Cost-utility analysis of proton pump inhibitors and other gastro-protective agents for prevention of gastrointestinal complications in elderly patients taking nonselective nonsteroidal anti-inflammatory agents.

BACKGROUND: The use of proton pump inhibitors (PPIs) among elderly patients using nonselective nonsteroidal anti-inflammatory drugs (nsNSAIDs) has increased; the price of PPIs is higher than that of majority of alternative treatment strategies. AIM: To evaluate the cost-effectiveness of nsNSAIDS + PPIs relative to alternative gastroprotective regimens in the prevention of GI complications among elderly patients (aged > or = 65 years). METHODS: An incremental cost-utility analysis, comparing PPIs with alternative gastroprotective regimens was conducted using a decision analytical model. Clinical outcomes, costs and utilities were derived from recently published studies. Probabilistic and deterministic sensitivity analyses were performed to test the robustness of the results to variation in model inputs and assumptions. RESULTS: The incremental cost-utility ratio (ICUR) of PPIs, relative to nsNSAID alone, was $206,315 per QALY gained or were more costly and less effective. Other co-prescribed treatment options had higher costs per QALY gained. In patients with a history of a complicated or uncomplicated ulcer, PPIs had ICURs of $24,277 and $40,876, respectively. CONCLUSIONS: Use of PPIs in all elderly patients taking nsNSAIDs is unlikely to represent an efficient use of finite healthcare resources. Co-prescribing PPIs, however, to elderly patients taking nsNSAIDs who have a history of complicated or uncomplicated ulcers appears to be economically attractive.

Systematic review: secondary prevention with band ligation, pharmacotherapy or combination therapy after bleeding from oesophageal varices.

BACKGROUND: Variable methods are available for secondary prevention after oesophageal variceal bleeding (EVB). AIM: To compare band ligation (BL), pharmacotherapy (PT) and BL+PT for EVB secondary prevention. METHODS: A systematic search of databases, references and meeting abstracts was conducted for randomized trials of BL, PT or BL+PT. The outcomes were mortality, rebleeding and adverse events. A random-effects model was used for meta-analyses. RESULTS: Twelve trials were included (6 BL vs. PT, 4 BL+PT vs. BL, 2 BL+PT vs. PT). All trials used beta-blockers +/- isosorbide mononitrate (ISMN) as PT. Mortality was not significantly different among trials. Rebleeding was not significantly different for BL vs. PT (RR 1.00, 95% CI 0.73-1.37). BL reduced rebleeding compared with PT for trials with mean beta-blocker dose <80 mg/day (RR 0.67, 95% CI 0.49-0.91). There were nonsignificant differences in rebleeding for BL+PT vs. BL (RR 0.57, 95% CI 0.31-1.08) and BL+PT vs. PT (RR 0.76, 95% CI 0.56-1.03). There was no difference in adverse events between BL vs. PT, but was higher with BL+PT vs. BL. CONCLUSION: Band ligation and PT alone are comparable for secondary prevention of rebleeding after EVB. Further trials with adequate PT dosing are required to determine the efficacy of combination BL+PT therapy.

[The Montreal definition and classification of gastroesophageal reflux disease: a global, evidence-based consensus paper]. / Die Montreal-Definition und -Klassifikation der gastroösophagealen Refluxkrankheit: Ein globales evidenzbasiertes Konsensus-Papier.

