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Drug Safety Feb 2012There is considerable debate regarding the negative impact of concomitant proton pump inhibitor (PPI) therapy on the antiplatelet efficacy of clopidogrel. (Review)
Review
BACKGROUND
There is considerable debate regarding the negative impact of concomitant proton pump inhibitor (PPI) therapy on the antiplatelet efficacy of clopidogrel.
AIM
The aim of this study was to perform a systematic review of studies that have evaluated the platelet function of patients receiving clopidogrel alone compared with those receiving both clopidogrel and PPIs.
METHODS
We searched MEDLINE, EMBASE and the Cochrane Controlled Trials Register in February 2011 for randomized and non-randomized studies that reported platelet function results in patients taking clopidogrel, with or without PPIs.
RESULTS
Our review included 19 studies (13 trials and 6 observational studies) involving 4693 patients. There was considerable heterogeneity in the study designs, patient characteristics, laboratory tests of platelet function, and drug exposure (dose and duration of PPI and clopidogrel). There was some evidence against omeprazole, with five of nine studies demonstrating a significant interaction with clopidogrel. The available platelet function data on esomeprazole (six studies) or pantoprazole (six studies) did not demonstrate a significant interaction. Of the six studies that statistically analysed platelet function data with omeprazole compared with pantoprazole, three showed a significantly greater interaction between omeprazole and clopidogrel, whereas three studies with limited sample sizes were unable to find a significant difference in the effects of omeprazole and pantoprazole.
CONCLUSION
Platelet function studies do not demonstrate a clear or consistent interaction between clopidogrel and PPIs. These studies are difficult to interpret given the lack of information on drug exposure (dose and duration), variation in laboratory methodology and lack of genetic information. Consequently, platelet function data are of uncertain clinical relevance in determining the risk of an adverse cardiovascular interaction between PPIs and clopidogrel. Clinicians should continue to clinically assess the gastrointestinal risk of the patients and make their prescribing decision for PPIs based on any anticipated benefits in reducing risk of peptic ulcers and gastrointestinal haemorrhage.
Topics: Blood Platelets; Clopidogrel; Drug Interactions; Esomeprazole; Humans; Omeprazole; Platelet Aggregation; Platelet Aggregation Inhibitors; Proton Pump Inhibitors; Randomized Controlled Trials as Topic; Ticlopidine
PubMed: 22204719
DOI: 10.2165/11594900-000000000-00000 -
PharmacoEconomics Jun 2011Intravenous esomeprazole (Nexium®) is approved in Europe for the prevention of rebleeding following therapeutic endoscopy for acute bleeding gastric or duodenal ulcers.... (Review)
Review
Intravenous esomeprazole (Nexium®) is approved in Europe for the prevention of rebleeding following therapeutic endoscopy for acute bleeding gastric or duodenal ulcers. In a pivotal clinical trial, patients with peptic ulcer bleeding and high-risk stigmata who received intravenous esomeprazole for 72 hours following endoscopic haemostatic therapy were significantly less likely than those receiving intravenous placebo to experience recurrent peptic ulcer bleeding at days 3, 7 and 30. In addition, the need for repeat endoscopic haemostatic therapy, the total amount of blood transfused and the number of additional hospital days required because of rebleeding were significantly lower in intravenous esomeprazole recipients than in intravenous placebo recipients. All patients received oral esomeprazole for 27 days following intravenous study drug administration. Intravenous esomeprazole was generally well tolerated in the pivotal trial, with infusion-site reactions being among the most commonly reported adverse events. Two pharmacoeconomic analyses conducted from a healthcare payer perspective used decision-tree models with 30-day time horizons to examine the cost effectiveness and cost utility of intravenous esomeprazole in patients with bleeding peptic ulcers who had undergone endoscopic haemostatic therapy. With regard to the incremental cost per bleed averted, intravenous esomeprazole was predicted to be dominant in Spain and cost effective in Sweden and the US compared with no intravenous esomeprazole. Efficacy results and resource utilization data from the pivotal clinical trial were inputted into this model, and the results of the analysis were generally robust to plausible variations in key variables. In the cost-utility analysis, which was conducted in the UK and is available as an abstract and poster, esomeprazole was considered to be the most cost-effective treatment alternative, compared with omeprazole or pantoprazole. For this analysis, clinical outcomes data were obtained from a systematic review and mixed treatment comparison (given the absence of head-to-head trial data), and utility values were proxied from the literature. In conclusion, intravenous esomeprazole prevents peptic ulcer rebleeding in patients who have undergone endoscopic haemostatic therapy. Pharmacoeconomic analyses support the use of intravenous esomeprazole following endoscopic haemostatic therapy in patients with peptic ulcer bleeding and high-risk stigmata.
