Family Practice Vol. 16, No. 5, 483-488
© Oxford University Press 1999
Helicobacter treatment with quadruple therapy in primary health care for patients with a history of ulcer disease
Department of General Practice and Social Medicine, University of Nijmegen, Nijmegen and
a Department of Internal Medicine, Sint Anna Hospital, Oss, The Netherlands.
Dr WA de Boer, Sint Anna Hospital, Department of Internal Medicine, Postbus 10, 5340 BE OSS, The Netherlands.
Lai JYL, de Grauw WJC and de Boer WA. Helicobacter treatment with quadruple therapy in primary health care for patients with a history of ulcer disease.Family Practice 1999; 16:483–488.
Received 12 October 1998;
Revised 27 April 1999;
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Abstract |
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 Top Abstract IntroductionPatients and methodsResultsDiscussionReferences |
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Background. Few patients with a history of peptic ulcer are treated by their GP for H. pylori infection, even though theoretical evidence supports such an approach.
Objectives. We aimed to determine the validity of this recommendation and to test the feasibility of quadruple therapy in primary health care.
Methods. In this prospective, non-randomized intervention study, 51 unselected patients with a history of proven ulcer disease received a 7-day quadruple therapy (lansoprazole, colloidal bismuth subcitrate, tetracycline and metronidazole) from their GP. Main outcome measures were: (i) endoscopically confirmed cure of the infection; (ii) results of serology at entry and at 6 months follow-up; (iii) quality of life at entry, at 6 weeks and at 6 months follow-up; (iv) gastric symptoms at entry, at 6 weeks and at 6 months follow-up; and (v) medication at entry and at 6 months follow-up.
Results. Quadruple therapy was well tolerated and there were no drop-outs with this regimen. Intention to treat cure rate was 48/51 (94%, 95% CI 87–100%), per protocol cure rate was 48/49 (98%, 95% CI 94–100%). 45/50 (90%) had positive serology at entry. IgG antibody titres decreased >40% in 95.2% of patients. Quality of life improved significantly after treatment, gastric symptoms decreased and medication use decreased.
Conclusions. GPs should be encouraged to identify patients with a history of ulcer disease and chronic use of acid suppressants and offer them treatment for H. pylori infection. This approach will cure the infection in almost all patients, it will improve the quality of life and decrease costs. Quadruple therapy does not lose efficacy when employed in primary care. Pre-treatment serological testing is potentially useful for narrowing down the treatment group to those with actual infection, and serology is promising as an easy and cheap follow-up instrument in primary health care.
Keywords. COOP, WONCA, general practice, Helicobacter pylori, quadruple therapy, ulcer.
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Introduction |
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TopAbstractIntroductionPatients and methodsResultsDiscussionReferences |
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Helicobacter pylori is the main aetiological agent in peptic ulcer disease. Cure of the infection prevents ulcer recurrence, so antimicrobial treatment is mandatory.1,2 The number of new ulcer patients is decreasing in developed countries. There is, however, a large pool of patients in general practice in whom ulcers were diagnosed and treated with conventional therapy 5–20 years ago. This group, with a history of ulcer disease, but no ulcer at the present time, has not been well studied.3 It is generally perceived that duodenal ulcer (DU) disease is a chronic relapsing life-long condition and that the risk of recurrence and complications does not diminish over time, unless patients are cured of the infection with H. pylori.3–6 The same holds true for patients with gastric ulcer(s) (GU).7 It has been suggested on theoretical grounds that patients with a history of ulcer disease can be treated with antimicrobials without prior testing for the presence of H. pylori.3,8,9 It would mean that the GP should identify this patient group (case finding) for treatment. Presently this is done by a minority of GPs.10 For the cure of this infectious disease the most effective therapy should be employed.11 Data regarding anti-Helicobacter therapy, however, are almost completely derived from hospital populations. Quadruple therapy is the regimen with the highest cure-rates:12–14 it is well evaluated in Dutch patients treated in a hospital setting.15–17 Some have suggested that it is too complex for general practice and suggested the use of simpler, but presumably also less effective, regimens.18,19 When confronted with such a view, most GPs are offended and feel they are in fact more capable of motivating the patients and explaining multi-drug regimens, because they have a better knowledge of the patient and his social context.
