Peptic ulcer primary prevention
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] ; Associate Editor(s)-in-Chief: Fahad Hasan, M.D.[2] Guillermo Rodriguez Nava, M.D. [3] Manpreet Kaur, MD [4]
Overview
Primary prevention of PUD focuses on: (1) identification and eradication of H. pylori infection before ulcer development; (2) gastroprotective co-therapy or substitution of safer drug classes in patients requiring NSAIDs or low-dose aspirin; (3) modification of lifestyle risk factors, including smoking cessation and reduction of excessive alcohol intake; and (4) stress ulcer prophylaxis in high-risk critically ill patients.
Primary Prevention
Helicobacter pylori Infection
H. pylori infection heightens the risk of PUD-related gastrointestinal bleeding by 1.7 times, and further amplifies gastrointestinal risk in patients co-exposed to NSAIDs or aspirin.[1]
Indications for Testing and Treatment
The Maastricht VI/Florence Consensus Report (2022) and the ACG Clinical Guideline (2024) endorse a "test-and-treat" strategy as the preferred approach for management of uninvestigated dyspepsia in patients without alarm features in populations with an H. pylori prevalence sufficient to justify the strategy.[2][3] The test-and-treat approach cures most underlying cases of PUD and prevents most potential cases of gastroduodenal disease.[4]
The Maastricht VI/Florence Consensus additionally states that H. pylori testing and treatment are advisable for:[2]
- High-risk patients already on long-term low-dose aspirin
- Naïve patients starting long-term NSAID therapy (with the addition of PPI co-therapy for those at high gastrointestinal risk even after eradication)
- Patients with a documented history of PUD (active or past)
In North America, the prevalence of H. pylori ranges between 30% and 40%, with disproportionately higher burden in non-White racial and ethnic populations, persons living in crowded or poor sanitary conditions, and first-generation immigrants from countries where H. pylori is endemic.[5]
Diagnostic Testing
Non-invasive preferred diagnostic tests include the urea breath test (UBT) and the stool antigen test (SAT). Serological testing is not recommended in low-prevalence populations unless pre-test probability is high (e.g., documented PUD).[6] Post-treatment test-of-cure should be performed universally at a minimum of four weeks after completing eradication therapy.[7]
For eradication regimens, please read the main article Helicobacter pylori infection medical therapy.
NSAID-Associated Ulcer Prevention
NSAIDs (including aspirin) represent the second major cause of PUD. Use of either aspirin or NSAIDs increases the risk of peptic ulcer disease and its complications in H. pylori-infected individuals; the risks are independent and additive.[8]
Risk Stratification
Gastrointestinal risk from NSAID use is stratified into low (no risk factors), moderate (one or two risk factors), and high (multiple risk factors, history of ulcer complications, or concomitant use of corticosteroids or anticoagulants).[9]
| Risk Category | Characteristics | Recommended Strategy |
|---|---|---|
| Low risk | No risk factors present | Use NSAID alone at lowest effective dose for shortest duration; avoid routine prophylaxis |
| Moderate risk | One or two of: age >60–65 years; high-dose NSAID; prior uncomplicated peptic ulcer; concurrent low-dose aspirin, corticosteroid, or anticoagulant use | Use COX-2 selective inhibitor alone, OR non-selective NSAID + PPI co-therapy; test and treat H. pylori |
| High risk | History of ulcer complications (bleeding, perforation, obstruction); multiple (≥3) risk factors; concomitant corticosteroid + anticoagulant + NSAID use | Avoid NSAIDs if clinically feasible; if NSAID required, use COX-2 inhibitor + PPI; test and treat H. pylori |
Gastroprotective Co-therapy
Two principal strategies reduce the risk of NSAID-induced peptic ulceration and mucosal injury:
- Co-therapy with a proton pump inhibitor (PPI), high-dose (double-dose) histamine H2 receptor antagonist (H2RA), or the synthetic prostaglandin E1 analogue misoprostol
- Substitution of a COX-2 selective inhibitor for a non-selective NSAID[9]