AIM: A world-wide recognised and accepted definition and classification of gastroesophageal reflux disease (GERD) would be highly desirable for research and clinical practice. The purpose of this project was to develop such a generally accepted definition and classification that could be used equally by patients, physicians, and supervisory bodies. METHODS: In order to ensure a consensus among the participating experts a modified delphi process with a step-wise selection modality was employed. For this the working group of five persons formulated a series of statements on the basis of a systematic search of the literature using three databases (Embase, Cochrane-Study register, Medline). Then these statements were developed further for two years, revised and finally passed as consensus. The consensus group consisted of 44 experts from 18 countries. Each key vote was held on the basis of a six-point scale. A "consensus" was considered to have been reached when two-thirds of the participants voted in favour of the respective statement. RESULTS: The level of agreement between the experts increased in the course of the multistep decision process, in the individual voting steps requiring at least two-thirds of the participants, the results were at first 86%, then 88% through to 94% and finally 100% in favour of the chosen statement. In the final voting, 94% of the final 51 statements were accepted by 90% of the consensus group. 90% of all statements were accepted unanimously or with only minor reservations. GERD was defined as a disease that is associated with troublesome symptoms and/or complications on account of reflux of stomach contents into the esophagus. The complaints are divided into esophageal and extra-esophageal syndromes. Among the novel aspects of this definition are the patient-orientated approach that is independent of endoscopic findings, the classification of the ailment into independent syndromes as well as the consideration of laryngitis, cough, asthma and dental problems as possible GERD syndromes. Furthermore, a new definition of suspected or demonstrated Barrett's esophagus is proposed. CONCLUSION: Irrespective of country-specific differences in terminology, language, prevalence and manifestations of this disease, evidence-based, world-wide valid consensus definitions are possible. A global consensus definition of GERD will simplify disease management, make mutual research possible and help in the design of generally valid studies. This will not only help the patient but also the physician and supervisory bodies.

One-week acid suppression trial in uninvestigated dyspepsia patients with epigastric pain or burning to predict response to 8 weeks' treatment with esomeprazole: a randomized, placebo-controlled study.

BACKGROUND: While empiric acid-suppressive therapy for uninvestigated dyspepsia patients with symptoms of epigastric pain or burning is standard practice, it is unknown whether an early response to therapy predicts outcome. AIM: To evaluate whether a 1-w acid suppression trial is effective for predicting 8-w response in such patients. METHODS: Helicobacter pylori-negative patients (aged 18-50 years) in primary care with uninvestigated epigastric pain or burning were randomized to esomeprazole 40 mg q.d.s. or b.d. for 1w, followed by esomeprazole 40 mg q.d.s. or placebo for 7w. Each day, patients rated the severity of their symptoms. RESULTS: Based on the last 3d, 1-w response rates were 39% (231 of 588) and 43% (258 of 596) with esomeprazole 40 mg q.d.s. and b.d., respectively. Based on the last 7d, response rates at 4w were 38% (283 of 738) and 25% (93 of 380) for esomeprazole and placebo, respectively, and 47% (339 of 716) and 34% (124 of 368), respectively, at 8w (both P < 0.001 vs. placebo). The sensitivity and specificity of esomeprazole treatment were 58% and 70%, respectively, at 8w. CONCLUSION: A 1-w acid suppression trial is of limited clinical value for predicting 8-w response in patients with symptoms of epigastric pain or burning. Esomeprazole provides greater symptom control than placebo at 4w and 8w.

Randomized-controlled trial of esomeprazole in functional dyspepsia patients with epigastric pain or burning: does a 1-week trial of acid suppression predict symptom response?

BACKGROUND: Early identification of true responders to acid suppression in functional dyspepsia patients with symptoms of epigastric pain or burning may enable clinicians to optimally tailor treatment. AIM: To evaluate whether a 1-w acid suppression trial is useful for identifying true responders in this population. METHODS: Patients (18-70 years) were randomized to either esomeprazole 40 mg q.d.s., b.d. or placebo for 1w, and then esomeprazole 40 mg q.d.s. or placebo for 7w. Epigastric pain and/or burning were recorded on a 4-point scale (0 = none, 3 = severe). Trial-week response was defined as symptom score sum < or = 1 on last 3d of therapy; response at 8w was symptom score sum < or = 1 over preceding 7d. RESULTS: 1-w response rates were 33% (199 of 597), 29% (188 of 629) and 23% (71 of 315) with esomeprazole q.d.s., esomeprazole b.d. and placebo, respectively (P = 0.002 for esomeprazole groups vs. placebo). At 8w, trial week sensitivity and specificity were 46% and 80%, respectively, for esomeprazole (40 or 80 mg), and 33% and 87%, respectively, for placebo. The positive and negative predictive values for esomeprazole were 60% and 69%. CONCLUSION: Response to a 1-w acid suppression trial is of limited use for predicting symptom response at 8w in patients with unexplained epigastric pain or burning.

