Validation of a symptom diary for patients with gastro-oesophageal reflux disease.

BACKGROUND: Symptom diaries are potentially attractive but, because of concerns about patient compliance, they have had limited use in clinical trials. We assessed the validity and responsiveness of a symptom diary for patients with gastro-oesophageal reflux disease. METHODS: We included 215 patients with gastro-oesophageal reflux disease after starting treatment for 4 weeks with 40 mg esomeprazole once daily. Patients recorded whether they experienced night-time heartburn (yes/no), the severity of daytime heartburn on a scale from 1 (no heartburn) to 4 (severe heartburn) and their antacid use. Patients also completed a number of disease-specific and preference-based Health-related Quality of Life questionnaires at baseline and follow-up. RESULTS: Consistent with a priori predictions, daytime heartburn showed moderate to strong correlations with the Quality of Life in Reflux and Dyspepsia questionnaire (0.36-0.67) and four scales of symptom severity (0.36-0.70) for baseline, follow-up and change scores, but low correlations with the Standard Gamble. Responsiveness of the daytime heartburn item was excellent with a mean change from baseline to follow-up of -1.3 (95% CI -1.4 to -1.1) and a standardized response mean of 1.33 while responsiveness of the daily antacid use item was moderate (mean change scores -1.8 tablets taken, 95% CI -2.3 to -1.3 and standardized response mean of 0.64). CONCLUSIONS: The excellent psychometric properties of this simple gastro-oesophageal reflux disease diary make it an attractive measure for future trials.

Do physicians correctly assess patient symptom severity in gastro-oesophageal reflux disease?

BACKGROUND: The accuracy of physicians' assessment of the severity of gastro-oesophageal reflux disease is unclear. AIM: To correlate physician and patient assessment of gastro-oesophageal reflux disease severity and its response to treatment. METHODS: Adult uninvestigated gastro-oesophageal reflux disease patients (n = 217) completed symptom and health-related quality of life questionnaires at baseline and after treatment with esomeprazole 40 mg p.o. daily. Pearson coefficients quantified correlations between physician assessments and patient responses. RESULTS: At baseline, the strongest correlations were heartburn severity (0.31), overall symptom severity (0.44) and a domain of the quality of life in reflux and dyspepsia questionnaire (0.31) (P < 0.001). Correlations of change with treatment were greater than baseline correlations: heartburn (0.39), overall symptoms (0.50) and global rate of change -- stomach problems (0.72, all P < 0.001). The mean difference between the physicians' assessment of change and the patients' global rating of change was 0.20 (95% confidence intervals: 0.10-0.29) with physicians overestimating benefit. CONCLUSIONS: Correlations were often significant, although weak to moderate and better with symptom severity than with health-related quality of life instruments as well as with change after therapy than at baseline. Increasing attention to health-related quality of life may help physicians better understand patients' experience. In clinical trials, treatment success should be assessed by the patient as well as the physician.

There is no difference in the disease severity of gastro-oesophageal reflux disease between patients infected and not infected with Helicobacter pylori.

BACKGROUND: The role of Helicobacter pylori in gastro-oesophageal reflux disease (GERD) is controversial. AIM: To compare the severity of GERD in infected vs. non-infected patients, as part of an ongoing randomized controlled trial that examines the impact of H. pylori eradication on GERD-related outcomes. METHODS: Consecutive GERD patients underwent urea breath testing and completed validated GERD symptom severity, and quality of life questionnaires as well as, 24-h pH-metry. These parameters, as well as demographics and endoscopic findings were assessed in double-blinded fashion and compared between H. pylori-infected and non-infected subjects. RESULTS: Helicobacter pylori-infected GERD patients (n=50) were significantly older and less educated than non-infected patients (n=51). They also used proton pump inhibitors less often but had no difference in symptoms (as measured with both the Spechler's Activity Index and the Gastrointestinal Symptom Rating Scale), quality of life, endoscopic findings or 24-h pH-metry findings. CONCLUSION: This prospective, double-blind study demonstrates, using excellent GERD quantifying measures including validated symptom severity scores, endoscopy, and 24-h pH-metry, that there exist no clinically significant differences in clinical or laboratory-related GERD manifestations between H. pylori-infected and non-infected GERD patients.

The cost-effectiveness of high-dose oral proton pump inhibition after endoscopy in the acute treatment of peptic ulcer bleeding.