Topics: Anti-Ulcer Agents; Esomeprazole; Humans; Injections, Intravenous; Omeprazole; Peptic Ulcer Hemorrhage; Secondary Prevention
PubMed: 21568358
DOI: 10.2165/11207430-000000000-00000 -
Pediatrics May 2011Use of proton-pump inhibitors (PPIs) for the treatment of gastroesophageal reflux disease (GERD) in children has increased enormously. However, effectiveness and safety... (Review)
Review
INTRODUCTION
Use of proton-pump inhibitors (PPIs) for the treatment of gastroesophageal reflux disease (GERD) in children has increased enormously. However, effectiveness and safety of PPIs for pediatric GERD are under debate.
OBJECTIVES
We performed a systematic review to determine effectiveness and safety of PPIs in children with GERD.
METHODS
We searched PubMed, Embase, and the Cochrane Database of Systematic Reviews for randomized controlled trials and crossover studies investigating efficacy and safety of PPIs in children aged 0 to 18 years with GERD for reduction in GERD symptoms, gastric pH, histologic aberrations, and reported adverse events.
RESULTS
Twelve studies were included with data from children aged 0-17 years. For infants, PPIs were more effective in 1 study (compared with hydrolyzed formula), not effective in 2 studies, and equally effective in 2 studies (compared with placebo) for the reduction of GERD symptoms. For children and adolescents, PPIs were equally effective (compared with alginates, ranitidine, or a different PPI dosage). For gastric acidity, in infants and children PPIs were more effective (compared with placebo, alginates, or ranitidine) in 4 studies. For reducing histologic aberrations, PPIs showed no difference (compared with ranitidine or alginates) in 3 studies. Six studies reported no differences in treatment-related adverse events (compared with placebo or a different PPI dosage).
CONCLUSIONS
PPIs are not effective in reducing GERD symptoms in infants. Placebo-controlled trials in older children are lacking. Although PPIs seem to be well tolerated during short-term use, evidence supporting the safety of PPIs is lacking.
Topics: 2-Pyridinylmethylsulfinylbenzimidazoles; Adolescent; Age Factors; Child; Child, Preschool; Cross-Over Studies; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Gastroesophageal Reflux; Humans; Incidence; Infant; Lansoprazole; Male; Netherlands; Omeprazole; Pantoprazole; Prognosis; Proton Pump Inhibitors; Randomized Controlled Trials as Topic; Risk Assessment; Treatment Outcome
PubMed: 21464183
DOI: 10.1542/peds.2010-2719 -
Alimentary Pharmacology & Therapeutics Sep 2009No randomized controlled trial (RCT) has compared all European-licensed standard- and double-dose PPIs for the healing of severe erosive oesophagitis. (Comparative Study)
Comparative Study Review
Systematic review: standard- and double-dose proton pump inhibitors for the healing of severe erosive oesophagitis -- a mixed treatment comparison of randomized controlled trials.
BACKGROUND
No randomized controlled trial (RCT) has compared all European-licensed standard- and double-dose PPIs for the healing of severe erosive oesophagitis.
