Comparison of clinical outcomes in cirrhotic patients presenting with acute variceal and non-variceal gastrointestinal bleeding

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This study aimed to compare clinical outcomes between AVB and NVB, and identify predictors of liver-related death following AVB. A retrospective, observational, single-center study including patients with acute GI bleeding from 2016 to 2022, divided into AVB and NVB groups. Outcomes included complications, rebleeding, further decompensation, and liver-related death. Survival was analyzed using Kaplan-Meier, and predictors were identified with Cox regression and ROC curves. A total of 154 patients were included. The NVB group (n = 57) was older (67 vs. 55 years, p < 0.001), had higher MELDNa scores (18 vs. 15, p = 0.016), and more ascites at admission (52.6% vs. 35.1%, p = 0.033). There were no significant differences between groups in in-hospital mortality, complications, rebleeding, further decompensation, or liver-related death during follow-up. In AVB patients, MELDNa independently predicted liver-related death at 30 and 90 days ( p < 0.001). AVB, whether a first or subsequent decompensation event, showed similar 30-day readmission rates and liver-related death. Clinical outcomes were similar between AVB and NVB. In AVB patients, MELDNa was an independent predictor of short-term liver-related mortality. Health sciences/Gastroenterology/Gastrointestinal diseases/Liver diseases/Liver cirrhosis Health sciences/Gastroenterology/Gastrointestinal diseases/Liver diseases/Portal hypertension acute gastrointestinal bleeding cirrhosis mortality variceal bleeding Figures Figure 1 Figure 2 INTRODUCTION Advanced chronic liver disease (ACLD) is the final stage of various chronic liver diseases, with high morbidity and mortality rates [ 1 ]. Its course transitions from compensated (cACLD) to decompensated (dACLD) states, with distinct prognoses and survival rates [ 2 – 4 ]. Decompensation signals the onset of liver-related complications. Progression of ACLD correlates with rising hepatic venous pressure gradient (HVPG), the best predictor of first decompensation [ 5 ]. Portal hypertension (PH) drives this progression and causes complications like gastroesophageal varices (GEV), ascites, hepatorenal syndrome (HRS), spontaneous bacterial peritonitis (SBP), and hepatic encephalopathy (HE) [ 6 – 8 ]. GEV develops at 8% per year, with rupture rates of 5–15% annually and at least 20% mortality [ 9 – 12 ]. Nonselective beta-blockers (NSBBs) are recommended in cACLD to lower portal pressure and prevent acute decompensation [ 13 , 14 ]. Non-variceal gastrointestinal bleeding (NVB) affects 20%-30% of ACLD patients, arising from PH-associated causes (PH gastropathy, gastric antral vascular ectasia [GAVE]) or unrelated causes (peptic ulcer disease [PUD], Mallory-Weiss syndrome [MWS], esophagitis) [ 15 ]. MWS is linked to heavy alcohol consumption, while PUD remains relevant in due to Helicobacter pylori and NSAID use [ 16 ]. Carvalho et al. showed that the rate of Helicobacter pylori testing and treatment in patients with ACLD is low [ 17 ]. Despite medical advances, NVB mortality remains 15–20% [ 18 ]. Observational studies show mixed results on mortality and re-hospitalization rates between AVB and NVB in ACLD patients [ 19 – 22 ]. The prognostic impact of bleeding etiology in ACLD remains unclear. This study aimed to compare clinical outcomes in ACLD patients with AVB and NVB and predict their clinical course. RESULTS COMPARISON OF CIRRHOTIC PATIENTS WITH AVB AND NVB Patients’ characteristics During the study period, 176 patients with ACLD presented with acute GI bleeding, of whom 154 fulfilled the inclusion and no exclusion criteria and were finally included in this study (Supplementary material - Figure 1). Based on endoscopic findings, they were divided into NVB (n = 57) and AVB (n = 97) groups (Figure 1). Table 1 and 2 condenses patients' baseline characteristics, index bleeding event, and in-hospital complications. The median age was 60 years and most patients were male (72.7%). At baseline, 75 (48.7%) patients had cACLD with 35 (46.7%) in stage 1 and 40 (53.3%) in stage 2 with GEV. Within patients with dACLD (n = 79, 51.3%), 18 (22.8%) were in stage 3, 39 (49.4%) in stage 4, and 22 (27.8%) in stage 5. The most common etiology for ACLD was alcoholic-related liver disease (61.7%). The NVB group of patients was