Atrial Fibrillation (AF), Drug-Related Side Effects and Adverse Reactions, Gastrointestinal Hemorrhage (Clinically Important, Upper), Upper Gastrointestinal Bleeding (UGIB)
Conditions
Keywords
Non-vitamin K antagonist oral anticoagulants (NOACs), potassium-competitive acid blocker (P-CAB), Upper gastrointestinal bleeding (UGIB)
Brief summary
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.
Interventions
DRUGFexuprazan
Fexuprazan 40 mg administered orally once daily for the duration of the study in combination with NOAC therapy.
DRUGNOAC therapy
Non-vitamin K antagonist oral anticoagulant therapy (e.g., apixaban, rivaroxaban, dabigatran, or edoxaban) administered according to approved labeling and guideline-recommended dosing.
Sponsors
Ewha Womans University Mokdong Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Intervention model description
rity trial. Approximately 1,000 high-risk patients with non-valvular atrial fibrillation receiving NOAC therapy will be randomized in a 1:1 ratio to fexuprazan plus NOAC therapy or NOAC therapy alone.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Clinically relevant upper gastrointestinal bleeding (CR-UGIB) | 12 months | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| ISTH major bleeding | 12 months | Major bleeding defined according to the International Society on Thrombosis and Haemostasis (ISTH) criteria. |
| Intracranial hemorrhage | 12 months | Occurrence of intracranial hemorrhage confirmed by neuroimaging or clinical diagnosis. |
| Ischemic stroke or systemic embolism | 12 months | Composite of ischemic stroke or systemic embolism confirmed by clinical and imaging criteria. |
| All-cause mortality | 12 months | Death from any cause during the follow-up period. |
| Net clinical outcome | 12 months | Composite of clinically relevant upper gastrointestinal bleeding, ischemic stroke/systemic embolism, intracranial hemorrhage, or all-cause death. |
Countries
South Korea
Contacts
CONTACTYeji Kim MD, PhD
Outcome results
None listed