Statins, metformin, and RAS inhibitors did not reduce variceal bleeding risk and mortality in a large, real-life cohort of patients with cirrhosis.

BACKGROUND: Previous experimental and clinical studies suggested a beneficial effect of statins, metformin, angiotensin-converting-enzyme inhibitors and angiotensin II receptor blockers (RASi) on portal hypertension. Still, their effects on hard cirrhosis-related clinical endpoints, such as variceal bleeding and bleeding-related mortality, remain to be investigated. METHODS: Thus, we recorded the use of statins, metformin and RASi in a large cohort of cirrhotic patients undergoing endoscopic band ligation (EBL) for primary (PP, n = 440) and secondary bleeding prophylaxis (SP, n = 480) between 01/2000 and 05/2020. Variceal (re-) bleeding and survival rates were compared between patients with vs. without these co-medications. RESULTS: A total of 920 cirrhotic patients with varices were included. At first EBL, median MELD was 13 and 515 (56%) patients showed ascites. Statins, metformin and RASi were used by 49 (5.3%), 74 (8%), and 91 (9.9%) patients, respectively. MELD and platelet counts were similar in patients with and without the co-medications of interest. Rates of first variceal bleeding and variceal rebleeding at 2 years were 5.2% and 11.7%, respectively. Neither of the co-medications were associated with decreased first bleeding rates (log-rank tests in PP: statins p = 0.813, metformin p = 0.862, RASi p = 0.919) nor rebleeding rates (log-rank tests in SP: statin p = 0.113, metformin p = 0.348, RASi p = 0.273). Similar mortality rates were documented in patients with and without co-medications for PP (log-rank tests: statins p = 0.630, metformin p = 0.591, RASi p = 0.064) and for SP (statins p = 0.720, metformin p = 0.584, RASi p = 0.118). CONCLUSION: In clinical practice, variceal bleeding and mortality rates of cirrhotic patients were not reduced by co-medication with statins, metformin or RASi. Nevertheless, we recommend the use of these co-medications by indication, as they may still exert beneficial effects on non-bleeding complications in patients with liver cirrhosis.

Continuous co-prescription of rebamipide prevents upper gastrointestinal bleeding in NSAID use for orthopaedic conditions: A nested case-control study using the LIFE Study database.

BACKGROUND: Rebamipide has been widely co-prescribed with non-steroidal anti-inflammatory drugs (NSAIDs) in Japan for decades. This study aimed to evaluate the effectiveness of rebamipide in preventing upper gastrointestinal bleeding in new users of NSAIDs without risk factors of NSAID-induced ulcers other than age. METHODS: A nested case-control study was conducted using medical claims data of 1.66 million inhabitants of 17 municipalities participating in Japan's Longevity Improvement & Fair Evidence study. The cohort entry (t0) corresponded to a new user of NSAIDs for osteoarthritis or low back pain. Patients with risk factors of NSAID-induced ulcers other than age were excluded. Cases were defined as patients who underwent gastroscopy for upper gastrointestinal bleeding (occurrence date was defined as index date). A maximum of 10 controls were selected from non-cases at the index date of each case by matching sex, age, follow-up time, and type and dosage of NSAIDs. Exposure to rebamipide was defined as prescription status from t0 to index date: Non-user (rebamipide was not co-prescribed during the follow-up period), Continuous-user (rebamipide was co-prescribed from t0 with the same number of tablets as NSAIDs), and Irregular-user (neither Non-user nor Continuous-user). Conditional logistic regression analysis was conducted to estimate each category's odds ratio compared to non-users. FINDINGS: Of 67,561 individuals who met the inclusion criteria, 215 cases and 1,516 controls were selected. Compared with that of Non-users, the odds ratios and 95% confidence interval were 0.65 (0.44-0.96) for Continuous-users and 2.57 (1.73-3.81) for Irregular-users. CONCLUSIONS: Continuous co-prescription of rebamipide significantly reduced the risk of upper gastrointestinal bleeding in an Asian cohort of new users of NSAIDs with osteoarthritis or low back pain without risk factors other than age.

Transjugular intrahepatic portosystemic shunt for recompensating decompensated cirrhosis?

Transjugular intrahepatic portosystemic shunt (TIPS) is a medical procedure that has been used to manage variceal bleeding and ascites in patients with cirrhosis. It can prevent further decompensation and improve the survival of high-risk decompensated patients. Recent research indicates that TIPS could increase the possibility of recompensation of decompensated cirrhosis when it is combined with adequate suppression of the causative factor of liver disease. However, the results of the studies have been based on retrospective analysis, and further validation is required by conducting randomized controlled studies. In this context, we highlight the limitations of the current studies and emphasize the issues that must be addressed before TIPS can be recommended as a potential recompensating tool.