significantly older than the AVBG group (67 ± 19 vs. 55 ± 19, p < 0.001) and had a documented higher use of antiplatelet agents (21.1% vs. 7.2%, p = 0.012). Figure 1. Regarding the index bleeding event, patients with NVB presented with higher MELDNa scores compared to those with AVB (18 ± 12 vs. 15 ± 8.5, p = 0.016) and a higher rate of ascites at admission (52.6% vs. 35.1%, p = 0.033). Hematological and biochemical laboratory investigations were similar with the exception that patients with NVB had higher serum urea (76 ± 55.8 vs. 54 ± 42 , p = 0.008) and creatinine levels (1.2 ± 0.9 vs. 0.9 ± 0.5 , p <0.001) compared to those with AVB. In-hospital complications During hospitalization, edematous-ascitic decompensation was the most frequent complication (22.7%). Both groups had similar overall complication rates; however, the NVB group had more infections (respiratory infections at 10.5%, urinary tract infections, and SBP at 26.3% vs. 9.3%) (p = 0.005). Fourteen patients (9.1%) experienced rebleeding, with no significant difference between NVB and AVB (14.0% vs. 6.2%; p = 0.102). All patients underwent endoscopy, and rescue treatments (TIPS, surgery) were unnecessary. Eleven patients (7.1%) died from liver-related complications, with death rates of 12.3% in NVB versus 4.1% in AVB (p = 0.101). Follow-up and clinical outcomes Median follow-up time was 23.0 months (max 85.2). Table 2 and Figure 2 summarize data for AVB and NVB groups. Of 143 patients alive, 22 (15.4%) were readmitted within 30 days post-bleed due to dACLD decompensation, with similar rates between groups (16.0% vs. 15.1%, p=0.881; overall p=0.913, Figure 2B). Liver-related death during follow-up was 24% in NVB versus 15.1% in AVB (p=0.290). Kaplan-Meier analysis showed no significant differences in 30-day (p=0.107) or 90-day (p=0.112) mortality, although NVB trended higher (Figures 2C, 2D). Over 90 days, dACLD patients at baseline had higher liver-related mortality than cACLD (p=0.028), regardless of bleeding etiology (Supplementary Material – Figure 2). Figure 2. CLINICAL COURSE FOLLOWING AVB AS THE FIRST OR FURTHER DECOMPENSATION Considering the prevalence of this PH complication, the AVB group was independently evaluated (n = 97). Patients were divided according to their clinical stage before the index bleeding event as cACLD – AVB as first decompensating event - or dACL D- AVB as further descompensatin. At admission, cACLD and dACLD patients with AVB were similar, except dACLD had lower hemoglobin (9.1 ± 2.6 vs. 8.1 ± 2.1, p=0.040). dACLD experienced more complications overall (29.4% vs. 58.7%, p=0.004), notably higher HE (3.9% vs. 17.4%, p=0.043), and trends toward increased edematous-ascitic decompensation, HRS, and infections (Table 3). Both groups had equal risks of rebleeding, 30-day readmission, and liver-related death (30 and 90 days). Kaplan-Meier estimates are in the supplementary material - Figure 3. Predictors of mortality following AVB Through the multivariate analysis, MELDNa score was identified as an independent predictor of mortality within 30 (HR = 1.16, 95%CI 1.09-1.23, p <0.001; see Table 4) and 90 days (HR = 1.18, 95%CI 1.12-1.25, p <0.001; see Table 5) in ACLD patients following AVB event. For 30-day mortality, the AUC was 0.869 (95% CI 0.77–0.97, p<0.001) with a cutoff of 23.5 (75% sensitivity, 89% specificity). For 90-day mortality, the AUC was 0.895 (95% CI 0.82–0.97, p<0.001) with the same cutoff (76.5% sensitivity, 91.6% specificity) (Supplementary material- Figure 4). DISCUSSION Acute GI bleeding is common in patients with ACLD and is associated with poorer outcomes compared to the general population [ 32 , 33 ]. Our study evaluated the clinical course of AVB and NVB in cirrhotic patients and found similar in-hospital complications between groups. However, NVB patients experienced more infection-related issues, in contrast to previous studies, which reported comparable complication rates except for a higher occurrence of acute kidney injury in variceal bleeding [ 34 , 35 ]. Our NVB group were older, had worse liver function at admission—evidenced by higher MELD, MELDNa scores and greater ascites prevalence—which likely predisposed them to more complications, including a higher risk of SBP, ultimately contributing to the higher rate of infection-related complications. There were no significant differences in rebleeding rates between groups, a finding that contrasts with studies reporting