Several observational studies have presented conflicting results on the association between the use of proton pump inhibitors (PPIs) or histamine H2 receptor antagonist (H2RA) and the risk of coronavirus disease 2019 (COVID-19). This systematic review and meta-analysis aimed to examine this association.

In July 2021, PubMed, Embase, Cochrane Central Register of Controlled Trials, and Web of Science were searched for articles investigating the relationship between the two main acid suppressants and COVID-19. Studies showing the effect estimates as hazard ratio (HR) for severe outcomes or incidence of COVID-19 were evaluated using a random-effects model.

A total of 15 retrospective cohort studies with 18,109 COVID-19 cases were included in the current meta-analysis. PPI use was significantly associated with severe outcomes of COVID-19 (hazard ratio [HR] = 1.53; 95% confidence interval [CI]: 1.20-1.95) but not with the incidence of COVID-19, whereas H2RA use was significantly associated with decreased incidence (HR = 0.86, 95% CI: 0.76-0.97). For subgroup analyses of PPIs, increased severe outcomes of COVID-19 were observed in < 60 years, active use, in-hospital use, and Asians. For subgroup analyses of H2RAs, decreased severe outcomes of COVID-19 were observed in > 60 years, while in-hospital use and use in Asia were associated with higher disease severity.

Close observation can be considered for COVID-19 patients who use PPIs to prevent severe outcomes. However, caution should be taken because of substantial heterogeneity and plausible protopathic bias.

The rate of rebleeding from peptic ulcers could differ between Asian and Western populations. This study aimed to determine whether the observed twofold difference in rebleeding rates in two similarly designed clinical trials (one in Hong Kong [n = 240], the other in a predominantly Western population [n = 764, ClinicalTrials.gov identifier: NCT00251979]) can be explained by differences in baseline patient characteristics.

Two-factor and multifactor analyses (adjusted by demographics, established risk factors for peptic ulcer and peptic ulcer bleeding, and disease severity variables) were performed using pooled data from the two studies. Cox regression analysis was used to predict the rebleeding risk at 3 days.

In the two-factor analysis (placebo vs esomeprazole/omeprazole and Western study vs Hong Kong study), data trended towards a reduced risk of rebleeding in the Western study (hazard ratio [HR] 0.69, 95% confidence interval [CI] 0.44-1.07, P = 0.094). The risk of rebleeding was similar in both studies after adjusted for multiple factors (HR 1.10, 95% CI 0.60-1.99, P = 0.767). The strongest predictor of rebleeding (apart from study drug) was a classification of American Society of Anesthesiologists (ASA) grade IV (HR 4.15, 95% CI 1.49-11.56, P = 0.006). When such patients were excluded, the difference in rebleeding rates between the studies reduced.

The difference in rebleeding rates between the two studies is explained by the factors in our analysis, most importantly a classification of ASA grade IV, suggesting that other differences, including ethnicity, did not influence the rebleeding rate.

High-dose intravenous esomeprazole is the only approved pharmacological treatment for the prevention of peptic ulcer rebleeding (currently approved in over 100 countries worldwide), but has not yet been approved in China. This study aimed to evaluate a high-dose esomeprazole intravenous regimen vs. an active control (cimetidine) for the prevention of rebleeding in Chinese patients with a high risk of peptic ulcer rebleeding who had undergone primary endoscopic hemostatic treatment.

This was a parallel-group study conducted at 20 centers in China. The study comprised a randomized, double-blind, intravenous treatment phase of 72 h in which 215 patients received either high-dose esomeprazole (80 mg + 8 mg/h) or cimetidine (200 mg + 60 mg/h), followed by an open-label oral treatment phase in which all patients received esomeprazole 40 mg tablets once daily for 27 days. The primary outcome was the rate of clinically significant rebleeding within the first 72 h after initial endoscopic hemostatic therapy. Secondary outcomes included the rates of clinically significant rebleeding within 7 and 30 days; proportions of patients who had endoscopic retreatment and other surgery due to rebleeding; and number of blood units transfused.

The rate of clinically significant rebleeding within 72 h was low overall (3.3%) and numerically lower in patients treated with esomeprazole compared with cimetidine (0.9% vs. 5.6%). Overall, the results of the secondary outcomes also showed a numerical trend towards superiority of esomeprazole over cimetidine. All treatments were well tolerated.

In this phase 3, multicenter, randomized trial conducted in China, esomeprazole showed a numerical trend towards superior clinical benefit over cimetidine in the prevention of rebleeding in patients who had successfully undergone initial hemostatic therapy of a bleeding peptic ulcer, with a similar safety and tolerability profile. These findings suggest that esomeprazole may be an alternative treatment option to cimetidine for this indication in China.

AstraZeneca.

ClinicalTrials.gov identifier, NCT01757275.

The optimal dosage of intravenous proton pump inhibitors (PPIs) for the prevention of peptic ulcer rebleeding remains unclear.

To compare the rebleeding rate of high-dose and standard-dose PPI use after endoscopic haemostasis.

A total of 201 patients with bleeding ulcers undergoing endoscopic treatment with epinephrine injection and heater probe thermocoagulation were randomised to receive a high-dose regimen (80 mg bolus, followed by pantoprazole 8 mg/h infusion, n = 100) or a standard-dose regimen (pantoprazole 40 mg bolus daily, n = 101). After 72 h, all patients were given 40 mg pantoprazole daily orally for 27 days.

There were no statistical differences in mean units of blood transfused, length of hospitalisation ≦5 days, surgical or radiological interventions and mortality within 30 days between two groups. Bleeding recurred within 30 days in six patients [6.2%, 95% confidence interval (CI) 1.3-11.1%] in the high-dose group, as compared to five patients (5.2%, 95% CI 0.6-9.7%) in the standard-dose group (P = 0.77). The stepwise Cox regression analysis showed end-stage renal disease, haematemesis, chronic obstructive pulmonary disease (hazard ratio: 37.15, 10.07, 9.12, 95% CI: 6.76-204.14, 2.07-49.01, 1.66-50.00 respectively) were independent risk factors for rebleeding and Helicobacter pylori infection was associated with lower risk of rebleeding (hazard ratio: 0.20, 95% CI: 0.04-0.94).

Following combined endoscopic haemostasis of bleeding ulcers, co-morbidities, haematemesis and H. pylori Status, but not PPI dosage, are associated with rebleeding (http://www.Clinical Trials.gov.ID: NCT00709046).

Randomised controlled trials (RCTs) evaluating the clinical effect of proton pump inhibitors (PPIs) in peptic ulcer (PU) bleeding yield conflicting results.

To evaluate the efficacy of PPIs in acute bleeding from PU using evidence from RCTs.

