Secondary prevention of dyspepsia aims to prevent symptom relapse and recurrence of the underlying lesion in patients who have already been diagnosed and treated. This includes treated uninvestigated dyspepsia, treated functional dyspepsia (FD), treated Helicobacter pylori-associated dyspepsia, and healed peptic ulcer disease (PUD). FD is a disorder of gut–brain interaction with a chronic, relapsing–remitting course.^[1][2] The main secondary prevention measures are:

• Confirmed and sustained H. pylori eradication
• The lowest effective acid suppression, with periodic deprescribing
• Removal or mitigation of NSAID exposure
• Psychological therapy and central neuromodulators for relapsing FD

• When H. pylori is the cause, eradication is the most durable secondary prevention measure.
  • In PUD, eradication reduces ulcer recurrence from ~50–60% to 0–2%.^[3]
  • Confirmed eradication essentially eliminates recurrent ulcer bleeding without the need for maintenance antisecretory therapy.^[5]
• Long-term follow-up (up to ~4.25 years) showed no ulcer recurrence in H. pylori-negative patients. Patients who remained H. pylori-positive relapsed progressively. Eradication therapy was superior to long-term maintenance antisecretory therapy.^[6]
• Confirm eradication with a test of active infection:^[2]
  • Use a urea breath test or monoclonal stool antigen test, not serology.
  • Test at least 4 weeks after completing therapy and at least 2 weeks after stopping PPI.
  • US post-eradication reinfection is uncommon (~1% per year; 95% CI 0.3–3%), except in Alaska Native populations (>8% per year); recurrent symptoms therefore rarely reflect true reinfection.^[7]
  • Failure to confirm eradication is a common cause of avoidable recurrence.
• Recurrent dyspepsia or ulcer after presumed successful eradication warrants retesting for active infection. Persistent infection or reinfection, not inadequate acid suppression, drives most true ulcer recurrence.^[6][3]
• In FD, H. pylori is considered causal only when eradication produces sustained symptom benefit.
  • The benefit is modest (NNT 14 for symptom cure, 9 for improvement; larger when eradication is confirmed, NNT 4.5), and most eradicated FD patients do not become symptom-free.^[7]
  • Recurrent FD symptoms should therefore not be reflexively attributed to reinfection.
• If eradication fails, vonoprazan-based regimens are an option in clarithromycin-resistant infection.^[8] Regimen details belong in the medical therapy microchapter.

• In H. pylori-negative FD, or FD persisting after eradication, PPI therapy is first-line.^[2][4]
  • Give a standard once-daily PPI for 4–8 weeks.
  • Stop it if the response is insufficient; dose escalation offers no benefit.
• Long-term PPI should not be continued without a withdrawal attempt every 6–12 months.^[2]
• The 2022 AGA Clinical Practice Update on PPI de-prescribing recommends:^[9]
  • Offer a de-prescribing trial to all patients without a definite chronic PPI indication. FD is not a definite chronic indication.
  • Step twice-daily users down to once-daily.
  • Either tapering or abrupt discontinuation is acceptable.
  • On-demand PPI, or an as-needed H2RA or antacid, is an effective partial de-prescribing strategy for breakthrough symptoms.
• Rebound acid hypersecretion can follow PPI withdrawal, even after only a few months of use.^[9][10]
  • Counsel patients in advance.
  • Consider a 2–4 week taper to improve the proportion who remain off therapy.
  • Symptoms persisting more than 2 months after discontinuation suggest a continuing indication.

• Discontinuing the NSAID heals ~95% of ulcers and reduces recurrence from ~40% to ~9%.^[3]
• If an NSAID must be continued, reduce recurrence by:^[3]
  • Co-prescribing a PPI
  • Eradicating H. pylori
  • Switching to a COX-2 inhibitor combined with a PPI
• In patients taking low-dose aspirin for secondary cardiovascular prevention who have had ulcer bleeding, continue (or promptly resume, typically within 1–7 days of hemostasis) aspirin with long-term PPI co-therapy rather than discontinuing it, and eradicate H. pylori if present. Aspirin plus PPI is superior to switching to clopidogrel alone for preventing rebleeding.^[5][8][11]

• Psychological comorbidity is common in FD and is a major contributor to relapse and healthcare utilization.^[1]
• Psychological therapy:
  • The ACG/CAG guideline recommends psychological therapy for FD not responding to drug therapy (conditional recommendation, very low quality evidence). The pooled NNT was 3 across 12 RCTs.^[2][1]
  • Benefits of cognitive behavioral therapy and gut-directed hypnotherapy appear durable and reduce healthcare utilization.^[12][1]
  • In one hypnotherapy trial, no treated patient required medical therapy at 1 year, compared with 82–90% of controls.^[12][1]
  • A 2022 meta-analysis (14 RCTs, 1,434 patients) found that psychological interventions improve dyspeptic symptoms and reduce anxiety and depression.^[13]
• Central neuromodulators are used for refractory or relapsing FD within a stepwise treatment algorithm.^[14][15]
  • Options include tricyclic antidepressants and 5-HT1A agonists such as buspirone for the postprandial distress subtype.
  • Benefit among central neuromodulators is concentrated in tricyclic antidepressants (NNT 6, greatest in epigastric-pain/EPS phenotypes); SSRIs are ineffective and most SNRIs are unproven.^[2][16]
  • Dosing belongs in the medical therapy microchapter.

• Sustained dietary measures (small, frequent, low-fat meals) and moderate exercise are low-risk adjuncts.
• Evidence that these measures prevent relapse is weak.^[4][14]

• Confirmatory eradication testing. The 2024 ACG guideline recommends universal post-treatment test of cure in all patients with dyspepsia treated for H. pylori, irrespective of symptom response, because symptom response correlates poorly with eradication success.^[7] Older frameworks that reserved confirmation for higher-risk patients are now superseded; residual uncertainty is limited mainly to unselected, low-risk, asymptomatic populations.
• Optimal deprescribing method: whether tapering reduces rebound more than abrupt discontinuation is unproven.^[9][10]
• Evidence for eradication therapy in preventing ulcer recurrence is rated very low quality in the Cochrane review, and older regimens limit applicability.^[17]
• Durability of FD symptom control with any modality is limited by the relapsing natural history. Dedicated relapse-prevention trials are few.^[14]

• Continuing indefinite standard- or double-dose PPI in FD without periodic withdrawal attempts.^[2]
• Failing to confirm H. pylori eradication, then mislabeling recurrent symptoms as refractory FD.^[2]
• Escalating PPI for recurrent ulcer instead of retesting for persistent H. pylori infection.^[6]
• Stopping cardioprotective aspirin after an ulcer instead of continuing it with PPI cover.^[5]
• Attributing rebound hyperacidity after PPI withdrawal to disease relapse, which leads to unnecessary lifelong PPI.^[10]
• Overlooking psychological comorbidity in patients with relapsing FD.^[1]