Combined use of NSAIDs with a PPI at standard doses is associated with a 3–4 fold reduction in the incidence of NSAID-induced gastric and duodenal ulcers, erosions, bleeding, and perforation in randomized clinical trials of H. pylori-negative patients at increased risk (age ≥60 years and/or history of ulcer).[9] PPIs are superior to H2RAs for prevention of low-dose aspirin-associated gastrointestinal erosion/ulcer (OR 0.28; 95% CI: 0.16–0.50) and bleeding (OR 0.28; 95% CI: 0.14–0.59).[10]
Misoprostol is significantly more effective than placebo, sucralfate, and ranitidine in the prevention of NSAID-related ulceration; however, its use is frequently limited by gastrointestinal side effects, primarily diarrhea and abdominal cramping, which reduce adherence.[9]
COX-2 Selective Inhibitors
COX-2 selective inhibitors (e.g., celecoxib, etoricoxib) are associated with a 74% relative risk reduction in combined gastroduodenal ulcers compared with non-selective NSAIDs (RR 0.26; 95% CI: 0.23–0.30), representing an absolute risk reduction of approximately 16%.[11] However, COX-2 selective inhibitors carry an increased risk of adverse cardiovascular events (including myocardial infarction) compared with naproxen and must be used with caution, particularly in patients with established coronary artery disease or multiple cardiovascular risk factors.[11] For patients at very high gastrointestinal risk requiring anti-inflammatory therapy, celecoxib plus PPI co-therapy is the preferred strategy.[9]
H. pylori Testing in NSAID Users
There is a potential advantage to testing for H. pylori infection and eradicating it in all patients requiring long-term NSAID therapy. Whether gastroprotective co-therapy is required after eradication of H. pylori depends on the individual patient's residual gastrointestinal risk profile.[9] The Maastricht VI/Florence Consensus reaffirms that testing and treatment are advisable for patients starting long-term NSAID therapy, with ongoing PPI co-therapy recommended for those remaining at high gastrointestinal risk even after successful eradication.[2]
Low-Dose Aspirin and Antiplatelet Therapy
Low-dose aspirin (75–325 mg/day) is the mainstay of antiplatelet therapy for secondary prevention of cardiovascular disease; however, even at doses as low as 75 mg/day, the risk of ulcer bleeding approximately doubles compared to non-users.[9] Patients requiring long-dose aspirin who are also infected with H. pylori should receive eradication therapy; in patients with a history of ulcer bleeding, eradication of H. pylori has been shown to be comparable to PPI therapy in preventing recurrent ulcer bleeding over 6 months among patients with active infection.[9]
Substitution of clopidogrel for aspirin is not a recommended strategy to reduce the risk of recurrent ulcer bleeding in high-risk patients, as it is inferior to the combination of aspirin plus PPI.[9]
Modification of Lifestyle Risk Factors
Smoking Cessation
Cigarette smoking is a well-established risk factor for PUD. Smoking more than 15 cigarettes per day compared with never smoking increases the risk of a perforated peptic ulcer more than threefold (RR 3.5; 95% CI 1.7–7.1).[12] Smoking impairs mucosal healing, decreases mucosal blood flow, and potentiates H. pylori-induced inflammation. Smoking cessation is recommended for all patients with PUD and for primary prevention; given the broad health benefits, all patients should be counseled to stop smoking.[13]
Mendelian randomization analyses have confirmed a causal effect of smoking initiation on both gastric ulcer and duodenal ulcer risk beyond that attributable to observational confounding.[13]
Alcohol Consumption
Excessive alcohol use irritates the gastric mucosa, stimulates acid production, and weakens mucosal defenses. Drinking more than 42 drinks per week increases the risk of a complicated peptic ulcer.[12] Alcohol may potentiate the effects of other risk factors such as H. pylori infection and NSAID use. Patients should be counseled to limit alcohol intake; current guidance suggests limiting consumption to no more than one alcoholic beverage per day.[13]
Dietary and Other Modifiable Factors
Contrary to historical belief, there is no robust evidence that dietary factors, spicy foods, or psychological stress directly cause PUD; current evidence does not support the use of bland diets or dietary restrictions for primary prevention. Nevertheless, stress management may contribute to overall gastrointestinal health, and patients with risk factors benefit from general healthy lifestyle counseling.
