Peptic Ulcer Disease Clinical Practice Guideline

[Mireille Kreines]

Themost common causes of peptic ulcer disease (PUD) are Helicobacter pylori infection and use of nonsteroidal anti-inflammatory drugs (NSAIDs). The test-and-treat strategy for detecting H. pylori is appropriate in situations where the risk of gastric cancer is low based on age younger than 55 years and the absence of alarm symptoms. Most other patients should undergo upper endoscopy to rule out malignancy and other serious causes of dyspepsia. Urea breath tests and stool antigen tests are most accurate for identifying H. pylori infection and can be used to confirm cure; serologic tests are a convenient but less accurate alternative and cannot be used to confirm cure. Treatment choices include standard triple therapy, sequential therapy, quadruple therapy, and levofloxacin-based triple therapy. Standard triple therapy is only recommended when resistance to clarithromycin is low. Chronic use of NSAIDs in patients with H. pylori infection increases the risk of PUD. Recommended therapies for preventing PUD in these patients include misoprostol and proton pump inhibitors. Complications of PUD include bleeding, perforation, gastric outlet obstruction, and gastric cancer. Older persons are at higher risk of PUD because of high-risk medication use, including antiplatelet drugs, warfarin, selective serotonin reuptake inhibitors, and bisphosphonates.

Dyspepsia is characterized by epigastric pain, discomfort, or a burning sensation.1 An important cause of dyspepsia is peptic ulcer disease (PUD), which includes gastric and duodenal ulcers. Although PUD is most commonly caused by Helicobacter pylori infection or use of nonsteroidal anti-inflammatory drugs (NSAIDs), other diagnoses should be considered (Table 1).

H. pylori, a gram-negative, helical, rod-shaped bacterium, colonizes the gastric mucosa of approximately one-half of the world population2 and an estimated 30% to 40% of the U.S. population.3 H. pylori is present in 95% of patients with duodenal ulcers and in 70% of those with gastric ulcers.4 It is typically transmitted via the fecal-oral route during early childhood and persists for decades. The bacterium is a known cause of gastric and duodenal ulcers5 and is a risk factor for mucosa-associated lymphoid tissue (MALT) lymphoma and gastric adenocarcinoma.6,7

The history and physical examination are important to identify patients at risk of ulcer, perforation, bleeding, or malignancy. However, a systematic review of models using risk factors, history, and symptoms found that they did not reliably distinguish between functional dyspepsia and organic disease.8 Therefore, the test-and-treat strategy for H. pylori is recommended for patients with dyspepsia who have no alarm symptoms.1

Urea breath tests require the ingestion of urea labeled with the nonradioactive isotope carbon 13 or carbon 14. Specificity and sensitivity approach 100%. Urea breath testing is one option for test of cure and should be performed four to six weeks after completion of eradication therapy. Proton pump inhibitors (PPIs) must be stopped for at least two weeks before the test, and accuracy is lower in patients who have had distal gastrectomy. Cost and inconvenience are disadvantages of this test.8

Stool antigen tests using monoclonal antibodies are as accurate as urea breath tests if a validated laboratory-based monoclonal test is used.1,11 They are cheaper and require less equipment than urea breath tests. Like urea breath tests, stool antigen tests detect only active infection and can be used as a test of cure. PPIs should be stopped for two weeks before testing, but stool antigen tests are not as affected by PPI use as are urea breath tests.

Serologic antibody testing detects immunoglobulin G specific to H. pylori in serum and cannot distinguish between an active infection and a past infection. Serologic tests may be most useful in mass population surveys and in patients who cannot stop taking PPIs (e.g., those with gastrointestinal bleeding or continuous NSAID use) because the tests are not affected by PPI or antibiotic use.1,2

Endoscopy with biopsy is recommended to rule out cancer and other serious causes in patients 55 years or older, or with one or more alarm symptoms. In patients who have not been taking a PPI within one to two weeks of endoscopy, or bismuth or an antibiotic within four weeks, the rapid urease test performed on the biopsy specimen provides an accurate, inexpensive means of diagnosing H. pylori infection.2 Patients who have been on these medications will require histology, with or without rapid urease testing. Culture and polymerase chain reaction allow for susceptibility testing but are not readily available for clinical use in the United States.

