Approach
The goal of therapy is to treat complications (e.g., active bleeding), eliminate the underlying cause whenever possible, relieve symptoms, and heal ulcers.
Active bleeding ulcer
Active gastrointestinal bleeding requires urgent evaluation.[62] Most bleeding can be treated endoscopically.
Endoscopy aids in confirming the diagnosis and identifying the cause of bleeding, as well as stopping the bleeding. A number of endoscopic tools can be used to stop bleeding including mechanical clips, thermal cautery, and hemostatic sprays.[63] Epinephrine (adrenaline) injection is no longer used as sole treatment but is used in combination with other endoscopic modalities.
After endoscopic hemostasis, high-dose proton-pump inhibitor (PPI) therapy, given either continuously or intermittently for 3 days, is recommended.[62][64][65] After 72 hours, twice-daily oral treatment with a PPI, for the first 2 weeks, is recommended.[62][64] These recommendations are based on high-quality evidence documenting a large relative risk reduction in further bleeding and mortality with postendoscopy PPI compared with placebo/no treatment.[64][66][67][68] Ongoing oral PPI therapy beyond these timeframes depends on the nature of the bleeding ulcer.[65]
The role of pre-endoscopic PPI therapy in patients who present with ulcer bleeding remains an area of ongoing debate.[69] International consensus recommendations recommend that pre-endoscopic PPI therapy can be considered on the basis that it may downstage the lesion or reduce the need for endoscopic hemostatic treatment, although it should not delay endoscopy.[69][70]
Patients with recurrent bleeding after endoscopic therapy for a bleeding ulcer should undergo repeat endoscopy and endoscopic therapy rather than undergo surgery or transcatheter arterial embolization. Repeat endoscopy and endoscopic therapy successfully prevents further bleeding in approximately three-quarters of these patients, with fewer complications than surgical therapy.[64]
According to guidelines from the American College of Gastroenterology (ACG), patients with bleeding ulcers who have failed endoscopic therapy should next be treated with transcatheter arterial embolization (TAE).[64] Failure of endoscopic therapy may be defined in various ways, including persistent bleeding after initial or subsequent endoscopic therapy and recurrent bleeding after repeat endoscopic therapy.[64] Although surgery is more effective in reducing further bleeding, TAE is associated with markedly fewer complications and is not associated with increased mortality. In clinical practice, surgery may be a better choice for the individual patient when taking into account comorbidities and current medical status as well as local expertise and availability of procedures (e.g., expertise of local interventional radiologists in TAE for upper gastrointestinal bleed and experience of local surgeons in ulcer surgery).[64]
Nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin, should be discontinued before treatment. If, however, a patient is taking aspirin for secondary cardiovascular prevention, aspirin should be continued in the acute phase.[62][71] If there is major hemorrhage, specialist hematologic advice should be sought.
If cardioprotective aspirin therapy is interrupted, this should be restarted as quickly as possible (ideally within 24 hours) of successful endoscopic hemostasis.[62][71]
One observational study in patients with acute myocardial infarction who developed peptic ulcer disease bleeding demonstrated reduced mortality in those who continued aspirin.[72] In another study, in patients at increased risk of cardiovascular disease, restarting low-dose aspirin (postendoscopic control of ulcer bleeding) reduced overall mortality, but was associated with increased recurrent bleeding.[73]
Blood transfusion can be considered to resuscitate acute volume loss; a more restrictive transfusion strategy (transfusion only for hemoglobin <7 g/dL) has been shown to significantly improve patient outcomes.[74]
After intervention, the presence of Helicobacter pylori should be assessed and the patient treated according to guidelines for patients with no active bleeding. Failure to address and treat H pylori infection is associated with recurrent bleeding.[75]
No active bleeding
The first step is to eliminate the underlying cause, followed by ulcer healing therapy. The major etiologic factors responsible for peptic ulceration are the use of NSAIDs and infection with H pylori . Presence of H pylori should be assessed as treatment is based on its presence or absence.
H pylori negative:
NSAIDs (including aspirin) should be discontinued, as this is the most likely cause of peptic ulcer in these patients. If this is not possible, or if the patient takes low-dose aspirin for prophylaxis of cardiovascular disease, prophylactic acid inhibitory therapy should be taken long term.[76] A cyclo-oxygenase (COX-2) inhibitor may be considered in preference to an NSAID to reduce the risk of gastroduodenal toxicity, including ulceration. One large randomized clinical trial found that celecoxib, at moderate doses, was noninferior to ibuprofen and naproxen with regard to cardiovascular safety in patients with arthritis.[77]
Ulcer healing therapy should then be instituted. In general, PPIs are the drug of choice for ulcer healing, given the simplicity of their dosing schedule and their efficacy. Both PPIs and H2 antagonists inhibit acid secretion, but PPIs inhibit acid secretion to a greater extent and heal peptic ulcers more rapidly.[78] H2 antagonists may, however, be used if the patient is unresponsive to PPIs.
Antacids are relatively ineffective and slow to produce healing and are also not recommended.
