Co-administration Of Proton Pump Inhibitors Research Articles

Electrospun zein/eudragit nanofibers based dual drug delivery system for the simultaneous delivery of aceclofenac and pantoprazole

Electrospun composite zein/eudragit nanofibers were developed with an aim to deliver two different classes of drugs simultaneously that would restrict/compensate the adverse effects of non-steroidal anti-inflammatory drugs (NSAIDs). Co-administration of proton pump inhibitors is beneficial for patients consuming NSAIDs for treating chronic ailments like arthritis. In this study, aceclofenac/pantoprazole loaded zein/eudragit S 100 nanofibers were developed using a single nozzle electrospinning process. The morphological analysis revealed the uniform and smooth surface of the drug loaded nanofibers. The physico-thermal characterization of nanofibers depicted the molecular integration of the drugs with the polymers and also confirmed that the drugs were evenly distributed in the nanofibers in an amorphous state. In vitro release studies ensure the efficiency of the developed fibers in sustaining the release of both the drugs up to 8h. In vivo animal experiments further confirmed that the co-administration of pantoprazole along with aceclofenac reduced the gastro-intestinal toxicity induced by NSAIDs. The histological evaluation revealed the preserved mucosal architecture of rat gastric tissue treated with drug loaded composite nanofibers. Thus, dual drug delivery system comprising polymers with different release characteristics has been successfully developed and further, oral delivery of aceclofenac with reduced side effects was achieved.

Multicenter Study of Voriconazole Pharmacokinetics and Therapeutic Drug Monitoring

Voriconazole is a first-line agent in the treatment of many invasive fungal infections and is known to display highly variable pharmacokinetics. Previous studies of voriconazole therapeutic drug monitoring (TDM) have suggested concentration monitoring to be clinically useful but have been limited by small patient samples at a single institution. This multicenter retrospective study aimed to investigate relationships between voriconazole concentration and clinical outcomes and adverse events and to assess clinical factors and drug interactions that may affect voriconazole concentration. Medical records were reviewed for patients who received voriconazole and had at least 1 concentration measured at seven hospitals in Australia. The study included 201 patients with 783 voriconazole trough concentrations. Voriconazole concentrations of <1.7 mg/liter were associated with a significantly greater incidence of treatment failure (19/74 patients [26%]) than concentrations of ≥1.7 mg/liter (6/89 patients [7%]) (P < 0.01). Neurotoxic adverse events (visual and auditory hallucinations) occurred more frequently at voriconazole concentrations of >5 mg/liter (10/31 patients [32%]) than at concentrations of ≤5 mg/liter (2/170 patients [1.2%]) (P < 0.01). Multiple regression analysis of voriconazole concentration identified associations between increasing patient weight, oral administration of voriconazole, and coadministration of phenytoin or rifampin and significantly reduced concentrations, and associations between increasing patient age and coadministration of proton pump inhibitors and increased concentrations. Coadministration of glucocorticoids was found to significantly reduce voriconazole concentrations, inferring a previously unreported drug interaction between glucocorticoids and voriconazole.

Evaluation of Potential Interactions between Mycophenolic Acid Derivatives and Proton Pump Inhibitors