Stress Ulcer Prophylaxis in Critically Ill Patients
Critically ill patients are at increased risk for stress-related mucosal disease. The 2024 Society of Critical Care Medicine (SCCM) and American Society of Health-System Pharmacists (ASHP) Guideline identifies the following as factors that likely increase the risk for clinically important stress-related upper gastrointestinal bleeding (UGIB) in critically ill adults:[14]
- Coagulopathy
- Shock (any cause)
- Chronic liver disease
Enteral nutrition probably reduces UGIB risk in critically ill patients and may reduce the need for pharmacological stress ulcer prophylaxis.[14] Mechanical ventilation alone, without other risk factors, does not constitute firm evidence for a requirement for stress ulcer prophylaxis per the 2024 SCCM/ASHP guideline.[14]
All critically ill adults with identified risk-increasing factors should receive either a PPI or H2RA at low dosage regimens to prevent UGIB.[14] Stress ulcer prophylaxis should be discontinued when critical illness resolves or the precipitating risk factor(s) are no longer present; discontinuation before transfer out of the intensive care unit (ICU) is necessary to prevent inappropriate continuation of acid suppression therapy outside the ICU setting.[14]
| Risk Factor | Grade of Evidence (2024 SCCM/ASHP) | Recommended Action |
|---|---|---|
| Coagulopathy | Likely increases risk of clinically important UGIB | Initiate PPI or H2RA at low dose |
| Shock (any etiology) | Likely increases risk of clinically important UGIB | Initiate PPI or H2RA at low dose |
| Chronic liver disease | Likely increases risk of clinically important UGIB | Initiate PPI or H2RA at low dose |
| Mechanical ventilation alone (without other risk factors) | No firm evidence as independent risk factor | Prophylaxis not mandated on this basis alone |
| Enteral nutrition | Probably reduces UGIB risk | Early enteral nutrition preferred; may reduce requirement for pharmacological prophylaxis |
Summary of Primary Prevention Strategies
| Intervention | Target Population | Key Recommendation |
|---|---|---|
| H. pylori eradication (test-and-treat) | Uninvestigated dyspepsia; patients starting long-term NSAIDs or aspirin; patients with H. pylori infection | Bismuth quadruple therapy (BQT) × 14 days preferred first-line when susceptibility unknown (2024 ACG) |
| PPI co-therapy with NSAIDs | Moderate-to-high GI risk NSAID users; all long-dose aspirin users with risk factors | PPI at standard dose; superior to H2RA for ulcer and bleeding prevention |
| COX-2 inhibitor substitution | Patients requiring anti-inflammatory therapy with moderate-to-high GI risk; without high cardiovascular risk | Reduces endoscopic ulcer risk by ~74% vs non-selective NSAIDs; use with PPI in highest-risk patients |
| Smoking cessation | All patients, especially those with additional PUD risk factors | Counsel all patients; smoking cessation reduces ulcer complications including perforation |
| Alcohol reduction | Excessive alcohol users with PUD risk factors | Limit to ≤1 drink/day; excessive alcohol independently increases ulcer complication risk |
| Stress ulcer prophylaxis | Critically ill adults with coagulopathy, shock, or chronic liver disease | PPI or H2RA at low dose; discontinue when risk factors resolve (2024 SCCM/ASHP) |
| H. pylori eradication in NSAID users | All patients initiating long-term NSAID therapy who test positive for H. pylori | Test and treat before or alongside NSAID initiation; add PPI if high residual GI risk persists post-eradication |
References
- ↑ Papatheodoridis GV, Archimandritis AJ. Role of Helicobacter pylori eradication in aspirin or non-steroidal anti-inflammatory drug users. World J Gastroenterol. 2005 Jul 7;11(25):3811-6. doi: 10.3748/wjg.v11.i25.3811. PMID: 15991274; PMCID: PMC4504877.
- ↑ 2.0 2.1 2.2 Malfertheiner P, Megraud F, Rokkas T, Gisbert JP, Liou JM, Schulz C, Gasbarrini A, Hunt RH, Leja M, O'Morain C, Rugge M, Suerbaum S, Tilg H, Sugano K, El-Omar EM; European Helicobacter and Microbiota Study group. Management of Helicobacter pylori infection: the Maastricht VI/Florence consensus report. Gut. 2022 Aug 8:gutjnl-2022-327745. doi: 10.1136/gutjnl-2022-327745. Epub ahead of print. PMID: 35944925.
- ↑ Chey, William D. MD, FACG1; Howden, Colin W. MD, FACG2; Moss, Steven F. MD, FACG3; Morgan, Douglas R. MD, MPH, FACG4; Greer, Katarina B. MD, MSEpi5; Grover, Shilpa MD, MPH6; Shah, Shailja C. MD, MPH7. ACG Clinical Guideline: Treatment of Helicobacter pylori Infection. The American Journal of Gastroenterology 119(9):p 1730-1753, September 2024. | DOI: 10.14309/ajg.0000000000002968
- ↑ Gisbert JP, Calvet X (2013). "Helicobacter pylori "Test-and-Treat" Strategy for Management of Dyspepsia: A Comprehensive Review". Clin Transl Gastroenterol. 4: e32. doi:10.1038/ctg.2013.2. PMID 23535826.