We searched CENTRAL, The Cochrane Library (Issue 4, 2004), MEDLINE (1966 to November 2004), EMBASE (1980 to November 2004), proceedings of major meetings to November 2004, and reference lists of articles. We contacted pharmaceutical companies and experts in the field.

RCTs of PPI treatment (oral or intravenous) compared with placebo or H(2)-receptor antagonist (H(2)RA) in acute bleeding from PU.

Two reviewers extracted data independently, assessed study validity, summarised studies and undertook meta-analysis. The influence of study characteristics on the outcomes was examined by subgroup analyses and meta-regression.

Twenty-four RCTs comprising 4373 participants in total were included. Statistical heterogeneity was found among trials for rebleeding (P = 0.04), but not for all-cause mortality (P = 0.24) or surgery (P = 0.45). There was no significant difference in all-cause mortality rates between PPI and control treatment; pooled rates were 3.9% on PPI versus 3.8% on control (odds ratio (OR) 1.01; 95% CI 0.74 to 1.40). PPIs significantly reduced rebleeding compared to control; pooled rates were 10.6% with PPI versus 17.3% with control treatment (OR 0.49; 95% CI 0.37 to 0.65). PPI treatment significantly reduced surgery compared with control; pooled rates were 6.1% on PPI versus 9.3% on control (OR 0.61; 95% CI 0.48 to 0.78). There was no evidence to suggest that results on mortality and rebleeding were dependent on study quality, route of PPI administration, type of control treatment or application of initial endoscopic haemostatic treatment. PPIs significantly reduced surgery compared with placebo but not when compared with H(2)RA. There was no evidence to suggest that study quality, route of PPI administration or application of initial endoscopic haemostatic treatment influenced results on surgery. PPI treatment appeared more efficacious in studies conducted in Asia compared to studies conducted elsewhere. All-cause mortality was reduced only in Asian studies; reductions in rebleeding and surgery were quantitatively greater in Asian studies. Among patients with active bleeding or non-bleeding visible vessel, PPI treatment reduced mortality (OR 0.53; 95% CI 0.31 to 0.91), rebleeding and surgery.

PPI treatment in PU bleeding reduces rebleeding and surgery compared with placebo or H(2)RA, but there is no evidence of an overall effect on all-cause mortality.

Upper gastrointestinal bleeding from peptic ulcer disease is a common clinical event, resulting in considerable patient morbidity and significant health care costs. Inhibiting gastric acid secretion is a key component in improving clinical outcomes, including reducing rebleeding, transfusion requirements, and surgery. Raising intragastric pH promotes clot stability and reduces the influences of gastric acid and pepsin. Patients with high-risk stigmata for ulcer bleeding (arterial bleeding, nonbleeding visible vessels, and adherent clots) benefit significantly from and should receive high-dose intravenous proton pump inhibitors (PPIs) after successful endoscopic hemostasis. For patients with low-risk stigmata (flat spots or clean ulcer base), oral PPI therapy alone is sufficient. For oozing bleeding (an intermediate risk finding), successful endoscopic hemostasis and oral PPI are recommended. Using intravenous PPIs before endoscopy appears to reduce the frequency of finding high-risk stigmata on later endoscopy, but has not been shown to improve clinical outcomes. High-dose oral PPIs may be as effective as intravenous infusion in achieving positive clinical outcomes, but this has not been documented by randomized studies and its cost-effectiveness is unclear.

Generic drugs contain the same active ingredient as an original drug and have their bioequivalence proved by pharmacokinetic tests. However, few studies have been reported on whether these bioequivalence studies infer pharmacodynamic equivalence. In this study, in eight healthy Helicobacter pylori-negative CYP2C19 extensive metabolizers, we compared the acid-suppressive effects of repeated administration of 15 mg of three brands of generic lansoprazole, Taiproton, Tapizol, and Lansoral, with those of the original lansoprazole, Takepron. Median intragastric pH value for 24-h and % pH > 4 for daytime (08:00-20:00 h) and night-time were significantly higher with any lansoprazole formulation, compared with the control (P < 0.05, Wilcoxon signed-rank test). However, during the daytime, % pH > 4 with Tapizol was significantly lower than the original (P < 0.05). Compared with the original, no significantly larger, but no small range of inter-subject variations were observed in these two parameters for each of the three brands of generic lansoprazole (Bartlett test). Pharmacokinetic bioequivalence tests do not necessarily guarantee pharmacodynamic equivalence.

Several studies have suggested that proton pump inhibitors are efficacious in preventing rebleeding when administered immediately after endoscopic treatments. However, there are limited clinical outcome data on the use of intravenous pantoprazole.

To evaluate the efficacy of intravenous pantoprazole after successful endoscopic treatment for peptic ulcer bleeding using evidence from randomized controlled trials (RCTs).

The Cochrane Library, MEDLINE, EMBASE and several Chinese databases up to July 2008 were searched. RCTs that compared the relative effectiveness of intravenous pantoprazole with placebo, H2 receptor antagonist or other agents for patients with peptic ulcer bleeding who were pretreated with successful endoscopic therapies were retrieved.

Five RCTs comprising a total of 821 participants were included in the final meta-analysis. Overall, there were significant differences in ulcer rebleeding (RR 0.31; 95% CI 0.18 to 0.53; pooled rates were 4.7% for pantoprazole and 15.0% for control), surgical intervention (RR 0.28, 95% CI 0.09 to 0.83; pooled rates were 1.4% in pantoprazole group versus 6.5% in control) and total length of hospital stay (weighted mean difference -1.53; 95% CI -1.91 to -1.16), but not on mortality (RR 0.72, 95% CI 0.29 to 1.81; pooled mortality rates were 1.9% for pantoprazole versus 2.8% for control) and blood transfusion requirements (weighted mean difference -0.53; 95% CI for random effects -1.04 to -0.02) when compared with control treatments. A series of subgroup analyses supported the results from the main analysis.

Intravenous administration of pantoprazole after endoscopic therapy for peptic ulcer bleeding reduces rates of ulcer rebleeding, surgical intervention and overall duration of hospital stay, but not mortality and blood transfusion requirements compared with placebo, H2 receptor antagonist or somatostatin.