higher rates in AVB [ 19 , 36 ]. In our cohort, rebleeding occurred in 14% of NVB patients, possibly due to older age and antiplatelet use. However, the heterogeneity of sources of GI bleeding in this group hinders any conclusions. The rebleeding rates for AVB have been reported to range from 19–30% [ 19 , 36 ], whereas we found a much lower rate. Silva et al. previosly reported a rebleeding rate of 8.6% in a portuguese cohort, in line with our findings [ 37 ]. Adherence to guideline-based therapy with somatostatin analogs and effective endoscopic treatment may have improved clinical outcomes [ 23 , 38 , 39 ]. Thirty-day readmission rates for further decompensation were similar between NVB and AVB groups. While some studies report readmission rates up to 7.8% [ 40 , 41 ], differences in patient selection may explain the higher rates in our cohort. In contrast, Ebhohon et al. observed a 30-day readmission rate of 31.4% in patients with underlying ACLD and prior liver-related hospitalization [ 42 ]. One study that included 746 chirrotic patients identified NVB as a risk factor for readmission 3 months after first decompensation. Non-variceal GI bleeding like portal hypertensive gastropathy and peptic ulcer disease in cirrhosis patients was difficult to control compared to varix bleeding due to limitations in the use of direct endoscopy therapy and poor wound healing due to decreased gastrointestinal mucosal flow [ 21 ]. This can cause recurrent acute or chronic GI bleeding, induce additional hepatic insults than other tolerable and adjustable events of AD, and lead to readmission after the first decompensation. Liver-related mortality was comparable between groups, although there was a trend for a higher mortality rate in the NVB group (33.3% in the NVB group vs. 18.6% in the AVB group), a finding that contrasts with recent research where AVB patients exhibited higher mortality rates [ 22 , 43 ]. This discrepancy may be explained by the fact that in previous studies AVB patients had more severe presentations upon admission, whereas in our cohort, NVB patients had worse liver function. This suggest that mortality may be more closely related to liver function than to the type of bleeding event. Indeed, regardless of the etiology of the index bleeding event, patients with prior decompensated cirrhosis had higher liver-related mortality rates throughout the 90-day follow-up. Nevertheless, both our study and recent research report lower mortality rates than those historically documented for AVB (33.5%) [ 19 ]. This decline may be at least partially attributed to advancements in the management of advanced chronic liver disease (ACLD), particularly in the acute care of gastrointestinal bleeding in the emergency setting, where the combined use of endoscopic and pharmacological therapies may have contributed to improved patient survival. We also examined outcomes following AVB as either a first or further decompensating event, observing higher in-hospital complication rates in patients with further decompensation (significantly higher rates of HE, but also a tendency to higher edematous-ascitic decompensation, HRS, and infections), despite comparable survival (30 and 90 days), 30-day readmission and rebleeding rate. In our cohort, both groups were very similar at baseline, including MELD scores at admission (median 14). The similarities extend to all clinical and analytical data evaluated at admission, except for hemoglobin levels, whose means were lower in the dACLD. Current studies suggested that the severity of the underlying liver disease and the acute bleeding episode have been demonstrated as poor prognostic factors of acute GI bleeding [ 19 ], which is alluded to by our findings. So, complications might be simply explained by the fact that dACLD patients have baseline worse liver function, being rational to think that their prognosis might be worse. Despite the Baveno VII consensus determined and established that the transition from compensated to decompensated cirrhosis leads to increased mortality risk and that further decompensation in cirrhosis is a prognostic stage linked with even higher mortality than first decompensation [ 23 ], these results were not supported by our study. On one hand, previous studies did not singly evaluate AVB as the index decompensating event, and it is known that patients with bleeding alone have better outcomes [ 23 ]. On the other hand, our