Abstract
Introduction
The principal effect of Helicobacter pylori infection is lifelong chronic gastritis, affecting up to 20% of younger adults but 50% to 80% of adults born in resource-rich countries before 1950.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of H pylori eradication treatment in people with a confirmed duodenal ulcer, a confirmed gastric ulcer, confirmed gastro-oesophageal reflux disease (GORD), confirmed non-ulcer dyspepsia, uninvestigated dyspepsia, localised B cell lymphoma of the stomach, and non-steroidal anti-inflammatory drug (NSAID)-related peptic ulcers? What are the effects of H pylori eradication treatment for preventing NSAID-related peptic ulcers in people with or without previous ulcers or dyspepsia? What are the effects of H pylori eradication treatment on the risk of developing gastric cancer? Do H pylori eradication treatments differ in their effects? We searched: Medline, Embase, The Cochrane Library, and other important databases up to September 2007 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 58 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: effects of H pylori eradication in different populations; relative effects of triple regimens, quadruple regimens, and sequential regimens.
Key Points
The principal effect of Helicobacter pylori infection is lifelong chronic gastritis, affecting up to 20% of younger adults but 50% to 80% of adults born before 1950 in resource-rich countries.
H pylori infection can be identified indirectly by the C13 urea breath test and stool antigen tests, which are more accurate than serology.
Transmission and prevalence rates are higher in areas of childhood poverty. Adult reinfection rates are less than 1% a year.
In people with H pylori infection, about 15% will develop a peptic ulcer and 1% will develop gastric cancer during their lifetime.
Eradication of H pylori makes healing of duodenal ulcers more likely and reduces the risk of bleeding with gastric and duodenal ulcers, either alone or when added to antisecretory drug treatment. Eradication also greatly reduces the risk of recurrence of a duodenal ulcer.
Eradication reduces recurrence after healing of a gastric ulcer; however, we don't know whether it increases healing of gastric ulcers.
Eradication of H pylori may reduce the risk of NSAID-related ulcers in people without previous ulcers; however, we don't know whether it reduces NSAID-related ulcers or bleeding in people with previous ulcers.
In areas of low prevalence of H pylori, few ulcers are caused by H pylori infection. Eradication may be less effective in preventing ulcers in these areas compared with higher-prevalence areas.
Eradication of H pylori reduces symptoms of dyspepsia, but not of GORD.
Eradicating H pylori has been shown to reduce dyspeptic symptoms in people with non-ulcer dyspepsia or uninvestigated dyspepsia compared with placebo.
Despite the association between H pylori infection and gastric cancer, no studies have shown a reduced risk after eradication treatment.
Gastric B cell lymphoma lesions may regress after H pylori eradication, but we don't know this for sure.
Quadruple and triple regimens seem equally effective at eradicating H pylori as first-line treatments. Quadruple regimens may be more effective as second-line treatment than triple regimens when a first-line triple regimen has failed to eradicate the infection. However, the evidence is limited in that, in comparisons of second-line quadruple versus triple regimens, most triple regimens did not contain a nitroimidazole.
Ten-day sequential therapy may be more effective at eradicating H pylori than a 7-day triple regimen.
Nitroimidazole-based triple regimens and amoxicillin-based triple regimens seem equally effective at eradicating H pylori. High-dose clarithromycin within an amoxicillin-based triple regimen seems more effective at eradicating H pylori than low-dose clarithromycin. However, the dose of clarithromycin within a nitroimidazole-based triple regimen does not seem to have an effect on eradication rates.
Triple regimens using different proton pump inhibitors seem equally effective at eradicating H pylori.
Pre-treatment with a proton pump inhibitor before triple regimen does not seem to increase H pylori eradication rates compared with no pre-treatment.
Two-week triple proton pump inhibitor regimens may be more effective than 1-week regimens for eradicating H pylori.
Lower eradication rates are achieved in people infected with strains of H pylori that are resistant to antibiotics included in the eradication regimen than are achieved in people infected with sensitive strains of H pylori.
Antibiotics can cause adverse effects such as nausea and diarrhoea. Bismuth may turn the stools black.
Clinical context
About this condition
Definition
Helicobacter pylori is a gram-negative flagellated spiral bacterium found in the stomach. Infection with H pylori is predominantly acquired in childhood. H pylori infection is not associated with a specific type of dyspeptic symptom. The organism is associated with lifelong chronic gastritis and may cause other gastroduodenal disorders. Diagnosis: H pylori can be identified indirectly by serology or by the C13 urea breath test. The urea breath test is more accurate than serology, with a sensitivity and specificity greater than 95%, and indicates active infection, whereas serology may lack specificity and cannot be used reliably as a test of active infection. Thus, the urea breath test is the test of choice where prevalence (and hence predictive value of serology) may be low, or where a "test of cure" is required. In some areas, stool antigen tests that have a similar performance to the urea breath test are now available. Population: This review focuses on H pylori-positive people throughout.
