Concomitant Use Of Clopidogrel Research Articles

Integrated Population Pharmacokinetics of Daprodustat in Patients with Chronic Kidney Disease with Anemia.

Daprodustat is a first-in-class hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) approved in the USA for treatment of anemia owing to chronic kidney disease (CKD) in dialysis-dependent adults and in Japan for treatment of CKD in dialysis- and non-dialysis dependent adults. This analysis characterized the population pharmacokinetics (PopPK) of daprodustat in adults with CKD and evaluated the influence of intrinsic and extrinsic factors. This PopPK analysis included data from one phase 2B and four phase 3 studies comprising 707 CKD subjects dose titrated to prespecified target hemoglobin levels with daprodustat doses ranging from 1 to 24 mg once daily and 2 to 48 mg given three times a week (TIW). Model development leveraged a previous phase 1/2 PopPK model. Stepwise covariate analysis included 20 extrinsic and intrinsic factors. Model evaluation used standard goodness-of-fit and visual predictive checks. Daprodustat PopPK was adequately characterized using a three-compartment distribution model with first-order elimination. The absorption phase was described using five transit compartments. Oral clearance and volume of distribution was 24.6 L/h and 26.9 L, respectively. Body weight dependence (with fixed allometric coefficients) of clearance and volume terms was a statistically significant covariate. Concomitant use of clopidogrel (moderate CYP2C8 inhibitor) decreased oral clearance, resulting in higher area under the plasma concentration-timecurve (AUC) ratio of 1.59 (90% CI: 1.39-1.82), subjects' dialysis status (non-dialysis versus dialysis) had an effect on absorption, with Cmax ratio of 1.19 (90% CI: 1.09-1.30). None of the other investigated intrinsic or extrinsic covariates, including concomitant administration with phosphate binders, oral iron and acid reducing agents resulted in a significant change in daprodustat systemic exposure. The PopPK of daprodustat in theCKD population with anemia was adequately characterized. Allometrically-scaled body weight on clearance and volume, dialysis status on absorption and clopidogrel on clearance were statistically significant covariates.

Temporal trends in use of antisecretory agents among patients administered clopidogrel-based dual antiplatelet therapy after percutaneous coronary intervention.

Antisecretory drugs are commonly prescribed with clopidogrel-based dual antiplatelet therapy (DAPT) to prevent gastrointestinal bleeding in high-risk patients after percutaneous coronary intervention (PCI). However, omeprazole and esomeprazole (inhibiting proton pump inhibitors [PPIs]) may increase cardiovascular event rates on co-administration with clopidogrel. This study aimed to examine trends in the use of antisecretory agents in patients administered clopidogrel-based DAPT and the concomitant use of clopidogrel and inhibiting PPIs. We used National Inpatient Sample data compiled by the Health Insurance Review & Assessment Service from 2009 to 2020. Further, we identified patients who were prescribed clopidogrel-based DAPT after PCI and investigated the concomitant use of antisecretory agents with clopidogrel. To verify the annual trend of drug utilization, we used the Cochran-Armitage trend test. From 2009 to 2020, the percentage of H2 receptor antagonist users decreased steadily (from 82.5% in 2009 to 25.3% in 2020); instead, the percentage of PPI users increased (from 23.7% in 2009 to 82.0% in 2020). The use of inhibiting PPI also increased (from 4.2% in 2009 to 30.7% in 2020). Potassium competitive acid blockers (P-CABs) were rarely used before 2019; however, in 2020, it accounted for 7.8% of the antisecretory users. Our study demonstrates that the use of inhibiting PPIs increased steadily in patients administered clopidogrel-based DAPT therapy. This is a major concern since the concomitant use of inhibiting PPIs with clopidogrel could increase the risk of cardiovascular events.