Symptom overlap in patients with upper gastrointestinal complaints in the Canadian confirmatory acid suppression test (CAST) study: further psychometric validation of the reflux disease questionnaire.

BACKGROUND: The reflux disease questionnaire (RDQ) is a short, patient-completed instrument. AIMS: To investigate the psychometric characteristics of the RDQ in patients with heartburn-predominant (HB) and non-heartburn predominant (NHB) dyspepsia. METHODS: HB (n = 388) and NHB (n = 733) patients were randomized to esomeprazole 40 mg daily or twice daily for 1 week, followed by 3 weeks of esomeprazole 40 mg daily. RESULTS: High factor loadings (0.78-0.86) supported the 'regurgitation' dimension of the RDQ. Overlapping factor loadings in the 'heartburn' and 'dyspepsia' dimensions suggested symptom overlap. All dimensions demonstrated high internal consistency (Cronbach's alpha: 0.79-0.90). Intra-class correlation coefficients over 4 weeks were good (0.66-0.85). The RDQ showed good responsiveness over 4 weeks of treatment, with high effect sizes (> or =0.80). Moderate or large symptom improvements were reported by 90% and 77% of HB and NHB patients, respectively, following treatment. Patients who responded to acid suppression also experienced symptom benefits in all RDQ dimensions. CONCLUSIONS: The RDQ is reliable, valid and responsive to change in HB and NHB patients. The symptom overlap is important but need not play a major role in determining treatment strategy as both patient groups benefited from proton pump inhibitor treatment.

Meta-analysis: Helicobacter pylori eradication treatment efficacy in children.

BACKGROUND: Several meta-analyses assessing the efficacy of anti-Helicobacter pylori treatment in adults have been published but a comparable meta-analysis in children is lacking. AIMS: To summarize the efficacy of treatments aimed at eradicating H. pylori in children and to identify sources of variation in treatment efficacy across studies. METHODS: We searched Medline, reference lists from published study reports, and conference proceedings for anti-H. pylori treatment trials in children. Weighted meta-regression models were used to find sources of variation in efficacy. RESULTS: Eighty studies (127 treatment arms) with 4436 children were included. Overall, methodological quality of these studies was poor with small sample sizes and few randomized-controlled trials. The efficacy of therapies varied across treatment arms, treatment duration, method of post-treatment assessment and geographic location. Among the regimens tested, 2-6 weeks of nitroimidazole and amoxicillin, 1-2 weeks of clarithromycin, amoxicillin and a proton pump inhibitor, and 2 weeks of a macrolide, a nitroimidazole and a proton pump inhibitor or bismuth, amoxicillin and metronidazole were the most efficacious in developed countries. CONCLUSIONS: Before worldwide treatment recommendations are given for eradication of H. pylori, additional well-designed randomized placebo-controlled paediatric trials are needed, especially in developing countries where both drug resistance and disease burden is high.

Comprehension and awareness of symptoms in women with dyspepsia.