Upper gastrointestinal bleeding secondary to ulcer disease is common and results in substantial patient morbidity and medical expense. After initial resuscitation to stabilize the patient, carefully performed endoscopy provides an accurate diagnosis and identifies high-risk ulcer patients who are likely to rebleed with medical therapy alone and will benefit most from endoscopic hemostasis. For patients with major stigmata of ulcer hemorrhage--active arterial bleeding, nonbleeding visible vessel, and adherent clot--combination therapy with epinephrine injection and either thermal coagulation (multipolar or heater probe) or endoclips is recommended. High-dose intravenous proton pump inhibitors are recommended as concomitant therapy after successful endoscopic hemostasis. Patients with minor stigmata or clean-based ulcers will not benefit from endoscopic treatment and should receive high-dose oral proton pump inhibitor therapy. Effective medical and endoscopic management of ulcer hemorrhage can significantly improve outcomes and decrease the cost of medical care by reducing rebleeding, transfusion requirements, and the need for surgery.

The aim of this study was to assess the efficacy and safety of esomeprazole 40 mg once daily (q.d.) in healing reflux oesophagitis at 4 and 8 weeks, and the efficacy of esomeprazole 20 mg q.d. for 12 weeks in the maintenance of remission.

A total of 235 patients with endoscopically proven reflux oesophagitis were enrolled in this study, which consisted of two phases (healing and maintenance therapy). Patients who showed complete endoscopic and symptomatic healing at the end of 4 or 8 weeks were switched to maintenance treatment with esomeprazole 20 mg q.d. for 12 weeks. The primary efficacy endpoint was healing of reflux oesophagitis at week 8. Secondary assessments included the proportion of patients with symptomatic relapse in the maintenance phase.

At the end of week 8, 88% (95% life-table confidence intervals [CI]: 84%, 92%) of patients were healed endoscopically and 90.6% of the patients were asymptomatic. Patient age, gender and Helicobacter pylori status had no effect on the efficacy of treatment. During the 12-week maintenance treatment phase, symptomatic relapse ratios were 0.5%, 2.2%, and 0%, for the first, second, and third 4-week periods, respectively. The proportions of patients satisfied with treatment were 95% and 99.4% at the end of acute and maintenance treatment, respectively. The most common adverse effects were headache, upper respiratory tract infection and abdominal pain.

Esomeprazole is effective in the healing of reflux oesophagitis, the resolution of heartburn, and in maintaining symptomatic remission. The effectiveness of esomeprazole in patients with gastroesophageal reflux disease is not affected by the presence of H. pylori.

A limited number of trials have investigated the efficacy of proton pump inhibitors for peptic ulcer bleeding, and some study design issues have been identified.

To present the design of a large trial evaluating the effects of intravenous esomeprazole on clinical outcomes in high-risk patients who have undergone endoscopic haemostasis for peptic ulcer bleeding.

The Peptic Ulcer Bleed study is an international, randomized, double-blind, placebo-controlled trial comparing either esomeprazole 80 mg intravenous bolus infusion for 30 min followed by esomeprazole 8 mg/h intravenously for 71.5 h, or placebo infusion for 72 h, after successful endoscopic haemostasis in patients with peptic ulcer bleeding and associated high-risk stigmata. All patients will receive once daily oral esomeprazole 40 mg for 27 days after intravenous therapy. The primary end point is the rate of clinically significant re-bleeding during the first 72 h after endoscopy. Secondary end points include: rate of re-bleeding during the first 7 and 30 days after treatment; length of hospitalization; mortality; blood transfusion; endoscopic re-treatment and surgery.

Expected 2008.

The carefully designed protocol and quality control measures represent a pragmatic approach to contemporary challenges in peptic ulcer bleeding management and, it is hoped, qualify the Peptic Ulcer Bleed study as a new standard for future interventional studies.

The findings of several studies suggest that proton-pump inhibitors (PPIs) suppress gastric acid more effectively in Helicobacter pylori-infected (Hp +) than in non-infected (Hp -) patients, but there has been no evaluation of the short-term clinical response.

Results of the first week of treatment with rabeprazole in Hp+ and Hp- patients with gastroesophageal reflux disease (GERD) were compared in a large prospective open-label, multicenter, cohort study in general and specialized practices. GERD patients were recruited on the basis of either typical symptoms alone or endoscopic results, assessed for H. pylori infection and treated with rabeprazole (20 mg). Heartburn and regurgitation symptoms were assessed daily during the first 7 days. Outcome parameters were calculated for both symptoms and compared between Hp+ and Hp- patients.

Data on 1548 patients (74.5% Hp-, 25.5% Hp + ) were available. Mean heartburn and regurgitation scores decreased during the first week. For both symptoms, more than 70% of the patients had "adequate" symptom relief at day 5, and more than 80% at day 7. "Complete" symptom relief was reached in more than 70% of patients. Mean onset of adequate symptom control was about 4 days. In Hp+ and Hp- patients there was no difference in response for any of the parameters.

Among patients treated with rabeprazole in clinical practice, H. pylori infection or its absence has no effect on the speed or degree of GERD symptom relief. Infected patients and non-infected patients can therefore be treated with a similar dose. When treating heartburn with rabeprazole, physicians do not need to consider the patient's H. pylori status and most patients (>80%) have adequate symptom relief after just a few days of treatment.

Proton pump inhibitor (PPI) therapy is widely used in the management of patients with ulcer bleeding. However, most randomized controlled trials (RCTs) have been conducted outside of the United States. Jensen and colleagues have conducted the first United States-based RCT to compare a PPI with an H(2)-receptor antagonist following appropriate endoscopic hemostatic treatment for patients with ulcer bleeding. Unfortunately, the trial had to be discontinued prematurely because of problems with enrolment. There was a statistically nonsignificant difference in rebleeding rates between the two treatment arms. A type II statistical error probably explains this apparent lack of efficacy. However, U.S. patients may also require higher doses of PPI for adequate control of intragastric acidity.

Randomised controlled trials (RCTs) evaluating the clinical effect of proton pump inhibitors (PPIs) in peptic ulcer (PU) bleeding yield conflicting results.

To evaluate the efficacy of PPIs in acute bleeding from PU using evidence from RCTs.

We searched CENTRAL, The Cochrane Library (Issue 4, 2004), MEDLINE (1966 to November 2004), EMBASE (1980 to November 2004), proceedings of major meetings to November 2004, and reference lists of articles. We contacted pharmaceutical companies and experts in the field.

RCTs of PPI treatment (oral or intravenous) compared with placebo or H(2)-receptor antagonist (H(2)RA) in acute bleeding from PU.

Two reviewers extracted data independently, assessed study validity, summarised studies and undertook meta-analysis. The influence of study characteristics on the outcomes was examined by subgroup analyses and meta-regression.