Incidence/ Prevalence
In the developed world, H pylori prevalence rates vary with year of birth and social class. Prevalence in many resource-rich countries tends to be much higher (50%–80%) in individuals born before 1950 compared with prevalence (<20%) in individuals born more recently. In many resource-poor countries, the infection has a high prevalence (80%–95%) irrespective of the period of birth. Adult prevalence is believed to represent the persistence of a historically higher rate of infection acquired in childhood, rather than increasing acquisition of infection during life.
Aetiology/ Risk factors
Overcrowded conditions associated with childhood poverty lead to increased transmission and higher prevalence rates. Adult reinfection rates are low — less than 1% a year.
Prognosis
H pylori infection is believed to be causally related to the development of duodenal and gastric ulceration, B cell gastric lymphoma, and distal gastric cancer. About 15% of people infected with H pylori will develop a peptic ulcer, and 1% of people will develop gastric cancer during their lifetime. One systematic review of observational studies (search date 2000; 16 studies, 1625 people) found that the frequency of peptic ulcer disease in people taking non-steroidal anti-inflammatory drugs (NSAIDs) was greater in those who were H pylori positive than in those who were H pylori negative (peptic ulcer: 341/817 [42%] in H pylori-positive NSAID users v 209/808 [26%] in H pylori-negative NSAID users; OR 2.12, 95% CI 1.68 to 2.67).
Aims of intervention
Eradication of H pylori; improvement in dyspeptic symptoms; improvement in ulcer healing; reduction in ulcer recurrence and complications; reduced mortality from peptic ulcer complications of gastric cancer; improved quality of life.
Outcomes
Under questions on treatments in people with confirmed ulcers: ulcer healing, ulcer recurrence, ulcer bleeding, and ulcer perforation or obstruction. Under questions on preventing ulcers: prevention of ulcers. Under questions on people with symptoms (confirmed GORD, non-ulcer dyspepsia, uninvestigated dyspepsia): symptom improvement (includes quality of life). Under the question on people at risk of developing gastric cancer: prevention of gastric cancer and regression of pre-cancerous lesions. Under the question on whether eradication treatments differ in their effects: eradication rates of H pylori.
Methods
Clinical Evidence search and appraisal September 2007. The following databases were used to identify studies for this review: Medline 1966 to September 2007, Embase 1980 to September 2007, and The Cochrane Library, Issue 3, 2007 (all databases). Additional searches were carried out using these websites: NHS Centre for Reviews and Dissemination (CRD) — for all databases, Turning Research into Practice (TRIP), and NICE. Abstracts of the studies retrieved were assessed independently by two information specialists using pre-determined criteria to identify relevant studies. Study design criteria for inclusion in this review were: published systematic reviews and RCTs in any language and including more than 20 individuals of whom more than 80% were followed up. Open studies were excluded unless the interventions could not be blinded. There was no minimum length of follow-up required to include studies. There is a wide range of combinations of eradication therapy available, and we have restricted our coverage to those regimens in common clinical use. In the question, "Do H pylori eradication regimens differ in their effects?", when assessing triple regimens, we have included only regimens consisting of a proton pump inhibitor plus two antibiotics chosen among clarithromycin, amoxicillin, or a nitroimidazole (either metronidazole or tinidazole). When assessing quadruple regimens, we have included only regimens consisting of a proton pump inhibitor, a bismuth salt (either bismuth citrate, bismuth subsalicylate, bismuth subnitrate, or tripotassium dicitratobismuthate), a nitroimidazole (either metronidazole or tinidazole), and tetracycline. Dose comparisons have been restricted to high-dose versus low-dose clarithromycin in triple regimens. When assessing sequential therapy, we have assessed only 5 days of dual therapy using a proton pump inhibitor plus amoxicillin followed by 5-day triple therapy using a proton pump inhibitor plus a macrolide plus a nitroimidazole. In addition, we use a regular surveillance protocol to capture harms alerts from organisations such as the FDA and the MHRA, which are added to the review as required. To aid readability of the numerical data in our reviews, we round many percentages to the nearest whole number. Readers should be aware of this when relating percentages to summary statistics such as relative risks (RRs) and odds ratios (ORs). We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table). The categorisation of the quality of the evidence (high, moderate, low, or very low) reflects the quality of evidence available for our chosen outcomes in our defined populations of interest. These categorisations are not necessarily a reflection of the overall methodological quality of any individual study, because the Clinical Evidence population and outcome of choice may represent only a small subset of the total outcomes reported, and population included, in any individual trial. For further details of how we perform the GRADE evaluation and the scoring system we use, please see our website (www.clinicalevidence.com).