Eradication heals most duodenal ulcers and greatly diminishes the risk of recurrent bleeding.3 A systematic review found that treatment of H. pylori infection is more effective than antisecretory noneradicating therapy (with or without long-term maintenance antisecretory therapy) in preventing recurrent bleeding from peptic ulcer.17 Current data suggest that increasing the duration of therapy to 14 days significantly increases the eradication rate.18

A seven- to 10-day triple drug regimen consisting of a PPI, amoxicillin 1 g, and clarithromycin 500 mg (Biaxin) twice daily has long been the first-line therapy to eradicate H. pylori. However, increasing resistance to clarithromycin is associated with declining eradication rates, now well below 80%.19 Therefore, this regimen is not recommended where the prevalence of clarithromycin-resistant strains of H. pylori exceeds 15% to 20%.1 An alternative triple drug regimen substitutes metronidazole 500 mg twice daily for amoxicillin. Adding probiotics to triple therapy, specifically Saccharomyces boulardii and Lactobacillus, has been shown to increase eradication rates (absolute increase of 9% and 5%, respectively) and decrease adverse effects of treatment, particularly diarrhea (absolute decrease of 14% and 7%, respectively).20,21

Compliance and tolerance rates of sequential therapy are similar to those of triple therapy but cost is lower, especially when the cost of failure of first-line therapy is considered. However, most studies were performed in Italy, and the ACG guideline states that sequential therapy requires validation in the United States.3

This is the traditional quadruple regimen and includes a bismuth salt (subsalicylate 525 mg or subcitrate potassium 420 mg), metronidazole 250 mg, and tetracycline 375 to 500 mg, all taken four times daily, in addition to a PPI taken twice per day.2 Bismuth-based quadruple therapy is often employed as salvage therapy if first-line treatment fails, but it may be used as first-line therapy in areas of high resistance or when cost is an important consideration. A three-in-one combination capsule containing bismuth subcitrate potassium, metronidazole, and tetracycline has been developed to help reduce the pill burden, but patients still have to take three capsules four times per day in addition to a PPI. The regimen is usually given for 10 to 14 days.

This is a 10-day regimen of a PPI and amoxicillin 1 g twice daily, and levofloxacin 500 mg (Levaquin) once daily. The ACG states that this regimen requires validation in the United States.3 It should be reserved for second-line therapy and is better tolerated than bismuth-based quadruple therapy.16

Risk factors for gastrointestinal toxicity from NSAID use include older age; chronic use of high-dose NSAIDs; use of aspirin, anticoagulants, or corticosteroids; and a history of ulcer.22 Therapies aimed at protecting the mucosa include the prostaglandin analogue misoprostol (Cytotec), histamine H2 receptor antagonists, a cyclooxygenase-2 (COX-2) inhibitor instead of a standard NSAID, and PPIs. A Cochrane review on the effectiveness of these therapies compared with placebo suggests that high-risk patients should take a COX-2 inhibitor with a PPI for the greatest gastrointestinal safety.23

Concerns have been raised about increased cardiovascular risk with the use of COX-2 inhibitors. The ACG22 and the Canadian Association of Gastroenterology 24 have each developed evidence-based guidelines for the prevention of NSAID-related ulcers in patients at risk of cardiovascular disease, including those with previous cardiovascular events. The recommendations are summarized in Table 4.22,24 NSAIDs are appropriate for patients with low risk of gastrointestinal complications, whereas cotherapy with a PPI or misoprostol is preferred for patients with gastrointestinal risk factors.22,24 Patients at low cardiovascular risk may take traditional NSAIDs or a COX-2 inhibitor; however, the Canadian Association of Gastroenterology suggests that the use of naproxen may be appropriate for patients at high cardiovascular risk.22,24

Although gastrointestinal symptoms are common in children, PUD is rare (24.8 per 100,000 children annually).29 Recurrent abdominal pain is not associated with H. pylori infection, and there is conflicting evidence regarding the association between epigastric pain and H. pylori infection.30 One study found that nausea, vomiting, and diarrhea were associated with H. pylori, but that abdominal pain and heartburn were not.31 An evidence-based clinical guideline developed by an international panel makes recommendations for H. pylori infection in children and adolescents. The best supported recommendations are presented in Table 5.32

The complications of PUD from any etiology include bleeding, perforation, and gastric outlet obstruction.33 Hemorrhage is the most common complication, with up to 15% of patients experiencing some degree of bleeding. In one study, the incidence of peptic ulcer hospitalizations was 5.65 per 1,000 person-years in patients taking NSAIDs without gastrointestinal protective therapy.33 Endoscopy is considered the standard of care for patients with gastrointestinal bleed and may allow for treatment of the ulcer at the same time.29

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