Proton-Pump Inhibitors to Prevent Gastrointestinal Bleeding - An Updated Meta-Analysis.

BACKGROUND: The goal of this systematic review was to examine the efficacy and safety of proton-pump inhibitors for stress ulcer prophylaxis in critically ill patients. METHODS: We included randomized trials comparing proton-pump inhibitors versus placebo or no prophylaxis in critically ill adults, performed meta-analyses, and assessed certainty of evidence using the Grading of Recommendations, Assessment, Development, and Evaluations approach. To explore the effect of proton-pump inhibitors on mortality based on disease severity, a subgroup analysis was conducted combining within-trial subgroup data from the two largest trials and assessed credibility using the Instrument for Assessing the Credibility of Effect Modification Analyses. RESULTS: Twelve trials that enrolled 9533 patients were included. Proton-pump inhibitors were associated with a reduced incidence of clinically important upper gastrointestinal bleeding (relative risk [RR], 0.51 [95% confidence interval (CI), 0.34 to 0.76]; high certainty evidence). Proton-pump inhibitors may have little or no effect on mortality (RR, 0.99 [95% CI, 0.93 to 1.05]; low certainty). Within-trial subgroup analysis with intermediate credibility suggested that the effect of proton-pump inhibitors on mortality may differ based on disease severity. Subgroup results raise the possibility that proton-pump inhibitors may decrease 90-day mortality in less severely ill patients (RR, 0.89; 95% CI, 0.80 to 0.98) and may increase mortality in more severely ill patients (RR, 1.08; 95% CI, 0.96 to 1.20]. Proton-pump inhibitors may have no effect on pneumonia and little or no effect on Clostridioides difficile infection (low certainty). CONCLUSIONS: High certainty evidence supports the association of proton-pump inhibitors with decreased upper gastrointestinal bleeding. Proton-pump inhibitors may have little or no effect on mortality, although a decrease in mortality in less severely ill patients and an increase in mortality in more severely ill patients remain possible. (PROSPERO number CRD42023461695.).

Navigating the controversy regarding antibiotic prophylaxis in acute variceal bleeding.

Antibiotic prophylaxis in patients with cirrhosis and acute variceal bleeding is part of the standard of care according to most clinical guidelines. However, with recent evidence arguing against antibiotic prophylaxis, the role of this intervention has become less clear.

Temporal trends in use of antisecretory agents among patients administered clopidogrel-based dual antiplatelet therapy after percutaneous coronary intervention.

BACKGROUND: Antisecretory drugs are commonly prescribed with clopidogrel-based dual antiplatelet therapy (DAPT) to prevent gastrointestinal bleeding in high-risk patients after percutaneous coronary intervention (PCI). However, omeprazole and esomeprazole (inhibiting proton pump inhibitors [PPIs]) may increase cardiovascular event rates on co-administration with clopidogrel. This study aimed to examine trends in the use of antisecretory agents in patients administered clopidogrel-based DAPT and the concomitant use of clopidogrel and inhibiting PPIs. METHODS: We used National Inpatient Sample data compiled by the Health Insurance Review & Assessment Service from 2009 to 2020. Further, we identified patients who were prescribed clopidogrel-based DAPT after PCI and investigated the concomitant use of antisecretory agents with clopidogrel. To verify the annual trend of drug utilization, we used the Cochran-Armitage trend test. RESULTS: From 2009 to 2020, the percentage of H2 receptor antagonist users decreased steadily (from 82.5% in 2009 to 25.3% in 2020); instead, the percentage of PPI users increased (from 23.7% in 2009 to 82.0% in 2020). The use of inhibiting PPI also increased (from 4.2% in 2009 to 30.7% in 2020). Potassium competitive acid blockers (P-CABs) were rarely used before 2019; however, in 2020, it accounted for 7.8% of the antisecretory users. CONCLUSIONS: Our study demonstrates that the use of inhibiting PPIs increased steadily in patients administered clopidogrel-based DAPT therapy. This is a major concern since the concomitant use of inhibiting PPIs with clopidogrel could increase the risk of cardiovascular events.

Evaluation of Aspirin Prescribing and Gastrointestinal Bleeding in Adults 60 Years of Age and Older in a Large, Academic Health System.

