Gastrointestinal (GI) complications are an important and most common problem from the use of long-term antithrombotic therapy, including antiplatelet agents and oral anticoagulants (OAC) (1-4). In terms of mechanistic pathways (5), aspirin blocks production of tissue prostaglandins (and its associated gastroprotective effects) via inhibition of the cyclooxygenase enzyme, increasing susceptibility to direct gastroduodenal mucosal injury. Adenosine diphosphate (ADP) blockers (e.g., clopidogrel, prasugrel, or ticagrelor) may impede the release of platelet-derived growth factors that contribute to angiogenesis and GI mucosal healing. By contrast, use of warfarin can be associated with the GI bleeding risk owing to its systemic anticoagulant effects via inhibition of key vitamin K–dependent clotting factors or lability in INR values and the direct-acting oral anticoagulants (DOACs) (e.g., dabigatran, rivaroxaban, apixaban, or edoxaban) may induce GI injury by a direct topical anticoagulant effect.Therefore, European and U.S. guidelines recommend that global gastroprotective strategies should be considered in most patients receiving antithrombotic agents (6-8). The 2017 European Society of Cardiology (ESC) focused update on dual antiplatelet therapy (DAPT) in coronary artery disease (CAD) recommended use of a proton-pump inhibitor (PPI) to minimize bleeding while on DAPT (class of recommendation [COR] 1 and level of evidence [LOE] B) (6). Although the evidence that a PPI does not increase the risk of cardiovascular events was generated with omeprazole (9), based on drug–drug interaction studies, omeprazole and esomeprazole would appear to have the highest propensity for clinically relevant interactions, while pantoprazole and rabeprazole have the lowest; thus, co-administration of omeprazole or esomeprazole with clopidogrel is generally not recommended. The 2019 ESC guidelines for the diagnosis and management of chronic coronary syndromes and 2020 ESC guidelines for the management of acute coronary syndromes proposed that concomitant use of a PPI is recommended in patients receiving aspirin monotherapy, DAPT, OAC monotherapy, dual antithrombotic therapy (DAT), or triple antithrombotic therapy (TAT) who are at high risk of gastrointestinal bleeding (COR 1 and LOE A) (7,10). Until recently, there have been limited randomized clinical trials (RCTs) to evaluated whether PPI therapy could reduce the risk of upper GI bleeding in patient receiving antithrombotic therapy. The COGENT (Clopidogrel and the Optimization of Gastrointestinal Events Trial) was a randomized, double-blind, double-dummy, placebo-controlled, phase III study to assess the efficacy and safety of a fixed-dose combination of clopidogrel (75mg) and omeprazole (20mg), as compared with clopidogrel alone (9). This study included patients at low risk of GI bleeding undergoing DAPT, in which those at high risk for GI bleeding were excluded. The trial results showed that there is no clinically significant cardiovascular interaction between PPIs and clopidogrel, whereas there is a significant reduction in GI bleeding with PPI use as compared with placebo. The COMPASS (Cardiovascular Outcomes for People Using Anticoagulant Strategies) trial was a 3x2 partial factorial double-blind trial involving 17,598 participants with stable CAD or peripheral artery disease (PAD). Participants were randomly assigned to groups given pantoprazole 40 mg daily or placebo, as well as rivaroxaban 2.5 mg twice daily with aspirin 100 mg once daily, rivaroxaban 5 mg twice daily, or aspirin 100 mg alone(11)Although the use of PPI has been regarded as the “gold-standard” gastroprotection strategy in patients who are at high-bleeding risk and receiving antithrombotic strategy, some concerns regarding safety of long-term PPI therapy have been continuously raised (12,13). Although the overall quality of evidence for PPI adverse events is low, long-term use of PPI use can be associated with increased risk

Cohort/Group Label

GI events in patients with cardiovascular disease

Cohort/Group Description

When taking antithrombotic therapy (antiplatelet drugs and oral anticoagulants) for patients with cardiovascular disease in a group of high-risk patients with gastrointestinal bleeding, The safety of P-CAB (tegoprazan 50 mg once a day) is evaluated through evaluation of changes in digestive blood tests and occurrence of adverse reactions after administration.

Not collect nor Archive

Patients with clinical indications of chronic antithrombotic therapy, either antiplatelets or OAC, for cardiovascular disease who are at high GI bleeding risk and agreed to participate in the study will be enrolled

Not Applicable

Gender

Age

Description

Inclusion Criteria : 
1. Patients 19 years of age or older with known cardiovascular disease in whom a requirement for chronic use of antithrombotic therapy (either antiplatelets or OAC). Specific clinical conditions that may confer a need for long-term antithrombotic therapy may include acute coronary syndrome and those with a history of myocardial infarction, stable or unstable angina, coronary or other arterial revascularization, stroke, transient ischemic attack, peripheral arterial disease, or atrial fibrillation. Concomitant use of a proton pump inhibitor is recommended in patients receiving aspirin monotherapy, DAPT (dual antiplatelet therapy), DAT (dual antithrombotic therapy), TAT (triple antithrombotic therapy.), or OAC monotherapy who are at high risk of gastrointestinal bleeding in order to reduce the risk of gastric bleeds (6,7,10).
2. On the basis of clinical guidelines (6,7,10,14-16) and expert consensus documents (17-19), we defined study population with increased risk of gastrointestinal bleeding if they had a least 1 or more criteria of the following characteristics. Eligible patients for randomization must meet at least 1 characteristics of these criteria:
*Definition of patients who are at high risk of gastrointestinal bleeding
a. Age ≥65 years
b. Concomitant use of OAC and any antiplatelet therapy (mono or DAPT) (i.e., DAT or TAT)
c. Long-term use of oral NSAIDs (non-steroidal anti-inflammatory drugs) or steroids or high dose NSAID therapy even during a relatively short-term period.
d. History of prior GI bleeding events at any time
e. History of a previously complicated ulcer
f. History of peptic ulcer disease or a previously uncomplicated ulcer 
g. Documented Helicobacter pylori infection
3. 3.	Patients who voluntarily participated in the written agreement