To evaluate the incidence of gastrointestinal (GI) complications in solid organ transplant (SOT) recipients, impact of the complications on transplant outcomes, and the potential interactions between mycophenolic acid (MPA) derivatives and proton pump inhibitors (PPIs). An unrestricted literature search (1980-January 2012) was performed with MEDLINE and EMBASE using the following key words: drug-drug interaction, enteric-coated mycophenolic acid, GI complications, mycophenolate mofetil, solid organ transplant, and proton pump inhibitor, including individual agents within the class. Abstracts from scientific meetings were also evaluated. Additionally, reference citations from identified publications were reviewed. Relevant English-language, original research articles and review articles were evaluated if they focused on any of the topics identified in the search or included substantial content addressing GI complications in SOT recipients or drug interactions. GI complications are frequent among SOT recipients, with some studies showing prevalence rates as high as 70%. Transplant outcomes among renal transplant recipients are significantly impacted by GI complications, especially in patients requiring immunosuppressant dosage reductions or premature discontinuation. To this end, PPI use among patients receiving transplants is common. Recent data demonstrate that PPIs significantly reduce the overall exposure to MPA after oral administration of mycophenolate mofetil. Similar studies show this interaction does not exist between PPIs and enteric-coated mycophenolic acid (EC-MPA). Unfortunately, most of the available data evaluating this interaction are pharmacokinetic analyses that do not investigate the clinical impact of this interaction. A significant interaction exists between PPIs and mycophenolate mofetil secondary to reduced dissolution of mycophenolate mofetil in higher pH environments. EC-MPA is not absorbed in the stomach; therefore, low intragastric acidity does not impact EC-MPA and bioavailability is maintained with this formulation during PPI coadministration. The clinical impact of this interaction is unknown, yet one can theorize that reduced exposure to MPA in SOT recipients can increase the risk of allograft rejection and/or failure.

Reducing co-administration of clopidogrel and proton pump inhibitors in acute coronary syndromes

Recent concerns about clopidogrel and proton pump inhibitor (PPI) co-administration in patients following an acute coronary syndrome (ACS) led us to investigate our practice. Guidance recommends that omeprazole and esomeprazole should not be co-administered with clopidogrel as they can decrease its efficacy. Pantoprazole and lansoprazole are safer for use in these cases. Patients discharged between August 2008 and July 2009 with a diagnosis of ACS, on both clopidogrel and any PPI, were identified using the pharmacy database. Their notes were retrospectively reviewed, the indication for a PPI was checked and whether an appropriate one had been prescribed was assessed. As a result of our findings a simple algorithm was introduced to set out guidance on appropriate use and junior doctors were informed of the new procedure. We then performed another audit of patients discharged between August 2009 and February 2010 to ensure that the guidelines were being followed. During the first phase of the audit 43 out of 91 patients (47.5%) received a PPI with clopidogrel. Following our intervention, re-auditing confirmed that clopidogrel and PPI co-administration had decreased significantly to 27 out of 101 patients (26.7%) (p = 0.018). Through a simple intervention with an algorithm and education of junior doctors we have shown that significant improvement and adherence to guidance can be achieved.

029 Cardiovascular risk in clopidogrel-treated patients according to cytochrome P450 2C19*2 loss-of-function allele and proton pump inhibitor coadministration

029 Cardiovascular risk in clopidogrel-treated patients according to cytochrome P450 2C19*2 loss-of-function allele and proton pump inhibitor coadministration

Posaconazole a Prophylactic Therapy in Cancer Patients: Analysis and Pharmacokinetics

Intorduction: Posaconazole (PZ), an antifungal prophylactic therapy in hematologic cancer patients, was added to Al-Amal Hospital formulary in 2010. The objectives of this study are: 1. To identify the practice guidelines and pharmacokinetics information regarding PZ use in Qatar and worldwide. 2. To conduct a drug use evaluation (DUE) report at Al-Amal Hospital. Methods: Literature review was conducted to answer the first objective. A retrospective DUE report was conducted to include 10 randomly chosen hematologic cancer patients who used PZ during the year 2010. Patients profiles were reviewed and data were collected into a pre-prepared collection sheet. Results: PZ was approved for prophylaxis in hematologic cancer patients →13 years in USA, Canada, and Australia, →18 years in the European Union and &gt;15 years in Qatar. PZ has low bioavailability that can be enhanced by co-administration of high fat meals and by dividing the total daily dose. Data regarding PZ TDM is controversial. PZ undergoes several drug-drug interactions. For example, co-administration of proton pump inhibitors may result in PZ sub-therapeutic levels. Co-administration of vincristine may result in higher neurological toxicity, mainly gastrointestinal problems, due to the inhibitory potency of PZ on cytochrome P450 enzymes. A patient receiving vincristine based chemotherapy protocol concurrently with PZ developed seizure. Another patient developed mild breakthrough fungal infection while on PZ prophylactically. Conclusion: The PZ regulations in Qatar are similar to the worldwide recommendations. The PZ practice in Al-Amal hospital abides by the regulations. Possible serious PZ drug-drug interactions, seizures, in hematologic cancer patients should be highlighted and carefully monitored.