AIM
To compare the effectiveness of licensed doses of PPIs for healing severe erosive oesophagitis (i.e. esomeprazole 40 mg, lansoprazole 30 mg, omeprazole 20 mg and 40 mg, pantoprazole 40 mg and rabeprazole 20 mg).
METHODS
Systematic review of CENTRAL, EMBASE and MEDLINE for RCTs in patients with erosive oesophagitis (completed October 2008). Endoscopically verified healing rates at 4 and 8 weeks were extracted and re-calculated if not analysed by intention-to-treat. A mixed treatment comparison was used to combine direct treatment comparisons with indirect trial evidence while maintaining randomization. Odds ratios (OR) are reported compared to omeprazole 20 mg.
RESULTS
A total of 3021 papers were identified in the literature search; 12 were of sufficient quality to be included in the analysis. Insufficient data were available to included rabeprazole. Esomeprazole 40 mg was found to provide significantly higher healing rates at 4 weeks [OR 1.84, 95% Credible Interval (95% CrI): 1.50 to 2.22] and 8 weeks (OR 1.91, 95% CrI: 1.13 to 2.88). No other PPI investigated had significantly higher healing rates than omeprazole 20 mg.
CONCLUSION
Esomeprazole 40 mg consistently demonstrates higher healing rates compared with licensed standard- and double-dose PPIs.
Topics: 2-Pyridinylmethylsulfinylbenzimidazoles; Anti-Ulcer Agents; Dose-Response Relationship, Drug; Esomeprazole; Esophagitis; Humans; Lansoprazole; Omeprazole; Proton Pump Inhibitors; Rabeprazole; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 19558609
DOI: 10.1111/j.1365-2036.2009.04077.x -
Canadian Journal of Gastroenterology =... Sep 2008Proton pump inhibitors (PPIs) have become the mainstay of treatment for and prevention of many serious gastrointestinal diseases. Laboratory and clinical evidence... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Proton pump inhibitors (PPIs) have become the mainstay of treatment for and prevention of many serious gastrointestinal diseases. Laboratory and clinical evidence suggests that the increase in gastric pH caused by PPIs may be linked to increased bacterial colonization of the stomach and may predispose patients to an increased risk for respiratory infections.
OBJECTIVE
To examine the association between PPI treatment and respiratory infections.
METHODS
A literature search was conducted using PubMed, MEDLINE and Cochrane databases of randomized, placebo-controlled trials evaluating the efficacy of PPIs. Studies that listed and quantified the specific adverse events of 'respiratory infection' or 'upper respiratory infection' (or equivalent), and compared their rates between PPIs and placebo were included. The chi(2) analysis was used to calculate the significance of association in individual studies and a meta-analysis of the selected studies was performed.
RESULTS
Of 7457 studies initially identified and 70 relevant randomized, controlled trials (RCTs) selected, seven studies met the inclusion criteria. A total of 16 comparisons for chi(2) analysis were possible given the multiple dosage arms used in several studies. PPIs included in the studies were esomeprazole, rabeprazole, pantoprazole and omeprazole. More than one-half of the studies showed a trend toward an association between PPI use and respiratory infections, although the majority of the studies failed to show a significant correlation. A single study using high-dose esomeprazole (40 mg) showed a significant association -4.3% rate of respiratory infections in the active group compared with 0% in the placebo group (P<0.05). Meta-analysis showed a trend toward an association between PPIs and respiratory infections, although it failed to reach significance (OR 1.42, 95% CI 0.86 to 2.35; P=0.17).
CONCLUSION
Although a trend was evident in both a chi(2) analysis of individual studies and a meta-analysis, the present review and meta-analysis failed to show a conclusive association between PPIs and respiratory infections. Very few RCTs actively sought out respiratory infections, which excluded the majority of RCTs identified. A well-structured, placebo-controlled prospective study would be needed to determine whether a true association between PPIs and respiratory infections exists.