Table.
GRADE Evaluation of interventions for Helicobacter pylori infection.
| Important outcomes | Eradication rates, Prevention of gastric cancer, Regression of pre-cancerous lesions, Symptom improvement, Ulcer bleeding, Ulcer healing, Ulcer perforation or obstruction, Ulcer prevention, Ulcer recurrence | ||||||||
| Studies (Participants) | Outcome | Comparison | Type of evidence | Quality | Consistency | Directness | Effect size | GRADE | Comment |
| What are the effects of H pylori eradication treatment in people with a confirmed duodenal ulcer? | |||||||||
| 2 (207) | Ulcer healing | Eradication treatment versus no eradication treatment | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for sparse data |
| At least 27 (at least 2509) | Ulcer recurrence | Eradication treatment versus no eradication treatment | 4 | 0 | –1 | 0 | 0 | Moderate | Consistency point deducted for statistical heterogeneity owing to inclusion of different regimens |
| 9 (825) | Ulcer bleeding | Eradication treatment versus antisecretory drugs | 4 | 0 | 0 | –1 | +1 | High | Directness point deducted for inclusion of both duodenal and gastric ulcer. Effect-size point added for RR <0.5 |
| 34 (3910) | Ulcer healing | Eradication treatment plus antisecretory drugs versus antisecretory drugs alone | 4 | 0 | 0 | 0 | 0 | High | |
| 4 (319) | Ulcer recurrence | Eradication treatment plus antisecretory drugs versus antisecretory drugs alone | 4 | 0 | 0 | 0 | 0 | High | |
| What are the effects of H pylori eradication treatment in people with a confirmed gastric ulcer? | |||||||||
| 11 (1104) | Ulcer recurrence | Eradication treatment versus no eradication treatment | 4 | 0 | 0 | 0 | +1 | High | Effect-size point added for RR <0.5 |
| 9 (825) | Ulcer bleeding | Eradication treatment versus antisecretory drugs | 4 | 0 | 0 | –1 | +1 | High | Directness point deducted for inclusion of both duodenal and gastric ulcer. Effect-size point added for RR <0.5 |
| 14 (1572) | Ulcer healing | Eradication treatment plus antisecretory drugs versus antisecretory drugs alone | 4 | 0 | 0 | 0 | 0 | High | |
| What are the effects of H pylori eradication treatment in people with NSAID-related peptic ulcers? | |||||||||
| 1 (195) | Ulcer healing | Eradication treatment versus antisecretory drugs alone | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for sparse data. Directness point deducted for narrow inclusion criteria |
| What are the effects of H pylori eradication treatment for preventing recurrence of NSAID-related peptic ulcers in people with previous ulcers or dyspepsia? | |||||||||
| 2 (502) | Ulcer prevention | Eradication treatment versus antisecretory drugs alone | 4 | –1 | –1 | –1 | 0 | Very low | Quality point deducted for incomplete reporting of results. Consistency point deducted for conflicting results. Directness point deducted for inclusion of different populations |
| What are the effects of H pylori eradication treatment for preventing NSAID-related peptic ulcers in people without previous ulcers? | |||||||||
| 2 (607) | Ulcer prevention | H pylori eradication versus no treatment or placebo | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for no ITT analysis |
| 1 (489) | Ulcer prevention | H pylori eradication treatment versus antisecretory drugs | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for incomplete reporting of results. Directness point deducted for small number of events (2 with triple eradication treatment, none with omeprazole) |
| What are the effects of H pylori eradication treatment in people with confirmed GORD? | |||||||||
| 2 (1748) | Symptom improvement | H pylori eradication treatment versus placebo | 4 | 0 | 0 | 0 | 0 | High | |
| What are the effects of H pylori eradication treatment on the risk of developing gastric cancer? | |||||||||
| 2 (3888) | Prevention of gastric cancer | H pylori eradication treatment versus placebo for the prevention of gastric cancer in people at high risk of cancer | 4 | 0 | 0 | 0 | 0 | High | |
| 1 (852) | Regression of pre-cancerous lesions | H pylori eradication treatment versus placebo for regression of pre-cancerous lesions | 4 | –1 | 0 | 0 | +1 | High | Quality point deducted for incomplete reporting of results. Effect-size point added for RR >2 |
| What are the effects of H pylori eradication treatment in people with confirmed non-ulcer dyspepsia? | |||||||||
| 13 (3186) | Symptom improvement | H pylori eradication treatment versus placebo | 4 | 0 | 0 | 0 | 0 | High | |
| What are the effects of H pylori eradication treatment in people with uninvestigated dyspepsia? | |||||||||
| 2 (478) | Symptom improvement | H pylori eradication treatment versus placebo in people with uninvestigated dyspepsia | 4 | 0 | 0 | 0 | 0 | High | |