Letter by Hnid and Chtioui Regarding Article, “Clinical Events as a Function of Proton Pump Inhibitor Use, Clopidogrel Use, and Cytochrome P450 2C19 Genotype in a Large Nationwide Cohort of Acute Myocardial Infarction: Results From the French Registry of Acute ST-Elevation and Non–ST-Elevation Myocardial Infarction (FAST-MI) Registry”

To the Editor: We read with interest the article by Simon et al1 regarding their recent study, from which we understand that the coadministration of proton pump inhibitors (PPIs) and clopidogrel after percutaneous coronary intervention is safe. The P450 enzyme system is responsible for the metabolism of clopidogrel.2,3 Hepatic cytochrome P450 (CYP) isoenzymes convert clopidogrel to its active metabolites through 2-step oxidation pathways.2, 4 The second pathway induces the formation of the active metabolite of clopidogrel.2, 3 The most important isoforms of human cytochrome P450 responsible of the transformation of …

Co-Administration of Proton Pump Inhibitors and Clopidogrel: A Systematic Review on Laboratory and Clinical Endpoints

Co-Administration of Proton Pump Inhibitors and Clopidogrel: A Systematic Review on Laboratory and Clinical Endpoints

1. Historical Perspective on the Pros and Cons of Coadministration of Proton Pump Inhibitors with Thienopyridine Antiplatelet Drugs (Clopidogrel and Prasugrel)

Proton pump inhibitors (PPI) are frequently prescribed with thienopyridine antiplatelet drugs (clopidogrel and prasugrel) for the prevention of upper gastrointestinal mucosal damages. However, recent studies have casted doubt on this combination, because several retrospective cohort studies have suggested a possible detrimental drug interaction between these drugs, particularly in patients undergoing percutaneous coronary intervention and stenting. Lines of robust in vitro and in vivo evidence have shown that PPIs are potent inhibitors of CYP2C19 activity in human liver microsomes and that PPIs reduce the production of the active metabolite of clopidogrel, thus attenuating its antiplatelet activity in patients. In addition, it is known that genetic polymorphism of CYP2C19 is associated with loss of CYP2C19 enzyme activity and that drug interactions of PPI with CYP2C19 substrate drugs occur only in subjects with the extensive metabolizer phenotype of CYP2C19. Because Asians possess higher allelic frequencies of loss-of-function alleles of this CYP isoform than Caucasians, they may be less susceptible to the drug interactions between PPI and thienopyridines. In contrast to clopidogrel, metabolic activation of prasugrel is not affected by PPIs, because multiple CYP isoforms are involved. At present, no prospective randomized studies have been reported, which provide reliable risk-benefit data for the coadministration of PPI with thienopyridine antiplatelet drugs both in Caucasians and Asians.

Interaction between clopidogrel and proton-pump inhibitors and management strategies in patients with cardiovascular diseases

Dual antiplatelet therapy (DAPT) with clopidogrel and aspirin has been successful in reducing ischemic events in a wide range of patients with cardiovascular diseases. However, the anti-ischemic effects of DAPT may also be associated with gastrointestinal (GI) complications including ulceration and bleeding particularly in ‘high risk’ and elderly patients. Current guidelines recommend the use of proton-pump inhibitors (PPIs) to reduce the risk of GI bleeding in patients treated with DAPT. However, pharmacodynamic studies suggest an effect of PPIs on clopidogrel metabolism with a resultant reduction in platelet inhibitory effects. Similarly, several observational studies have demonstrated reduced clopidogrel benefit in patients who coadministered PPIs. Although recent US Food and Drug Administration and European Medicines Agency statements discourage PPI (particularly omeprazole) and clopidogrel coadministration, the 2009 AHA/ACC/SCAI PCI guidelines do not support a change in current practice in the absence of adequately powered prospective randomized clinical trial data. The data regarding pharmacologic and clinical interactions between PPI and clopidogrel therapies are herein examined and treatment strategies are provided.