Exclusion Criteria :
1. Active bleeding at the time of inclusion or a history of hereditary or acquired hemostatic disorder
2. Previous chronic use of a PPI, P-CAB, H2 receptor blocker, sucralfate or misoprostol.
3. Any clinical contraindication to use of antithrombotic therapies (antiplatelet agents or OAC).
4. Hemodynamic unstable conditions at the time of inclusion: cardiogenic shock at the time of randomization, refractory ventricular arrhythmias, or congestive heart failure (New York Heart Association class IV).    
5. Baseline severe anemia (Hgb <8 g/dl at baseline) or transfusion within 4 weeks before randomization
6. Baseline severe thrombocytopenia (platelet count <50,000/mm3) 
7. Renal failure-dependent on dialysis or severe renal insufficiency (creatinine clearance <15 ml/min)
8. Severe chronic liver disease (defined as variceal hemorrhage, ascites, hepatic encephalopathy, or jaundice)
9. Hypersensitivity or contraindication to PPI, P-CAB, any of the product components, or substituted benzimidazoles 
10. Systemic treatment with strong CYP 3A4 and p-glycoprotein (P-gp) inhibitors (e.g., systemic azole antimycotics, such as ketoconazole, and human immunodeficiency virus [HIV]-protease inhibitors, such as ritonavir) 
11. Patients who take atazanavir, nelfinavir or rilpivirine-containing products (see Drug-Drug interaction section)
12. Clinically significant laboratory abnormality at screening (estimated glomerular filtration rate (eGFR) <15 mL/min or elevated liver enzyme [AST, ALT, ALP, total bilirubin] > 3 times upper normal limit [UNL] or any other condition that, in the opinion of the Investigator, precludes participation in the study 
13. Any known or suspected malignancy
14. Subjects with non-cardiac co-morbidities with life expectancy less than 12 months
15. Women who are pregnant or breastfeeding or female subjects, premenopausal who are not surgically sterile, or, if sexually active not practicing an effective method of birth control (e.g., prescription oral contraceptives, contraceptive injections, intrauterine device, double-barrier method, contraceptive patch, male partner sterilization) before entry and throughout the study; and, for those of childbearing potential, who have a positive pregnancy test at screening
16. Participation in another clinical study within 12 months

1. liver function abnormalities

6months after enrollment

2. hypergastrinemia

6months after enrollment

3. enteric infection

6months after enrollment

1. Overt upper gastrointestinal bleeding (confirmed by means of upper endoscopy or CT);

6months after enrollment

2. Overt upper gastrointestinal bleeding of unknown origin

6months after enrollment

3. Bleeding of presumed occult gastrointestinal origin with documented decrease in hemoglobin of ≥ 2 g/dL or decrease in hematocrit ≥ 10% from baseline;

6months after enrollment

4. Symptomatic gastroduodenal ulcer (confirmed by means of endoscopy or CT) without evidence of gastrointestinal bleeding;

6months after enrollment

5. Persistent pain of presumed gastrointestinal origin (duration ≥ 3 days) with underlying multiple erosive disease (5 or more gastroduodenal erosions confirmed by means of endoscopy);

6months after enrollment

6. Obstruction;

6months after enrollment

7. Perforation

6months after enrollment

This clinical study was conducted to verify the safety of potassium competitive gastric acid secretion inhibitors for gastrointestinal protection in the group of high-risk patients with gastrointestinal bleeding under antithrombotic treatment. A total of 330 patients were registered and a prospective observational study was conducted, and the safety evaluation variables of the test drug were measured and compared. As a result, liver function abnormalities and gastrointestinal infections set as the primary safety variable were not observed, and hypergastrinemia was observed in 12 cases, in about 4% of all patients. Through this, it was confirmed that there was no significant abnormality in safety by using potassium competitive gastric acid secretion inhibitors, and there was no significant association with the test drug even in secondary safety variables and significant harmful cases. In addition, in the laboratory results observed while taking the drug, there was no significant change in the basal level and liver after taking the drug. Through this, it is believed that long-term safety of more than 6 months was proven when potassium competitive gastric acid secretion inhibitor (Tegoprazan 50mg) was administered in patients with high risk of digestive system bleeding receiving antithrombotic treatment.
Based on this, it is expected that a randomized clinical study comparing existing proton pump inhibitors with potassium competitive gastric acid secretion inhibitors can be conducted in patients with high risk of gastrointestinal bleeding.