BACKGROUND: Recent data suggest a role for high-dose oral proton pump inhibition in ulcer bleeding. AIM: To compare the cost-effectiveness of oral high-dose proton pump inhibition to both high-dose intravenous proton pump inhibition and placebo administration. METHODS: The model adopted a 30-day time horizon, and focused on patients with ulcer haemorrhage initially treated endoscopically for high-risk stigmata. Re-bleeding rates were set a priori based on non-head-to-head data from the literature, and charges and lengths of stay from a national American database. Sensitivity analyses were carried across a broad range of clinically relevant assumptions. RESULTS: Re-bleeding rates for patients receiving intravenous, oral, or placebo therapies were 5.9%, 11.8%, and 27%, respectively. The mean lengths of stay and costs for admitted patients with and without re-bleeding were 4.7 and 3 days; $11,802, and $7993, respectively. High-dose intravenous proton pump inhibition was more effective and less costly (dominant) than high-dose oral proton pump inhibition with incremental savings of $136.40 per patient treated. The oral high-dose strategy in turn dominated placebo administration. Results remained robust according to one- and two-way sensitivity analyses. CONCLUSION: In patients undergoing endoscopic haemostasis, subsequent high-dose intravenous proton pump inhibition is more cost-effective than high-dose oral proton pump inhibition, which in turn dominates placebo. The results from this exploratory-type cost analysis require confirmation by head-to-head prospective trials performed in Western populations.

High-dose intravenous proton pump inhibition following endoscopic therapy in the acute management of patients with bleeding peptic ulcers in the USA and Canada: a cost-effectiveness analysis.

BACKGROUND: The efficacy of high-dose intravenous proton pump inhibition has recently been shown, yet its cost-effectiveness remains poorly studied. AIM: To assess the cost-effectiveness of this approach separately for American and Canadian health care settings. METHODS: A validated decision model included patients with bleeding ulcers after successful endoscopic haemostasis. Probabilities were determined from the literature, and charges and lengths of stay from national databases. A third-party payer perspective was adopted over a 30-day time horizon. RESULTS: Re-bleeding rates were 5.9% for patients who received high-dose intravenous proton pump inhibition and 22.9% for those who did not. Hospitalization costs for patients with and without re-bleeding were 11,802 US dollars and 7993 US dollars, and 5220 Canadian dollars and 2696 Canadian dollars, respectively. High-dose intravenous proton pump inhibition was more effective and less costly than the alternative of not administering it. The cost-effectiveness ratios for high-dose and no high-dose intravenous proton pump inhibition were 9112 US dollars and 11,819 US dollars (3293 dollars and 4284 dollars for the Canadian case), respectively. Sensitivity and threshold analyses showed that the results were robust across a wide range of clinically relevant assumptions. CONCLUSION: In the USA and Canada, administering high-dose intravenous proton pump inhibition for 3 days is both more effective and less costly than not doing so for patients with bleeding ulcers after successful endoscopic haemostasis.

Multilaboratory comparison of proficiencies in susceptibility testing of Helicobacter pylori and correlation between agar dilution and E test methods.

Susceptibility testing was performed at seven Canadian microbiology laboratories and the Helicobacter Reference Laboratory, Halifax, Nova Scotia, Canada, to assess susceptibility testing proficiency and the reproducibility of the results for clarithromycin and metronidazole and to compare the Epsilometer test (E test) method to the agar dilution reference method. Control strain Helicobacter pylori ATCC 43504 (American Type Culture Collection) and 13 clinical isolates (plus duplicates of four of these strains including ATCC 43504) were tested blindly. The National Committee for Clinical Laboratory Standards (NCCLS) guidelines for agar dilution testing were followed, and the same suspension of organisms was used for agar dilution and E test. Antimicrobials and E test strips were provided to the investigators. Methods were provided on a website (www.Helicobactercanada.org). Each center reported MICs within the stated range for strain ATCC 43504. Compared to the average MICs, interlaboratory agreements within 2 log(2) dilutions were 90% (range, 69 to 100%) for clarithromycin by agar dilution, with seven very major errors [VMEs], and 85% (range, 65 to 100%) by E test, with three VMEs. Interlaboratory agreements within 2 log(2) dilutions were 83% (range, 50 to 100%) for metronidazole by agar dilution, with six VMEs and eight major errors (MEs), and 75% (range, 50 to 94%) by E test, with four VMEs and four MEs. At lower and higher concentrations of antibiotic, E test MICs were slightly different from agar dilution MICs, but these differences did not result in errors. When a standardized protocol based on NCCLS guidelines was used, most participants in this study correctly identified clarithromycin- and metronidazole-susceptible and -resistant strains of H. pylori 93% of the time by either the agar dilution or E test method, and the numbers of errors were relatively equivalent by both methods.