Risk of recurrent myocardial infarction with the concomitant use of clopidogrel and proton pump inhibitors

The association between myocardial infarction (MI) and co-administration of proton pump inhibitors (PPIs) and clopidogrel remains controversial. To quantify the association between concomitant use of PPIs and clopidogrel and occurrence of recurrent MI. We conducted a case-control study within a cohort of acute MI patients in PHARMO Record Linkage System (1999-2008). The cases were patients readmitted for MI. PPI exposure was categorized as current (3-1 days before MI), past (30-3 days before MI), or no use (>30 days before MI). We used conditional logistic regression analyses. Among 23 655 patients hospitalized following MI, we identified 1247 patients readmitted for MI. Among clopidogrel users, current PPI use was associated with an increased risk of recurrent MI (OR: 1.62, 95% CI: 1.15-2.27) when compared with no PPI use, but not when compared with past PPI use (OR: 0.95, 95% CI: 0.38-2.41). Among clopidogrel non-users, current PPI use was associated with an increased risk of recurrent MI (OR: 1.38, 95% CI: 1.18-1.61) when compared with no PPI use. The apparent association between recurrent MI and use of PPIs with clopidogrel depends on the design, and is affected by confounding by indication. The association is not present when (un)measured confounding is addressed by design.

A Clinical Pharmacokinetic Drug-Drug Interaction Study of Arbaclofen Placarbil, a Novel Reflux Inhibitor, With Esomeprazole

Purpose: Arbaclofen placarbil (AP), a novel reflux inhibitor, is an actively transported prodrug of the R isomer of baclofen (RB). AP is currently under investigation as an adjunct to proton pump inhibitors (PPI) for the treatment of gastroesophageal reflux disease (GERD) in patients who remain symptomatic on PPIs. The purpose of this study was to assess the potential for pharmacokinetic (PK) drug-drug interaction between AP and esomeprazole. Methods: In this open-label, 2-treatment, 2-period, sequential design study, 15 healthy adult subjects were treated with sustained-release AP 60 mg qd for 5 days, followed by AP 60 mg + esomeprazole 40 mg qd for 5 days. There was a 3-day titration period and a 5-day tapering period for AP. Steady-state AP and RB concentrations were determined on days 8 and 13, using LC/MS/MS methods. PK parameters were estimated using noncompartmental analysis and compared for AP and AP + esomaprazole (days 8 and 13) using ANOVA. Results: Fifteen subjects completed the study. AP was well absorbed and rapidly converted to RB. Mean RB Css,max and AUCss,24 values were 144 ng/mL and 1480 ng*h/mL, respectively, for AP alone, and were 124 ng/mL and 1270 ng*h/mL, respectively, when AP was dosed with esomeprazole. Mean Css,max and AUCss,24 of RB were each decreased by approximately 14% when AP was coadministered with esomeprazole. Statistical analysis showed no significant treatment effect on the PK parameters at level α=0.05. The 90% confidence intervals of ratio of means included 1. Levels of the intact prodrug were low and transient for both treatments (Mean of % [AP AUClast to RB AUClast] of ≤ 10). There was no effect on AP exposure when AP was coadministered with esomeprazole. Both AP and AP+ esomaprazole treatments were generally safe and well tolerated. There were no clinically significant changes in laboratory values, vital signs, or ECG parameters. Conclusion: There was no clinically relevant or statistically significant drug-drug interaction when AP was administered with esomeprazole. The results of this study suggest that no AP dose adjustment is needed with coadministration of PPIs. Disclosure: All authors are employees of XenoPort, Inc. The study was funded by XenoPort, Inc.