Effects of treatment with clopidogrel with or without proton pump inhibitor omeprazole on the risk of ischemic stroke: a nationwide cohort study

Most proton pump inhibitors (PPIs) inhibit the bioactivation of clopidogrel to its active metabolite. There is controversy concerning whether PPIs alter the effectiveness of clopidogrel in reducing the risk of ischemic stroke (IS). We therefore aimed to examine the risk of IS associated with concomitant use of clopidogrel and omeprazole, a PPI commonly used in clinical settings. We conducted a retrospective cohort study using the National Health Insurance Research Database of Taiwan dated from 2000 to 2013. The study cohorts comprised 407 patients diagnosed with acute coronary syndrome (ACS) and with concomitant use of clopidogrel and omeprazole (the exposed cohort), 814 ACS patients with single use of clopidogrel (the comparison cohort), and 230 ACS patients with concurrent use of clopidogrel and pantoprazole (the reference cohort). The primary outcome was incident IS. The hazard ratios (HRs) and 95% confidence intervals (CIs) derived from the time-dependent Cox regression model were used to assess the association between concomitant use of clopidogrel and omeprazole and the risk of IS. The incidence rate of IS was significantly higher in the exposed cohort (81.67 per 1000 person-years) than in the comparison cohort (57.45 per 1000 person-years), resulting in an adjusted HR of 1.39 (95% CI 1.03–1.74). By contrast, there was no significant difference in the risk of IS between the exposed and reference cohorts (adjusted HR 1.11; 95% CI 0.81–1.52). The present study revealed that patients taking both clopidogrel and omeprazole was associated with an increased risk of IS.

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

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

Proton pump inhibitors and gastroprotection in patients treated with antithrombotic drugs: A cardiologic point of view.

Aspirin, other antiplatelet agents, and anticoagulant drugs are used across a wide spectrum of cardiovascular and cerebrovascular diseases. A concomitant proton pump inhibitor (PPI) treatment is often prescribed in these patients, as gastrointestinal complications are relatively frequent. On the other hand, a potential increased risk of cardiovascular events has been suggested in patients treated with PPIs; in particular, it has been discussed whether these drugs may reduce the cardiovascular protection of clopidogrel, due to pharmacodynamic and pharmacokinetic interactions through hepatic metabolism. Previously, the concomitant use of clopidogrel and omeprazole or esomeprazole has been discouraged. In contrast, it remains less known whether PPI use may affect the clinical efficacy of ticagrelor and prasugrel, new P2Y12 receptor antagonists. Current guidelines recommend PPI use in combination with antiplatelet treatment in patients with risk factors for gastrointestinal bleeding, including advanced age, concurrent use of anticoagulants, steroids, or non-steroidal anti-inflammatory drugs, and Helicobacter pylori (H. pylori) infection. In patients taking oral anticoagulant with risk factors for gastrointestinal bleeding, PPIs could be recommended, even if their usefulness deserves further data. H. pylori infection should always be investigated and treated in patients with a history of peptic ulcer disease (with or without complication) treated with antithrombotic drugs. The present review summarizes the current knowledge regarding the widespread combined use of platelet inhibitors, anticoagulants, and PPIs, discussing consequent clinical implications.

Potential drug-drug interactions in drug therapy for older adults with chronic coronary syndrome at hospital discharge: A real-world study.

Introduction: Polypharmacy are commonly observed among older adults with cardiovascular disease. However, multiple medications lead to increased risk of drug-drug interactions (DDIs). Therefore, identification and prevention actions related to harmful DDIs are expected in older adults. The study aimed to describe the prevalence of potential DDIs (pDDIs) in discharge prescriptions among older adults with chronic coronary syndrome (CCS). Methods: A single-center cross-sectional study was performed in a tertiary public hospital in Beijing, China. CCS patients aged 65 years and above who were admitted to cardiology wards over a 3-month period and alive at discharge were included. Electronic medical records and discharge prescriptions were reviewed. pDDIs were evaluated through the Lexi-Interact online. Results: pDDIs were identified in 72.9% of the 402 individuals (n = 293). A total of 864 pDDIs were obtained. 72.1% of patients were found with C DDIs (n = 290) and 20.3% were categorized in D and X DDIs (n = 82). The only X DDI was between cyclosporine and atorvastatin. Under category D, glycemia alterations within antidiabetics and increased chances of bleeding with antithrombotic were the most common. Concomitant use of clopidogrel and calcium channel blockers was a frequent situation within category C, followed by synergic blood pressure lowering agents and increased rosuvastatin concentration induced by clopidogrel. Conclusion: DDIs exposure was common in older CCS. DDIs screening tools should be introduced to alert potential adverse effects. Prescribers need to rigorously review or modulate therapies to prevent DDI-related adverse outcomes. Clinical pharmacists should be more involved in complex drug regimen management.

