ABSTRACT
Background
Direct oral anticoagulants (DOACs) are the cornerstone of thromboembolic prevention in patients with atrial fibrillation, venous thromboembolism, or other cardiovascular conditions. However, DOAC use is associated with an increased risk of bleeding, with gastrointestinal (GI) bleeding being the most common site of major bleeding. Proton pump inhibitors (PPIs) are reasonably used during combined antithrombotic therapy or based on individual bleeding risk; nonetheless, evidence supporting their benefit in patients receiving DOAC therapy remains limited.
Methods
The Gastrointestinal protection Using proton-pump inhibitor in pAtients who RequireD Oral AntiCoagulants (GUARD-OAC) trial is a prospective, multicenter, open-label, randomized controlled trial evaluating the GI protective effect of PPI coadministration with DOAC. Eligible participants are patients with cardio- or cerebrovascular disease requiring long-term anticoagulation (≥1 year), who are currently receiving or initiating DOAC therapy, and have a HAS-BLED score of ≥1. The primary outcome is a composite of upper GI clinical events, including bleeding, symptomatic gastroduodenal ulcer, persistent pain of presumed GI origin with underlying multiple erosive disease, obstruction, or perforation. The secondary outcomes are the individual components of the primary outcome, GI symptoms or signs, cardiovascular or all bleeding events, and all-cause mortality. Assuming a 40% relative risk reduction of the primary outcome in the PPI plus DOAC group compared to the DOAC alone group, a total of 3,846 patients will be enrolled and followed for one year. A Clinical Events Committee will adjudicate clinical outcomes and adverse events for causality and attribution, and an independent Data Safety Monitoring Board will oversee the study. The GUARD-OAC trial is funded by the Ministry of Health & Welfare, Republic of Korea.
Conclusions
The GUARD-OAC trial is the first randomized controlled trial exploring the efficacy of PPI cotherapy in patients receiving DOACs, providing evidence that may inform future guidelines on GI protection in this population.
Trial registration
Clinical Research Information Service, Identifier KCT0006848.
Background
Since their introduction in the late 2000s, ,,, direct oral anticoagulants (DOACs) have been widely adopted for thromboembolic prevention in patients with atrial fibrillation (AF), venous thromboembolism, and other cardiovascular conditions. However, the use of DOACs is associated with an increased risk of bleeding, an inherent side effect of anticoagulation therapy. Among bleeding complications, gastrointestinal (GI) bleeding has presented as the most common single site of major bleeding in pivotal trials, accounting for nearly half of all major anticoagulant-related bleeding. ,,, These events not only contribute to significant morbidity and mortality but also increase the risk of thromboembolic complications due to temporary or permanent discontinuation of anticoagulation. As the population ages and the indications for DOAC therapy expand, the burden of DOAC-related GI bleeding is expected to rise. Therefore, preventing GI bleeding events is critical to minimize associated healthcare costs and achieve the therapeutic goals of DOACs.
Proton pump inhibitors (PPIs) are key therapy in the treatment and prevention of upper GI bleeding and various acid-related digestive system diseases. , Guidelines recommend PPI use in patients at elevated risk of GI bleeding during combined antithrombotic therapy [antiplatelet therapy and/or oral anticoagulants (OAC)]. , However, randomized clinical trials supporting the recommendation have primarily included patients receiving dual antiplatelet therapy or low-dose anticoagulation and/or aspirin. Although several observational studies have shown potential benefit from PPI in DOAC users, randomized clinical trial data on the benefit of PPI in GI protection in patients using standard dose DOAC are lacking. , Meanwhile, current guidelines consider PPI and DOAC cotherapy reasonable in patients at potentially high risk of GI bleeding and recommend individualized therapy according to the perceived bleeding risk.
Given the clinical importance of preventing GI complications (mainly, bleeding) in patients with DOAC and limited data on large-scale randomized clinical trials specifically addressing the protective effect of PPIs in this population, there is a clear need for robust evidence evaluating the efficacy and safety of PPIs in patients receiving DOAC. The Gastrointestinal protection Using proton-pump inhibitor in pAtients who RequireD Oral AntiCoagulants (GUARD-OAC) trial was designed to fill this knowledge gap by assessing the GI protective effect of PPI coadministration in patients requiring long-term DOAC therapy.