Efficacy and safety of single-triple capsules of bismuth biskalcitrate, metronidazole and tetracycline, given with omeprazole, for the eradication of Helicobacter pylori: an international multicentre study.

BACKGROUND: The high prevalence of Helicobacter pylori resistance to metronidazole demands treatments more effective than standard bismuth-based triple therapy against these strains. AIM: To evaluate the H. pylori eradication rate in both metronidazole-sensitive and -resistant strains following quadruple therapy using single-triple capsules of bismuth biskalcitrate, metronidazole and tetracycline, given with omeprazole. METHODS: One hundred and seventy valid patients with duodenal ulcer, gastric ulcer or non-ulcer dyspepsia were treated in eight centres located in five countries. H. pylori was confirmed at baseline using 13C-urea breath test, histology and/or culture. Patients received three single-triple capsules q.i.d. and omeprazole, 20 mg b.d., for 10 days. Each capsule contained bismuth biskalcitrate, 140 mg (as 40 mg Bi2O3 equivalent), metronidazole, 125 mg, and tetracycline, 125 mg. 13C-Urea breath test was repeated at least 4 and 8 weeks post-treatment. RESULTS: Overall eradication rates were 93% (158/170) by modified intention-to-treat analysis and 97% (142/146) by per protocol analysis. Eradication rates were 93% (40/43) and 95% (38/40) for strains resistant to metronidazole and 95% (82/86) and 99% (75/76) for strains sensitive to metronidazole by modified intention-to-treat and per protocol analysis, respectively. CONCLUSION: This omeprazole-bismuth biskalcitrate-metronidazole-tetracycline 10-day regimen is a very effective and well-tolerated treatment, which overcomes metronidazole resistance.

Helicobacter DNA in bile: correlation with hepato-biliary diseases.

BACKGROUND: Helicobacter has been identified in isolated cases of hepato-biliary diseases, but its role in the pathogenesis of these conditions remains unclear. AIM: To determine whether Helicobacter could be detected in bile obtained at endoscopic retrograde cholangiopancreatography, and to evaluate the prevalence of this infection in patients with hepato-biliary diseases. METHODS: Bile was collected from 125 patients with various hepato-biliary diseases undergoing endoscopic retrograde cholangiopancreatography. Among them, 75 were diagnosed with biliary stones, 15 with pancreatico-biliary malignancies and four with primary sclerosing cholangitis. The detection of Helicobacter in DNA extracted from these bile samples was performed using Helicobacter genus-specific primers (capable of detecting 100-1000 organisms/mL). RESULTS: Helicobacter was detected in all positive controls. Only three samples had polymerase chain reaction inhibitors. All remaining bile samples (122 patients with hepato-biliary diseases) were negative for Helicobacter DNA. CONCLUSIONS: Helicobacter can be detected in bile samples using polymerase chain reaction. This infection, however, was not present in any of our patients diagnosed with gallstones or hepato-biliary malignancies, raising doubt as to the possible association between Helicobacter and these entities. Given the low sample size of patients with primary sclerosing cholangitis, more studies are required to determine whether an association exists with this condition.

Treatment of Helicobacter pylori infection.

It has been 2 decades since the rediscovery of Helicobacter pylori. Since that time, enormous advances have occurred: H. pylori is clearly felt to be a cause of peptic ulcer disease and gastric malignancies such as mucosa associated lymphoid tissue (MALT) lymphoma and a carcinogenic factor for gastric adenocarcinoma. These associations have led to clear indications for H. pylori treatment in certain conditions, but in other diseases where the associations are not as clear, the indications also remain relatively controversial. Clear indications for H. pylori treatment include patients with duodenal and gastric H. pylori associated ulcers and MALT lymphoma. In uninvestigated dyspepsia, there are also very clear benefits to H. pylori treatment whereas in non-ulcer dyspepsia, the benefits are controversial. H. pylori is certainly a risk factor for gastric adenocarcinoma but eradication of this infection has not yet been shown to reduce or eliminate the risk of developing this condition. The effect of H. pylori treatment in patients with gastroesophageal reflux disease is also unclear. There is a potential benefit in the prevention of atrophic gastritis but a potential disadvantage is the worsening of reflux disease, which has been suggested by certain studies. In addition, the interaction between H. pylori and nonsteroidal anti-inflammatory drugs (NSAIDs) appears quite complicated. Although there have been several advances in the last 2 decades with regards to the treatment of H. pylori, several controversies still exist, attesting to the requirement for further research.

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.

Gastroesophageal reflux and hyperacidity in chronic renal failure.