Background National guidelines no longer recommend adults 60 years of age and older to begin treatment with low-dose daily aspirin for primary prevention of atherosclerotic cardiovascular disease (CVD) due to a lack of proven net benefit and a higher risk of bleeding. Objective The objective of this cross-sectional retrospective analysis was to evaluate the appropriateness of low-dose aspirin prescribing and subsequent gastrointestinal bleeding in older persons receiving primary care in a large academic health system. Setting Large, academic health system within Colorado. Patients Patients with an active order for daily low-dose aspirin as of July 1, 2021, were assessed for appropriateness based on indication (primary vs secondary prevention) and use of a concomitant proton-pump inhibitor (PPI). Incident gastrointestinal bleeds (GIBs) in the subsequent 12 months and GIB risk factors were also evaluated. Results A total of 19,525 patients were included in the analysis. Eighty-nine percent of patients identified as White and 54% identified as male. Of the total cohort, 44% had CVD and 19% were co-prescribed a PPI. GIB occurred in 247 patients (1.27%) within the subsequent year. Risk factors significantly associated with a GIB within 1 year included: history of GIB, history of peptic ulcer disease, other esophageal issue (esophagitis, Barrett's esophagus, Mallory Weiss tears, etc.), 75 years of age or older, and history of gastroesophageal reflux disease. Conclusion This evaluation found that many older persons at this institution may be inappropriately prescribed aspirin, providing opportunities for pharmacists to improve medication safety by deprescribing aspirin among primary prevention patients or potentially co-prescribing a PPI in secondary prevention patients.

Widespread use of proton pump inhibitors or potassium-competitive acid blocker has changed the status of gastrointestinal bleeding in patients with ischemic heart disease: real-world data from high volume centers.

BACKGROUND: Although proton pump inhibitors (PPIs) or potassium-competitive acid blocker (PCAB) are useful in peptic ulcer prevention, their efficacy in preventing other gastrointestinal bleeding remains unclear. This study aimed to identify the status of gastrointestinal bleeding in the modern era when PPIs are widely used. METHODS: This study included patients who underwent percutaneous coronary intervention (PCI) between 2018 and 2019 at two high-volume centers. Patients were categorized based on whether they experienced gastrointestinal bleeding within 2 years of PCI into groups A (patients who experienced gastrointestinal bleeding within 2 years after PCI) and B (patients who did not experience gastrointestinal bleeding). RESULTS: Groups A and B included 21 (4.1%) and 494 (95.9%) patients, respectively (a total of 515 patients). Age at the initial PCI (77.8±2.4 and 72.0±0.5 years in groups A and B, respectively; p = 0.02), weight (53.8±3.2 and 61.8±0.7 kg in groups A and B, respectively; p = 0.01), and concomitant warfarin use (14.3% and 2.0% in groups A and B, respectively; p = 0.0005) were significantly different between the groups. The high bleeding risk rate (90.5% and 47.6% in groups A and B, respectively; p = 0.0001) was significantly different between the groups. A total of 95.9% of patients were taking PPIs or PCAB without significant differences between the groups. However, only one patient, who was taking steroids, had a gastric ulcer during PCAB treatment. CONCLUSIONS: Acid-related upper gastrointestinal bleeding is largely controlled by PPIs in post-PCI patients. Furthermore, the risk factors for non-acid-related bleeding include older age, lower weight, and concomitant warfarin use.

Prevention of delayed bleeding after resection of large colonic polyps.

A significant problem encountered in the resection of large, complex colonic polyps is delayed bleeding. This can occur up to two weeks after the procedure and is a significant source of comorbidity. Untreated it can prove life threatening. It is therefore a priority of modern endoscopy to develop and employ techniques to minimaize this. In this article we will review and discuss the evidence base and controversies in this field, with cold EMR technique, Post-EMR clip closure, and topical haemostatic agents.

Protocol implementation during the COVID-19 pandemic: experiences from a randomized trial of stress ulcer prophylaxis.