Surrogates of the Left Ventricular Thrombus Resolution: A Retrospective Data Review.

The left ventricular thrombus is one of the serious complications of ischemic cardiomyopathy. In this study, we aimed to search for the independent factors to predict the resolution of left ventricular thrombus. This retrospective study included all patients with coronary artery disease, aged above 18 years old, and with the thrombus at the apical location of the left ventricle. Demographic, clinical, and echocardiographic characteristics of the patients were recorded. Major adverse cardiovascular events developed within the follow-up period were recorded. The time in the therapeutic range of each patient was calculated. The presence of left ventricular thrombus beyond 180 days despite warfarin usage was classified as persistent left ventricular thrombus. The study included 174 subjects (169 males and 5 females). The mean age of the study population was 54.5 ± 11.0 years. The number of patients in whom the left ventricular thrombus resolved with treatment in less than 180 days was 56 (32.2%). Median anticoagulation time in the study population was 252 [150-480] days and the meantime in the therapeutic range of the patients was 54 ± 19%. The time in therapeutic range value of the groups was similar (P=.593). It was found that concomitant clopidogrel use (P=.003) and left ventricular thrombus area (P < .001) were the independent predictors of left ventricular thrombus resolution within less than 180 days in the logistic regression analysis. Concomitant use of clopidogrel was found to be associated with left ventricular thrombus resolution but left ventricular thrombus size was related to left ventricular thrombus persistency. Although standard 3-6 months of anticoagulation is advised for left ventricular thrombus, considering the presence of these predictors in such patients may guide the physicians to individualize the treatment.

Surrogates of the Left Ventricular Thrombus Resolution: A Retrospective Data Review.

The left ventricular thrombus is one of the serious complications of ischemic cardiomyopathy. In this study, we aimed to search for the independent factors to predict the resolution of left ventricular thrombus.This retrospective study included all patients with coronary artery disease, aged above 18 years old, and with the thrombus at the apical location of the left ventricle. Demographic, clinical, and echocardiographic characteristics of the patients were recorded. Major adverse cardiovascular events developed within the follow-up period were recorded. The time in the therapeutic range of each patient was calculated. The presence of left ventricular thrombus beyond 180 days despite warfarin usage was classified as persistent left ventricular thrombus.The study included 174 subjects (169 males and 5 females). The mean age of the study population was 54.5 ± 11.0 years. The number of patients in whom the left ventricular thrombus resolved with treatment in less than 180 days was 56 (32.2%). Median anticoagulation time in the study population was 252 [150-480] days and the meantime in the therapeutic range of the patients was 54 ± 19%. The time in therapeutic range value of the groups was similar (P=.593). It was found that concomitant clopidogrel use (P=.003) and left ventricular thrombus area (P < .001) were the independent predictors of left ventricular thrombus resolution within less than 180 days in the logistic regression analysis.Concomitant use of clopidogrel was found to be associated with left ventricular thrombus resolution but left ventricular thrombus size was related to left ventricular thrombus persistency. Although standard 3-6 months of anticoagulation is advised for left ventricular thrombus, considering the presence of these predictors in such patients may guide the physicians to individualize the treatment.

A Combination of Aspirin and Clopidogrel Predict More Favorable Dynamics of Platelet Reactivity versus Clopidogrel Alone in the Acute Phase of Minor Stroke.