Twenty-four RCTs comprising 4373 participants in total were included. Statistical heterogeneity was found among trials for rebleeding (P = 0.04), but not for all-cause mortality (P = 0.24) or surgery (P = 0.45). There was no significant difference in all-cause mortality rates between PPI and control treatment; pooled rates were 3.9% on PPI versus 3.8% on control (odds ratio (OR) 1.01; 95% CI 0.74 to 1.40). PPIs significantly reduced rebleeding compared to control; pooled rates were 10.6% with PPI versus 17.3% with control treatment (OR 0.49; 95% CI 0.37 to 0.65). PPI treatment significantly reduced surgery compared with control; pooled rates were 6.1% on PPI versus 9.3% on control (OR 0.61; 95% CI 0.48 to 0.78). There was no evidence to suggest that results on mortality and rebleeding were dependent on study quality, route of PPI administration, type of control treatment or application of initial endoscopic haemostatic treatment. PPIs significantly reduced surgery compared with placebo but not when compared with H(2)RA. There was no evidence to suggest that study quality, route of PPI administration or application of initial endoscopic haemostatic treatment influenced results on surgery. PPI treatment appeared more efficacious in studies conducted in Asia compared to studies conducted elsewhere. All-cause mortality was reduced only in Asian studies; reductions in rebleeding and surgery were quantitatively greater in Asian studies. Among patients with active bleeding or non-bleeding visible vessel, PPI treatment reduced mortality (OR 0.53; 95% CI 0.31 to 0.91), rebleeding and surgery.

PPI treatment in PU bleeding reduces rebleeding and surgery compared with placebo or H(2)RA, but there is no evidence of an overall effect on all-cause mortality.

Proton-pump inhibitors reduce re-bleeding and surgical intervention, but not mortality, after ulcer bleeding.

To examine the effects of proton-pump inhibitor treatment on transfusion requirements and length of hospital stay in patients with ulcer bleeding.

For the Cochrane Collaboration meta-analysis of randomized-controlled trials of proton-pump inhibitor therapy for ulcer bleeding, outcomes of transfusion requirements and hospital stay were summarized, respectively, as mean (+/-s.d.) units transfused and hospital days. We calculated weighted mean difference with 95% confidence interval. We also performed subgroup analyses according to geographical origin of the randomized-controlled trials.

There was significant heterogeneity among randomized-controlled trials for either outcome. Overall, proton-pump inhibitor treatment marginally reduced transfusion requirements (WMD = -0.6 units; 95% CI: -1.1 to 0; P = 0.05) and length of hospitalization (WMD = -1.1 days; 95% CI: -1.5 to -0.7; P < 0.0001). Most of the randomized-controlled trials did not state precise criteria for administering blood transfusion and discharging patients, thereby limiting the strength of conclusions on the pooled effects.

Proton-pump inhibitor treatment for ulcer bleeding produces small, but potentially important, reductions in transfusion requirements and length of hospitalization.

Helicobacter pylori infection was reported to affect gastric acid secretion. We investigated the heartburn symptoms of patients with gastro-oesophageal reflux disease during sequential treatment with 40 mg of famotidine or 15 mg of lansoprazole to clarify whether H. pylori infection influences symptomatic response to anti-secretory therapy.

The subjects were 33 gastro-oesophageal reflux disease patients, who had already been treated with a full dose of H2 receptor antagonist. First, famotidine at 20 mg b.i.d. was administered to the patients for 8 weeks. Second, famotidine was replaced with 15 mg of lansoprazole once in the morning for 8 weeks. Finally, 20 mg of famotidine was administered b.i.d. for 8 weeks instead of lansoprazole. Gastro-oesophageal reflux disease symptoms were assessed using an original visual analogue scale.

The sequential symptomatic responses to famotidine and lansoprazole administration indicated that gastro-oesophageal reflux disease symptoms of patients during low-dose lansoprazole treatment were significantly less than those during famotidine treatment. Remission of symptoms was obtained significantly more often by famotidine therapy in patients with H. pylori infection than in patients without H. pylori infection.

Low-dose lansoprazole is more effective than full-dose famotidine for the control of symptoms in patients with gastro-oesophageal reflux disease, and H. pylori infection influences the symptomatic response to H2 receptor antagonists.

Several epidemiological data indicate that H. pylori infection prevalence in patients with gastroesophageal reflux disease (GERD) is lower than that reported in respective controls, which would suggest that the organism plays a protective role against this disease. On the other hand, most studies demonstrate that the presence of the infection in patients with GERD does not negatively affect the therapeutic efficacy of proton pump inhibitors (PPIs), and, in case of negatively influencing it, the effects are not clinically relevant and are easily controllable with standard antisecretory treatment. Therefore, the decision to administer H. pylori eradication treatment to a patient should not be influenced by the concomitant presence of GERD. In most cases, H. pylori eradication does not seem to induce GERD development, and it does not seem to worsen GERD when it was already present. Nevertheless, when the gastritis pattern is unknown before the antibiotic administration, the effect of H. pylori eradication on gastric acid secretion and the incidence of GERD is unpredictable. In the exceptional cases in which H. pylori eradication could have negative effects on GERD, its clinical relevance will be limited, and reflux symptoms or endoscopic esophagitis will favourably respond to the standard PPI antisecretory treatment. Therefore, again, when H. pylori eradication is indicated in a particular patient, the concomitant diagnosis of GERD should not change our attitude. Finally, is has recently been recommended to eradicate H. pylori infection in those patients with GERD needing long-term treatment with PPI, as some studies have reported that these drugs induce, in presence of the organism, an atrophic gastritis, with the consequent risk of gastric cancer. However, most of these studies have important methodological defects, and several authors have reported contrary results. In any case, the appearance in the gastric mucosa of clinically relevant lesions, such as intestinal metaplasia, dysplasia or adenocarcinoma, in patients treated with PPI for several years, has not yet been demonstrated, although this could simply be a problem of time. This question seems to be too controversial to be answered with the available data, and we should wait until new studies clarify this topic. In the meantime, as it occurs with any controversial indication, the decision of the doctor facing a patient infected by H. pylori and needing maintenance therapy with PPIs should be assessed on a case by case basis.

Proton-pump inhibitors reduce re-bleeding rates after ulcer bleeding. However, there is significant heterogeneity among different randomized-controlled trials.

To see whether proton-pump inhibitors for ulcer bleeding produced different clinical outcomes in different geographical locations.

This was a post hoc analysis of our Cochrane Collaboration systematic review and meta-analysis of proton-pump inhibitor therapy for ulcer bleeding. Sixteen randomized-controlled trials conducted in Europe and North America were pooled and re-analysed separately from seven conducted in Asia. We calculated pooled rates for 30-day all-cause mortality, re-bleeding and surgical intervention and derived odds ratios and numbers needed to treat with 95% confidence intervals.