Methods and analyses
Study design
The GUARD-OAC trial is an ongoing prospective, multicenter, open-label, randomized controlled trial evaluating the GI protective effect of PPI therapy in patients requiring long-term use of DOAC. The primary objective is to evaluate the efficacy and safety of PPI and DOAC cotherapy. Participants are randomly assigned 1:1 to either the PPI group (lansoprazole 15 mg capsule daily) or the no-PPI group. In addition to their existing DOAC regimen, participants will receive either lansoprazole 15 mg or no additional drug, depending on their randomization group, for 1 year ( Figure 1 ). The investigational drug, lansoprazole 15 mg capsule, is to be taken orally once daily on an empty stomach in the morning, followed by the morning dose of the DOAC after a meal. Randomization is performed using a computer-generated sequence via an interactive web response system. Randomization is stratified by the site of enrollment, and the entire process, including access to and management of allocation information, is conducted independently of the investigators.
Study design and follow-up schedule. DOAC, direct oral anticoagulant; PPI, proton pump inhibitor; EQ-5D, European quality of life–5 dimensions.
The study protocol has been reviewed and approved by the corresponding ethics committees at all participating centers. The trial is registered at Clinical Research Information Service, Identifier KCT0006848. All enrolled participants provided written informed consent.
Study population
The GUARD-OAC trial enrolls 3,846 subjects from 32 participation centers in the Republic of YKorea (Supplementary Table I). Eligible participants are patients with cardio- or cerebrovascular disease requiring long-term anticoagulation (≥1 year), who are currently receiving or initiating DOAC therapy, and have a HAS-BLED score of at least 1. The threshold of a HAS-BLED score of 1 was selected to exclude only patients at minimal bleeding risk and to enhance the representativeness of DOAC-treated participants, adopting a pragmatic approach. Participants are excluded if they are taking concomitant medications or have undergone procedures that may influence gastric acid secretion. Participants receiving concomitant medications that are contraindicated for use with PPIs or DOACs are also excluded. A complete listing of the inclusion and exclusion criteria is provided in Table 1 .
Table 1
GUARD-OAC eligibility criteria.
| Inclusion criteria | |
|---|---|
| Individuals who meet all of the following criteria | |
| 1 | Individuals with cardio- or cerebrovascular disease requiring long-term anticoagulation (≥1 year), who are currently receiving or initiating DOAC therapy. |
| 2 | Individuals with HAS-BLED score ≥1. |
| 3 | Individuals aged 19 years or older who have voluntarily signed the written consent form. |
| Exclusion criteria | |
| 1 | Individuals who have taken prohibited concomitant medications a) within 2 weeks prior to enrollment or who require ongoing treatment with such medications at the time of enrollment. |
|
a)
Prohibited concomitant medications:
PPIs, potassium-competitive acid blockers (P-CABs), histamine H2 receptor antagonists (H2 RAs), bismuth-containing agents, anticholinergics, gastrin inhibitors, mucosal protectants, any DOAC contraindicated concomitant drugs, and lansoprazole contraindicated concomitant drugs. |
|
| 2 | Individuals with active bleeding at the time of enrollment, or a history of congenital or acquired coagulation disorders. |
| 3 | Individuals who have undergone major surgeries that may affect gastric acid secretion, such as upper gastrointestinal resection, acid secretion inhibition procedures, or extensive gastric mucosal resection. However, simple perforation repair surgery, appendectomy, cholecystectomy, and laparoscopic resection of benign tumors are excluded. |
| 4 | Individuals with current or past history of Zollinger-Ellison syndrome or other gastric acid secretion disorders. |
| 5 | Individuals with clinical contraindications to anticoagulant therapy. |
| 6 | Individuals who are hemodynamically unstable at the time of enrollment. |
| 7 | Individuals with severe anemia (hemoglobin <8 g/dL) at screening or a history of blood transfusion within 4 weeks prior to randomization. |
| 8 | Individuals with severe thrombocytopenia at screening (platelet count <50,000/mm³). |
| 9 | Individuals with end-stage renal disease requiring dialysis or with severe renal impairment (creatinine clearance <15 mL/min). |
| 10 | Individuals with severe chronic liver disease, defined by the presence of variceal bleeding, ascites, hepatic encephalopathy, or jaundice. |
| 11 | Individuals with hypersensitivity to, or contraindications for, PPIs. |
| 12 | Individuals receiving dual antiplatelet therapy at the time of enrollment. |
| 13 | Individuals with systemic administration of strong CYP3A4 and P-glycoprotein inhibitors (e.g., azole-class antifungal agents, HIV protease inhibitors like ritonavir) |
| 14 | Individuals taking medications including atazanavir, nelfinavir, or rilpivirine |
| 15 | Individuals with clinically significant abnormalities at screening as judged by the investigator (e.g., elevation of liver function tests, with AST, ALT, or total bilirubin levels greater than three times the upper limit of normal). |
| 16 | Individuals with a known a) or suspected b) malignant disease. |
|
a) Individuals with a history of malignancy within the past 5 years.