Background: The combined use of clopidogrel and aspirin is recommended for the short-term (21 days) therapy of minor stroke or transient ischemic attack. Previous studies have demonstrated its efficacy and superiority over treatment with a single antiplatelet agent. However, there is insufficient support for the advantages of such therapy based on platelet function testing. We aimed to compare the effect of the concomitant use of clopidogrel and aspirin versus clopidogrel alone on the dynamics of platelet reactivity over time to determine the appropriate antiplatelet treatment strategy for minor strokes. Methods: We enrolled 74 ischemic stroke subjects, including 38 minor strokes. Platelet reactivity was assessed by impedance aggregometry (Multiplate Analyzer) 48 and 96 h after a first 75 mg dose of clopidogrel, using the acetylsalicylic acid platelet inhibition (ASPI) test and the adenosine diphosphate (ADP) test. Dual antiplatelet therapy was strictly reserved only to minor strokes, as the other strokes received clopidogrel alone in the secondary prevention. The dynamics of platelet reactivity refer to the difference between two assessments, and a decrease in values over time was considered favorable. Results: The incidence of clopidogrel non-responsiveness was 64.8%, and this was similar in the group of minor strokes and the group of more disabling strokes. We indicated diabetes mellitus as an independent predictor of high on-clopidogrel platelet reactivity (Odds ratio OR 5.69 95% Confidence Interval CI 1.13–41.26, p = 0.0386). Among minor strokes treated with dual antiplatelet therapy, in relation to clopidogrel, we reported a trend toward more favorable dynamics of platelet reactivity over time compared to the group using clopidogrel alone (p = 0.0652 vs. p = 0.3384, respectively). We identified five predictors (sex, female; small-vessel disease; no diabetes; no hyperlipidemia; and no alcohol abuse) related to a significant decrease in platelet reactivity over time with respect to clopidogrel. No significant dynamics of platelet reactivity when using aspirin were found. Conclusions: Our findings, based on the favorable dynamics of platelet reactivity over time in relation to clopidogrel, confirm the usefulness of dual antiplatelet therapy in minor strokes and support the continuation of the secondary prevention with clopidogrel alone rather than aspirin, particularly among identified beneficiaries of such a strategy.

Evaluation of serious bleeding signals during concomitant use of clopidogrel and hypnotic drugs

BackgroundIn a previous drug-drug interaction (DDI) screening study intended to generate hypotheses, clopidogrel + either eszopiclone or zolpidem (vs. clopidogrel alone) were associated with serious bleeding. ObjectivesTo confirm or refute these DDI signals and examine associations with other hypnotics in an independent population of United States Medicaid beneficiaries MethodsWe employed a bi-directional self-controlled case series design in eligible individuals concomitantly exposed to one of 12 hypnotics (precipitants, exposures of interest) plus either clopidogrel (the object drug) or pravastatin (the negative control object drug). The outcome was hospital presentation with serious bleeding. Using conditional Poisson regression, we calculated confounder-adjusted rate ratios (RRs) and 95% confidence intervals for serious bleeding during clopidogrel + precipitant use (vs. clopidogrel alone). To distinguish a DDI from a precipitant’s inherent effect on bleeding, we divided effect measures by the adjusted RR for the corresponding pravastatin + precipitant pair to obtain ratios of RR (RRRs). ResultsAmong 23,194 users of clopidogrel and 3824 of pravastatin who experienced serious bleeding during an active prescription for one of these agents, confounder-adjusted RRRs for serious bleeding were 6.63 (0.39–113.01) and 0.77 (0.53–1.11) with eszopiclone and zolpidem, respectively, whereas confounder-adjusted RRRs for other hypnotics ranged from 0.18 (0.04–0.85) for triazolam to 1.79 (0.16–20.44) for zaleplon. Statistical imprecision therefore precluded us from confirming or refuting these prior signals with eszopiclone and zolpidem. ConclusionsWhile we could not confirm or refute previously identified DDI signals, numerically elevated RRRs for serious bleeding with several clopidogrel + hypnotic pairs warrant further examination.

Risk of major adverse cardiovascular events for concomitant use of clopidogrel and proton pump inhibitors in patients inheriting CYP2C19 loss-of-function alleles: meta-analysis.