There was no significant heterogeneity for any outcome. Reduced all-cause mortality was seen in the Asian randomized-controlled trials (odds ratios = 0.35; 95% confidence interval: 0.16-0.74; number needed to treat = 33), but not in the others (odds ratios = 1.36; 95% confidence interval: 0.94-1.96; number needed to treat--incalculable). There were significant reductions in re-bleeding and surgery in both sets of randomized-controlled trials, but the effects were quantitatively greater in Asia.

Proton-pump inhibitor therapy for ulcer bleeding has been more efficacious in Asia than elsewhere. This may be because of an enhanced pharmacodynamic effect of proton-pump inhibitors in Asian patients.

To assess the efficacy of the 8-week therapy with esomeprazole 40 mg vs. pantoprazole 40 mg for healing erosive oesophagitis (EE) as part of a management study.

Patients had a history of gastro-oesophageal reflux disease symptoms (> or =6 months) and had suffered heartburn on at least 4 of the 7 days preceding enrollment. Endoscopies were performed to grade EE severity using the Los Angeles (LA) classification system at baseline, 4 and 8 weeks (if unhealed at 4 weeks). Heartburn severity was recorded by patients on diary cards. The primary end point was healing of EE by week 8 of treatment.

Of 3170 patients randomized, the intent-to-treat population consisted of 3151 patients (63% male, mean age: 50.6 years, 27% Helicobacter pylori-positive). Esomeprazole 40 mg healed a significantly greater proportion of EE patients than pantoprazole 40 mg at both 4 weeks (life table estimates: esomeprazole 81%, pantoprazole 75%, P < 0.001) and 8 weeks (life table estimates: esomeprazole 96%, pantoprazole 92%, P < 0.001). The median time to reach sustained heartburn resolution was 6 days in patients receiving esomeprazole and 8 days with pantoprazole (P < 0.001).

Esomeprazole 40 mg is more effective than pantoprazole 40 mg for healing EE and providing resolution of associated heartburn.

The presence of the gastric pathogen, Helicobacter pylori influences acid suppression by proton pump inhibitors and treatment outcome in patients with gastro-oesophageal reflux disease.

To determine the influence of H. pylori infection on effectiveness of rabeprazole in primary and secondary care patients with gastro-oesophageal reflux disease.

Patients from primary and secondary care centres with uninvestigated gastro-oesophageal reflux disease (based on symptoms only) and investigated gastro-oesophageal reflux disease (endoscopically confirmed oesophagitis or endoscopy-negative reflux disease) were tested for H. pylori and treated with rabeprazole 20 mg once daily for 4-8 weeks in a non-randomized, multicentre, open-label study. Primary end-point for treatment effectiveness was complete resolution of both heartburn and acid regurgitation at 4-8 weeks; secondary end-point was quality of life as registered with the Psychological General Well-being Index.

Data of 1787 patients could be analysed; mean duration of treatment was 36.3 days. At the evaluation visit 76.9% were heartburn-free, 77.7% regurgitation-free and 71% had complete symptom resolution. Overall Psychological General Well-being Index scores improved accordingly. Treatment was equally effective in patients with or without H. pylori infection, but more effective in patients with oesophagitis when compared with symptomatic gastro-oesophageal reflux disease.

The effectiveness of rabeprazole in gastro-oesophageal reflux disease is not affected by the presence of H. pylori infection.

Proton pump inhibitors (PPIs) taken twice daily do not effectively control night-time intragastric pH; nocturnal acid breakthrough (NAB) (arbitrarily defined as intragastric pH < 4 lasting longer than 1 h) occurs in more than 75% of patients. The effectiveness of PPIs depends rather on the Helicobacter pylori status.

To investigate the effectiveness of two regimens of omeprazole in H. pylori-positive subjects as well as the occurrence of NAB.

Fifteen otherwise healthy H. pylori-positive subjects participated in this randomized, crossover, double-blind study.

Night-time intragastric pH-metry was performed before (baseline) and on day 7 of two treatment courses with omeprazole (1 x 20 mg and 2 x 20 mg). A 14-day (minimum) wash-out period was respected between the two treatment courses.

Group medians (10-90% confidence intervals) for night-time intragastric pH (22:30-06:30 h) were as follows: baseline, 2 (1-6.1); 1 x 20 mg, 5 (3.3-6.9; P < 0.001 versus baseline); instead of, 2 x 20 mg, 6.3 (4.9-7.1; P < 0.001 versus baseline, P = 0.02 versus omeprazole 1 x 20 mg). The percentage of time with intragastric pH < 3 was 65.4% during baseline (P < 0.05 versus both omeprazole regimens), 27% with once-daily omeprazole (P = 0.001 versus omeprazole 2 x 20 mg) and 0% with twice-daily omeprazole. NAB occurred in eight (53.3%) subjects with once-daily omeprazole and in no subject taking twice-daily omeprazole.

In H. pylori-positive subjects, twice-daily omeprazole is highly effective in controlling nocturnal intragastric acidity. NAB does not occur in those subjects and there is no need to add bedtime H2-receptor antagonists to this regimen.

The interaction of Helicobacter pylori (H. pylori) and non steroidal anti-inflammatory drugs (NSAIDs) on the development of gastro-duodenal ulcers and their complications is complex and controversial. From a clinical point of view, the question is whether or not H. pylori infection should be tested and eradicated in patients treated or about to be treated by NSAIDs or low-dose aspirin. Contradictory results have been reported in epidemiological studies. Recent data suggest that H. pylori-NSAID interaction may be different depending on the type of treatment, non aspirin NSAIDs or low-dose aspirin, the gastric or duodenal localization of ulcer and the strains of H. pylori. Controlled randomized studies suggest that eradication of H. pylori may be beneficial in NSAID-naïve patients but not in those already on long term NSAID therapy. Recommendations are proposed for different subgroups of patients. In NSAID users presenting with gastro-duodenal ulcer or complications, H. pylori screening and eradication are indicated. In patients treated or about to be treated by NSAIDs, the "test and treat" H. pylori strategy is recommended if there is a history of gastroduodenal ulcer or complications. Whether this strategy should be generalized preventively in patients without ulcer history is still controversial and deserves further studies.