- ↑ Shah SC, Halvorson AE, Lee D, Bustamante R, McBay B, Gupta R, Denton J, Dorn C, Wilson O, Peek R Jr, Gupta S, Liu L, Hung A, Greevy R, Roumie CL. Helicobacter pylori Burden in the United States According to Individual Demographics and Geography: A Nationwide Analysis of the Veterans Healthcare System. Clin Gastroenterol Hepatol. 2024 Jan;22(1):42-50.e26. doi: 10.1016/j.cgh.2023.05.016. Epub 2023 May 26. PMID: 37245717; PMCID: PMC11552088.
- ↑ Xu AA, Graham DY. Things We Do for No Reason™: Serum Serologic Helicobacter pylori Testing. J Hosp Med. 2021 Nov;16(11):691-693. doi: 10.12788/jhm.3638. PMID: 34328849; PMCID: PMC8577700.
- ↑ Aumpan N, Mahachai V, Vilaichone RK. Management of Helicobacter pylori infection. JGH Open. 2022 Nov 21;7(1):3-15. doi: 10.1002/jgh3.12843. PMID: 36660052; PMCID: PMC9840198.
- ↑ Ji KY, Hu FL. Interaction or relationship between Helicobacter pylori and non-steroidal anti-inflammatory drugs in upper gastrointestinal diseases. World J Gastroenterol. 2006 Jun 28;12(24):3789-92. doi: 10.3748/wjg.v12.i24.3789. PMID: 16804960; PMCID: PMC4087923.
- ↑ 9.0 9.1 9.2 9.3 9.4 9.5 9.6 9.7 9.8 Lanza FL, Chan FK, Quigley EM (2009). "Guidelines for prevention of NSAID-related ulcer complications". Am J Gastroenterol. 104 (3): 728–738. doi:10.1038/ajg.2009.115. PMID 19240698.
- ↑ Mo C, Sun G, Wang YZ, Lu ML, Yang YS (2015). "PPI versus Histamine H2 Receptor Antagonists for Prevention of Upper Gastrointestinal Injury Associated with Low-Dose Aspirin: Systematic Review and Meta-analysis". PLoS One. 10 (7): e0131558. doi:10.1371/journal.pone.0131558. PMID 26153055.
- ↑ 11.0 11.1 Rostom A, Muir K, Dube C, Lanas A, Jolicoeur E, Tugwell P (2007). "Gastrointestinal safety of cyclooxygenase-2 inhibitors: a Cochrane Collaboration systematic review". Clin Gastroenterol Hepatol. 5 (7): 818–828. doi:10.1016/j.cgh.2007.03.011. PMID 17678920.
- ↑ 12.0 12.1 Andersen IB, Bonnevie O, Jørgensen T, Sørensen TI (2000). "Smoking and alcohol intake as risk factors for bleeding and perforated peptic ulcers: a population-based cohort study". Epidemiology. 11 (4): 434–439. doi:10.1097/00001648-200007000-000120. PMID 10939015.
- ↑ 13.0 13.1 13.2 Liu Y, Xiao Z, Ye K, Xu L, Zhang Y. Smoking, alcohol consumption, diabetes, body mass index, and peptic ulcer risk: A two-sample Mendelian randomization study. Front Genet. 2023 Jan 6;13:992080. doi: 10.3389/fgene.2022.992080. PMID: 36685897; PMCID: PMC9852705.
- ↑ 14.0 14.1 14.2 14.3 14.4 MacLaren R, Dionne JC, Granholm A, Alhazzani W, Szumita PM, Olsen K, Barletta JF, Møller MH, Karvellas CJ, Wischmeyer P, DePriest A, Carlos V, Argetsinger D, Carothers JJ, Lee R, Napolitano L, Perri D, Naylor DF. Society of Critical Care Medicine and American Society of Health-System Pharmacists Guideline for the Prevention of Stress-Related Gastrointestinal Bleeding in Critically Ill Adults. Crit Care Med. 2024 Aug 1;52(8):e421-e430. doi: 10.1097/CCM.0000000000006330. Epub 2024 Jul 15. PMID: 39007578.