In this prospective study, GPs identified patients with a history of ulcer disease and treated them with 1 week of quadruple therapy. The aim of the study was to determine prospectively whether the patients would benefit from such an approach and to determine whether or not prior and follow-up serology testing should be performed. The third objective of this study was to evaluate the tolerability and cure rate of quadruple therapy when it is prescribed by GPs.
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Patients and methods |
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TopAbstractIntroductionPatients and methodsResultsDiscussionReferences |
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In the period of November 1995–1996, 10 GPs were asked to randomly select five patients with a history of ulcer disease documented by endoscopy or radiography and who were still taking acid suppressants to control symptoms. Identification of patients was done when they requested a repeat prescription for acid-reducing drugs or by computer search during consultation. Patients were excluded when aged < 18 or >75 years; when it was documented that the ulcer had been induced by aspirin or NSAIDs, when they had used antibiotics for unrelated disease within the 30 days prior to inclusion or when they had a documented allergy for the drugs used in quadruple therapy. Oral and written informed consent were obtained.
Medication and compliance
Without prior confirmation of H. pylori status all were treated with lansoprazole 30 mg b.d. days 1–10, colloidal bismuth subcitrate 120 mg q.i.d. days 4–10, tetracycline 500 mg q.i.d. days 4–10 and metronidazole 500 mg t.i.d. days 4–10. Because successful treatment outcome is highly dependent on patient compliance,20 all patients were told that with good adherence to the 7-day quadruple regimen, cure rates are very high, and furthermore that recurrence is highly unlikely. Based on these facts, patients were asked whether they would prefer to continue chronic acid suppressive medication or to take a 1-week quadruple therapy. In addition, the procedure was simplified by a printed prescription and written instruction about how and when to take the medication. Patients were informed about possible side-effects and were requested to fill out a standard questionnaire regarding side-effects and tolerability.21 Post-therapy, a tablet count was performed as a measure of compliance.
Definition of cure
At least 6 weeks after cessation of therapy, all patients were endoscoped to test for cure. Cure was defined if all eight biopsies from antrum and corpus (culture, histology and CLO-test) were H. pylori negative. The long-term recurrence rate is 0% if the combination of these three individual tests are negative.6
Serology
Blood samples were collected before and 6 months after treatment. A qualitative latex agglutination test (Pyloriset Dry®, Orion diagnostica, Espoo, Finland) was used for rapid detection of Helicobacter pylori antibodies in serum on the initial sample.22 At the end of the follow-up period, stored baseline and 6-months follow-up sera were pooled and processed together in the same batch of an ELISA-kit in order to minimize assay variability. We used the Pyloriset IgG® (Orion diagnostica, Espoo, Finland), which we have validated in an earlier study.23 A 40% decrease in titre of this essay has 100% sensitivity and 100% specificity as compared with endoscopy and breath test in a large group of 794 patients.24 The seroconversion level was 300.
Questionnaires
The Dartmouth COOP functional status assessment charts/WONCA (COOP/WONCA) assess seven domains of functional health: physical activities, feelings, daily activities, social activities, change in health, overall health and pain.25–27 Each domain is covered by a single question to be answered on a five-point scale and is supported by a pictograph representing the options. The scores are calculated for each chart separately. The charts are available in more than 12 languages. Patients were asked to fill out these self-administered charts prior to, and at 6 weeks and 6 months after treatment.
A gastric symptoms list (epigastric pain during the day, epigastric pain during the night, postprandial epigastric pain, nausea, pyrosis, bad breath, bloating, vomiting, early satiety, belching) was used to obtain more detailed information about dyspeptic complaints at the initial, 6 weeks and 6 months follow-up visits. Use of antacids and acid suppressive medication was reported prior to antibiotic treatment and at the last follow-up visit for the entire follow-up period.
