Role of Helicobacter pylori eradication in the prevention of peptic ulcer in NSAID users

Helicobacter pylori (H. pylori) and non-steroidal anti-inflammatory drug (NSAID) are independent risk factors for peptic ulcers and ulcer complications and they have additive or synergistic effects. A meta-analysis showed that the OR for the incidence of peptic ulcer was 61.1 in patients infected with H. pylori and also taking NSAID when compared to patients uninfected with H. pylori and not taking NSAID. H. pylori eradication may prevent NSAID-induced ulcers in NSAID naive patients. In patients receiving long-term NSAID, proton pump inhibitor(PPI) is more effective in the prevention of ulcer recurrence and bleeding. However, H. pylori eradication should be considered in patients receiving long -term PPI maintenance treatment to prevent the development of corpus gastritis and gastric atrophy.     

Pathogenesis of gastric and duodenal ulcer in the elderly

In the elderly, H. pylori infection and nonsteroidal anti-inflammatory drug(NSAID) use are most important risk factors for peptic ulcer disease. It is now recognized that, in patients with H. pylori infection, nonatrophic antral-predominant gastritis results in increased acid secretion, which is seen in duodenal ulcer patients, whereas corpus-predominant gastritis and pangastritis result in decreased acid secretion, that are seen in patients with proximal gastric ulcer and gastric cancer. These physiological changes are considered to be related to disease outcome. On the other hand, NSAIDs induced gastrointestinal toxicity is primarily due to the inhibition of mucosal prostaglandin synthesis in the gastric mucosa, which subsequently impairs the gastric cytoprotective factors. These two factors may independently, or even synergistically, cause the development of peptic ulcer disease in the elderly.     

Future for basic and clinical studies on peptic ulcer disease

Since the discovery of H. pylori, various causes of peptic ulcer disease is reevaluated, and only four factors are now considered most important; H. pylori infection, gastric acid, NSAID administration, and mental and physical stress. Among them, gastric acid is an aggravating factor, and gastric acid alone can hardly develop peptic ulcers. The relationship between H. pylori infection and stress has been studied at Hanshin-Awaji great earthquake occurred in 1995. Immediately after the earthquake, the number of patients with peptic ulcer disease has been greatly increased, and those patients were considered to be typical cases of stress ulcers. Interestingly, however, it was found that 83.2% of the patients were infected with H. pylori. The data suggested that stress ulcer developed in those infected with H. pylori. In contrast, the relationship between H. pylori infection and NSAID in the development of ulcer disease is more complex. It is still unclear whether H. pylori infection is an additive effect for development of peptic ulcer disease by NSAID administration or not.     

Ulcer and gastritis

As in previous years, developments in the field of ulcers and gastritis have been dominated by new findings related to Helicobacter pylori. With the decrease in the frequency of H. pylori infection, the relative proportion of non-H. pylori ulcers has increased. Attempts to reduce the endoscopy workload by H. pylori or CagA screening have not been successful, and are probably ill-advised. It has become increasingly clear that curing H. pylori infection will not automatically lead to complete relief of symptoms in patients with duodenal ulcer disease. Post-therapy confirmation of cure will probably become the norm. Studies comparing omeprazole to misoprostol or ranitidine for nonsteroidal anti-inflammatory drug (NSAID) ulcer prevention in true NSAID ulcers have shown that omeprazole is equal to full-dose misoprostol for ulcer healing and to the lowest useful dose of misoprostol for ulcer prevention. H2-receptor antagonists cannot be recommended for NSAID ulcer healing or prevention. Elimination of H. pylori increases the prevalence of gastroesophageal reflux disease in a population in such a way that superficially, there appears to be a choice between more gastroesophageal reflux disease or multifocal atrophic gastritis. The risk of developing adenocarcinoma of the esophagogastric junction is many times (10-fold to 60-fold) less than the risk of developing gastric cancer from CagA-positive H. pylori infection with multifocal atrophic gastritis - the "protective" lesion.     

