Background Non-vitamin K antagonist oral anticoagulants (NOACs) are recommended for stroke prevention in non-valvular atrial fibrillation (AF). Although NOACs substantially reduce intracranial hemorrhage, upper gastrointestinal bleeding (UGIB) remains a frequent and clinically consequential complication. Proton pump inhibitors (PPIs) may reduce UGIB risk; however, concerns regarding long-term safety and pharmacodynamic variability persist. Fexuprazan, a potassium-competitive acid blocker (P-CAB), provides rapid and sustained acid suppression independent of acid activation and CYP2C19 metabolism. No randomized trial has evaluated P-CAB therapy for prevention of UGIB in anticoagulated patients.

Methods FENOX is a multicenter, prospective, randomized, open-label, blinded-endpoint (PROBE) superiority trial. Approximately 1,000 high-risk patients with non-valvular AF initiating NOAC therapy will be randomized 1:1 to receive fexuprazan plus NOAC therapy or NOAC therapy alone. High-risk enrichment includes advanced age, renal impairment, concomitant antiplatelet therapy, prior ulcer disease, or elevated HAS-BLED score. The primary endpoint is clinically relevant upper gastrointestinal bleeding (CR-UGIB) at 12 months, defined according to ISTH criteria. All events will be adjudicated by an independent blinded Clinical Events Committee. Primary analyses will follow the intention-to-treat principle using time-to-event methods.

Results The planned sample size provides 80% power to detect a 50% relative risk reduction in CR-UGIB, assuming a 12-month incidence of 10% in the control group. Interim safety monitoring will be conducted under independent oversight.

Conclusion FENOX is the first randomized trial designed to evaluate a P-CAB-based gastroprotective strategy for prevention of clinically relevant UGIB in high-risk patients receiving NOAC therapy. By integrating high-risk enrichment, pragmatic design, and blinded endpoint adjudication, the study aims to provide rigorous evidence to inform gastroprotective strategies in anticoagulated populations.

Inclusion Criteria:

• Age ≥18 years

• Documented non-valvular atrial fibrillation

• Receiving or initiating therapy with a non-vitamin K antagonist oral anticoagulant (NOAC) at guideline-recommended dosing

• At least one high-risk factor for upper gastrointestinal bleeding, including:

  • Age ≥75 years
  • Chronic kidney disease (eGFR <60 mL/min/1.73 m²)
  • Concomitant antiplatelet therapy
  • Concomitant use of nonsteroidal anti-inflammatory drugs (NSAIDs) or corticosteroids
  • Prior peptic ulcer disease or upper gastrointestinal bleeding
  • HAS-BLED score ≥3

Exclusion Criteria:

• Active gastrointestinal bleeding at the time of screening
• Requirement for mandatory long-term proton pump inhibitor (PPI) therapy that cannot be discontinued
• Severe hepatic dysfunction
• Life expectancy <1 year
• Known hypersensitivity or contraindication to fexuprazan
• Participation in another interventional clinical trial that may interfere with study outcomes

Individual participant data (IPD) that underlie the results reported in this study, after de-identification, will be shared.

Data will be made available to qualified researchers who provide a methodologically sound research proposal. Proposals should be directed to the corresponding author. Data access will be granted following review and approval by the study steering committee and execution of a data use agreement.