Systematic review of proton pump inhibitors for the acute treatment of reflux oesophagitis

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.     

Cost effectiveness of proton pump inhibitors in gastro-oesophageal reflux disease without oesophagitis: comparison of on-demand esomeprazole with conventional omeprazole strategies

OBJECTIVES: To evaluate the cost effectiveness of on-demand treatment with esomeprazole 20mg compared with two alternative omeprazole treatment strategies for the long-term management of patients with gastro-oesophageal reflux disease (GORD) without oesophagitis. DESIGN: A simple Markov model was designed to compare the cost effectiveness of on-demand esomeprazole 20mg therapy for 6 months with a strategy consisting of intermittent 4-week acute treatment courses of omeprazole 20mg once daily or a strategy consisting of continuous omeprazole treatment (20mg once daily) following acute treatment of first relapse while on no drug treatment (a commonly used conventional care strategy). Relapse probabilities were based on pooled results from two 6-month placebo-controlled clinical studies of on-demand esomeprazole 20mg treatment in patients with GORD without oesophagitis and on results from a GORD study with a 6-month untreated follow-up. The expected number of relapses per patient was used as the effectiveness measure. SETTING AND PERSPECTIVE: Patient management assumptions were based on a UK physician survey. The cost-effectiveness analysis considered UK direct medical costs from the perspective of the National Health Service. RESULTS: The pooled analysis showed that after 6 months treatment, 90% of patients could control symptoms effectively with on-demand esomeprazole 20mg. The expected number of relapses per patient was estimated at 0.10 for on-demand esomeprazole, 0.57 to 1.12 for intermittent omeprazole and 0.47 to 0.75 for conventional omeprazole treatment. The esomeprazole strategy incurred considerably lower direct medical costs (16 to 61%) than either omeprazole strategy. CONCLUSION: On-demand treatment with esomeprazole 20mg is cost effective compared with two alternative omeprazole treatment strategies in patients with GORD without oesophagitis.     

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.     

Systematic review: maintenance treatment of gastro-oesophageal reflux disease with proton pump inhibitors taken 'on-demand'

BACKGROUND: Proton pump inhibitors (PPI) therapy 'on-demand' is often used as an alternative to continuous maintenance therapy in gastro-oesophageal reflux disease (GERD). AIM: We conducted a systematic review with the specific objectives to ascertain whether on-demand PPI therapy was effective in preventing symptomatic relapse and to assess the relative efficacy of on-demand vs. continuous PPI maintenance strategy. METHODS: Randomized-controlled clinical trials comparing on-demand PPI vs. placebo or on-demand vs. continuous PPI therapy in GERD patients were identified by searching the Medline database and the Cochrane Controlled Trials Register. RESULTS: Seventeen studies were found which met inclusion criteria. Out of the 17 studies: five investigated exclusively patients with non-erosive reflux disease (NERD), four patients with NERD and mild oesophagitis, two patients with erosive oesophagitis only, and two patients with uninvestigated GERD symptoms, respectively. Four further studies were not investigating the effectiveness of the therapies but primarily pharmacoeconomic or quality of life parameters. CONCLUSIONS: On the basis of the analysis of 17 studies, we can conclude that on-demand therapy with currently available PPI appears to be effective in the long-term management of patients with NERD or mild and uninvestigated forms of GERD, but not in patients with (severe) erosive oesophagitis.     

Race affects healing of erosive oesophagitis in patients treated with proton pump inhibitors

Aliment Pharmacol Ther 2011; 34: 487–493

Summary

Background Erosive oesophagitis appears to be more common in white vs. nonwhite patients with gastro‐oesophageal reflux disease (GERD). Aim To evaluate the association between race and erosive oesophagitis healing in patients with GERD treated with once‐daily proton pump inhibitors (PPIs). Methods Data from five double‐blind trials of once‐daily treatment with esomeprazole 40 mg vs. omeprazole 20 mg or lansoprazole 30 mg for erosive oesophagitis healing (evaluated at weeks 4 and 8 by endoscopy) were pooled and stratified by baseline race and Los Angeles (LA) severity grade. Multiple logistic regression models were fit with erosive oesophagitis healing (dependent variable) and race (independent variable), with adjustments for treatment, study, baseline LA grade, age, gender, BMI, Helicobacter pylori status, hiatal hernia and interactions of these factors with race. Results Of 11 027 patients, 91% were white. Nonwhite (n = 978) and black (n = 613) patients were less likely to have severe baseline erosive oesophagitis (LA grade C or D) than white patients [adjusted OR: 0.69 (95% CI, 0.61–0.79) and 0.67 (0.57–0.78), respectively; P < 0.0001]. At week 8, nonwhite and black patients had lower healing rates than white patients [OR: 0.75 (0.63–0.89) and 0.67 (0.54–0.83), respectively; P ≤ 0.001]. Greater odds of healing were associated with less severe baseline LA grade, increasing age, hiatal hernia, esomeprazole treatment (vs. lansoprazole or omeprazole) and lansoprazole treatment (vs. omeprazole) (all P ≤ 0.0009); no factor interacted significantly with race. Conclusions Nonwhite patients with GERD had less severe baseline erosive oesophagitis, but were less likely than white patients to have erosive oesophagitis healing after 8‐week PPI therapy.     