Background Efficacy of clopidogrel may be diminished due to either co-administration of proton pump inhibitors or carrying CYP2C19 loss-of-function alleles. However, patients may be at greater risk of major adverse cardiovascular events if taking clopidogrel together with proton pump inhibitors and also inherited the CYP2C19 loss-of-function alleles which may cause further reduction of clopidogrel efficacy. This is due to the cumulative effects of drug-drug interactions and drug-gene interactions collectively referred to as multifactorial drug-gene interactions. Aim of the review The aim of this analysis was to estimate aggregated risk of major adverse cardiovascular events for either coronary heart disease or stroke patients with multifactorial drug-gene interactions versus clopidogrel alone with or without drug-gene interactions. Methods Literatures were searched using different resources based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Meta-analysis was performed using RevMan software following either fixed/random effects model based on the levels of heterogeneity. A p value < 0.05 (2-sided) was considered statistically significant. Results In total, five studies consisting 8,802 patients of coronary artery diseases or stroke were included in this meta-analysis in which 3,767 were prescribed clopidogrel alone, 1,931 were concomitantly taking clopidogrel and PPIs, 2,146 were carrying CYP2C19 loss-of-function alleles and 958 were taking both clopidogrel and proton pump inhibitors while also carrying CYP2C19 loss-of-function alleles. It was found that patients with multifactorial drug-gene interactions were associated with significantly increased risk of major adverse cardiovascular events compared to those taking clopidogrel alone without CYP2C19 loss-of-function alleles (12% vs. 5.8%; RR 1.73; 95% CI 1.12-2.67; p = 0.01). Patients with multifactorial drug-gene interactions were also associated with significantly increased risk of major adverse cardiovascular events compared to drug-gene interactions (RR 1.63; 95% CI 1.31-2.03; p < 0.0001). Patients taking clopidogrel with proton pump inhibitors were also associated with 35% significantly increased risk of major adverse cardiovascular events compared to those taking only clopidogrel (RR 1.35; 95% CI 1.11-1.65; p = 0.003). Conclusion Patients inheriting CYP2C19 loss-of-function alleles have significantly increased risk of major adverse cardiovascular events when taking clopidogrel and proton pump inhibitors concurrently.

Cost-Effectiveness and Cost-Utility Analysis of the Use of Clopidogrel and Pantoprazole in Comparison with Clopidogrel and Omeprazole for the Secondary Prevention of Myocardial Infarction in Iran.

Objective:Gastrointestinal bleeding, a side effect of clopidogrel, is usually prevented by proton-pump inhibitors (PPIs). Due to omeprazole's inhibitory effects on the liver enzyme CYP2C19, its concomitant use with clopidogrel is argued to increase the risk of myocardial infarction (MI) recurrence, as CYP2C19 activates clopidogrel. Pantoprazole as an alternative PPI has shown no inhibitory effect on CYP2C19. This study investigates the cost-effectiveness of concomitant use of clopidogrel and pantoprazole in MI patients compared to the simultaneous use of clopidogrel and omeprazole.Methods:We used the Markov-modeling technique with a hypothetical cohort of 1000 acute MI patients aged 55 years using Microsoft Excel 2013 software. The study was done from the payer perspective, and a lifetime horizon with 1-year cycles was considered in the model. Life-years gained (LYG) and quality-adjusted life-years (QALYs) were used to quantify the health effects of these interventions. Two separate scenarios of public tariffs and private tariffs with various discount rates (0%, 3%, and 7.2% discounts (only for costs)) were evaluated, and an incremental cost-effectiveness ratio (ICER) was used to report the results. One-way and probabilistic sensitivity analyses were used to deal with uncertainty. Data were sourced from published literature and tariff book of the Iranian ministry of health.Findings:The estimated ICERs were 342 USD/QALY and 236 USD/LYG per patient for the base-case scenario.Conclusion:Abiding by the WHO threshold for cost-effectiveness, the concomitant use of pantoprazole and clopidogrel can be considered cost-effective compared to the use of omeprazole and clopidogrel.

ANMCO/AIGO Intersocietary consensus document: Gastroprotection in patients receiving antiplatelet and/or anticoagulant drugs

Aspirin and P2Y12 receptor antagonists are widely used across the spectrum of cardiovascular and cerebrovascular diseases. Gastrointestinal complications, including ulcer and bleeding, are relatively common during antiplatelet treatment and, therefore, concomitant proton pump inhibitor (PPI) treatment is often prescribed. However, potential increased risk of cardiovascular events has been suggested for PPIs, and, in recent years, it has been discussed whether these drugs may reduce the cardiovascular protection by aspirin and, even more so, clopidogrel. Indeed, pharmacodynamic and pharmacokinetic studies suggested an interaction through CYP2C19 between PPIs and clopidogrel, which could translate into clinical inefficacy, leading to higher rates of cardiovascular events. The Food and Drug Administration and the European Medicines Agency sent a warning in 2010 discouraging the concomitant use of clopidogrel with omeprazole or esomeprazole. In addition, whether the use of PPIs may affect the clinical efficacy of the new P2Y12 receptor antagonists, ticagrelor and prasugrel, remains less known. According to current guidelines, PPIs in combination with antiplatelet treatment are recommended in patients with risk factors for gastrointestinal bleeding, including advanced age, concurrent use of anticoagulants, steroids or non-steroidal anti-inflammatory drugs, and Helicobacter pylori infection. Like traditional anticoagulants, novel oral anticoagulants may cause gastrointestinal bleeding. Results from both randomized clinical trials and observational studies suggest that high-dose dabigatran (150 mg bid), rivaroxaban and high-dose edoxaban (60 mg daily) are associated with a higher risk of gastrointestinal bleeding as compared with warfarin. However, the usefulness of PPIs in patients receiving these anticoagulants deserves to be further demonstrated. Given the large number of patients treated with antithrombotic drugs and PPIs, even a minor reduction of platelet inhibition or anticoagulant effect potentially carries a considerable clinical impact. The present joint statement by ANMCO and AIGO summarizes the current knowledge regarding the widespread use of platelet inhibitors, anticoagulants, and PPIs in combination. Moreover, it outlines evidence supporting or opposing drug interactions between these drugs and discusses consequent clinical implications.