The prevalence of H. pylori infection and PUD seem not to be different in CRF patients as compared with the general population. However, PUD in CRF patients seems to have some unique features-namely, lack of pain and higher associations with bleeding, with post-bulbar location, and with multiple ulcers. No increase in GERD has been proven in adults, but several studies demonstrate increased GERD in pediatric CRF patients. The causes of the increase in GERD may include delayed gastric emptying owing to altered myoelectric activity, or perhaps to an increased production of gastric acid, but evidence for the latter is small. Importantly, treating the problem may lead to better nutrition and higher albumin levels, thus improving patient prognosis.

Implications of antibiotic resistance in the management of Helicobacter pylori infection: Canadian Helicobacter Study Group.

Eradication of Helicobacter pylori from the gastric and duodenal mucosa is an important clinical goal in the treatment of infected patients with peptic ulcer disease and other H pylori-associated conditions. Although several oral drug combination regimens are associated with eradication rates of approximately 85% in controlled trials, the success rate in patients infected with a resistant strain of H pylori is closer to 75%. Resistance to metronidazole and clarithromycin, which are common components of combination treatment regimens, is of greatest concern. Reported rates of H pylori resistance to various antibiotics vary considerably. In Canada, the data documenting H pylori susceptibility are limited but suggest that resistance to these antibiotics varies geographically and within specific treatment groups. Although susceptibility testing is not a prerequisite for initial treatment of individual patients infected with H pylori, formal efforts to identify and monitor both the causes and prevalence of antibiotic resistance across Canada are a much needed step in the ongoing management of this important infection. Recommended treatment regimens may be useful, even for treating apparently resistant H pylori strains. However, it is important to understand the mechanisms of the development of resistant strains to manage patients with treatment failure better.

Epidemiology of the antibiotic resistance of Helicobacter pylori in Canada.

BACKGROUND: The rate of Helicobacter pylori resistance to antibiotics determines the cure rate of treatment regimens containing such antibiotics. AIMS: To review the literature to determine the rates of H pylori resistance to metronidazole and clarithromycin in Canada, and whether these rates vary in different regions of Canada. METHODS: The literature was reviewed extensively for the prevalence of antibiotic-resistant H pylori in Canada by searching MEDLINE from January 1980 to May 1999, as well as abstracts of the American Gastroenterology Association Digestive Disease Week, Canadian Digestive Disease Week and The European H pylori Study Group Meetings from January 1995 to May 1999. RESULTS: Eleven studies that estimated H pylori resistance to metronidazole resistance and nine that estimated resistance to clarithromycin in Canada were identified. Rates of resistance for metronidazole and clarithromycin varied from 11% to 48% and 0% to 12%, respectively. Studies that obtained their estimates using the E-test and those that did not clearly exclude patients who had undergone previous attempts at H pylori eradication had higher estimates of resistance, accounting for this variability in results. CONCLUSIONS: The prevalence of primary H pylori resistance in Canada appears to be 18% to 22% for metronidazole and less than 4% for clarithromycin. These rates appear to be consistent across the different regions studied in Canada, but many regions have not been studied.

Genetic variability determinants of Helicobacter pylori: influence of clinical background and geographic origin of isolates.

Helicobacter pylori has an unusual pattern of genetic variation, which complicates research on this organism. To gain a better understanding of the forces behind this phenomenon, the extent to which recombination and single point mutations affect genetic variability in H. pylori was quantified and the influence of both geographical distance and clinical background were assessed. Site-directed restriction-endonuclease digestion of 2 gene fragments was performed on 168 isolates from Montreal and Berlin. Allelic diversity was found to be much higher for H. pylori than for other bacterial species. This finding is consistent with those of previous studies on H. pylori that were conducted using other techniques. However, nucleotide diversity was within the range reported for other bacterial species. Phylogenetic analysis found no grouping of strains with clinical background or geographical origin. Recombination at a rate that resulted in linkage equilibrium within genes can explain these observations.

Is Helicobacter pylori eradication associated with gastroesophageal reflux disease?