围术期预防使用质子泵抑制剂的合理性评价

目的:调查某院围术期预防性使用质子泵抑制剂的使用现状,评价使用合理性。方法:抽取某院2016年1—12月围术期预防使用质子泵抑制剂的病例共3798例,采用回顾性分析法从用药指征、用法用量、疗程、药物选择等方面评价预防用药的合理性。结果:预防用药的合理率为7.35%,不合理用药例次累计5214次。主要表现为:无指征预防用药2278例次(43.69%)、用法用量不适宜1696例次(32.53%)和疗程过长1190例次(22.82%)。结论:围术期预防使用质子泵抑制剂的不合理现象较为突出,亟待使用标准和规范来促进该类药物的合理使用。     

Systematic review: Rebound acid hypersecretion after therapy with proton pump inhibitors

BACKGROUND: The occurrence and the clinical relevance of rebound acid hypersecretion after discontinuation of proton pump inhibitors is unclear. AIM: To perform a systematic review of rebound acid hypersecretion after discontinuation of proton pump inhibitors. METHODS: PubMed, Embase and Central were searched up to October 2005 with indexed terms. RESULTS: Eight studies were included, sample size was 6-32. The studies used both basal and stimulated acid output as parameters to study rebound acid hypersecretion and assessed these at different time points and with variable methods. Five studies (including four randomized studies) did not find any evidence for rebound acid hypersecretion after proton pump inhibitor therapy. Of the remaining three studies, the duration of proton pump inhibitor therapy was the longest and two of these studies were the only to assess Helicobacter pylori status of their study subjects. These two studies suggested that rebound acid hypersecretion may occur in H. pylori-negatives after 8 weeks of proton pump inhibitors. CONCLUSIONS: Studies that have investigated rebound acid hypersecretion after cessation of proton pump inhibitor treatment are heterogenic in design, methods and outcome. There is some evidence from uncontrolled trials for an increased capacity to secrete acid in H. pylori-negative subjects after 8 weeks of treatment. There is no strong evidence for a clinically relevant increased acid production after withdrawal of proton pump inhibitor therapy.     

The basis for the decreased response to proton pump inhibitors in gastro-oesophageal reflux disease patients without erosive oesophagitis

BACKGROUND: The reason why heartburn in gastro-oesophageal reflux disease subjects without oesophagitis is less responsive to proton pump inhibitors than heartburn in those with erosive oesophagitis is not known. METHODS: Gastric and oesophageal pH were determined in 26 subjects with gastro-oesophageal reflux disease at baseline and on days 1, 2 and 8 of treatment with 20 mg omeprazole or 20 mg rabeprazole in a randomized, two-way cross-over fashion. The presence or absence of erosive oesophagitis at baseline was documented by upper gastrointestinal endoscopy. RESULTS: At a given value of the integrated gastric acidity during treatment with a proton pump inhibitor, the probability of pathological oesophageal reflux was significantly higher in subjects with no oesophagitis than in those with erosive oesophagitis. This occurred because the post-prandial gastric acidity in subjects with no oesophagitis showed a decreased response to the antisecretory agent. CONCLUSIONS: Compared with gastro-oesophageal reflux disease subjects with erosive oesophagitis, those with no oesophagitis are relatively refractory to the pharmacodynamic effects of proton pump inhibitors on the post-prandial integrated gastric acidity.     

Pharmacogenetics of the proton pump inhibitors: a systematic 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.     

Systematic review: the efficacy of intermittent and on-demand therapy with histamine H2-receptor antagonists or proton pump inhibitors for gastro-oesophageal reflux disease patients