Exposure and response analysis of aleglitazar on cardiovascular risk markers and safety outcomes: An analysis of the AleCardio trial.

AimsThe AleCardio trial aimed to characterize the efficacy and safety of peroxisome proliferator‐activated receptor‐αγ agonist aleglitazar in patients with type 2 diabetes mellitus and acute coronary syndrome. The trial terminated early because of futility and safety signals. We evaluated whether the safety signals could be attributed to increased exposure to aleglitazar.Materials and MethodsThe AleCardio trial enrolled 7226 patients to receive aleglitazar 150 μg or matching placebo on top of standard care. A population pharmacokinetic analysis was conducted in a pharmacokinetic substudy to identify covariates that explained interindividual variability in exposure. Subsequently, the effect of these covariates on surrogate and clinical outcomes was assessed in the full patient population.ResultsConcomitant administration of clopidogrel was identified as a covariate that influenced the apparent clearance of aleglitazar. Patients using clopidogrel had a mean predicted area under the plasma‐concentration‐time curve (AUC0–24) of 174.7 ng h/mL (SD: ±112.9 ng h/mL) versus 142.2 ng h/mL (SD: ±92.6 ng h/mL) in patients without clopidogrel. The effect of aleglitazar compared with placebo on HbA1c, haemoglobin, serum creatinine and adiponectin was modified by concomitant clopidogrel use (P for interaction 0.007, 0.002, <0.001 and < 0.001, respectively).ConclusionsConcomitant use of clopidogrel was identified as a covariate that explained interindividual variability in exposure to aleglitazar. Patients using clopidogrel showed an additional lowering of HbA1c, at the expense of an additional decrease in haemoglobin, and an increase in serum creatinine and adiponectin. Clopidogrel is a moderate inhibitor of CYP2C8. Because aleglitazar is metabolized by CYP2C8, a pharmacokinetic interaction could explain differences in exposure and response to aleglitazar.

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.

PDB11 - Concomitant use of Repaglinide and Clopidogrel And Risk Of Hypoglycemia: A Population-Based Nested Case-Control Study

A small trial showed a decreased glucose level of healthy subjects induced by concomitant use of clopidogrel and repaglinide. However, evidence of the link between the hypoglycemic risk in diabetic patients and this potential drug interaction remains lacking. The goal of this research is to investigate whether concomitant use of repaglinide and clopidogrel is associated with an increased risk of hypoglycemia. This was a nested case-control study using the nationwide claims database in Taiwan. Diabetic patients who ever treated with repaglinide or nateglinide were included in this study (n=110,654). Cases were defined as hospital admissions or emergency room visits due to hypoglycemia. Concomitant use of repaglinide and clopidogrel within 3 days before the hypoglycemic event was the exposure of interest. For each case, up to four controls were randomly selected and matched by age, sex, type of glinide exposure (repaglinide or nateglinde) and the duration of follow-up. The adjusted results were generated by conditional logistic regressions. A total of 1,014 cases and 3,600 matched controls were identified. Concomitant use of repaglinide and clopidogrel was associated with an increased risk of hypoglycemia compared to repaglinide alone (adjusted odds ratio [AOR]: 2.280, 95% confidence interval [Cl]: 1.504, 3.457). No significant increase in the hypoglycemic risk was found in the two pairs of drug concomitants for negative controls: the synchronous use of nateglinide and clopidogrel (AOR: 1.062, 95% Cl: 0.021, 54.526) and the concurrent use of repaglinide and aspirin (without clopidogrel use) (AOR: 1.170, 95% Cl: 0.894, 1.533). Our study suggested that a clinically significant drug-interaction between clopidogrel and repaglinide might exist and could cause increased risk for hypoglycemic events.