OBJECTIVES: A recent report has suggested an association between Helicobacter pylori eradication and the development of gastroesophageal reflux disease (GERD). We therefore assessed the incidence of GERD among comparable patients having undergone successful versus failed H. pylori eradication in a controlled trial. We also compared the H. pylori strains in the subjects that developed GERD to those that did not. METHODS: Patients with a history of proven duodenal ulcer and H. pylori infection were randomised into a H. pylori eradication study. Patients subsequently underwent gastroscopy with gastric biopsies every 3 months for 1 yr. At each visit, the presence of GERD symptoms and endoscopic esophagitis were noted, and the incidence of these variables among patients in whom H. pylori eradication was successful was compared to those in whom it was not. In a subgroup, the presence of the cagA, cagE, and vacA genotypes and of cagA antibodies were determined. RESULTS: Of 98 patients randomized into this study, 11 dropped out before determination of H. pylori eradication, leaving 87 patients with analyzable results. H. pylori eradication was successful in 63 (72%). By the end of the follow-up period, patients with GERD symptoms or endoscopic esophagitis were more prevalent in the successful than in the failed eradication group (37% [95% CI: 25-50%] vs 13% [95% CI: 3-32%], p = 0.04, 95% CI for the difference: 6-42%), as were patients with GERD symptoms alone (29% [95% CI: 18-41%] vs 8% [95% CI: 1-27%], p = 0.04, 95% CI for the difference: 4-36%) or esophagitis alone (21% [95% CI: 12-33%] vs 4% [95% CI: 0-21%], p = 0.10, 95% CI for the difference: 4-29%, respectively). Multivariate analysis revealed no significant association between the incidence of symptoms or esophagitis and age, gender, Quetelet index, caffeine or alcohol intake, smoking, weight change, or the presence of a hiatus hernia. There were also no differences in the prevalence of H. pylori genotypes from patients who developed GERD as compared to those who did not. CONCLUSIONS: In this patient population, the incidence of new GERD-type symptoms or endoscopic esophagitis was greater in patients in whom successful eradication was achieved. This difference does not appear to be attributable to weight gain, habits, or specific H. pylori strains.

cagE is a virulence factor associated with Helicobacter pylori-induced duodenal ulceration in children.

This study was undertaken to determine whether infection with Helicobacter pylori strains that contain the cagE gene was associated with duodenal ulceration in children. The presence of flaA, cagA, and cagE genes was determined by polymerase chain reaction in H. pylori previously cultured from 29 children. Twelve (92%) of 13 children with duodenal ulcers were infected with cagE-positive isolates, compared with only 5 (31%) of 16 with gastritis alone (P<.01). Infection of gastric cells in tissue culture by cagE-positive H. pylori resulted in greater increments in interleukin-8 levels compared with cagE-negative strains (2.3+/-0.1 vs. 1.3+/-0.2 ng/mL in AGS cells [P<.005]; 1.5+/-0.3 vs. 0.5+/-0.2 ng/mL in KATO-III cells [P<.05]). H. pylori-containing cagE was associated with the presence of duodenal ulceration in children. Enhanced chemokine production after infection with cagE-positive H. pylori could affect disease outcome.

Association of Helicobacter pylori genotype with gastroesophageal reflux disease and other upper gastrointestinal diseases.

OBJECTIVE: Helicobacter pylori (H. pylori) is a recognized pathogen, but it may also have a protective effect for gastroesophageal reflux disease (GERD). We compared the prevalence of potential virulence factors (cagA, cagE, vacA genotypes) in GERD to other upper gastrointestinal diseases and controls. METHODS: A total of 405 patients underwent gastroscopy with H. pylori isolation and serum testing. Patient diagnostic subgroups were prospectively defined. Genotypes were determined by amplification using polymerase chain reaction. CagA antibodies were determined by western blot, enzyme-linked immunosorbent, and flow microsphere immunofluorescent assays. RESULTS: Patients were grouped as follows: nonulcer dyspepsia (26%), GERD (20%), gastric ulcer (17%), duodenal ulcer (12%), gastric cancer (6%), or controls (19%). The cagA gene was present in 94-97% of subjects in all categories, but the cagA antibody was less prevalent in nonulcer dyspepsia (69%, 95% CI: 48-86%, p = 0.02) and GERD (69%, CI: 39-91%, p < 0.05) than in those with gastroduodenal pathology including gastric ulcer, duodenal ulcer, and gastric cancer (92%, CI: 81-98%). The cagE gene and vacA S1 genotype were more frequent in patients with gastroduodenal pathology (p < 0.01). GERD was associated with a significantly lower rate of vacA S1 genotype than controls (29% (CI: 10-56%) versus 80% (CI: 59-93%), p < 0.01). The vacA S1 genotype was associated with the presence of cagA antibodies. CONCLUSIONS: The cagE and vacA S1 genotypes are more prevalent in patients with peptic ulcer or gastric cancer, suggesting a potential function in virulence for these genes. However, the vacA S1 genotype was also more prevalent in controls than GERD, suggesting a potential protective effect against GERD.