Helicobacter pylori infection and the use of nonsteroidal anti-inflammatory drugs (NSAIDs) can each result in gastric or duodenal ulcer(s) and ulcer complications. Together, H. pylori infection and NSAIDs account for approximately 90% of peptic ulcer disease. In 2003, the results of studies suggest, and guidelines recommend, the careful selection of anti-inflammatory drugs - NSAIDs or selective COX-2 inhibitors (coxibs) based upon patients gastrointestinal history and use of aspirin therapy. Testing for, and cure of, H. pylori infection is recommended in patients prior to the initiation of NSAID therapy and in those who are currently receiving NSAIDs and have a history of dyspepsia, peptic ulcer or ulcer complications. For patients who present with peptic ulcer bleeding but require NSAIDs long-term, H. pylori eradication therapy should be considered, followed by continuous proton pump inhibitor prophylaxis to prevent re-bleeding, regardless of which kind of NSAID (nonselective NSAID /coxib) is being prescribed. Routine testing for, and eradication of, H. pylori infection has not been recommended for current takers of NSAIDs with no or low risk of complications. The management of patients taking low-dose aspirin is complex, but eradication of H. pylori infection alone in those with a past history of bleeding does not guarantee complete protection and therefore a proton pump inhibitor should also be given. The success of eradication therapy should always be confirmed, because of the risk of ulcer recurrence and bleeding in H. pylori-infected patients who require anti-inflammatory treatments.

Peptic ulcer (PU) bleeding is associated with substantial morbidity, mortality and healthcare cost. Randomised controlled trials (RCTs) evaluating the clinical effect of proton pump inhibitors (PPIs) in peptic ulcer bleeding have yielded conflicting results.

To evaluate the efficacy of PPIs in the management of acute bleeding from PU using evidence from RCTs.

We performed a search of CENTRAL, The Cochrane Library (Issue 3, 2003), MEDLINE (1966 to February 2003) and EMBASE (1980 to February 2003) and proceedings of recent major meetings through to February 2003. We searched the reference lists of articles and contacted pharmaceutical companies and experts in the field for additional published or unpublished data.

RCTs of PPI treatment (oral or intravenous) compared with either placebo or H(2)-receptor antagonist (H(2)RA) in patients with acute bleeding from PU were included if they met pre-defined criteria.

Two reviewers extracted data independently on a purpose-designed data extraction form. Validity of included studies was assessed by adequacy of randomisation method and other pre-defined criteria. Studies were summarised and meta-analysis was undertaken. The influence of factors on the outcomes was assessed.

Twenty-one RCTs with a total of 2915 participants were included. Statistical heterogeneity was found among trials for rebleeding (P = 0.05), but not for mortality (P = 0.26) or surgery (P = 0.42). There was no significant difference in mortality rates between PPI and control treatment; pooled rates were 5.2% on PPI versus 4.6% on control (odds ratio (OR) 1.11; 95% CI 0.79 to 1.57). PPI treatment significantly reduced rates of surgical intervention compared with control; pooled rates were 8.4% on PPI versus 13.0% on control (OR 0.59; 95% CI 0.46 to 0.76). PPIs significantly reduced rebleeding compared to control; pooled rates were 10.6% with PPI (range: 0% to 24.4%) versus 18.7% with control treatment (range: 2.3% to 39.1%), the OR was 0.46 (95% CI 0.33 to 0.64). Results on mortality and rebleeding rates were independent of route of PPI administration, type of control treatment or application of initial endoscopic haemostatic treatment. Surgical intervention rates varied with type of control (PPI significantly reduced surgical intervention rates compared with placebo and not when compared with H(2)RA) but not with route of PPI administration or application of initial endoscopic haemostatic treatment.

PPI treatment in PU bleeding reduces rebleeding and surgical intervention rates in studies comparing treatment with placebo or H(2)RA, but there is no evidence of an effect on mortality.

The eradication of Helicobacter pylori decreases the antisecretory activity of omeprazole and lansoprazole. Rabeprazole is a potent proton pump inhibitor that may not be affected as greatly by H. pylori status.

To compare the effect of H. pylori eradication on intragastric acidity and plasma gastrin during dosing with lansoprazole, omeprazole, rabeprazole and placebo.

Twenty-four healthy H. pylori-infected volunteers were studied on day 7 of dosing with placebo, lansoprazole 30 mg, omeprazole 20 mg and rabeprazole 20 mg, before and at least 5 weeks after H. pylori eradication. On each occasion, the 24-h intragastric acidity was measured by gastric aspiration. Plasma gastrin concentrations were measured hourly from 08.00 to 13.00 h.

Sixteen subjects completed the study. For all three drugs and placebo, H. pylori eradication increased intragastric acidity, particularly nocturnal acidity, and decreased plasma gastrin. There were no differences between the three drugs with respect to 24-h acidity, percentage of time pH > 4 or 5-h plasma gastrin, either before or after H. pylori eradication. Before eradication, the percentage nocturnal time at pH > 3 was significantly greater during rabeprazole than during lanso-prazole dosing.

The increase in intragastric acidity seen after H. pylori eradication during dosing with proton pump inhibitors is a drug-class effect, particularly affecting nocturnal acid control. This is related to increased spontaneous intragastric acidity after H. pylori eradication.

The acid inhibitory effect of proton pump inhibitors is reported to be greater in the presence than in the absence of an H. pylori infection. This study was undertaken to test the hypothesis that the acid inhibitory effect of omeprazole given twice a day is greater in H. pylori infected healthy volunteers than in the same individuals following eradication because of differences in the pharmacodynamics of omeprazole, greater duodenogastric reflux, the effects of ammonia produced by the H. pylori, or lower gastric juice concentrations of selected cytokines, which may inhibit gastric acid secretion.

We undertook 24-hour pH-metry in 12 H. pylori-positive healthy volunteers: (1) when on no omeprazole; (2) when on omeprazole 20 mg bid for 8 days; (3) 2 months after eradication of H. pylori and when on no omeprazole; and (4) after eradication of H. pylori and when on omeprazole 20 mg twice a day.

In subjects given omeprazole, eradication of H. pylori reduced pH and percentage pH >or= 3, as well as increasing the area under the H+ concentration-time curve. These differences were not due to alterations in (1) gastric juice concentrations of IL-1alpha, IL-8, IL-13, epidermal growth factor, or bile acids; (2) serum gastrin concentrations; or (3) the pharmacokinetics of omeprazole. There was no change in the difference in the H+ concentration-time curve 'without omeprazole' minus 'with omeprazole', when comparing 'after' versus 'before' eradication of H. pylori.

Eradication of H. pylori was not associated with an alteration in the acid inhibitory potency when comparing the difference in gastric acidity 'with' versus 'without' omeprazole. When the results were expressed by simply taking into account the acid measurements while on omeprazole before versus after eradication of H. pylori, the acid inhibition with omeprazole was greater in the presence than in the absence of a H. pylori infection. The clinical significance of the small difference is not clear.