Abstract P274: Cross-sectional Analysis of Baseline Characteristics for New Users of Vorapaxar (PAR-1 Antagonist) and P2Y 12 Inhibitors

Introduction: Vorapaxar is indicated for the reduction of thrombotic events in patients with a prior myocardial infarction (MI) or peripheral arterial disease (PAD), and contraindicated in patients with a prior stroke, transient ischemic attack (TIA), or intracranial hemorrhage (ICH). This is the first descriptive study of vorapaxar in US clinical practice. Objectives: Main objective was to describe baseline characteristics of vorapaxar new users. For context, P2Y 12 new users were also examined, with indications summarized in Table 1. Methods: Cross-sectional analysis of vorapaxar new users ≥18 years with ≥1 prescription between June 2014 - June 2016 identified in Symphony Health’s outpatient pharmacy claims database linked to private practitioner claims and hospital data. Concomitant clopidogrel use was defined with overlapping days of supply. Medical history was defined using a 1-year baseline period. Results: The analysis included 1,362 vorapaxar (44% with clopidogrel), 975,023 clopidogrel, 133,724 ticagrelor, and 98,101 prasugrel new users (Table 1). Most ticagrelor (87%) and prasugrel (85%) users had evidence of coronary artery disease (CAD) compared with 52% of clopidogrel and 58% of vorapaxar users. In contrast, &lt;1% of ticagrelor and prasugrel users had PAD but no CAD vs. 6% of clopidogrel and 15% of vorapaxar users. The proportion of vorapaxar users (44%) with PAD, alone or with CAD, was 3-5 times larger than P2Y 12 users. PAD was more prevalent for vorapaxar with (50%) vs. without (39%) clopidogrel. Contraindications were infrequent for vorapaxar users - no ICH, &lt;4% with stroke or TIA. Median time from recent MI to therapy start was 6 months for vorapaxar vs. 3 days for ticagrelor and prasugrel and 7 days for clopidogrel. Vorapaxar users were mostly male and on average ~65 years old. Conclusions: The majority of vorapaxar new users had a history of CAD and/or PAD, with PAD prevalence more than twice that of P2Y 12 new users. Contraindications were infrequent.

Nonsteroidal anti-inflammatory drug choice and adverse outcomes in clopidogrel users: A retrospective cohort study.

ObjectiveTo examine the comparative safety of individual NSAIDs when given concomitantly with clopidogrel.MethodsWe conducted a retrospective cohort study using Medicaid claims from five US states during 1999–2010, supplemented with Medicare claims for dual-enrollees. The exposure of interest was the first concomitant use of clopidogrel and one of the 10 selected NSAIDs after a 1-year baseline period. The outcomes were: all-cause mortality; acute myocardial infarction (AMI)/ischemic stroke; and gastrointestinal bleeding (GIB)/intracranial hemorrhage (ICH). We calculated the hazard ratio of each NSAID for each outcome, with ibuprofen as the reference drug, using high-dimensional propensity score-adjusted proportional-hazards regression models.ResultsOf 1,060,412 clopidogrel users, 268,114 concomitant NSAID users met inclusion/exclusion criteria, contributing 48,483 person-years. We observed 2,463 deaths, 2,822 AMI/ischemic stroke outcomes, and 2,620 GIB/ICH outcomes, for unadjusted incidence rates of 50.8, 58.6, and 54.3 per 1,000 person-years, respectively. Compared with ibuprofen and controlling for potential confounders, rofecoxib (hazard ratio [HR] = 1.22; 95% confidence interval [CI]: 1.04, 1.43) and valdecoxib (HR = 0.66; 95% CI: 0.48, 0.92) showed higher and lower hazards of mortality, respectively. Indomethacin showed an increased AMI/ischemic stroke hazard (HR = 1.38; 95% CI: 1.09, 1.74). For GIB/ICH, indomethacin (HR = 2.18; 95% CI: 1.74, 2.73), diclofenac (HR = 1.65; 95% CI: 1.39, 1.97), naproxen (HR = 1.47; 95% CI: 1.28, 1.70), and rofecoxib (HR = 1.26; 95% CI: 1.08, 1.48) showed higher hazards, and valdecoxib (HR = 0.73; 95% CI: 0.55, 0.98) showed a lower hazard.ConclusionThe bleeding risks of individual NSAIDs varied more markedly than thrombotic risks when used concomitantly with clopidogrel. Moreover, bleeding risk and thrombotic risk among individual NSAIDs did not appear to be inversely related to each other in the presence of clopidogrel. Further studies are needed to elucidate underlying biological mechanisms and help clinical decision-making for a better NSAID choice in clopidogrel users.

