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.
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
Age ≥75 years
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
Parallel
Fexuprazan
DrugFexuprazan 40 mg administered orally once daily for the duration of the study in combination with NOAC therapy.
NOAC therapy
DrugNon-vitamin K antagonist oral anticoagulant therapy (e.g., apixaban, rivaroxaban, dabigatran, or edoxaban) administered according to approved labeling and guideline-recommended dosing.
Clinically relevant upper gastrointestinal bleeding (CR-UGIB)
Clinically relevant upper gastrointestinal bleeding (CR-UGIB) defined as either: 1. ISTH-defined major upper gastrointestinal bleeding, or 2. clinically relevant non-major upper gastrointestinal bleeding requiring emergency department visit, hospitalization, endoscopic intervention, blood transfusion, or temporary interruption of NOAC therapy. All events will be adjudicated by an independent blinded Clinical Events Committee.
ISTH major bleeding
Major bleeding defined according to the International Society on Thrombosis and Haemostasis (ISTH) criteria.
Intracranial hemorrhage
Occurrence of intracranial hemorrhage confirmed by neuroimaging or clinical diagnosis.
Ischemic stroke or systemic embolism
Composite of ischemic stroke or systemic embolism confirmed by clinical and imaging criteria.
All-cause mortality
Death from any cause during the follow-up period.
Adverse events
Any adverse events reported during the study period.
Serious adverse events
Serious adverse events defined according to standard regulatory criteria.
Drug discontinuation due to adverse events
Permanent discontinuation of study medication due to adverse events.
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