BACKGROUND: Overlapping symptoms of gastro-oesophageal reflux disease and dyspepsia are a problem for physicians and patients. AIM: This study explored comprehension of dyspepsia symptoms and associated medical terminology among women with symptoms of dyspepsia. METHODS: The US women aged > or = 18 years with dyspepsia (defined by Rome II criteria) were recruited in two phases, via direct mail, the Internet, clinical investigators and/or gastroenterologists. In phase I, subjects took part in an hour-long telephonic interview comprising open-ended questions relating to symptom frequency/duration, triggers/patterns and severity. During phase II, subjects took part in a 45-min telephonic interview, which explored their understanding of dyspepsia symptoms and their predominant or most bothersome symptom. RESULTS: Subjects with 'pure' dyspepsia (without overlapping symptoms of gastro-oesophageal reflux disease or irritable bowel syndrome) were sought, but of 777 subjects screened, most were excluded because of gastrointestinal comorbidities (irritable bowel syndrome, gastro-oesophageal reflux disease). Only 85 (11%) subjects had 'pure' dyspepsia of whom 11 withdrew. Of the 74 subjects interviewed, 70% were unfamiliar with the term 'dyspepsia'. Subjects reported several symptoms, including bloating (65%), gas (50%), nausea (41%) and discomfort (36%). Most subjects could distinguish between symptom bothersomeness and severity, and between pain and discomfort. Terms such as 'satisfactory relief', 'central upper abdominal discomfort', 'early satiety' and 'postmeal fullness' were often misunderstood. CONCLUSIONS: Subjects with 'pure' dyspepsia are rare, because of comorbidities. Dyspepsia-related terminology is often misunderstood by subjects.

Bismuth-based quadruple therapy with bismuth subcitrate, metronidazole, tetracycline and omeprazole in the eradication of Helicobacter pylori.

BACKGROUND: A previous study showed that 14 days of qid bismuth-based triple therapy with tetracycline 500 mg, metronidazole 250 mg and colloidal bismuth subcitrate 120 mg resulted in excellent Helicobacter pylori eradication rates (89.5%). The present study looked at a shorter treatment period by adding omeprazole and by reducing the dose of tetracycline. METHODS: One hundred sixty-one patients with H pylori confirmed by histology and (13)carbon urea breath test were included in the study. They were treated for seven days with bismuth subcitrate 120 mg plus metronidazole 250 mg plus tetracycline 250 mg qid plus omeprazole 20 mg bid (OBMT). Patients were 18 to 75 years of age and had dyspepsia with or without a history of peptic ulcer. Patients with irritable bowel syndrome, active ulcer or previous attempt at eradication, or those who had used antibiotics or antiulcer drugs in the previous 30 days were excluded. Eradication was determined by two (13)carbon urea breath tests done one and three months, respectively, after treatment. Strains with minimal inhibitory concentrations of 8 microg/mL or higher were considered to be resistant to metronidazole. RESULTS: The overall per protocol eradication rate was 84%-89.5% in metronidazole-sensitive and 70.8% in metronidazole-resistant strains. Modified intent-to-treat analysis resulted in a 80% eradication rate--82.5% in metronidazole-sensitive and 66.7% in metronidazole-resistant strains. Only one patient discontinued treatment because of adverse events. CONCLUSIONS: The OBMT regimen used in this study is safe and effective against metronidazole-sensitive H pylori strains.

A dose-ranging, placebo-controlled, randomized trial of alosetron in patients with functional dyspepsia.

BACKGROUND: Functional dyspepsia is characterized by upper abdominal pain or discomfort. AIM: To assess the benefit of the 5-HT3-receptor antagonist alosetron in a pilot, dose-ranging, placebo-controlled, multicentre, randomized clinical trial. METHODS: A total of 320 functional dyspepsia patients received placebo (n=81), or alosetron 0.5 mg b.d. (n=77), 1.0 mg b.d. (n=79) or 2.0 mg b.d. (n=83) for 12 weeks, followed by 1 week of follow-up. Primary efficacy was the 12-week average rate of adequate relief of upper abdominal pain or discomfort. Secondary endpoints assessed pain and upper gastrointestinal symptoms. RESULTS: Twelve-week average rates of adequate relief of pain or discomfort were 46% (95% CI: 37-54%), 55% (95% CI: 46-63%), 55% (95% CI: 47-64%) and 47% (95% CI: 38-55%) in the placebo, 0.5 mg, 1.0 mg and 2.0 mg alosetron groups, respectively. Alosetron 0.5 mg or 1.0 mg showed potential benefit over placebo for early satiety and postprandial fullness. Females showed greater responses compared to males. Patients with adequate relief had significantly (P < 0.001) greater reductions in severity and frequency of functional dyspepsia symptoms than those without adequate relief. Constipation was the most commonly reported adverse event. CONCLUSIONS: Alosetron showed potential benefit in relieving functional dyspepsia symptoms compared to placebo. Patients with adequate relief of upper abdominal pain or discomfort showed improvements in multiple functional dyspepsia symptoms.