The risk of lower gastrointestinal bleeding in low-dose aspirin users.

Aspirin increases the risk of gastrointestinal bleeding. To investigate the risk of lower gastrointestinal bleeding (LGIB) in aspirin users. Low-dose (75-325mg daily) aspirin users and controls matched by age, gender and enrollment time in a 1:5 ratio were selected from 1 million randomly sampled subjects in the National Health Insurance Research Database of Taiwan. Cox proportional hazard regression models were developed to evaluate the predictors of LGIB with adjustments for age, gender, comorbidities including coronary artery disease, ischaemic stroke, diabetes, hypertension, chronic kidney disease, liver cirrhosis, chronic obstructive pulmonary disease, dyslipidemia, uncomplicated peptic ulcer disease, history of peptic ulcer bleeding, and concomitant use of clopidogrel, ticlopidine, warfarin, nonsteroidal anti-inflammatory drugs (NSAIDs), cyclooxygenase-2 inhibitors, steroids, proton pump inhibitors (PPIs), histamine-2 receptor antagonists (H2RAs), nitrates, alendronate, selective serotonin reuptake inhibitors (SSRIs) and calcium channel blockers. A total of 53805 aspirin users and 269025 controls were included. Aspirin group had a higher incidence of LGIB within 1year than control group (0.20% vs 0.06%, P<.0001). Aspirin (hazard ratio [HR]: 2.75, 95% confidence interval [CI]: 2.06-3.65), NSAIDs (HR: 8.61, 95% CI: 3.28-22.58), steroids (HR: 10.50, 95% CI: 1.98-55.57), SSRIs (HR: 11.71, 95% CI: 1.40-97.94), PPIs (HR: 8.47, 95% CI: 2.26-31.71), and H2RAs (HR: 10.83, 95% CI: 2.98-39.33) were significantly associated with LGIB. The risk of LGIB was higher in low-dose aspirin users than in aspirin nonusers in this nationwide cohort. Low-dose aspirin, NSAIDs, steroids, SSRIs, PPIs and H2RAs were independent risk factors for LGIB.

Increased risk of paclitaxel-induced peripheral neuropathy in patients using clopidogrel: a retrospective pilot study.

Paclitaxel-induced peripheral neuropathy (PIPN) is one of the serious adverse events associated with paclitaxel-based cancer treatments. A recent case study showed that the antiplatelet agent clopidogrel inhibits paclitaxel metabolism via cytochrome P450 (CYP) 2C8, resulting in severe PIPN. The aim of this study was to determine the impact of clopidogrel as a risk factor for the development of PIPN, using a retrospective cohort study. Data from paclitaxel-treated patients with or without clopidogrel and low-dose aspirin treatment were retrieved from medical charts. A total of 161 adult patients were included in this study: 135 were controls, 9 were clopidogrel-treated and 17 were aspirin-treated. The clopidogrel group had a greater proportion of males and a higher rate of comorbidities, such as diabetes mellitus and dyslipidemia, than the control group. However, patient characteristics were similar between the clopidogrel and aspirin groups. Severe PIPN was diagnosed in 3 (2.2%) and 2 (22.2%) patients in the control and clopidogrel groups, respectively (odds ratio: 12.0; p=0.031). No patients in the aspirin group presented with severe neuropathy. These pilot data suggest that concomitant treatment with clopidogrel leads to a greater risk of PIPN. The avoidance of concomitant clopidogrel use may be effective in reducing clopidogrel-associated PIPN.