Differential Effects of Omeprazole and Pantoprazole on the Pharmacodynamics and Pharmacokinetics of Clopidogrel in Healthy Subjects: Randomized, Placebo-Controlled, Crossover Comparison Studies

Four randomized, placebo-controlled, crossover studies were conducted among 282 healthy subjects to investigate whether an interaction exists between clopidogrel (300-mg loading dose/75-mg/day maintenance dose) and the proton-pump inhibitor (PPI) omeprazole (80 mg) when they are administered simultaneously (study 1); whether the interaction, if any, can be mitigated by administering clopidogrel and omeprazole 12 h apart (study 2) or by increasing clopidogrel to 600-mg loading/150-mg/day maintenance dosing (study 3); and whether the interaction applies equally to the PPI pantoprazole (80 mg) (study 4). Relative to levels after administration of clopidogrel alone in studies 1,2,3, and 4, coadministration of PPI decreased the AUC(0-24) of the clopidogrel active metabolite H4 by 40, 47, 41, and 14% (P ≤ 0.002), respectively; increased maximal platelet aggregation (MPA) induced by 5 micromol/l adenosine diphosphate (ADP) by 8.0, 5.6, 8.1, and 4.3% (P ≤ 0.014), respectively; and increased the vasodilator-stimulated phosphoprotein phosphorylation-platelet reactivity index (VASP-PRI) by 20.7, 27.1, 19.0 (P < 0.0001), and 3.9% (P = 0.3319), respectively. The results suggest that a metabolic drug-drug interaction exists between clopidogrel and omeprazole but not between clopidogrel and pantoprazole.

The interaction between clopidogrel and proton pump inhibitors (PPI): is there any clinical relevance?

The potential interaction between clopidogrel and proton pump inhibitors (PPI) in patients with acute coronary syndrome (ACS) raises serious concerns for cardiologists. However, in patients on this combination of drugs, there is no conclusive evidence of an increase in adverse cardiovascular events. From pharmacologic and pharmacodynamic perspectives, there is a real interaction between clopidogrel and PPIs because of the competitive inhibition of CYP2C19 isoenzyme which is required for biotransformation of clopidogrel to its active metabolite. The consequent decrease in the availability of this active metabolite leads to attenuation of antiplatelet efficacy of clopidogrel. In several observational trials, it was shown that decreased antiplatelet effect of clopidogrel due to PPIs may translate into poor cardiovascular outcomes. However, an incomplete RCT (COGENT) and a post hoc analysis of two large trials (PRINCIPLE-TIMI 44 and TRITON-TIMI 38 trial) showed no significant adverse cardiovascular events with this combination. Caution is however needed in patients who are hypometabolizers of clopidogrel putting them at a higher risk of adverse coronary events. Since 3% of patients are likely to be hypometabolizers of clopidogrel, routine combination of clopidogrel and PPIs should be avoided. There is a heightened awareness of this interaction following multiple advisory warnings. At the same time, one should not withhold PPIs in patients who are at a high risk of developing gastrointestinal (GI) bleeding. In these patients, selected choices of PPI such as pantoprazole may be helpful and for low risk patients, serious consideration should be given to H2 receptor antagonists or antacids. Therefore, while not compromising the cardioprotective effect of antiplatelet agents, the gastroprotective benefit of PPI should be strongly considered in patients who need both. Health care providers should remain alert to more outcome data. Future researchers will need to demonstrate the safety of coadministration of PPIs and clopidogrel and trials should be powered to detect major adverse cardiovascular events and facilitate risk stratification based on genetic polymorphism.