Treatment and prevention of gastric ulcers in elderly persons

Treatment and prevention of gastric ulcers is not different between young and elderly patients. Eradication therapy for H. pylori infection should be made for elderly patients with H. pylori-gastric ulcers, because the incidence of adverse events is not higher than in young patients. NSAIDs are often given elderly persons, and aging is a risk factor of the development of NSAID-related ulcer. If elderly patients have some risk factors (high dose NSAID therapy, past history of uncomplicated ulcers or concurrent use of aspirin, corticosteroids or anticoagulants), prophylactic therapy for NSAID-ulcers should be made.     

Management of NSAID-induced ulcer disease.

The use of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with an increased risk of gastric and duodenal ulcers, especially in patients with previous ulcer disease, heavy smokers, patients who are taking steroids and those with other illnesses. In patients at risk for gastroduodenal complications, prophylactic therapy with misoprostol or an H2-receptor antagonist should be considered. If ulcers occur during NSAID therapy, the anti-inflammatory drug should be discontinued and standard ulcer-healing therapy instituted. If NSAID therapy must be continued, ulcer healing may be prolonged.     

The effect of helicobacter pylori eradication on NSAID-induced gastrointestinal toxicity

OBJECTIVE: To review the data to determine whether Helicobacter pylori eradication alters nonsteroidal antiinflammatory drug (NSAID)-induced gastrointestinal toxicity. DATA SOURCE: Literature accessed through MEDLINE from 1966 to May2000 and abstracts of recently presented data at scientific meetings. DATA SYNTHESIS: NSAID use and H. pylon infection are independent risk factors for the development of gastrointestinal ulcers. An evaluation of the relationship between these two risk factors and the impact of H. pylori eradication on NSAID-induced gastrointestinal toxicity was conducted. CONCLUSIONS: H. pylori colonization and NSAID use are independent risk factors for the development of gastrointestinal ulcers. The data regarding the interaction between these two risk factors in the development of gastrointestinal ulcers are conflicting. Eradication of H. pylori does not appear to decrease the risk of NSAID-induced gastrointestinal toxicity in the majority of patients. As there is little evidence to support a clear benefit of eradicating H. pylori in patients requiring NSAID therapy, routine screening for and eradication of H. pylori in these patients is not recommended.     

Pathologic characteristics of gastric ulcer in the aged

The use of aspirin continues to increase as a result of accumulation of evidence of benefits in treatment strategies for cardiovascular disease. These antiplatelet agents, however, have recognizable risks of gastrointestinal complications such as ulceration and related bleeding. Based on the published guidelines in Japan, the cause of gastric ulcer is divided roughly into Helicobacter pylori infection and nonsteroidal antiinflammatory drug (NSAID) including aspirin. With the decrease of H. pylori infection rate in a young and that of ulcer recurrence by H. pylori eradication therapy, the cases with peptic ulcer that is come from H. pylori infection have decreased in Japan. On the other hand, gastric ulcer based on the use of aspirin and NSAID have increased. The author reviewed pathologic characteristics of gastric ulcer in the aged in this report.     

Guideline for prophylaxis and treatment of NSAID-associated gastric ulcerations

Both Helicobacter pylori (H. pylori) infection and non-steroidal anti-inflammatory drug (NSAID) administration independently and significantly increase the risk of peptic ulceration and ulcer bleeding as its complication. Because of increasing ratio of the senior generation in Japan, the relative role of NSAID including low-dose aspirin as an anti-platelet therapy, will be more important in the pathogenesis of peptic ulcerations. In order to prevent peptic ulcerations, one of the major adverse events of NSAID, a series of selective COX-2 inhibitors has been developed and some of them have been widely used clinically. However, long-term use of a COX-2 inhibitor may be associated with higher risk of cardiovascular events and strokes. Herein, we focus on prophylaxis and treatment of NSAID-associated gastric ulcerations.     

Ulcers and gastritis

This article reviews recently published literature regarding ulcers and gastritis. Although endoscopy is the most useful procedure for diagnosis in the upper gastrointestinal tract, complications do occur, and procedure-related costs are significant. The appropriate indication for endoscopy has recently been debated. Helicobacter pylori is known to be an important pathogen involved in gastric and duodenal inflammation. Peptic ulcer disease and severe gastric mucosal injury are caused by virulent strains, and many reports have focused on CagA. Follow-up studies on surveillance endoscopy in patients with peptic ulcer or gastritis report that patients with atrophic gastritis and intestinal metaplasia are at significantly higher risk for gastric cancer. H. pylori eradication sometimes causes gastroduodenal erosion and reflux esophagitis, and the mechanisms involved have been revealed. Proton-pump inhibitors are useful in the treatment of ulcers caused by nonsteroidal anti-inflammatory drugs (NSAIDs), reflux esophagitis, and for preventing rebleeding after endoscopic hemostasis, but the effect of long-term acid suppression on the gastric mucosa is still a matter of debate. H. pylori infection and NSAID intake are both risk factors for peptic ulcer disease, and are important aspects in this field.     