AIM: To perform a systematic review on the efficacy of intermittent and on-demand therapy with either histamine H2-receptor antagonists or proton pump inhibitors for patients with erosive oesophagitis or symptomatic heartburn. METHOD: We conducted randomized-controlled trials of non-continuous therapy in gastro-oesophageal reflux disease patients. RESULTS: Fourteen studies met inclusion criteria. Because of variation in outcome measures statistical pooling of results was not possible. Results were analysed qualitatively. Four studies evaluated intermittent therapy of treatment 3 days a week with omeprazole 20 mg or daily with ranitidine which were not efficacious compared to a daily proton pump inhibitor. Famotidine 10 and 20 mg, ranitidine 75 mg and cimetidine 200 mg were efficacious in five on-demand studies for relief of symptomatic heartburn episodes. In three of four studies, evaluating only non-erosive (endoscopy-negative) gastro-oesophageal reflux disease patients, esomeprazole 20 and 40 mg and omeprazole 10 and 20 mg a day were efficacious using willingness to continue as an endpoint. Lansoprazole 30 mg and omeprazole 20 mg maintained symptom control in 60-70% of healed oesophagitis patients. CONCLUSIONS: Intermittent proton pump inhibitor or H2-receptor antagonist therapy is not effective in maintaining control in oesophagitis patients. H2-receptor antagonists are effective for relief of heartburn episodes. On-demand proton pump inhibitor therapy may work in a proportion of non-erosive gastro-oesophageal reflux disease patients.     

促动力药联合质子泵抑制剂与单独质子泵抑制剂治疗胃食管反流疾病疗效的荟萃分析

本研究旨在系统评价促动力药联合质子泵抑制剂与单独质子泵抑制剂治疗胃食管反流疾病的疗效,为临床用药提供循证参考.通过检索PubMed和Embase英文数据库,收集促动力药联合质子泵抑制剂与单独使用质子泵抑制剂治疗胃食管反流疾病的随机对照研究,采用RevMan 5.3偏倚风险评分工具对纳入研究进行质量评估并按预先设定的数据...     

Systematic review: the use of proton pump inhibitors and increased susceptibility to enteric infection

BACKGROUND: The use of proton pump inhibitors (PPIs) is increasing worldwide. Suppression of gastric acid alters the susceptibility to enteric bacterial pathogens. AIM This systematic review was undertaken to examine the relationship between PPI use and susceptibility to enteric infections by a specific pathogen based on published literature and to discuss the potential mechanisms of PPI enhanced pathogenesis of enteric infections. METHODS PubMed, OVID Medline Databases were searched. Search terms included proton pump inhibitors and mechanisms of, actions of, gastric acid, enteric infections, diarrhoea, Clostridium difficile, Salmonella, Shigella and Campylobacter. RESULTS The use of PPIs increases gastric pH, encourages growth of the gut microflora, increases bacterial translocation and alters various immunomodulatory and anti-inflammatory effects. Enteric pathogens show variable gastric acid pH susceptibility and acid tolerance levels. By multiple mechanisms, PPIs appear to increase susceptibility to the following bacterial enteropathogens: Salmonella, Campylobacter jejuni, invasive strains of Escherichia coli, vegetative cells of Clostridium difficile, Vibrio cholerae and Listeria. We describe the available evidence for enhanced susceptibility to enteric infection caused by Salmonella, Campylobacter and C. difficile by PPI use, with adjusted relative risk ranges of 4.2-8.3 (two studies); 3.5-11.7 (four studies); and 1.2-5.0 (17 of 27 studies) for the three respective organisms. CONCLUSIONS Severe hypochlorhydria generated by PPI use leads to bacterial colonisation and increased susceptibility to enteric bacterial infection. The clinical implication of chronic PPI use among hospitalized patients placed on antibiotics and travellers departing for areas with high incidence of diarrhoea should be considered by their physicians.     

Comparison of risk factors and clinical responses to proton pump inhibitors in patients with erosive oesophagitis and non-erosive reflux disease

Background  There has been no report on the response to proton pump inhibitor (PPI) therapy and on-demand or the relapse rate of non-erosive reflux disease (NERD) and erosive oesophagitis in Korea.
Aim  To compare the risk factors, clinical symptoms and PPI responses between patients with erosive oesophagitis and NERD patients.
Methods  A survey was performed prospectively in the erosive oesophagitis (205 patients) and NERD group (200 patients). Clinical symptoms, risk factors and PPI responses were analysed. On-demand therapy and the relapse rate of GERD symptoms were investigated during a one-year follow-up.
Results  BMI ≥ 25 (OR 3.0, 95% CI 1.1–8.3), alcohol use (OR 2.9, 95% CI 1.0–8.3), hiatal hernia (OR 5.0, 95% CI 1.2–20) and triglyceride ≥150 mg/dL (OR 4.0, 95% CI 1.7–10) were more common in the erosive oesophagitis group than in the NERD group by multivariate analysis. The ratio of oesophageal to extra-oesophageal symptoms was higher in the erosive oesophagitis group compared with the NERD group ( P  <   0.001). The PPI response rates at 8 weeks were different ( P  =   0.02); refractory rates were higher in the NERD group (16.7%) compared with the erosive oesophagitis group (6.0%). However, there was no significant difference between the two groups in on-demand therapy or the relapse rate.
Conclusion  These results suggest that the underlying pathogenic mechanisms of erosive oesophagitis and NERD are distinct.