatment platelet reactivity (OTR) testing in predicting major adverse cardiac events (MACE) in stable coronary artery disease (CAD) patients receiving drug-eluting stents (DES) under dual antiplatelet (clopidogrel plus aspirin) therapy. BACKGROUND: The role of pharmacogenetics and OTR in predicting MACE-death, myocardial infarction, or stent thrombosis-in stable CAD patients scheduled for DES implantation is still debated. METHODS: Patients with stable CAD treated by DES implantation (n = 1,432) were genotyped with a TaqMan OpenArray (Applied Biosystems, Carlsbad, California) and assessed for OTR with the VerifyNow P2Y12 test (Accumetrics Inc., San Diego, California). Genes tested were ABCB1, CYP1A2, CYP2B6*9, CYP2C8*3, CYP2C9*2, CYP2C19, CYP3A4, CYP3A5*3, P2RY12, and PON1CYP2C19. High OTR was defined as P2Y12 reaction units ≥230. The endpoint at 12-month follow-up was MACE occurring during antiplatelet therapy. RESULTS: All groups that were stratified for loss-of-function variants of the cytochrome P450 gene CYP2C19 had significant hazard ratios (HR) for MACE (genotypic HR: 1.41, 95% confidence interval [CI]: 1.06 to 1.89, p = 0.01; allelic HR: 1.56, 95% CI: 2.26 to 1.2, p = 0.01). Variants of other clopidogrel-pathway genes were not significantly associated with MACE. When OTR was assessed, clinical significance was found only in high-risk diabetic (HR: 2.11, 95% CI: 1.29 to 3.45, p < 0.001) and chronic kidney disease (HR: 2.03, 95% CI: 1.03 to 4.02, p = 0.04) patients. CONCLUSIONS: CYP2C19 metabolizer status is an independent predictor of MACE after DES implantation and can be used for prognostication in all stable CAD patients. High OTR, as assessed by the VerifyNow P2Y12 test, is an independent predictor of MACE only for high-risk subsets, that is, patients with diabetes or chronic kidney disease.

Esomeprazole and aspirin fixed combination for the prevention of cardiovascular events.

Low dose aspirin therapy plays a fundamental role in both the primary and secondary prevention of cardiovascular events. Although the evidence using low dose aspirin for secondary prevention is well-established, the decision to use aspirin for primary prevention is based on an evaluation of the patient's risk of cardiovascular events compared to their risk of adverse events, such as bleeding. In addition to the risk of bleeding associated with long term aspirin administration, upper gastrointestinal side effects, such as dyspepsia often lead to discontinuation of therapy, which places patients at an increased risk for cardiovascular events. One option to mitigate adverse events and increase adherence is the addition of esomeprazole to the medication regimen. This review article provides an evaluation of the literature on the concomitant use of aspirin and esomeprazole available through February 2013. The efficacy, safety, tolerability, cost effectiveness, and patient quality of life of this regimen is discussed. A summary of the pharmacokinetic and pharmacodynamic interactions between aspirin and esomeprazole, as well as other commonly used cardiovascular medications are also reviewed. The addition of esomeprazole to low dose aspirin therapy in patients at high risk of developing gastric ulcers for the prevention of cardiovascular disease, significantly reduced their risk of ulcer development. Pharmacokinetic and pharmacodynamic studies suggested that esomeprazole did not affect the pharmacokinetic parameters or the antiplatelet effects of aspirin. Therefore, for those patients who are at a high risk of developing a gastrointestinal ulcer, the benefit of adding esomeprazole likely outweighs the risks of longer term proton pump inhibitor use, and the combination can be recommended. Administering the two agents separately may also be more economical. On the other hand, for those patients at lower risk of developing a gastrointestinal ulcer, both the additional risk and cost make the inclusion of a proton pump inhibitor unwarranted.