Topics: Clinical Trials as Topic; Community-Acquired Infections; Humans; Proton Pump Inhibitors; Respiratory Tract Infections
PubMed: 18818790
DOI: 10.1155/2008/821385 -
Alimentary Pharmacology & Therapeutics Oct 2008The evidence on whether high-dose proton pump inhibitors (PPIs) increase cure rates of Helicobacter pylori treatment has not been previously assessed. (Comparative Study)
Comparative Study Meta-Analysis
BACKGROUND
The evidence on whether high-dose proton pump inhibitors (PPIs) increase cure rates of Helicobacter pylori treatment has not been previously assessed.
AIM
To evaluate the evidence on the usefulness of high-dose PPI in standard triple therapy by performing a systematic review and a meta-analysis.
METHODS
A systematic search was performed in multiple databases and in the abstracts submitted to the Digestive Diseases Week, the European Helicobacter Study Group congress and the United European Gastroenterology Week. Randomized trials comparing a standard dose of a PPI with high-dose PPI both twice a day in triple therapy combining a PPI plus clarithromycin and either amoxicillin or metronidazole were selected. Relative risk (RR) and 95% confidence intervals (95% CIs) for all comparisons were calculated using Review Manager.
RESULTS
Six studies fulfilled the inclusion criteria. All used triple therapy for 7 days. A mean intention-to-treat cure rate of 82% was achieved with high-dose PPI and one of 74% with standard dose (RR: 1.09; 95% CI: 1.01-1.17). Subgroup analysis showed that the maximum increase was observed when the PPI compared were omeprazole 20 mg or pantoprazole 40 mg vs. esomeprazole 40 mg.
CONCLUSION
High-dose PPI seems more effective than standard-dose for curing H. pylori infection in 7-day triple therapy.
Topics: 2-Pyridinylmethylsulfinylbenzimidazoles; Drug Administration Schedule; Esomeprazole; Helicobacter Infections; Helicobacter pylori; Humans; Omeprazole; Pantoprazole; Proton Pump Inhibitors
PubMed: 18644011
DOI: 10.1111/j.1365-2036.2008.03807.x -
Alimentary Pharmacology & Therapeutics Sep 2006No randomized controlled trial has compared all the licensed standard dose proton pump inhibitors in the healing of reflux oesophagitis. (Comparative Study)
Comparative Study Meta-Analysis Review
BACKGROUND
No randomized controlled trial has compared all the licensed standard dose proton pump inhibitors in the healing of reflux oesophagitis.
AIM
To compare the effectiveness of esomeprazole with licensed standard dose proton pump inhibitors for healing of reflux oesophagitis (i.e. lansoprazole 30 mg, omeprazole 20 mg, pantoprazole 40 mg and rabeprazole 20 mg).
METHODS
Systematic review of CENTRAL, BIOSIS, EMBASE and MEDLINE for randomized controlled trials in patients with reflux oesophagitis. Searching was completed in February 2005. Data on endoscopic healing rates at 4 and 8 weeks were extracted and re-analysed if not analysed by intention-to-treat. Meta-analysis was conducted using a fixed effects model.
RESULTS
Of 133 papers identified in the literature search, six were of sufficient quality to be included in the analysis. No studies were identified comparing rabeprazole with esomeprazole. A meta-analysis of healing rates of esomeprazole 40 mg compared with standard dose proton pump inhibitors gave the following results: at 4 weeks [relative risk (RR) 0.92; 95% CI: 0.90, 0.94; P < 0.00001], and 8 weeks (RR 0.95; 95% CI: 0.94, 0.97; P < 0.00001). Publication bias did not have a significant impact on the results. The results were robust to changes in the inclusion/exclusion criteria and using a random effects model.
CONCLUSION
Esomeprazole consistently demonstrates higher healing rates when compared with standard dose proton pump inhibitors.