BACKGROUND: During the COVID-19 pandemic, many intensive care units (ICUs) halted research to focus on COVID-19-specific studies. OBJECTIVE: To describe the conduct of an international randomized trial of stress ulcer prophylaxis (Re-Evaluating the Inhibition of Stress Erosions in the ICU [REVISE]) during the pandemic, addressing enrolment patterns, center engagement, informed consent processes, data collection, a COVID-specific substudy, patient transfers, and data monitoring. METHODS: REVISE is a randomized trial among mechanically ventilated patients, comparing pantoprazole 40 mg IV to placebo on the primary efficacy outcome of clinically important upper gastrointestinal bleeding and the primary safety outcome of 90-day mortality. We documented protocol implementation status from March 11th 2020-August 30th 2022. RESULTS: The Steering Committee did not change the scientific protocol. From the first enrolment on July 9th 2019 to March 10th 2020 (8 months preceding the pandemic), 267 patients were enrolled in 18 centers. From March 11th 2020-August 30th 2022 (30 months thereafter), 41 new centers joined; 59 were participating by August 30th 2022 which enrolled 2961 patients. During a total of 1235 enrolment-months in the pandemic phase, enrolment paused for 106 (8.6%) months in aggregate (median 3 months, interquartile range 2;6). Protocol implementation involved a shift from the a priori consent model pre-pandemic (188, 58.8%) to the consent to continue model (1615, 54.1%, p < 0.01). In one new center, an opt-out model was approved. The informed consent rate increased slightly (80.7% to 85.0%, p = 0.05). Telephone consent encounters increased (16.6% to 68.2%, p < 0.001). Surge capacity necessitated intra-institutional transfers; receiving centers continued protocol implementation whenever possible. We developed a nested COVID-19 substudy. The Methods Centers continued central statistical monitoring of trial metrics. Site monitoring was initially remote, then in-person when restrictions lifted. CONCLUSION: Protocol implementation adaptations during the pandemic included a shift in the consent model, a sustained high consent rate, and launch of a COVID-19 substudy. Recruitment increased as new centers joined, patient transfers were optimized, and monitoring methods were adapted.

Beta-blockers or Placebo for Primary Prophylaxis (BOPPP) of oesophageal varices: study protocol for a randomised controlled trial.

BACKGROUND: Liver disease is within the top five causes of premature death in adults. Deaths caused by complications of cirrhosis continue to rise, whilst deaths related to other non-liver disease areas are declining. Portal hypertension is the primary sequelae of cirrhosis and is associated with the development of variceal haemorrhage, ascites, hepatic encephalopathy and infection, collectively termed hepatic decompensation, which leads to hospitalisation and mortality. It remains uncertain whether administering a non-selective beta-blocker (NSBB), specifically carvedilol, at an earlier stage, i.e. when oesophageal varices are small, can prevent VH and reduce all-cause decompensation (ACD). METHODS/DESIGN: The BOPPP trial is a pragmatic, multicentre, placebo-controlled, triple-blinded, randomised controlled trial (RCT) in England, Scotland, Wales and Northern Ireland. Patients aged 18 years or older with cirrhosis and small oesophageal varices that have never bled will be recruited, subject to exclusion criteria. The trial aims to enrol 740 patients across 55 hospitals in the UK. Patients are allocated randomly on a 1:1 ratio to receive either carvedilol 6.25 mg (a NSBB) or a matched placebo, once or twice daily, for 36 months, to attain adequate power to determine the effectiveness of carvedilol in preventing or reducing ACD. The primary outcome is the time to first decompensating event. It is a composite primary outcome made up of variceal haemorrhage (VH, new or worsening ascites, new or worsening hepatic encephalopathy (HE), spontaneous bacterial peritonitis (SBP), hepatorenal syndrome, an increase in Child-Pugh grade by 1 grade or MELD score by 5 points, and liver-related mortality. Secondary outcomes include progression to medium or large oesophageal varices, development of gastric, duodenal, or ectopic varices, participant quality of life, healthcare costs and transplant-free survival. DISCUSSION: The BOPPP trial aims to investigate the clinical and cost-effectiveness of carvedilol in patients with cirrhosis and small oesophageal varices to determine whether this non-selective beta-blocker can prevent or reduce hepatic decompensation. There is clinical equipoise on whether intervening in cirrhosis, at an earlier stage of portal hypertension, with NSBB therapy is beneficial. Should the trial yield a positive result, we anticipate that the administration and use of carvedilol will become widespread with pathways developed to standardise the administration of the medication in primary care. ETHICS AND DISSEMINATION: The trial has been approved by the National Health Service (NHS) Research Ethics Committee (REC) (reference number: 19/YH/0015). The results of the trial will be submitted for publication in a peer-reviewed scientific journal. Participants will be informed of the results via the BOPPP website ( www.boppp-trial.org ) and partners in the British Liver Trust (BLT) organisation. TRIAL REGISTRATION: EUDRACT reference number: 2018-002509-78. ISRCTN reference number: ISRCTN10324656. Registered on April 24 2019.