* Individuals who have achieved complete remission of a tumor and remained recurrence-free for more than 5 years from the date of remission, as well as those whose tumors were completely removed via endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD), with no expected impact on gastric acid secretion and who have remained recurrence-free for more than 3 years, may be included. |
|
| b) Individuals with alarm symptoms suggestive of malignancy [e.g., significant unintentional weight loss, recurrent vomiting, odynophagia, dysphagia, hematemesis, melena, hematochezia (excluding hemorrhoids), or anemia] are excluded. However, those presenting with such alarm symptoms may be included if endoscopic examination confirms the absence of malignancy. | |
| 17 | Individuals whose life expectancy is less than one year due to noncardiac diseases. |
| 18 | Pregnant women or women of childbearing potential. |
| 19 | Individuals who are scheduled to undergo surgery requiring hospitalization during the clinical trial or who require surgical treatment. |
| 20 | Individuals who have participated in another randomized clinical trial within the past 12 months. |
ALT , alanine aminotransferase; AST , aspartate aminotransferase; DOAC , direct oral anticoagulants; HIV , human immunodeficiency virus; PPI , proton pump inhibitor.
Rationale for the selection of investigational drug
Among antisecretory agents, PPIs are the only drugs consistently shown to be associated with a lower risk of upper GI bleeding in patients receiving OACs. , Notably, our observational cohort study using a nationwide claims database demonstrated that PPI and DOAC cotherapy was associated with a lower risk of upper GI bleeding requiring hospitalization or red blood cell transfusion in patients with AF on DOAC therapy. We also validated the gastroprotective effect of PPI and DOAC cotherapy in high-risk patients with AF, such as those with a history of upper GI bleeding. Based on the findings from these meta-analyses and observational studies, we designed the current trial to evaluate a gastroprotective strategy using PPI in patients requiring long-term DOAC therapy.
Previous studies have demonstrated minimal differences in clinical efficacy among various PPIs. Lansoprazole has shown efficacy in a randomized clinical trial for preventing the recurrence of ulcer-related complications after Helicobacter pylori eradication in patients on long-term low-dose aspirin. Its long-term safety has been well established, with evidence supporting continuous use for over 6 years—an important consideration when evaluating prophylactic treatment in patients requiring extended anticoagulation. Additionally, other PPIs, such as omeprazole and esomeprazole, have been shown to reduce the exposure of clopidogrel’s active metabolite, a potentially coadministered drug in this population. Given lansoprazole’s neutrality with respect to clinical efficacy, cardiovascular safety, and long-term use, it was selected as the investigational drug for this trial.
Randomized clinical trial evaluating the efficacy of PPIs in patients receiving combined antithrombotic therapy (antiplatelet therapy and/or OAC) or dual antiplatelet therapy utilized pantoprazole 40 mg or omeprazole 20 mg daily. , However, unlike combined or dual antiplatelet therapy, which is generally prescribed for a limited duration, most participants in our trial are expected to require lifelong DOAC therapy. Therefore, our trial’s design must account for the implications of potential long-term PPI use. Notably, low-dose PPIs (i.e., half the standard dose) have been shown to provide sufficient gastroprotection against nonsteroidal anti-inflammatory drug (NSAID)-related gastroduodenal ulcers. ,, In support of this, our observational cohort study also demonstrated that low-dose PPI use was consistently associated with a reduced risk of significant upper GI bleeding (UGIB) in patients with AF receiving DOAC therapy. Based on this evidence, we considered low-dose PPI use to be a reasonable choice for the study intervention.