Antimicrobial susceptibility testing of Helicobacter pylori in a large multicenter trial: the MACH 2 study.

Culture and susceptibility testing of Helicobacter pylori strains was performed in a large multinational, multicenter randomized clinical trial. Culture was carried out on gastric biopsy samples obtained from 516 patients at entry and had a sensitivity of 99% when the [(13)C]urea breath test was used as a reference. Susceptibility testing was performed for clarithromycin and metronidazole on 485 strains by an agar dilution method and the epsilometer test (Etest) and for amoxicillin by an agar dilution method only. Resistance to clarithromycin (>1 microgram/ml) was found in 3% of the H. pylori strains, with a perfect correlation between Etest and agar dilution methods. Resistance to metronidazole (>8 microliter/ml) was found in 27% of the strains by agar dilution, but there were important discrepancies between it and the Etest method. No resistance to amoxicillin was found. The logarithms of the MICs of the three antibiotics against susceptible strains had a distribution close to normal. The impact of resistance was tested in the four arms of the trial. There were not enough clarithromycin-resistant strains to evaluate the impact of resistance on the cure rate of clarithromycin-based regimens. For metronidazole-resistant strains, the impact noted in the clarithromycin-metronidazole arm was partially overcome when omeprazole was added (76% eradication for resistant strains versus 95% for susceptible strains). Secondary resistance to clarithromycin occurred in strains from 12 of 105 patients (11.4%) after the failure of a clarithromycin-based regimen to effect eradication. The detection of point mutations in clarithromycin-resistant strains was performed by a combination of PCR and restriction fragment length polymorphism. Mutations (A2142G and 2143G) were found in all strains tested except one. This study stresses the importance of performing susceptibility tests in clinical trials in order to explain the results of different treatments.

Lack of effect of treating Helicobacter pylori infection in patients with nonulcer dyspepsia. Omeprazole plus Clarithromycin and Amoxicillin Effect One Year after Treatment (OCAY) Study Group.

BACKGROUND: It is uncertain whether treatment of Helicobacter pylori infection relieves symptoms in patients with nonulcer, or functional, dyspepsia. METHODS: We conducted a double-blind, multicenter trial of patients with H. pylori infection and dyspeptic symptoms (moderate-to-very-severe pain and discomfort centered in the upper abdomen). Patients were excluded if they had a history of peptic ulcer disease or gastroesophageal reflux disease and had abnormal findings on upper endoscopy. Patients were randomly assigned to seven days of treatment with 20 mg of omeprazole twice daily, 1000 mg of amoxicillin twice daily, and 500 mg of clarithromycin twice daily or with omeprazole alone and then followed up for one year. Treatment success was defined as the absence of dyspeptic symptoms or the presence of minimal symptoms on any of the 7 days preceding the 12-month visit. RESULTS: Twenty of the 348 patients were excluded after randomization because they were not infected with H. pylori, were not treated, or had no data available. For the remaining 328 patients (164 in each group), treatment was successful for 27.4 percent of those assigned to receive omeprazole and antibiotics and 20.7 percent of those assigned to receive omeprazole alone (P=0.17; absolute difference between groups, 6.7 percent; 95 percent confidence interval, -2.6 to 16.0). After 12 months, gastritis had healed in 75.0 percent of the patients in the group given omeprazole and antibiotics and in 3.0 percent of the patients in the omeprazole group (P<0.001); the respective rates of H. pylori eradication were 79 percent and 2 percent. In the group given omeprazole and antibiotics, the rate of treatment success among patients with persistent H. pylori infection was similar to that among patients in whom the infection was eradicated (26 percent vs. 31 percent). There were no significant differences between the groups in the quality of life after treatment. CONCLUSIONS: In patients with nonulcer dyspepsia, the eradication of H. pylori infection is not likely to relieve symptoms.