Acute upper gastrointestinal bleeding: comparison between recent users and nonusers of nonsteroidal anti-inflammatory drugs

BACKGROUND AND STUDY AIMS: To determine clinical, endoscopic, and outcome differences between recent users and nonusers of nonsteroidal anti-inflammatory drugs (NSAIDs) presenting with upper gastrointestinal bleeding (UGIB). PATIENTS AND METHODS: A total of 330 consecutive patients who presented with clinical manifestations of UGIB underwent urgent endoscopy after clinical assessment within 12 h of admission. The patients were divided into two groups, depending on whether there was a positive or negative history of recent NSAID use. Urgent endoscopy followed by endoscopic hemostasis and/or biopsy, as needed, was performed by the same endoscopist, who was blinded to the patients' clinical status. RESULTS: The baseline characteristics, clinically estimated severity of UGIB, and outcome did not differ between the two groups. Recent NSAID users were found to bleed from an ulcer more frequently (P=0.009) than nonusers of NSAIDs, the latter more often having a history of peptic ulcer or UGIB (P=0.02). Bleeding ulcers were mostly duodenal in the NSAID group and gastric in the non-NSAID group (P<0.001). Helicobacter pylori infection was significantly more common among NSAID users (P<0.01). The group of NSAID users included a significantly greater proportion of alcohol abusers (P=0.01), who were found to bleed mostly from erosive gastritis. CONCLUSIONS: Recent NSAID users were found to bleed from ulcers, mostly duodenal, and to have H. pylori infection more frequently than UGI bleeders with a negative history of NSAID consumption. Alcohol abuse was also more common among NSAID users. The severity of bleeding and the outcome did not differ between the two groups.     

Clinical features of peptic ulcer disease in the elderly

Peptic ulcer disease in the elderly is considered to be more serious disorder than that in younger patients because of the presence of more risk factors and complications. Bleeding and perforation are the most frequent ulcer complications. Nonsteroidal anti-inflammatory drugs(NSAIDs)-induced ulcer is more prevalent, and atypical symptoms often lead to a delay in diagnosis and treatment in the elderly patients. These two factors may contribute to the greater mortality in the elderly. The treatment is directed toward gastric acid suppression in combination with elimination of causative factors such as H. pylori infection or NSAIDs, and the control for comorbid medical conditions. It is important to avoid unnecessary medications and clinicians should pay attention to drug interactions, especially some kinds of H2 receptor antagonists.     

Guidelines for the management of Helicobacter pylori--Maastricht III-2005 and Japanese guidelines

The guidelines on the management of Helicobacter pylori were updated at the European Helicobacter study group third Maastricht consensus conference in March 2005. Especially, this conference emphasis on the management of non ulcer dyspepsia, GERD, and the patients who use non steroidal anti-inflammatory drug. Eradication of H. pylori is recommended in patients with peptic ulcer, low grade MALT lymphoma, atrophic gastritis, unexplained iron deficiency anemia, chronic idiopathic thrombocytopenic purpura and first degree relatives of patients with gastric cancer. H. pylori eradication is less effective than proton pomp inhibitor(PPI) treatment in preventing ulcer recurrence in long term NSAIDs users. This meeting also emphasized on the relationship between H. pylori and gastric cancer. The guideline concluded that H. pylori eradication has the potential to reduce the risk of gastric cancer development. Japanese guideline in 2003 does not mention the effect of eradication for prevention of gastric cancer. The H. pylori eradication and new strategy should be desirable for global strategy of gastric cancer prevention.     