Topics: 2-Pyridinylmethylsulfinylbenzimidazoles; Clinical Trials as Topic; Enzyme Inhibitors; Esomeprazole; Esophagitis, Peptic; Humans; Lansoprazole; Omeprazole; Pantoprazole; Proton Pump Inhibitors; Rabeprazole; Treatment Outcome
PubMed: 16918878
DOI: 10.1111/j.1365-2036.2006.03074.x -
European Journal of Gastroenterology &... Jan 2004To perform a systematic review on the efficacy of pantoprazole based therapies in Helicobacter pylori eradication, and to conduct a meta-analysis comparing the efficacy... (Meta-Analysis)
Meta-Analysis Review
AIM
To perform a systematic review on the efficacy of pantoprazole based therapies in Helicobacter pylori eradication, and to conduct a meta-analysis comparing the efficacy of pantoprazole and other proton pump inhibitors (PPIs) when co-prescribed with antibiotics.
METHODS
Studies evaluating pantoprazole combined with antibiotics were considered. Only randomized clinical trials comparing pantoprazole and other PPIs when co-prescribed with antibiotics, and differing only in the PPI (pantoprazole vs other), were eligible for inclusion in the meta-analysis. Bibliographical searches in several electronic databases, and manual search of abstracts from congresses, were conducted. The percentage (weighted mean) of patients with eradication success was calculated. Meta-analysis was performed combining the odds ratios (ORs) of the individual studies in a global OR.
RESULTS
The mean eradication rate with pantoprazole plus clarithromycin for 14 days was 60%. Cure rates with 7 day pantoprazole based triple regimens were higher: pantoprazole, amoxicillin and clarithromycin (78%); pantoprazole, clarithromycin and nitroimidazole (84%); and pantoprazole, amoxicillin and nitroimidazole (74%). Twelve studies comparing pantoprazole and other PPIs were selected for the meta-analysis, including 534 and 603 patients, respectively. The mean eradication rate for H. pylori using pantoprazole plus antibiotics was 83%, and 81% when other PPIs were used (OR = 1; 95% confidence interval (CI) from 0.61 to 1.64). When sub-analysis was performed, including only studies comparing pantoprazole with omeprazole, or pantoprazole with lansoprazole, differences were also statistically non-significant. The meta-analysis of the six studies prescribing equivalent doses of all PPIs demonstrated similar results with pantoprazole and with other PPIs (OR = 1.07; 95% CI from 0.71 to 1.62), the results being statistically homogeneous.
CONCLUSIONS
Pantoprazole achieves similar cure rates to those of omeprazole and lansoprazole when co-prescribed with antibiotics for the eradication of H. pylori infection.
Topics: 2-Pyridinylmethylsulfinylbenzimidazoles; Anti-Infective Agents; Benzimidazoles; Drug Therapy, Combination; Enzyme Inhibitors; Helicobacter Infections; Helicobacter pylori; Humans; Omeprazole; Pantoprazole; Proton Pump Inhibitors; Randomized Controlled Trials as Topic; Sulfoxides
PubMed: 15095858
DOI: 10.1097/00042737-200401000-00014 -
Pharmacotherapy Apr 2003Cytochrome P450 (CYP) 2C19 mediates the major metabolic transformations of the proton pump inhibitors (PPIs) omeprazole, pantoprazole, lansoprazole, esomeprazole, and... (Review)
Review