Misoprostol is another option for the prevention of NSAID-induced gastric ulcers in patients who need to continue NSAID therapy.[79]
H pylori positive:
If the patient is taking an NSAID (including aspirin), it should be discontinued if possible. Guidelines recommend that H pylori positive patients taking long-term low-dose aspirin, or a long-term NSAID for arthritis, should be offered eradication therapy.[39][49][50]
Eradication therapy leads to ulcer healing and a dramatic decrease in ulcer recurrence.[80] [
]
[ ]
Most regimens are 70% to 90% efficacious in practice, limited mainly by antibiotic resistance and patient adherence to the regimen. Therapy should not be prescribed without documented infection. The ACG recommends empiric first-line regimens for treatment-naive patients with H pylori infection. Optimized bismuth quadruple therapy, consisting of a standard-dose PPI plus bismuth plus tetracycline plus metronidazole for 14 days is the preferred first-line regimen when antibiotic susceptibility is unknown. This regimen may be used in patients with or without a penicillin allergy.[50]
Other regimens that can be considered first-line for patients with no penicillin allergy include: rifabutin triple therapy (omeprazole plus amoxicillin plus rifabutin) for 14 days; or potassium-competitive acid blocker dual therapy (vonoprazan plus amoxicillin) for 14 days. Potassium-competitive acid blocker triple therapy (vonoprazan plus clarithromycin plus amoxicillin) is another option, but should be avoided in patients with previous exposure to macrolide antibiotics.[48][50]
European guidelines also recommend bismuth quadruple therapy as initial treatment in both areas with clarithromycin resistance rates greater or less than 15%. If this treatment fails, levofloxacin triple or quadruple therapy is recommended, followed by clarithromycin triple or quadruple therapy, and if this fails rifabutin triple therapy is recommended. In areas where the clarithromycin resistance rate is known to be less than 15%, initial therapy can alternatively be started with clarithromycin triple therapy and if it fails the sequence of bismuth quadruple therapy, levofloxacin triple or quadruple therapy, and rifabutin triple therapy is followed. Fourteen days of treatment are recommended.[52]
All regimens contain antibiotics and therefore may cause diarrhea, promote opportunistic infections, and interfere with absorption of many other drugs, including oral contraceptives.
There is insufficient evidence to suggest that the use of probiotic therapy improves the efficacy or tolerability of H pylori eradication therapy.[50]
Check for eradication of H pylori at least 1 month after the end of therapy with an appropriately conducted urea breath test, fecal antigen test, or biopsy-based test.[50][52] Continuation of acid suppressive therapy after treatment of infection is not necessary in most patients.
If the first treatment fails, at least one alternative regimen should be tried. Second-line regimens should avoid the antibiotics that were given in the first-line regimen.[48][49] If the organism cannot be eradicated despite repeated attempts, long-term acid suppression therapy may be necessary to control symptoms.
In patients who have persistent H pylori infection despite receiving a previous course of eradication therapy, any subsequent treatment is considered second-line (or third-line if they have had two previous courses).[50] Choice of regimen will depend on previous treatments. The ACG provides guidance on suggested regimens and it would also be advisable to consult local guidance.[50]
To best optimize the management of H pylori infection, eradication therapy should be based on patterns of local and individual antimicrobial resistance, if possible.[81][82] Next-generation sequencing on gastric biopsies to determine antimicrobial susceptibility has been shown to increase the likelihood of successful treatment compared to conventional empirical therapy.[83] However, H pylori culture and molecular testing is not widely available in all countries.[84]
Recurrent or refractory ulcers
Long-term maintenance acid-suppression therapy may be used in selected high-risk patients (e.g., frequent recurrences, large or refractory ulcers) with or without H pylori infection.[85] The preferred regimen and duration of therapy is uncertain, although most clinicians use a PPI.
A prostaglandin analog such as misoprostol should be used in patients with NSAID-associated ulcers refractory to acid suppression therapy.[79] Prior to embarking on this course, compliance with therapy and unknowing or continuing use of aspirin or NSAIDs should be ascertained.
Safety of chronic proton-pump inhibitor therapy
PPIs are an effective treatment for peptic ulcer disease.[45] Concerns exist, however, over their long term use.
Retrospective analyses suggest an association between PPI use and osteoporosis, pneumonia, dementia, stroke, and all-cause mortality.[86][87][88][89][90][91][92] But these studies are unable to establish a causal relationship.[93]
A prospective analysis of more than 200,000 participants in three big studies, over a combined 2.1 million person-years of follow-up, found that regular use of PPIs was associated with a higher risk of developing type 2 diabetes (HR 1.24, 95% CI 1.17 to 1.31). The risk of diabetes increased with duration of PPI use.[94]
In possibly the largest prospective randomized PPI trial for any indication (n=17,958 patients with cardiovascular disease), no significant difference in adverse effects was reported between pantoprazole and placebo at 3 years (53,000 patient years of follow up), aside from a possible increase in enteric infection.[95]
One smaller prospective, multicenter double blind study, including 115 healthy postmenopausal women, found that 26 weeks of treatment with a PPI has no clinically meaningful effects on bone homeostasis.[96]
A systematic review and meta-analysis that included more than 600,000 patients found no relationship between the use of PPIs and increased risk of dementia.[97] This was also the conclusion of another meta-analysis of just over 200,000 patients, where no clear evidence was found to suggest an association between PPI use and risk of dementia.[98]
A cohort study of more than 700,000 patients in the UK showed an association between PPI use and all-cause mortality.[99] However, significant confounding effects mean that conclusions about causality cannot be made.[99]
PPIs are associated with changes in the microbiome. The clinical significance of these changes is uncertain.[100]
PPIs should only be prescribed for appropriate indications and should be limited to the warranted therapeutic duration of therapy. Based on current data, the overall benefits of PPI treatment outweigh the potential risks in most patients.
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