Statistics
The scores on the COOP/WONCA charts and the gastric symptoms list were analysed using the SAS (Statistical Analysis System) version 6.11 procedure PROC MIXED using a fixed-effects repeated measurements analysis for the initial, 6 weeks and 6 months visit scores.28
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Results |
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TopAbstractIntroductionPatients and methodsResultsDiscussionReferences |
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A total of 51 ulcer patients from 10 different GPs entered the study. The mean age was 51 years (range 25.8–69.6 years). Thirty-four (67%) were male and 28 (55%) were smokers. In 34 patients a DU had been diagnosed, in 13 a GU and in 4 both a DU and GU. This diagnosis was made by endoscopy (n = 24), barium meal (n = 12) or by both methods (n = 15). Mean time from first ulcer manifestation to treatment was 16.7 years (range 1–40 years). Eight (16%) had a history of peptic ulcer bleeding, two (4%) had a history of ulcer perforation and nine (18%) had gastric surgery. All 51 patients could finish the regimen as prescribed; no one dropped out. Compliance was excellent and a tablet count at the first return visit, 6 weeks post-treatment, showed that 49 had empty medicine boxes. One patient returned five tablets, one patient two tablets, and two patients one tablet as proof of a missed dose somewhere during the treatment course. Two patients took the medication but refused endoscopy, and they are counted as treatment failure in the intention to treat analysis (worst case scenario), even though serology suggests that they are both also cured. Forty-eight patients had all biopsy tests negative for H. pylori. Therefore, the intention to treat cure rate was 48/51 (94%, 95% CI 87–100%). The per protocol cure-rate was 48/49 (98%, 95% CI 94–100%).
Side-effects
Data from the questionnaire on side-effects21 are available for 49 patients. Nine patients (18%) chose category a (no side-effects), 28 (57%) chose category b (mild side-effects), four (8%) chose category c (moderate side-effects), 8 (16%) chose category d (severe side-effects, work not possible) but no one chose category e (severe side-effects, early treatment discontinuation = drop-out). The most frequent side-effects were taste disturbance (41%), diarrhoea (46%) and dizziness (41%), but these were never the reason to stop the treatment prematurely.
Serology
Blood samples were collected from 51 patients pretreatment and 48 patients 6 months post-treatment. In retrospect, only 42/51 (80%) patients had a positive latex screening test pre-treatment, but 45 out of 50 were serologically H. pylori-positive in the ELISA assay (in one patient, the amount of blood collected was insufficient on which to perform the ELISA essay). Five patients tested negative in the ELISA and the latex essay. Four of these five patients reported a moderate improvement; in one patient gastric symptoms recurred after 6 months. None, however, needed acid-reducing medication at the end of the follow-up. Serum pairs were available from 47/51 (92%) patients. Of those with a positive pre-treatment sample, 40/42 showed a decrease in titre of >40% (95.2%), 38 of >50% (90.5%) and 35 of >60% (83.3%) at 6 months. The two patients who refused endoscopy both also showed a significant decrease of titre. The first 12 800 to 2000 (–84%); the other patient showed a decrease of more than 73% (1100 to < 300). Both are therefore almost certainly cured. The one patient that was not cured had a 12.5% (from 1600 to 1800) increase of titre at 6 months.
Questionnaires
COOP/WONCA Charts were returned by 48 patients pre-treatment, by 46 patients at 6 weeks and by 45 patients at 6 months post-treatment. Analysis was based on patients with a complete set of symptoms. The mean scores with standard error of each COOP/WONCA category are shown in Table 1
. The domains social activities (1.4) and daily activities (1.9) have low pre-treatment scores, whereas high pre-treatment scores are found for pain (2.6) and overall health (3.1). There was a highly significant improvement in functional health for change in health, pain (P < 0.001), feelings and overall health (P < 0.01). No significance was found for physical fitness or social activities. Table 1 shows that major improvement in functional health is mainly achieved shortly after eradication therapy and, moreover, maintained after 6 months follow-up.
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Gastric symptoms
Table 2
shows the percentage of patients suffering from gastric complaints before, after 6 weeks and after 6 months of therapy. At baseline more than 50% of patients had epigastric pain during daytime, heartburn, bloating and belching; 45% complained about epigastric pain during the night and 35% of postprandial epigastrical pain. Almost all categories decreased significantly except for nausea, bad breath and vomiting. After 6 months of therapy, compared to the baseline data, only 19% of patients suffered from epigastric pain during the day (P < 0.001), 11% during night (P < 0.001) and 14% postprandial (P < 0.01). Significant improvement could also be reported for heartburn (P < 0.001), bloating (P < 0.001), early satiety (P < 0.001) and belching (P < 0.01).