Patients with reflux esophagitis (grade II or III, Savary-Miller, intention-to-treat, n=256, age range 19-82 years) were randomly assigned to a double-blind, double-dummy treatment with either pantoprazole 40 mg once daily or ranitidine 150 mg twice daily. After 4 weeks, each patient was clinically and endoscopically assessed. Failure to heal required a further 4 weeks of treatment and a new evaluation thereafter. After 4 weeks, healing of lesions was confirmed in 63% (69 out of 109) of patients receiving pantoprazole and in 22% (25 out of 113) receiving ranitidine (P < 0.001, per protocol population). After 8 weeks, the cumulative healing rates were 88% and 46%, respectively (P < 0.001). Complete freedom from esophagitis-related symptoms (acid eructation, heartburn, pain while swallowing) was greater in the pantoprazole than in ranitidine group after 2 and 4 weeks (74% vs. 47%; 87% vs. 52%, respectively, P < 0.001). After 4 weeks, the healing rate was 76% in Helicobacter pylori (Hp)-positive vs. 45% in Hp-negative patients treated with pantoprazole (P < 0.01). The Hp status did not influence healing rates in patients treated with ranitidine. The most frequent adverse events in the pantoprazole group were diarrhea and somnolence (2-3% of patients), and in the ranitidine group, headache, diarrhea, dizziness, increase of liver enzymes and pruritus (2-4% of patients). In conclusion, pantoprazole was more effective than ranitidine in the healing rate and relief from reflux esophagitis-associated symptoms, and Hp infection was associated with higher healing rate during therapy with pantoprazole but not with ranitidine.

The prevalence of Helicobacter pylori infection is steadily decreasing in developing countries, and this has been paralleled by an increasing incidence of gastroesophageal reflux disease (GERD) and adenocarcinomas of the esophagus and of the esophagogastric junction. The prevalence of H. pylori infection, which is on the decline in Europe and in the United States, is probably related to improvements in sanitary conditions and socioeconomic status. These epidemiological data do not support a role for H. pylori in the pathogenesis of GERD, but at the same time suggest a negative association with the rising incidence in esophageal diseases. While H. pylori infection clearly does not cause GERD, it may protect certain susceptible individuals from the development of GERD and its complications. There are conflicting reports that GERD can develop after H. pylori eradication and that proton pump inhibitors are less effective in suppressing intragastric acidity in H. pylori negative patients--reasons not to eradicate H. pylori in GERD patients. On the contrary, other data suggest an increase in the development of atrophic gastritis in GERD patients (H. pylori positive) on long-term proton pump inhibitor therapy - a reason to eradicate H. pylori. Preexisting lower esophageal sphincter dysfunction, susceptibility to GERD, unmasking of latent GERD, and patterns and severity of gastritis may be important factors contributing to the development of GERD rather than just the presence or absence of infection with H. pylori.

Management of gastroesophageal reflux disease (GERD) is based on the concept that gastric contents, principally acid and pepsin, are responsible for esophageal injury and symptoms of reflux disease. Pharmacologic management in the year 2001 revolves around the basic principle that control of intragastric pH correlates with esophageal healing and, subsequently, symptom relief. Although the majority of patients respond to a single daily dose of a proton pump inhibitor, many patients with reflux disease are "refractory" even to twice daily doses of these drugs. Potential reasons for this less than optimal response can be found when carefully examining the intragastric pH responses of healthy subjects and patients with GERD to these agents when taken at various times of the day, in proximity to meals, and in higher doses. In the past several years, we have explored many of these issues in attempting to understand the mechanisms behind incomplete response to proton pump inhibitors, using combined intragastric and intraesophageal pH monitoring. The "lessons learned" from these and supportive studies are the subject of this review.

Although Helicobacter pylori infection remains the single most common cause of peptic ulcer, an increasing proportion of patients have H. pylori -negative ulcers. The proportion is higher in the USA--and possibly Australia--than elsewhere. Although the precise aetiology of these ulcers is often unknown, some are caused by the use of aspirin or non-steroidal anti-inflammatory drugs. In areas with a high prevalence of H. pylori -negative ulcers, the empirical treatment of H. pylori infection for newly diagnosed peptic ulcer disease should be discouraged. All such patients should have documentation of their H. pylori status before treatment. Patients with H. pylori -negative ulcers may have the more serious ulcer diathesis and are likely to require long-term management with acid-suppressing drugs. Proton pump inhibitors are likely to be the drugs of choice; patients may be relatively refractory to H(2)-receptor antagonists. The optimal duration of treatment is undefined but might be lifelong. There are no prospective studies of the efficacy of surgery or mucosal-protective agents in the treatment of H. pylori -negative ulcers.

The medical treatment of gastro-oesophageal reflux disease is accomplished with the appropriate use of anti-secretory therapy, principally H(2)-receptor antagonists and proton pump inhibitors. In fact, there is a direct correlation between the length of time, in terms of the number of hours per day that the intragastric pH is above 4, and the healing of the oesophagitis. Nowadays, H(2)-receptor antagonists are of limited use as primary treatment, being inferior to proton pump inhibitors in both healing and symptom relief. Although the majority of patients can be effectively managed with carefully titrated doses of proton pump inhibitors, a small number will continue to show difficulty in the management of their disease, principally because of inadequate nocturnal acid control. These patients may benefit from a combination of proton pump inhibitors twice daily with an H(2)-receptor antagonist at bedtime. This article reviews the use of H(2)-antagonists, proton pump inhibitors and their combination in the management of the patient with gastro-oesophageal reflux disease.

Results from epidemiological studies and therapeutic clinical trials have shown that Helicobacter pylori infection causes acute and chronic active gastritis and is the initiating factor for the majority of peptic ulcer disease. Eradication of the infection with antibiotics resolves gastritis and restores normal gastric physiology, accelerates healing of peptic ulcer disease, and virtually eliminates recurrence of duodenal ulcer disease. The infection also plays an important role in the initiation and/or progression of gastric atrophy and intestinal metaplasia, which may eventually lead to the development of distal gastric cancer. Furthermore, almost all patients with gastric MALT lymphoma are infected with H. pylori and cure of the infection leads to histological regression of the tumor and maintains the regression in over 80% of patients during long-term follow-up. Preliminary uncontrolled data from Japan show that eradication of the infection significantly reduced metachronous intestinal-type gastric cancer following initial endoscopic resection of early gastric cancer and might also prevent the progression of gastric adenoma to gastric dysplasia or gastric cancer. Although this overwhelming evidence has demonstrated that H. pylori infection is bad for humans, some have questioned the wisdom of eradicating the infection in all those infected. Their arguments are largely based on hypothesis and circumstantial evidence: 1) Less than 20% of all H. pylori infected persons will develop significant clinical consequences in their lifetime. 2) H. pylori strains are highly diverse at a genetic level and are of different virulence. 3) The antiquity of H. pylori infection in humans and their co-evolution suggests that H. pylori may be a commensal to humans. Eradication of H. pylori may remove some beneficial bacterial strains and may provoke esophageal disease or gastric cancer at the cardia. However, careful review of the literature confirms that H. pylori infection is a serious pathogen albeit in a minority of those infected. It remains for carefully designed prospective studies, rather than hypothesis to make changes in the current consensus position.