Drug-Drug Interaction Profiles of Proton Pump Inhibitors

Proton pump inhibitors (PPIs) are widely prescribed for the treatment of gastric acid-related disorders and the eradication of Helicobacter pylori. In addition, they are routinely prescribed for the prevention of gastrointestinal bleeding in patients receiving a dual antiplatelet therapy consisting of clopidogrel and aspirin (acetylsalicylic acid) after myocardial infarction or percutaneous coronary intervention and stenting. Because PPIs are given to these patients for long periods, there is a concern about the potential for clinically significant drug-drug interactions (DDIs) with concomitantly administered medications. Because PPIs give rise to profound and long-lasting elevation of intragastric pH, it is not surprising that they interfere with the absorption of concurrent medications. Drug solubility may be substantially reduced at neutral pH compared with acidic conditions. In this context, PPIs have been shown to reduce the bioavailability of many clinically relevant drugs (e.g. ketoconazole, atazanavir) by 50% or more compared with the control values. Soon after the introduction of omeprazole (a prototype PPI) into the market, it was reported that omeprazole was associated with 30% and 10% reductions in systemic clearance of diazepam and phenytoin, respectively. In vitro studies demonstrating the inhibitory effects of omeprazole on the metabolism of these drugs with human liver microsomes gave a mechanistic explanation for the DDIs. Numerous subsequent studies have been performed to investigate the DDI potential of PPIs associated with the metabolic inhibition of cytochrome P450 (CYP) enzyme activities; however, most such attempts have failed to find clinically relevant results. Nevertheless, recent large-scale clinical trials have raised concerns about possible DDIs between PPIs and an antiplatelet drug, clopidogrel. It has been suggested that coadministration of PPIs with a dual antiplatelet therapy consisting of clopidogrel and aspirin may attenuate the anti-aggregation effects of those medications and augment the risk of cardiovascular ischaemic events. There is a possibility that PPIs may elicit detrimental effects by inhibiting CYP2C19-dominated metabolism of clopidogrel to its active metabolite. Further studies are urgently required to clarify the mechanism of this DDI and to explore new aspects of the DDI potential of PPIs.

Cardiovascular Risk in Clopidogrel-Treated Patients According to Cytochrome P450 2C19*2 Loss-of-Function Allele or Proton Pump Inhibitor Coadministration: A Systematic Meta-Analysis

The aim of this study was to assess the association between the loss-of-function cytochrome P450 2C19 (CYP2C19)*2 variant (10 studies, 11,959 patients) or the use of proton pump inhibitors (PPIs) (13 studies, 48,674 patients) and ischemic outcomes (major adverse cardiovascular events [MACE]) in patients treated with clopidogrel.In clopidogrel-treated patients, increased cardiovascular risk has been identified with the loss-of-function CYP2C19*2 allele or the use of PPIs, some of them CYP2C19 inhibitors. To further estimate the effect of a reduction in activity of this enzyme, the authors performed a meta-analysis of the studies available.The meta-analysis was performed on 23 studies using the odds ratio (OR) as the parameter of efficacy, with a fixed-effect model. The end points were MACE, mortality, or stent thrombosis.Of the 11,959 patients, carriers of the loss-of-function CYP2C19*2 allele (28% [n = 3,418]) displayed a 30% increase in the risk for MACE compared with noncarriers (9.7% vs. 7.8%; OR: 1.29; 95% confidence interval [CI]: 1.12 to 1.49; p < 0.001). This single gene variant (CYP2C19*2) was also associated with an excess of mortality (1.8% vs. 1.0%; OR: 1.79; 95% CI: 1.10 to 2.91; p = 0.019; n = 6,225) and of stent thrombosis (2.9% vs. 0.9%; OR: 3.45; 95% CI: 2.14 to 5.57; p < 0.001; n = 4,905). This increased risk was apparent in both heterozygotes and homozygotes and was independent of the baseline cardiovascular risk. PPI users (42% [n = 19,614]) displayed increased risk for MACE (21.8% vs. 16.7%; OR: 1.41; 95% CI: 1.34 to 1.48; p < 0.001) and mortality (12.7% vs. 7.4%; OR: 1.18; 95% CI: 1.07 to 1.30; p < 0.001; n = 23,977) compared with nonusers. The impact of PPI use was, however, significantly influenced by baseline cardiovascular risk, being significant only in high-risk patients.In this global meta-analysis, reduced CYP2C19 function appears to expose clopidogrel-treated patients to excess cardiovascular risk and mortality. Conflicting results among studies may be explained by differences in types and/or levels of risk of patients.