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Use of medication
Due to the inclusion criteria, all patients were on chronic acid-suppressive therapy pre-treatment; 44 patients used H2RA and seven PPI to control symptoms. In addition, seven patients used antacids as well. There was a sharp reduction in the use of acid-suppressing medication after 6 months. Out of 50 patients, only two patients still used H2RA (4%), two used PPI (4%) and another two used antacids to control dyspeptic symptoms. One patient moved, and use of medication could not be traced afterwards.
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Discussion |
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TopAbstractIntroductionPatients and methodsResultsDiscussionReferences |
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Based on these findings, GPs should be encouraged to identify patients using chronic acid-reducing medication with a history of ulcer disease and offer them treatment for H. pylori infection. Peptic ulcer disease has major morbidity.29 GPs are not always aware of the great benefit of antibiotics for peptic ulcer patients,10,30,31 and anti-Helicobacter therapy has rarely been studied in primary health care.10,30,32–35 A recent English study showed that only 30% of patients with previously documented ulcers received antibiotics.10 Hippisley-Cox et al. showed that pragmatic eradication of H. pylori infection in primary care is likely to be cost-effective.36 In this prospective, non-randomized intervention study, which included patients with a history of proven ulcer disease, we demonstrated that the quadruple regimen is feasible in general practice. It had a reasonable side-effect profile. Quadruple therapy will cure the infection in almost all patients and improves quality of life.
The cure rate of the quadruple regimen was extremely high and comparable to the cure rates achieved in hospital populations in The Netherlands15–17 and elsewhere.37–42 This high efficacy probably obviates the need to test for cure, which is a great advantage in primary health care. The regimen is effective in metronidazole-sensitive and resistant strains,15,43 and the physician therefore does not have to worry about antibiotic resistance, which is a second advantage of this regimen. If it nevertheless fails, a clarithromycin-containing regimen can be used as second-line ‘rescue’ therapy. Data regarding antimicrobial resistance were not collected pre-treatment, but prevalence of metronidazole resistance is between 15 and 20% in our area.44 The only patient that was not cured was retreated with lansoprazole, amoxicillin and clarithromycin for 10 days and was cured with this regimen. Even though the high pre-test likelihood of cure suggests that routine investigation for cure is unnecessary, a test for cure may be necessary in the occasional patient with recurrent symptoms or when the GP wants to evaluate his performance in curing this disease. The group of chronic patients treated in this study were diagnosed with a DU and/or a GU in the past. All were taking acid suppressants and had, as the gastric symptom questionnaire showed, recurrent symptoms, but since they had had their illness for many years, most of them had accepted these symptoms and did not visit their physician for this purpose. Apparently they had learned to accept their symptoms and used chronic acid suppressants. Such a group of patients is highly motivated and compliant if causal therapy is offered. Four patients with a negative latex test but positive ELISA probably present a false-negative latex test. The five patients with negative ELISA as well as negative latex could have been truly negative or also false negative. The negative predictive value of serology is low due to the high prevalence of infection in this category of patients. Therefore, the latex screening test as compared to ELISA has limited value. Had we relied on ELISA to select patients for treatment, five patients (10%) would have received a different treatment and these five may possibly have been treated while not being infected. Prach et al.45 found that in a cohort of 145 patients receiving long-term H2-antagonists for chronic DU, 11.7% were Helicobacter negative, a figure close to the 10% we have found in this prospective study. ELISA can therefore be used to select patients and to avoid antibiotic treatment in a small subset of patients with a history of ulcer disease. The costs of serological testing for the whole cohort, however, must be weighed against this small number (10%) of possible unnecessary therapies. Cost-effectiveness and decision analyses of this clinical problem suggest that GPs can indeed treat patients with an ulcer history without prior serological testing.8,9
We found a significant improvement of most quality-of-life categories after quadruple therapy, the number of gastro-intestinal symptoms decreased and the consumption of drugs diminished. These data suggest that treating patients with a history of ulcer disease in primary health care is worthwhile since it greatly improves well-being. It is at present unknown whether knowledge of treatment results affects patient behaviour with regard to drug taking or further medical consumption. Serology is the only method that GPs can perform individually without relying on others. It is objective, relatively cheap and patient-friendly. A decrease in antibody titres rather than seroconversion is the criterion for successful treatment. It has been proven that a 40% decrease of titre at 6 months proves cure of the infection with a specificity of 100%.6,24 In our study, 40/42 (95.2%) patients showed such a decrease. Recently, it was shown that a percentage of DU patients who have been successfully treated for H. pylori developed signs of gastro-esophageal reflux disease.46,47 A variety of possible explanations for this phenomenon were given.48 We could not confirm these findings; in our study, pyrosis was mentioned by 60% of patients before treatment but only by 25% 6 months later. The decrease in use of medication also suggests that reflux disease had at 6 months not emerged as a new problem.