Improvement of quality of care provided to outpatients with hepatic cirrhosis after an educational intervention.

OBJECTIVE: A set of indicators has been reported to measure the quality of care for cirrhotic patients, and previously published studies report variable adherence rates to these indicators. This study aimed to assess the quality of care provided to cirrhotic outpatients before and after an educational intervention by determining its impact on adherence to quality indicators. METHODS: We conducted a quasi-experimental, cross-sectional study including 324 cirrhotic patients seen in 2017 and 2019 at a tertiary teaching hospital in Spain. Quality indicators were assessed in five domains: documentation of cirrhosis etiology, disease severity assessment, hepatocellular carcinoma (HCC) screening, variceal bleeding prophylaxis, and vaccination. After identifying areas for improvement, an educational intervention was implemented. A second evaluation was performed after the intervention to assess changes in adherence rates. RESULTS: Before the intervention, adherence rates were excellent (>90%) for indicators related to variceal bleeding prophylaxis and documentation of cirrhosis etiology, acceptable (60-80%) for HCC screening and disease severity assessment, and poor (<50%) for vaccinations. After the educational intervention, there was a statistically significant improvement in adherence rates for eight indicators related to HCC screening (70-90%), disease severity assessment (90%), variceal bleeding prophylaxis (>90%), and vaccinations (60-90%). CONCLUSION: Our study demonstrates a significant improvement in the quality of care provided to cirrhotic outpatients after an educational intervention. The findings highlight the importance of targeted educational interventions to enhance adherence to quality indicators in the management of cirrhosis.

Management of Anticoagulant and Antiplatelet Agents in Acute Gastrointestinal Bleeding and Prevention of Gastrointestinal Bleeding.

Managing gastrointestinal bleeding in patients using antithrombotic agents remains challenging in clinical practice. This review article provides a comprehensive and evidence-based approach to managing acute antithrombotic-related gastrointestinal bleeding, focusing on the triage of patients, appropriate resuscitation, and timely endoscopy. The latest clinical practice guidelines are highlighted to guide decisions concerning the use of reversal agents, temporary interruption, and resumption of antithrombotic drugs. Additionally, preventive measures are discussed to lower the risk of future bleeding and minimize complications among patients prescribed antithrombotic drugs.

The Role of Endoscopy for Primary and Secondary Prophylaxis of Variceal Bleeding.

Cirrhosis is associated with a high morbidity and mortality. One of the most serious and unpredictable complication of cirrhosis, with a high mortality rate, is bleeding from esophagogastric varices. Endoscopic screening of varices followed by primary prophylactic treatment with beta blockers or band ligation in the presence of large esophageal varices will reduce the variceal bleeding rates and thereby reduce mortality risks in those with advanced cirrhosis. There is a paucity of data on primary prophylaxis of gastric varices but secondary prophylaxis includes glue injection, balloon-occluded retrograde transvenous obliteration, or transjugular intrahepatic portosystemic shunting with coil embolization.

Effectiveness of antibiotic prophylaxis for acute esophageal variceal bleeding in patients with band ligation: A large observational study.

BACKGROUND: Esophageal variceal bleeding is a severe complication associated with liver cirrhosis and typically necessitates endoscopic hemostasis. The current standard treatment is endoscopic variceal ligation (EVL), and Western guidelines recommend antibiotic prophylaxis following hemostasis. However, given the improvements in prognosis for variceal bleeding due to advancements in the management of bleeding and treatments of liver cirrhosis and the global concerns regarding the emergence of multidrug-resistant bacteria, there is a need to reassess the use of routine antibiotic prophylaxis after hemostasis. AIM: To evaluate the effectiveness of antibiotic prophylaxis in patients treated for EVL. METHODS: We conducted a 13-year observational study using the Tokushukai medical database across 46 hospitals. Patients were divided into the prophylaxis group (received antibiotics on admission or the next day) and the non-prophylaxis group (did not receive antibiotics within one day of admission). The primary outcome was composed of 6-wk mortality, 4-wk rebleeding, and 4-wk spontaneous bacterial peritonitis (SBP). The secondary outcomes were each individual result and in-hospital mortality. A logistic regression with inverse probability of treatment weighting was used. A subgroup analysis was conducted based on the Child-Pugh classification to determine its influence on the primary outcome measures, while sensitivity analyses for antibiotic type and duration were also performed. RESULTS: Among 980 patients, 790 were included (prophylaxis: 232, non-prophylaxis: 558). Most patients were males under the age of 65 years with a median Child-Pugh score of 8. The composite primary outcomes occurred in 11.2% of patients in the prophylaxis group and 9.5% in the non-prophylaxis group. No significant differences in outcomes were observed between the groups (adjusted odds ratio, 1.11; 95% confidence interval, 0.61-1.99; P = 0.74). Individual outcomes such as 6-wk mortality, 4-wk rebleeding, 4-wk onset of SBP, and in-hospital mortality were not significantly different between the groups. The primary outcome did not differ between the Child-Pugh subgroups. Similar results were observed in the sensitivity analyses. CONCLUSION: No significant benefit to antibiotic prophylaxis for esophageal variceal bleeding treated with EVL was detected in this study. Global reassessment of routine antibiotic prophylaxis is imperative.