041 Clopidogrel and proton pump inhibitors: can near patient testing help to inform dual prescription?

Clopidogrel is relatively contraindicated in patients at risk of gastrointestinal bleeding. To reduce this risk, proton-pump inhibitors (PPI) which are often co-prescribed. Many PPIs undergo hepatic metabolism by the cytochrome (CYP) P450 isoenzymes, thus CYP P450-metabolised drugs, including clopidogrel become vulnerable to drug-drug interaction. Gilard et al first highlighted the negative impact of PPIs, on the pharmacodynamic response to clopidogrel in the randomised, double-blind Omeprazole CLopidogrel Aspirin (OCLA) trial. A randomised trial of omeprazole and pantoprazole conducted by Cuisset et al also demonstrated that after 1 month, patients receiving pantoprazole had significantly better platelet response to clopidogrel than those receiving omeprazole. Population-based studies have suggested that concomitant use of PPI with clopidogrel results in significantly increased risk of adverse outcomes. Anxieties brought on by such studies have been largely allayed by the recently presented results of the COGENT trial. This major randomised controlled trial, comparing clopidogrel with omeprazole vs clopidogrel alone demonstrated no difference in the risk of cardiovascular events between groups. We assessed the impact of PPI co-prescription on clopidogrel response using a verified near patient test, prospectively in 269 patients (mean age 63±11, 85 female) admitted with high risk ACS (characterised by electrocardiographic changes of ischaemia and/or raised troponin I). Loading and maintenance of clopidogrel was as per contemporary UK practice. Eighty-eight patients were prescribed a PPI concomitantly as in-patients. Platelet response to clopidogrel in whole blood samples, taken at the time of angiography, was assessed using a VerifyNow analyser (Accumetrics, California, US). Of the 269 patients recruited, 151 (56%) proceeded to PCI, 40 (15%) underwent coronary artery bypass grafting (CABG), 78 (29%) were treated medically. The clinical endpoint was adverse clinical events (ACE) at 18 months (death, MI, repeat revascularisation, CABG, stroke or unplanned cardiovascular hospitalisation). Co-administration of PPI and clopidogrel was associated with significantly reduced clopidogrel P2Y12 activity (p=0.022) (Abstract 41 Figure 1a) but not clinical outcome (ACE, p=0.123, Abstract 41 Figure 1b). Groups were well matched for age, gender, body mass index, current smoking, presence of diabetes and hyperlipidaemia. More patients in the PPI group had suffered a previous MI (36% vs 20%, p=0.007) and had received previous PCI treatment (20% vs 8%, p=0.005). As near patient tests of clopidogrel activity find their position in the care of patients with ischaemic heart disease, physicians may wish to use this technology to test patients at high risk of stent thrombosis who are also taking medications which pose a risk of inhibiting platelet clopidogrel response.