In this prospective study, we have demonstrated that it is worthwhile for GPs to search for patients with a history of ulcer disease who are using acid-reducing medication and to treat such patients with antimicrobials. We found that quadruple therapy is a highly effective, well-tolerated anti-Helicobacter regimen in the primary health care setting. Prevalence of infection in this patient category is very high and treatment without prior H. pylori testing can therefore be propagated. Although serology can be used before treatment to narrow down the treatment group, this may not be cost-effective unless one wants to do serological follow-up as well. If follow-up is nevertheless deemed necessary, a 40% reduction of the initial antibody titre in the IgG-ELISA (Pyloriset IgG®) is a potentially useful test for the GP.
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Acknowledgments |
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We thank the GPs who participated: HJM Schulte, J de Leur, I van Bavel, JP van der Krogt, CW Brink, WJC de Grauw, J Roffelsen, J Keulers, WH van der Laan and HJ van Herwaarden. We thank PM Schneeberger for performing the serology test, and EH van de Lisdonk and C van Weel for reviewing the article. We also thank Hoechst-Marion-Roussel for printing the case-record forms.
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References |
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1 Walsh JH, Peterson WL. The treatment of Helicobacter pylori infection in the management of peptic ulcer disease. N Engl J Med 1995; 33: 984–991.
2
Soll AH. Consensus statement. Medical treatment of peptic ulcer disease. Practice guidelines. JAMA 1996; 275: 622–629.
3 Neil GA et al. Do ulcers burn out or burn on? Managing duodenal ulcer diathesis in the Helicobacter pylori era. Am J Gastroenterol 1997; 92: 387–392.[Web of Science][Medline]
4 Hopkins RJ, Girardi LS, Turney EA. Relationship between Helicobacter pylori eradication and reduced duodenal and gastric ulcer recurrence: a review. Gastroenterology 1996; 110: 1244–1252.[Web of Science][Medline]
5 Lerang F, Moum B, Ragnhildstveit E et al. A comparison between omeprazole-based triple therapy and bismuth based triple therapy for the treatment of Helicobacter pylori infection: a prospective randomized 1-yr follow-up study. Am J Gastroenterol 1997; 92: 653–658.[Web of Science][Medline]
6 Lai JYL, de Boer WA, Driessen WMM, Geuskens LM. Long-term follow-up after cure of H. pylori infection with 4 days of quadruple therapy. Aliment Pharmacol Ther 1996; 10: 645–650.[Web of Science][Medline]
7
Axon ATR, O'Morain CA, Bardhan KD et al. Randomised double blind contolled study of recurrence of gastric ulcer after treatment for eradication of Helicobacter pylori. Br Med J 1997; 314: 565–568.
8
McCort JT, Fendrick AM. Management of patients with known duodenal ulcer disease but unknown Helicobacter pylori status: a decision analysis. Gut 1996; 39(suppl 2): A22.
9
Fendrick AM, McCort JT, Bloom BS. Clinical and economic effects of immediate Helicobacter eradication for patients with documented peptic ulcer disease but unknown Helicobacter pylori status. Gut 1996; 39(suppl 2): A31.
10 Bodger K, Daly MJ, Heatley RV. Prescribing patterns for dyspepsia in primary care: a prospective study of selected general practitioners. Aliment Pharmacol Ther 1996; 10: 889–895.[Web of Science][Medline]
11 de Boer WA, Tytgat GNJ. The best therapy for Helicobacter pylori infection. Should efficacy or side effect profile determine our choice? Scand J Gastroenterol 1995; 30: 401–407.[Web of Science][Medline]
12 van der Hulst RWM, Keller JJ, Rauws EAJ, Tytgat GNJ. Treatment of Helicobacter pylori infection in humans: a review of the world literature. Helicobacter 1996; 1: 6–19.[Medline]
13 Treiber G. The influence of drug dosage on Helicobacter pylori eradication: a cost-effectiveness analysis. Am J Gastroenterol 1996; 91: 246–257.[Web of Science][Medline]
14 Chiba N, Hunt RH. Bismuth, metronidazole and tetracycline and acid suppression in H. pylori eradication: a meta-analysis. Gut 1996; 39(suppl 2): A36–A37.