Preventing variceal rebleeding in cirrhotic patients with portal vein thrombosis: A systematic review and meta-analysis.

BACKGROUND AND AIM: Preventing rebleeding is crucial, but the best prevention technique for patients with cirrhosis and portal vein thrombosis (PVT) remains debatable. Therefore, this systematic review and meta-analysis compared a transjugular intrahepatic portosystemic shunt (TIPS) with endoscopic therapy (ET) plus nonselective beta-blockers (NSBBs) for preventing variceal rebleeding in this patient population. METHODS: The PubMed, Embase, Cochrane Library, and Web of Science databases were searched from their inception until May 18, 2023. The studies were screened using predetermined criteria, relevant data were extracted, and pooled analyses were performed using the Reviewer Manager 5.4.1 software. RESULTS: We retrieved 1032 studies, of which 5 studies comprising a total of 272 patients were included. The postoperative variceal rebleeding rate was significantly lower in the TIPS group than in the ET + NSBBs group (odds ratio [OR] = 0.19, 95% confidence interval [CI] = 0.11-0.35, P < 0.05, I2 = 0%), but the portal vein recanalization rate was higher (OR = 7.92, 95% CI = 3.04-20.67, P < 0.05, I2 = 0%). The rates of hepatic encephalopathy (HE) and mortality did not differ between the groups. CONCLUSIONS: Our results suggest that TIPS prevents variceal rebleeding without increasing the hepatic encephalopathy risk more effectively than ET plus NSBBs, but this benefit did not translate into improved survival. Thus, it may be preferable to ET plus NSBBs for preventing variceal rebleeding in patients with cirrhosis and PVT. However, more large-scale and multicenter randomized controlled trials involving other patient populations are required to verify the clinical efficacy of both these treatments and ensure generalizability.

Reduction of Upper Gastrointestinal Bleeding Risk With Proton Pump Inhibitor Therapy in Asian Patients With Atrial Fibrillation Receiving Direct Oral Anticoagulant: A Nationwide Population-based Cohort Study.

BACKGROUND & AIMS: In patients with atrial fibrillation (AF) receiving direct oral anticoagulant (DOAC), upper gastrointestinal bleeding (UGIB) is a serious complication. There are limited data on the benefit of preventive proton pump inhibitor (PPI) use to reduce the risk of UGIB in DOAC users. METHODS: We included patients with AF receiving DOAC from 2015 to 2020 based on the Korean Health Insurance Review and Assessment database. The propensity score (PS) weighting method was used to compare patients with PPI use and those without PPI use. The primary outcome was hospitalization for UGIB. Weighted hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) were evaluated using the Cox proportional hazards regression model. RESULTS: A total of 165,624 patients were included (mean age: 72.2 ± 10.8 years; mean CHA2DS2-VASc score: 4.3 ± 1.8; mean HAS-BLED score: 3.3 ± 1.2). Among them, 99,868 and 65,756 were in the non-PPI group and PPI group, respectively. During a median follow-up of 1.5 years, the PPI group was associated with lower risks of hospitalization for UGIB and UGIB requiring red blood cell transfusion than non-PPI group (weighted HR, 0.825; 95% CI, 0.761-0.894 and 0.798; 95% CI, 0.717-0.887, respectively, both P < .001). The benefits of PPI on the risk of hospitalization for UGIB were greater in those with older age (≥75 years), higher HAS-BLED score (≥3), prior GIB history, and concomitant use of antiplatelet agent (all P-for-interaction < .1). Low-dose PPI was consistently associated with a lower risk of significant UGIB by 43.6-49.3% (P < .001). CONCLUSIONS: In this large Asian cohort of patients with AF on DOAC, PPI co-therapy is beneficial for reducing the risk of hospitalization for UGIB, particularly in high-risk patients.