Cytochrome P450 (CYP) 2C19 mediates the major metabolic transformations of the proton pump inhibitors (PPIs) omeprazole, pantoprazole, lansoprazole, esomeprazole, and rabeprazole. Genetic polymorphism of CYP2C19 can lead to significant phenotypic variation in the activity of this isoenzyme and thus in the metabolism of PPIs. We systematically reviewed the pharmacogenetic studies of PPIs with respect to the effects of CYP2C19 polymorphism on the clinical outcomes of PPI therapy. We searched MEDLINE (January 1966-August 2002) and EMBASE (January 1988-August 2002) for English-language articles on the pharmacogenetics of PPIs; the search was supplemented by a bibliographic review of all relevant articles. Seventeen pertinent citations were identified, and the quality (level) of evidence for each was categorized according to the rating scale of the United States Preventive Services Task Force. We found that the relationship between CYP2C19 genetic polymorphism and clinical outcomes after PPI therapy has not yet been clearly delineated. Virtually all pharmacogenetic studies of PPIs have been performed in Japanese men; thus, the clinical relevance of CYP2C19 genetic polymorphism in non-Asian patients and women is unknown. Differences among dual- and triple-therapy drug regimens make it difficult to compare H. pylori eradication studies and assess their applicability to current practice patterns. Drug adherence, a pivotal factor in the success of eradication therapy, was addressed in only four trials. Future directions for research include performing more studies with larger sample sizes, particularly in non-Asian populations and women; measuring plasma PPI concentrations to directly correlate H. pylori infection and ulcer cure rates with plasma drug availability; expanding the study population to patients with gastroesophageal reflux disease; and exploring the influence of CYP3A4 in the success or failure of PPI therapy. Although CYP2C19 genotyping is currently only a research instrument, it may be a valuable clinical tool in select patients to ensure optimal PPI therapy.
Topics: Aryl Hydrocarbon Hydroxylases; Clinical Trials as Topic; Cytochrome P-450 CYP2C19; H(+)-K(+)-Exchanging ATPase; Humans; Mixed Function Oxygenases; Pharmacogenetics; Polymorphism, Genetic; Proton Pump Inhibitors; Proton Pumps
PubMed: 12680476
DOI: 10.1592/phco.23.4.460.32128 -
Alimentary Pharmacology & Therapeutics Nov 2001Esomeprazole is a new proton pump inhibitor, which has been compared to omeprazole for the treatment of reflux oesophagitis in clinical trials. (Comparative Study)
Comparative Study Meta-Analysis
BACKGROUND
Esomeprazole is a new proton pump inhibitor, which has been compared to omeprazole for the treatment of reflux oesophagitis in clinical trials.
AIM
To compare the effectiveness of esomeprazole with the recommended dose of proton pump inhibitors in the healing of reflux oesophagitis, using omeprazole as a common comparator.
METHODS
Systematic review of randomized controlled trials. Extraction and re-analysis of data to provide 'intention-to-treat' results. Meta-analysis using a Fixed Effects model.
RESULTS
A meta-analysis of healing rates of esomeprazole 40 mg compared to omeprazole 20 mg gave the following results: at 4 weeks (relative risk 1.14; 95% CI: 1.10, 1.18) and 8 weeks (RR 1.08; 95%CI: 1.05, 1.10). Other proton pump inhibitors compared to omeprazole 20 mg are as follows: lansoprazole 30 mg at 4 weeks (RR 1.02; 95%CI: 0.97, 1.08) and 8 weeks (RR 1.01; 95%CI: 0.97, 1.06); pantoprazole 40 mg at 4 weeks (RR 0.99; 95%CI: 0.91, 1.07) and 8 weeks (RR 0.98; 95%CI: 0.93, 1.04); rabeprazole 20 mg at 4 weeks (RR 1.00; 95%CI: 0.87, 1.14) and 8 weeks (RR 0.98; 95%CI: 0.91, 1.05).
CONCLUSIONS
Esomeprazole has demonstrated higher healing rates than omeprazole at 4 and 8 weeks. Other proton pump inhibitors (lansoprazole, pantoprazole and rabeprazole) have not shown higher healing rates when compared with omeprazole.
Topics: Administration, Oral; Dose-Response Relationship, Drug; Enzyme Inhibitors; Esomeprazole; Esophagitis, Peptic; Humans; Omeprazole; Proton Pump Inhibitors; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 11683686
DOI: 10.1046/j.1365-2036.2001.01128.x