Randomized Active-Controlled Trial Evaluating Fexuprazan (Fexuclue Tab) for Prevention Upper Gastrointestinal Bleeding in High Bleeding Risk Patients Receiving Dual Antiplatelet Therapy After Coronary Intervention

Summary

The use of antiplatelet agents inevitably increases the risk of bleeding, which is associated with increasing the risk of mortality. Gastrointestinal bleeding, including upper gastrointestinal bleeding, is the most common bleeding complication, accounting for about two-thirds of bleeding events associated with dual antiplatelet therapy (DAPT). The use of proton pump inhibitors (PPIs) has been investigated to reduce the risk of gastrointestinal bleeding, with the COGENT study being the only large study to report a reduction in gastrointestinal bleeding with PPI use. However, smaller randomized trials and meta-analyses have reported conflicting results regarding the efficacy of PPI use. In addition, PPIs require caution when used in conjunction with P2Y12 inhibitors such as clopidogrel, as they may reduce the antiplatelet effect and increase the risk of thrombotic events. Currently, European clinical guidelines recommend prescribing PPIs as gastrointestinal protective agents to all patients, while ACCF/ACC/AHA clinical guidelines recommend prescribing PPIs only to patients at high risk of upper gastrointestinal bleeding and prohibit their universal use. With an increase in coronary stenting among elderly and high-risk patients with coronary artery disease, the population at high risk of bleeding is also increasing. Approximately 20% of patients were identified to be at high risk of bleeding within 1 year after coronary artery intervention according to the BARC 3 or 5 bleeding criteria. Additionally, it is known that East Asians, including Koreans, are at a higher risk of upper gastrointestinal bleeding due to various genetic and environmental factors. Therefore, efforts to prevent gastrointestinal bleeding during the period of dual antiplatelet therapy after stent insertion are even more necessary. Potassium-competitive acid blockers (P-CABs) are a new class of H+/K+ ATPase inhibitors used to treat gastrointestinal acid-related disorders such as gastroesophageal reflux disease, peptic ulcers, and Helicobacter pylori infections. Unlike proton pump inhibitors, which bind to the proton pump, P-CABs competitively and reversibly inhibit the potassium site of H+/K+ ATPase, leading to relatively long-lasting inhibition of acid secretion. The newly developed drug Fexuprazan (FexuclueⓇ) has been proven effective through phase III clinical trials for patients with erosive esophagitis, and it is confirmed to be activated more quickly than the PPI, Ezomezole, and to have a sustained drug effect throughout the night. Therefore, in this double-blind, randomized, active-controlled study, we aim to evaluate the preventive effect of Fexuprazan (FexuclueⓇ) with improved gastrointestinal protection on upper gastrointestinal bleeding in high-risk patients who require dual antiplatelet therapy.

Eligibility

Inclusion Criteria:

* All four conditions below must be met.

  1. Patients who are 20 years of age or older, have undergone coronary artery stent implantation for coronary artery disease, and require dual antiplatelet therapy for 6 months or longer.
  2. Patients are considered to be at high bleeding risk if at least 1 criteria are met (Based on clinical recommendations (6,7,10,14-16) and expert consensus documents (17-19)) 1) Age ≥65 y 2) Low body weight (\<55 Kg for men, \<50 Kg for women) 3)Hemoglobin \<11g/dL 4) Platelet count \<100×109/L 5) Severe CKD: eGFR \<30mL/min/1.73m2,5 or on hemodialysis 6) Anticipated use of long-term oral anticoagulation (warfarin or direct-acting oral anticoagulants) 7) Long-term use of oral NSAIDs or steroids 8) Heart failure 9) A history of previous gastric or duodenal ulcer. 10) A history of previous gastrointestinal bleeding. 11)Previous or confirmed Helicobacter pylori infection
  3. A voluntary participant in this clinical trial who has provided written consent, or a legal guardian who has provided written consent on behalf of the participant.
  4. Those who agree to use a medically valid method of contraception\* (including conditions in which pregnancy is medically impossible) during the clinical trial period Women who are medically unable to become pregnant can participate in this clinical trial: women who have undergone menopause (amenorrhea for more than 24 months), hysterectomy, salpingectomy, or bilateral oophorectomy, etc.
* Medically valid contraceptive methods: intrauterine device (Loop, Mirena), physical barrier method (male condom, female condom (femidom)), subcutaneous contraception (Implanon, etc.), long-acting contraceptive injection, or tubectomy and ligation, vasectomy, etc. ( However, oral contraceptives cannot be used during this clinical trial, and it is recommended to use double contraception to prevent pregnancy while participating in this trial.)

Exclusion Criteria:

1. Patients who have a hypersensitivity reaction to the components of this clinical trial drug or benzimidazole-based drugs or have a history of clinically significant hypersensitivity reaction
2. Patients with contraindications to antiplatelet agents, such as allergies.
3. Genetic blood coagulation disorders
4. Cases in which the investigator determines that the use of dual antiplatelet therapy is difficult due to severe liver cirrhosis, thrombocytopenia, or other medical conditions.
5. Hemodynamically unstable at the time of randomization (cardiogenic shock, uncontrolled arrhythmia, severe heart failure: NYHA Class IV).
6. Patients with warning symptoms suspected of digestive malignancy (unintentional significant weight loss, recurrent vomiting, dysphagia, hematemesis, melena, etc.) within the past 3 months
7. Patients with malignancy or serious illnesses with an expected survival of less than 1 year.
8. Severe anemia (hemoglobin \< 8 g/dL) or blood transfusion within 4 weeks of randomization.
9. Active liver disease or impaired liver function (AST or ALT greater than three times the upper limit of normal).
10. Advanced renal dysfunction: eGFR less than 30 mLmin/1.73m2 or patients receiving dialysis
11. Patients taking drugs contraindicated for this clinical trial drug (e.g., patients taking atazanavir, nelfinavir, or rilpivirine-containing preparations)
12. Patients with genetic problems such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption
13. Concurrently taking CYP 3A4 and p-glycoprotein (P-GP) inhibitors.
14. Dementia or individuals unable to understand the trial procedures or comply with the trial requirements
15. Pregnant or breastfeeding women, or women planning to become pregnant
16. Individuals with active infections, significant hematologic, renal, metabolic, gastrointestinal, endocrine disorders, or any other reason the investigator deems the subject unsuitable for participation in the clinical trial

Conditions3

Interventions2

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