Effect of comedication with proton pump inhibitors (PPIs) on post-interventional residual platelet aggregation in patients undergoing coronary stenting treated by dual antiplatelet therapy

Introduction Currently, there is an intense debate about whether comedication with proton pump inhibitors (PPIs) weakens the antiplatelet effect of clopidogrel in patients undergoing coronary stent implantation. Competing mechanisms on the hepatic cytochrome 2C19 level are proposed. The aim of this study was to assess the impact of PPI treatment on clopidogrel response by measuring the ex vivo platelet aggregation in patients with coronary intervention. Methods 1425 consecutive patients with symptomatic coronary artery disease undergoing percutaneous coronary intervention were enrolled in this single centre study. PPI comedication was defined as PPI intake ≥ 1 week prior to a 600 mg clopidogrel loading dose. PPI treatment was based on physician preference. Residual platelet aggregation (RPA) was measured by optical aggregometry. To correct for potential selection bias, propensity score matching was applied. Results RPA was significantly higher in PPI-treated patients compared with non-PPI-users (final aggregation 34.0% vs. 29.8%, p < 0.001). Low responder defined as RPA in the upper tertile were more often found in PPI-users. After adjustment for relevant confounders, PPI treatment was independently associated with higher RPA-levels. Discussion We demonstrated that peri-procedural co-administration of PPIs significantly decreases the effect of clopidogrel on RPA. To assess if clopidogrel-PPI interaction results in a higher susceptibility for cardiovascular events remains subject to further investigations.

Co‐administration of proton pump inhibitors delays elimination of plasma methotrexate in high‐dose methotrexate therapy

To assess whether or not co-administration of proton pump inhibitors (PPIs) is a risk factor for delayed elimination of plasma methotrexate (MTX) in high-dose MTX (HDMTX) therapy for malignant diseases. To assess the effects of PPI co-administration on elimination of plasma MTX, we examined plasma MTX concentration data on 171 cycles of HDMTX therapy performed in 74 patients. We performed multiple logistic regression analysis to evaluate PPI co-administration as a risk factor. Inhibitory potencies of omeprazole, lansoprazole, rabeprazole and pantoprazole on MTX transport via breast cancer resistance protein (BCRP, ABCG2) were also investigated in an in vitro study using membrane vesicles expressing human BCRP. We identified co-administration of PPIs as a risk factor for delayed elimination (odds ratio 2.65, 95% confidence interval 1.03, 6.82) as well as renal and liver dysfunction. All four PPIs inhibited BCRP-mediated transport of MTX, with half-maximal inhibitory concentrations of 5.5-17.6 microM--considerably higher than the unbound plasma concentrations of the PPIs. Our results support previous findings suggesting that PPI co-administration is associated with delayed elimination of plasma MTX in patients with HDMTX therapy. This drug interaction, however, cannot be explained solely by the inhibitory effects of PPIs on BCRP-mediated MTX transport.

Incidence of serious upper gastrointestinal bleeding in patients taking non-steroidal anti-inflammatory drugs in Japan.

Upper gastrointestinal bleeding is a major adverse event of non-steroidal anti-inflammatory drugs (NSAIDs), and co-administration of proton pump inhibitors and H2 receptor antagonists has been established as a means of preventing such an effect. However, the incidence of bleeding associated with NSAID-induced ulcers under conditions where such strong anti-acid agents are used for prevention has yet to be clarified. We aimed to determine the annual incidence of serious upper gastrointestinal ulcer bleeding among Japanese patients in whom NSAIDs were used in our hospital. Before commencing the study, we recommended to all the physicians in our hospital the best method for caring for NSAID users, focusing on the concomitant use of proton pump inhibitors or H2 receptor antagonists. We conducted a cohort study involving 17,270 patients for whom NSAIDs had been newly prescribed. Bleeding from gastric ulcers was observed in 8 of the 17,270 patients using NSAIDs (0.05%). The pooled incidence rate for bleeding was calculated as 2.65 (95% confidence interval, 2.56-2.74) and 1.29 (1.27-1.31) per 1,000 patient years for low-dose aspirin and non-aspirin NSAID users, respectively. None of the bleeding ulcer patients required blood transfusion or were in serious condition. In conclusion, gastric ulcer bleeding occurred in low-dose aspirin or non-aspirin NSAID users, but its incidence was low and outcomes were not serious when adequate preventive measures were taken.