Gastroesophageal reflux disease (GERD) affects more than one third of the population. It is generally a chronic condition and has the potential to be serious. Some patients with GERD experience persistent daytime or nighttime heartburn and some sustain severe damage, including ulceration, stricture, and Barrett's esophagus, which can predispose to development of adenocarcinoma. Extraesophageal manifestations of GERD can include otolaryngologic, respiratory, and cardiac problems. Severe GERD responds best to agents that suppress gastric acid secretion. Of these, proton pump inhibitors (PPIs) provide the most effective control of gastric acidity and are, therefore, the medical treatment of choice. In fact, nonresponse to a PPI should raise the suspicion that the diagnosis is not GERD. Proton pump inhibitors are quickly becoming the treatment of choice for GERD, especially for severe or refractory cases. For patients whose GERD is refractory even to PPIs or who are unwilling to face years of PPI therapy, antireflux surgery remains an option.

There is growing interest in the relationship between H. pylori infection and gastro-oesophageal reflux disease (GORD). However, this relationship is complex, as yet not fully elucidated, and probably based on a multiplicity of factors. The prevalence of H. pylori infection in patients with GORD is similar, more often lower than in matched controls. There is a negative correlation between H. pylori infection and the severity of GORD. There are many hypothetical mechanisms by which H. pylori infection may protect from the development of GORD. Conversely, there are many possible mechanisms by which H. pylori infection could theoretically foster the GORD. Patients after H. pylori eradication may develop GORD, and this seems to suggest a protective role of H. pylori infection, but other possible explanations include weight gain after H. pylori eradication, changes in dietary habits and smoking, and pre-existing GORD. H. pylori infected patients treated by various acid-inhibiting therapies such as proton pump inhibitors (PPIs), H2-receptors antagonists (H2-RA) or vagotomy, have an increase of their corpus gastritis severity, both in the activity of inflammation and in the density of organisms. Long-term therapy of GORD in H. pylori infected may lead to rapid progression of atrophic gastritis intestinal metaplasia and dysplasia, and increase the risk of developing gastric cancer. More recently it has been shown that H. pylori infection may interfere with the acid suppressive therapies used for treating GORD. In our opinion the progression of gastritis depends on the threshold of acid output at which H. pylori can 'flourish'. Recently interest is growing on gastric transitional zones and Helicobacter ecology. Any decrease of acid secretion changes the behaviour of H. pylori: the activity of gastritis improves in the antrum, but it deteriorates in the body. During proton pump inhibitor treatment, H. pylori redistribution occurs within the stomach, from an antral to a corpus or fundus prevalent pattern; corpus-fundus gastritis, exacerbated by PPI therapy, may result both in a diminished acid secretion and gastro-oesophageal reflux. The interest in Barrett's oesophagus is growing due to the associated risk of adenocarcinoma. The literature seems to demonstrate that the prevalence of H. pylori infection of the stomach in Barrett's oesophagus patients is not different from that exhibited by controls, roughly one-third of the subjects. Intestinal metaplasia of the gastric cardia seems to be equally frequent in patients with and without GORD. Finally, it appears unlikely that a causal relationship exists between H. pylori infection and Barrett's-associated adenocarcinoma.

The relationship between gastro-oesophageal reflux disease (GERD) and Helicobacter pylori is unclear. Recent data indicate that H. pylori probably exerts a protective effect against GERD. In recent years, the interaction between H. pylori, proton pump inhibitors and GERD has been widely studied. Currently available proton pump inhibitors produce significantly higher intragastric pH in H. pylori-positive patients than in those who are H. pylori negative, and this phenomenon may be clinically relevant. The mechanisms responsible for this difference in efficacy are not fully understood, although there are two major theories. Ammonia, produced by H. pylori, is able to neutralize gastric acid, and thus apparently increase the effect of acid suppressive agents (the 'ammonia theory'). The other theory is that decrease in acid output is due to the development of corpus gastritis during treatment with a proton pump inhibitor (the 'gastritis theory'). Treatment strategies to overcome this lowered sensitivity to acid suppression are to increase the frequency/dose of a proton pump inhibitor or to add an H2-receptor antagonist in the evening-but both have pharmaco-economic implications. An agent that could provide adequate pH control regardless of H. pylori status would be highly beneficial in the treatment of GERD, and may also lower treatment costs.

In patients with severe gastro-oesophageal reflux disease (GERD), proton pump inhibitors are being used increasingly in twice-daily regimens to improve control of gastric acidity. Few data exist to compare the ability of the most-often used proton pump inhibitors, omeprazole and lansoprazole, to control gastric acid at twice-daily dosage regimens. Nocturnal acid breakthrough, defined as gastric pH < 4.0 continuously for > 60 min, may compromise treatment goals in patients with GERD.

To compare the effects of omeprazole 20 mg b.d. or lansoprazole 30 mg b.d. on gastric acidity and the relative ability of each dosage regimen to prevent acid breakthrough.

In a crossover pharmacodynamic study, 20 healthy volunteers (10 male, 10 female, mean age 38 years) were given omeprazole 20 mg b.d. or lansoprazole 30 mg b.d. for 7 days each, in a randomized manner. Each dosage regimen was separated by a minimum 7-day period where no medication was administered. On day 7 of each regimen, 24-h intragastric pH-metry was performed. The percentage of time for which gastric pH was below 4.0 and 3.0, the occurrence of daytime and nocturnal acid breakthrough, and the duration of action of each regimen were compared. Non-parametric statistics for paired data were used.

The percentage time for which gastric pH was below 4.0 was significantly lower with omeprazole 20 mg b.d. (median 14.8%) than with lansoprazole 30 mg b. d. (median 24.2; P=0.0372). Fourteen subjects showed more effective acid control when taking omeprazole; these were significantly more often H. pylori-negative patients compared with those for whom acid control was better on lansoprazole (P < 0.001). Nocturnal acid breakthrough occurred in seven patients (35%) on omeprazole and in 10 (50%) on lansoprazole (N.S.).

In healthy volunteers, twice-daily dosing of omeprazole 20 mg b.d. appears to be significantly more effective than lansoprazole 30 mg b.d. in controlling gastric acidity. The clinical importance of such a difference remains to be defined in GERD patients.