15 de Boer WA, Driessen WMM, Jansz AR, Tytgat GNJ. Effect of acid suppression on efficacy of treatment for Helicobacter pylori. Lancet 1995; 345: 817–820.[Web of Science][Medline]
16 de Boer WA, Driessen WMM, Jansz AR, Tytgat GNJ. Quadruple therapy compared with dual therapy for eradication of Helicobacter pylori in ulcer patients. Eur J Gastroenterol Hepatol 1995; 7: 1189–1194.[Web of Science][Medline]
17 de Boer WA, van Etten RJXM, Lai JYL, Schneeberger PM, van de Wouw BAM, Driessen WMM. Effectiveness of quadruple therapy using lansoprazole instead of omeprazole in curing Helicobacter pylori infection. Helicobacter 1996; 1: 145–150.[Medline]
18 Hackelsberger A, Malfertheiner P. A risk-benefit assessment of drugs used in the eradication of Helicobacter pylori infection. Drug Safety 1996; 15: 30–52.[Web of Science][Medline]
19 Harris A, Misiewicz JJ, Hitting H. pylori for four (editorial). Lancet 1995; 345: 806–807.[Web of Science][Medline]
20 de Boer WA. How to achieve a near 100% cure rate for Helicobacter pylori infection in peptic ulcer patients. J Clin Gastroenterol 1996; 22: 313–316.[Web of Science][Medline]
21 de Boer WA, Thys JC, Borody TJ, Graham DY, O'Morain C, Tytgat GNJ. Proposal for use of a standard side effect scoring system in studies exploring H. pylori treatment regimens. Eur J Gastroenterol Hepatol 1996; 8: 641–643.[Web of Science][Medline]
22 Lozniewski A, de Korwin JD, Conroy MC, Plenat F, Weber M. Evaluation of Pyloriset dry, a new rapid agglutination test for Helicobacter pylori antibody detection. J Clin Microbiol 1996; 34: 1773–1775.[Abstract]
23 van de Wouw BAM, de Boer WA, Jansz AR, Roymans RTJM, Staals APG. Comparison of three commercially available enzyme-linked immunosorbent assays and biopsy dependent diagnosis for detecting H. pylori infection. J Clin Microbiol 1996; 34: 94–97.[Abstract]
24 Lerang F, Haug JB, Moum B et al. Accuracy of IgG serology and other tests in confirming Helicobacter pylori eradication. Scand J Gastroenterol 1998; 33: 710–715.[Web of Science][Medline]
25 van Weel C, Kohnig-Zahn C, Touw-Otten FWMM, van Duijn NP, Meyboom-de Jong B. Measuring Functional Health Status with the COOP/WONCA Charts: a Manual. Groningen: Noordelijke Centrum voor Gezondheidsvraagstukken (NCG)/Northern Centre of Health Care Research (NCH)
26 Nelson EC, Wasson JJ, Kirk J et al. Assessment of function in routine clinical practice. Description of the COOP Chart method and preliminary findings. J Chron Dis 1987; 40(suppl 1): 55S–64S.
27 Nelson EC, Landgraf JM, Hays RD et al. The COOP Function Charts. A system to measure patient function in physicians office. In: Classification Committee of WONCA. Functional status in primary care. New York: Springer, 1990.
28 SAS Procedure Guide, Version 6. 3rd edn. Cary, NC: SAS Institute Inc., 1990.
29 Sonnenberg A, Everhart JE. Health impact of peptic ulcer in the United States. Am J Gastroenterol 1997; 92: 614–620.[Web of Science][Medline]
30 Penston JG, Mistry KR. Eradication of Helicobacter pylori in general practice. Aliment Pharmacol Ther 1996; 10: 139–145.[Web of Science][Medline]
31 Fendrick AM, Hirth RA, Chernew ME. Differences between generalist and specialist physicians regarding Helicobacter pylori and peptic ulcer disease. Am J Gastroenterol 1996; 91: 1544–1548.[Web of Science][Medline]
32 Delaney BC. Role of Helicobacter pylori in gastrointestinal disease: implications for primary care of a revolution in management of dyspepsia. Br J Gen Pract 1995; 45: 489–494.[Web of Science][Medline]
33
Hobbs FDR, Delaney BC, Rowsby M, Kenkre JE. Effect of Helicobacter eradication therapy on dyspeptic symptoms in primary care. Fam Pract 1996; 13: 225–228.