| 8 (at least 3178) | Symptom improvement | Initial H pylori testing plus eradication treatment versus management based on initial endoscopy or versus empirical eradication treatment | 4 | 0 | –1 | –1 | 0 | Low | Consistency point deducted for conflicting results. Directness point deducted for uncertainty of applicability of results to both primary and secondary care settings |
| Do H pylori eradication treatments differ in their effects? | |||||||||
| 5 (1128) | Eradication rates | Quadruple regimen versus triple regimen as first-line treatment | 4 | 0 | 0 | 0 | 0 | High | |
| 3 (184) | Eradication rates | Quadruple regimens versus triple regiments as second-line treatment | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for sparse data. Directness point deducted for inclusion of regimens of different durations |
| 6 (2146) | Eradication rates | Sequential eradication regimens versus triple eradication regimens as first-line treatment | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for incomplete reporting of data. Directness point deducted for all studies being conducted in centres in a single country |
| 21 (3998) | Eradication rates | Nitroimidazole-based versus amoxicillin-based triple regimens as first-line treatment | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting |
| 25 (5324) | Eradication rates | Triple regimens using different proton pump inhibitors versus each other as first-line treatment | 4 | 0 | 0 | 0 | 0 | High | |
| 7 (892) | Eradication rates | Higher-dose clarithromycin-based triple regimens versus lower-dose clarithromycin-based triple regimens as first-line treatment | 4 | 0 | –1 | 0 | 0 | Moderate | Consistency point deducted for different results between SR and subsequent RCTs |
| 9 (773) | Eradication rates | Pre-treatment with proton pump inhibitor versus no pre-treatment | 4 | 0 | 0 | 0 | 0 | High | |
| 10 (2592) | Eradication rates | 14-day triple regimen versus 7-day triple regimen as first-line treatment | 4 | 0 | –1 | 0 | 0 | Moderate | Consistency point deducted for different results between SR and subsequent RCTs |
We initially allocate 4 points to evidence from RCTs, and 2 points to evidence from observational studies. To attain the final GRADE score for a given comparison, points are deducted or added from this initial score based on preset criteria relating to the categories of quality, directness, consistency, and effect size. Quality: based on issues affecting methodological rigour (e.g., incomplete reporting of results, quasi-randomisation, sparse data [<200 people in the analysis]). Consistency: based on similarity of results across studies. Directness: based on generalisability of population or outcomes. Effect size: based on magnitude of effect as measured by statistics such as relative risk, odds ratio, or hazard ratio.
Glossary
- Antisecretory treatment
A treatment that reduces the production of acid by the stomach. These treatments may either be H2 receptor antagonists or proton pump inhibitors.
- Bismuth
A compound containing a bismuth salt, such as bismuth subsalicylate or bismuth citrate.
- High-quality evidence
Further research is very unlikely to change our confidence in the estimate of effect.
- Low-quality evidence
Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
- MALT
Mucosa-associated lymphoid tissue (MALT) is constitutionally found in the intestine but not in the stomach. MALT lymphoma is also known as B cell gastric lymphoma.
- Moderate-quality evidence
Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
- Proton pump inhibitor
A drug that directly inhibits the mechanism within the stomach that secretes acid; examples are esomeprazole, lansoprazole, omeprazole, pantoprazole, or rabeprazole.
- Quadruple regimens
H pylori eradication regimen consisting of four components: a proton pump inhibitor, a bismuth salt, a nitroimidazole (either metronidazole or tinidazole), and tetracycline.
- Quadruple regimens
Helicobacter pylori eradication regimen consisting of a proton pump inhibitor plus bismuth plus metronidazole plus tetracycline.
- Sequential therapy
Involves 10-day H pylori eradiction treatment: 5-day dual therapy with proton pump inhibitor plus amoxicillin followed by 5-day triple therapy with proton pump inhibitor plus macrolide plus a nitroimidazole.
- Triple regimens
H pylori eradication regimen consisting of three components: a proton pump inhibitor plus two antibiotics (either clarithromycin or amoxicillin), and a nitroimidazole (either metronidazole or tinidazole).
- Very low-quality evidence
Any estimate of effect is very uncertain.
Disclaimer
The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients. To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.
Contributor Information
Grigorios I Leontiadis, Division of Gastroenterology , McMaster University, Hamilton ON, Canada.
Professor Paul Moayyedi, Director, Division of Gastroenterology, McMaster University, Hamilton ON, Canada.
Alexander Charles Ford, Leeds Gastroenterology Institute, St James’s University Hospital, Leeds, UK.
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