Prevention of anti‐inflammatory drug‐induced gastrointestinal damage: Benefits and risks of therapeutic strategies

Patients who take non‐steroidal anti‐inflammatory drugs (NSAIDs) may develop serious gastrointestinal (GI) side effects in both the upper and lower GI tract. Those at risk should be considered for prevention with misoprostol, proton pump inhibitor (PPI) or COX‐2 selective inhibitor (coxib) therapy. A coxib or an NSAID+PPI combination is considered to have comparable GI safety profiles, but evidence from direct comparison is limited. PPIs are effective in the prevention of upper GI events in endoscopy trials and in a few, small, outcome trials in patients at risk. Coxibs have been evaluated in endoscopic ulcer studies and clinical outcome trials, and shown to significantly reduce the risk of upper GI ulcer and complications. Moreover, unlike PPIs, coxibs significantly reduce toxicity in the lower GI tract compared with NSAIDs. Coxibs and possibly some NSAIDs also increase the risk of developing serious cardiovascular events, an effect which may depend on the drug, dose and duration of therapy. It is not known whether concomitant low‐dose aspirin use, which occurs in more than 20% of patients, will reduce the incidence of cardiovascular events, although concomitant aspirin increases the risk of developing serious GI events in patients taking either an NSAID or a coxib. Such patients may require additional PPI co‐therapy. Current prevention strategies with an NSAID+PPI, misoprostol or a coxib must be considered in the individual patient with GI and cardiovascular risk factors. A PPI+coxib is indicated in those at highest risk (e.g. previous ulcer bleeding). PPI therapy must be considered for the treatment and prevention of NSAID‐induced dyspepsia.     

Clinical features and diagnosis of non-steroidal anti-inflammatory drugs induced ulcers of the stomach

Helicobacter pylori (H. pylori) infection and non-steroidal anti-inflammatory drugs (NSAIDs) or aspirin induce serious gastrointestinal ulcer and bleeding. Also both H. pylori infection and NSAIDs or aspirin use independently and significantly increase the risk of peptic ulcer and its complications. Interestingly, it has been reported that no evidence exists that reducing the dose or using modified release formulations such as enteric-coated of aspirin would reduce the incidence of ulcer bleeding. Selective COX-2 inhibitors use shows a low relative risk of ulcer bleeding than NSAIDs. However, when combined with aspirin, the differences between selective COX-2 inhibitors and NSAIDs tend to disappear. NSAIDs/aspirin dominantly develops multiple ulcers from the angulus to the antrum regardless of H. pylori infection. In contrast, the irregular shape of ulcer is more frequently detected in patients taking NSAIDs in comparison with H. pylori-associated ulcer, but the association was not seen in cases taking aspirin. This result indicates that the mechanism of ulcer formation may be different between NSAIDs and aspirin.     

Update on Helicobacter pylori treatment

One half of the world's population has Helicobacter pylori infection, with an estimated prevalence of 30 percent in North America. Although it is unclear whether eradication of H. pylori improves symptoms in patients with nonulcer dyspepsia, there is strong evidence that eradication of this bacteria improves healing and reduces the risk of recurrence or rebleeding in patients with duodenal or gastric ulcer. A "test-and-treat" strategy is recommended for most patients with undifferentiated dyspepsia. With this approach, patients undergo a noninvasive test for H. pylori infection and, if positive, are treated with eradication therapy. This strategy reduces the need for antisecretory medications as well as the number of endoscopies. The urea breath test or stool antigen test is recommended. Until recently, the recommended duration of therapy for H. pylori eradication was 10 to 14 days. Shorter courses of treatment (i.e., one to five days) have demonstrated eradication rates of 89 to 95 percent with the potential for greater patient compliance. A one-day treatment course consists of bismuth subsalicylate, amoxicillin, and metronidazole, all given four times with a one-time dose of lansoprazole. In children with documented H. pylori infection, however, all regimens should continue to be prescribed for seven to 14 days until short-course treatment is studied and its effectiveness has been established in this population.     

Characteristic clinical features of NSAID ulcer

Following the increase of elder people, the proportion of NSAID ulcer has started to rise. NSAID ulcer has characteristic clinical features compared with H. pylori ulcer, such as no abdominal pain and sudden bleeding. And it is reported that the mortality rate of NSAID ulcer is higher than that of non-NSAID ulcer. So clinicians have to find NSAID ulcer as soon as possible. And when we see a patient suffering from anemia, we should examine the presence of NSAID ulcer with an endoscope. In evaluating patients taking NSAID, it is important for clinicians to note the characteristic features of NSAID ulcer.     