34
Ryder SD, O'Reilly S, Miller RJ, Ross J, Jacyna MR, Levi AJ. Long term acid suppressing treatment in general practice. Br Med J 1994; 308: 827–830.
35 Rosengren H, Polson RJ. The role of screening for Helicobacter pylori in patients with duodenal ulceration in the primary health care setting. Br J Gen Pract 1996; 46: 177–179.[Web of Science][Medline]
36 Hippisley-Cox J, Pringle M. A pilot study of a randomized controlled trial of pragmatic eradication of Helicobacter pylori in primary care. Br J Gen Pract 1997; 47: 375–377.[Web of Science][Medline]
37 Kung NNS, Sung JJY, Yuen NWF et al. Anti-Helicobacter pylori treatment in bleeding ulcers: randomized controlled trial comparing 2-day versus 7-day bismuth quadruple therapy. Am J Gastroenterol 1997; 92: 438–441.[Web of Science][Medline]
38 Hosking SW, Ling TKW, Yung MY et al. Randomised controlled trial of short term treatment to eradicate H. pylori in patients with duodenal ulcer. Br Med J 1992; 305: 502–504.
39 Hosking SW, Ling TKW, Chung SCS et al. Duodenal ulcer healing by eradication of H. pylori without anti-acid treatment. Randomised controlled trial. Lancet 1994; 343: 508–510.[Web of Science][Medline]
40 Sung JJY, Leung VKS, Chung SCS et al. Triple therapy with sucralfate, tetracycline and metronidazole for Helicobacter associated duodenal ulcers. Am J Gastroenterol 1995; 90: 1424–1427.[Web of Science][Medline]
41 Vautier G, Scott BB. A one week quadruple eradication regimen for Helicobacter pylori in routine clinical practice. Aliment Pharmacol Ther 1997; 11: 107–108.[Web of Science][Medline]
42 Bolin TD, Korman MG, Engelman JL, Nicholson FB. Lansoprazole and bismuth triple therapy in the eradication of Helicobacter pylori. Gastroenterology 1997; 112: A76.
43 de Boer WA, Tytgat GNJ. How to treat H. pylori infection. Should treatment strategies be based on testing bacterial susceptibility? A personal viewpoint. Eur J Gastroenterol Hepatol 1996; 8: 709–716.[Web of Science][Medline]
44 van Zwet AA, de Boer WA, Schneeberger PM, Weel J, Jansz AR, Thys JC. Prevalence of primary Helicobacter pylori resistance to metronidazole and clarithromycin in The Netherlands. Eur J Clin Microb Infect Dis 1996; 15: 861–864.[Web of Science][Medline]
45 Prach AT, Senior BW, Hopwood D, McBride PDP, Kerr MA, Murray FE. Helicobacter pylori infection status in relation to antibiotic and non-steroidal prescribing in patients on maintenance treatment for chronic duodenal ulcer. Eur J Gastroenterol Hepatol 1997; 9: 251–256.[Web of Science][Medline]
46 Labenz JB, Tillenburg B, Peitz U, Borsch G. Long-term consequences of Helicobacter pylori eradication: clinical aspects. Scand J Gastroenterol 1996; 31(suppl 215): 111–115.[Web of Science][Medline]
47
Sacca N, De Medici A, Rodina S, Giglio A. Reflux oesofagitis: a complication of Helicobacter pylori eradication therapy. Gut 1996; 39(suppl 3): A35.
48 Tytgat GNJ. Role of Helicobacter pylori infection in gastro-oesophageal reflux disease. In Hunt RH, Tytgat GNJ (eds). Helicobacter pylori. Basic Mechanisms to Clinical Cure 1996. Kluwer: Dordrecht, 1996.
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  W A DE BOER and G N J TYTGAT Search and treat strategy to eliminate Helicobacter pylori associated ulcer disease Gut, April 1, 2001; 48(4): 567 - 570. [Full Text] [PDF]
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