Study endpoints and follow-up
The primary outcome is the composite of upper GI clinical events including GI bleeding, symptomatic gastroduodenal ulcer, GI pain with erosive disease, obstruction, or perforation. The key secondary outcomes include upper GI clinical events, GI signs and symptoms, cardiovascular events, major and minor bleeding as defined by the International Society on Thrombosis or Haemostasis (ISTH), , Bleeding Academic Research Consortium (BARC), and Thrombolysis in Myocardial Infarction (TIMI) definitions, and all-cause death. A complete list of prespecified primary and secondary outcomes is provided in Table 2 .
Table 2
GUARD-OAC study outcomes.
| Primary outcomes | |
|---|---|
| The primary outcome is the composite of upper gastrointestinal clinical events, including: | |
| 1 | Overt upper gastrointestinal bleeding. |
| Bleeding of gastroduodenal origin manifested by melena and/or hematemesis with confirmation of gastroduodenal ulcer or erosion by endoscopic or radiographic examination. | |
| 2 | Gastrointestinal bleeding of unknown origin. |
| Bleeding in the gastrointestinal tract, manifested by melena and/or hematemesis without confirmed identification of a gastrointestinal bleeding lesion by endoscopic or radiographic examination. | |
| 3 | Bleeding of presumed occult gastrointestinal origin. |
|
Bleeding in the gastrointestinal tract meeting the following criteria, without confirmed identification of a gastrointestinal bleeding lesion by endoscopic or radiographic examination, and in the absence of a known cause of anemia, thereby considered to be attributed to gastrointestinal bleeding.
1) Decrease in hemoglobin of at least 2 g/dL or 2) Decrease in hematocrit of at least 10% from prerandomization or 3) Transfusion of at least 2 units of packed whole or red blood cells. |
|
| 4 | Symptomatic gastroduodenal ulcer |
| Gastroduodenal ulcer manifested by at least one gastrointestinal symptom that persists for at least 3 days with confirmation of ulcer by endoscopic or radiographic examination. An ulcer is defined as any mucosal break at least 3 mm in greatest diameter that has unequivocal depth. | |
| 5 | Persistent pain of presumed gastrointestinal origin with underlying multiple erosive disease |
| Pain of presumed gastrointestinal origin that persists for ≥3 days, with confirmation of 5 or more gastroduodenal erosions by endoscopy. An erosion is defined as a mucosal break of any diameter without depth. | |
| 6 | Obstruction |
| Gastrointestinal obstruction confirmed by endoscopic or radiographic examination. | |
| 7 | Perforation |
| Gastrointestinal perforation confirmed by endoscopic or radiographic examination. | |
| Secondary outcomes | |
| 1 | The composite of the following upper gastrointestinal bleeding events: |
|
1) Overt upper gastrointestinal bleeding or
2) Gastrointestinal bleeding of unknown origin or 3) Bleeding of presumed occult gastrointestinal origin. |
|
| 2 | The following lesions identified on upper endoscopy in symptomatic patients. |
|
1) Gastroduodenal ulcer
2) Multiple (5 or more) gastroduodenal erosions 3) Erosive gastroesophageal reflux disease |
|
| 3 | Occurrence of gastrointestinal signs and symptoms. |
| Epigastric soreness, dyspepsia, abdominal pain, nausea, vomiting, hematochezia, melena, or endoscopic evaluation due to symptoms. | |
| 4 | Time from randomization to first occurrence of gastrointestinal signs and symptoms. |
| 5 | The composite of the following cardiovascular events: |
| Cardiovascular death, acute coronary syndrome, ischemic or hemorrhagic stroke, transient ischemic attach, or pulmonary embolism | |
| 6 | The individual component of the cardiovascular events. |
| Cardiovascular death, acute coronary syndrome, ischemic or hemorrhagic stroke, transient ischemic attach, or pulmonary embolism | |
| 7 | The composite of bleeding events |
|
All major bleeding
a)
or minor bleeding.
b)
a), b) are defined by ISTH, BARC, and TIMI major and minor bleeding |
|
| 8 | The individual component of the composite bleeding events. |
|
All major bleeding:
1) Upper gastrointestinal major bleeding (upper GI major bleeding) 2) All major bleeding events other than upper gastrointestinal major bleeding (nonupper GI major bleeding) |
|
|
All minor bleeding:
1) Upper gastrointestinal minor bleeding (upper GI minor bleeding) 2) All minor bleeding events other than upper gastrointestinal minor bleeding (nonupper GI minor bleeding) |
|
| 9 | All-cause death |
| 10 | All potential adverse effects of PPIs |
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