Position of NSAIDs in causal factors of peptic ulcer

The cause of peptic ulcer is classified into five categories; infectious, drug-induced, hyperacidic, secondary, and idiopathic. Among these factors, H. pylori infection and non-steroidal anti-inflammatory drugs including aspirin (NSAIDs) are most important for development of gastroduodenal ulcer. More than 95 percent of gastroduodenal ulcers are associated with H. pylori or NSAIDs. Therefore, the frequency of non-H. pylori non-NSAIDs ulcer is very low. NSAIDs have the effect to inhibit synthesis of cyclooxygenase-1 (COX 1) and COX-2. This inhibitory action induces analgesic and anti-inflammatory effects. On the other hand, inhibitory action for COX-1 reduces the production of prostaglandin that is related to protective effect for gastrointestinal mucosa. Its mechanism is able to induce gastroduodenal ulcer. Since the elderly population in Japan is rising, the number of patients who need NSAIDs treatment is expected to increase in near future.     

Medical treatment of peptic ulcer disease.

Our understanding of PUD and its treatment has improved dramatically during the past 15 years. During this time, many new effective drugs have been approved by the FDA, and possibly even more potent and effective therapies are now being evaluated. The H2-blockers, sucralfate, and antacids heal over 90% of duodenal ulcers in 6 to 8 weeks, and H2-blockers heal about 80% of gastric ulcers by 8 weeks and over 90% by 12 weeks. The new, more potent pump blockers (omeprazole) promise to be even more effective drugs, even for the healing of patients who are taking NSAIDS. However, the potential hazards of marked, long-term acid suppression must still be evaluated. Maintenance therapy with H2-blockers or sucralfate, ideally used for patients who would otherwise have frequent symptomatic recurrences of duodenal ulcer disease or who have had complications, reduces the relapses, especially symptomatic relapses. Maintenance therapy with H2-blockers also seems to reduce the recurrences of GUD, but this use has not yet received FDA approval. Elimination of H. pylori infection with antibiotics may prove to reduce recurrent ulcer disease and negate the need for maintenance therapy. Colloidal bismuth subcitrate alone, which suppresses but does not eradicate H. pylori infection, seems to be an effective ulcer drug and may even reduce the rate of early recurrences. Effective ulcer therapy, especially if it prevents recurrent disease, may reduce the complications of PUD, but this expectation has yet to be established. The use of prophylactic cytoprotective prostaglandins (misoprostol) reduces the incidence of NSAID-induced GUD.     

Prevention of anti-inflammatory drug-induced gastrointestinal damage: benefits and risks of therapeutic strategies

Patients who take non-steroidal anti-inflammatory drugs (NSAIDs) may develop serious gastrointestinal (GI) side effects in both the upper and lower GI tract. Those at risk should be considered for prevention with misoprostol, proton pump inhibitor (PPI) or COX-2 selective inhibitor (coxib) therapy. A coxib or an NSAID+PPI combination is considered to have comparable GI safety profiles, but evidence from direct comparison is limited. PPIs are effective in the prevention of upper GI events in endoscopy trials and in a few, small, outcome trials in patients at risk. Coxibs have been evaluated in endoscopic ulcer studies and clinical outcome trials, and shown to significantly reduce the risk of upper GI ulcer and complications. Moreover, unlike PPIs, coxibs significantly reduce toxicity in the lower GI tract compared with NSAIDs. Coxibs and possibly some NSAIDs also increase the risk of developing serious cardiovascular events, an effect which may depend on the drug, dose and duration of therapy. It is not known whether concomitant low-dose aspirin use, which occurs in more than 20% of patients, will reduce the incidence of cardiovascular events, although concomitant aspirin increases the risk of developing serious GI events in patients taking either an NSAID or a coxib. Such patients may require additional PPI co-therapy. Current prevention strategies with an NSAID+PPI, misoprostol or a coxib must be considered in the individual patient with GI and cardiovascular risk factors. A PPI+coxib is indicated in those at highest risk (e.g. previous ulcer bleeding). PPI therapy must be considered for the treatment and prevention of NSAID-induced dyspepsia.