survival analysis might be different with a longer follow-up. D'Amico et al. identified MELD and Child-Pugh scores as long-term survival predictors in decompensated cirrhosis, with similar prognostic value [ 44 ]. Durand et al. suggested MELD's advantage lies in its objective biological variables, less prone to subjective judgment or external influence than ascites and HE [ 2 , 26 , 45 ]. In our population, MELDNa effectively predicted 30- and 90-day mortality with an optimal cut-off of 23.5, aligning with recent studies, though with different cut-offs (Acharya et al. used 32.14 [ 46 ]). While some studies [ 47 – 49 ] suggest age, bilirubin, and systolic blood pressure as mortality predictors, our model found no significant results. Recalibrating MELDNa with additional variables could improve its accuracy in predicting mortality in cirrhotic patients with AVB. Our study is limited by its retrospective design, single-center inclusion, and small sample size, which may hinder detection of subtle differences and introduce bias. While not fully representative, our center serves a diverse population across a large region. This is the first study comparing GI bleeding etiologies in ACLD, offering a novel perspective. It generates hypotheses for future large-scale research to better understand ACLD, acute GI bleeding, and their clinical outcomes. In summary, our study suggests that the etiology of GI bleeding may not significantly influence the clinical course of cirrhotic patients, as key outcomes were similar between AVB and NVB. However, AVB as a further decompensating event was associated with higher in-hospital complication rates, though survival remained comparable. Additionally, MELDNa proved to be a reliable predictor of mortality in cirrhotic patients following AVB. Future research should explore enhanced predictive models incorporating additional variables to further optimize clinical management. MATERIALS/PATIENTS AND METHODS Study design and sample selection We performed a retrospective, observational, single-center study in patients with ACLD admitted with acute GI bleeding at the Gastroenterology Department that underwent emergency upper and/or lower GI endoscopy, between january 2016 to january 2022. ACLD was diagnosed based on clinical, biochemical, imaging, and/or histological criteria. Acute GI bleeding was any clinical evidence of hematemesis, melena, rectal hemorrhage, or/and hematochezia. Patients with previous transjugular intrahepatic portosystemic shunt placement; orthotopic liver transplantation (OLT); hepatocellular carcinoma; occlusive portal vein thrombosis; non-cirrhotic portal hypertension; anemia without clinical evidence of an acute GI bleeding event; significant cardiovascular, pulmonary disease or chronic kidney disease requiring renal replacement therapy were excluded. Definitions and variables The first acute GI bleeding in the study period was classified as the index bleeding event. Baseline patient characteristics were registered: gender, age at admission, cirrhosis etiology, current medication use (beta-blockers, antiplatelet agents, and anticoagulation), presence of GEV, previous AVB, variceal bleeding prophylaxis (primary vs. secondary) and clinical stage of cirrhosis. Patients were classified according to the recently defined clinical stages, adapted from Baveno VII and D’Amico et al [ 4 , 23 ]. cACLD was divided into 2 stages (S1 or S2), based on the absence or presence of clinical sginificant PH (CSPH). CSPH was defined by the presence of varices or by transient elastography (TE) +/- platelet count. dACLD was characterized by the development of at least one decompensating event, i.e., clinically overt ascites, variceal bleeding, and clinically overt HE. Since the prognostic weight of covert HE remains to be defined, it was not considered in this cohort. Patients with dACLD were sub-classified into 3 additional stages: S3: history of acute variceal bleeding; S4: first non-bleeding decompensation (i.e., ascites); S5: further decompensation as defined by either (i) ascites plus bleeding, (ii) refractory ascites according to International Ascites Club criteria [ 30 ], (iii) hepatorenal syndrome, or (iv) spontaneous bacterial peritonitis (defined as an absolute neutrophil count > 250 cells/mm 3 on paracentesis [SBP]). At the index bleeding event, clinical and analytical data were registered. Child-Pugh [ 24 ], MELD [ 25 ], MELDNa [ 26 ], and CLIF-AD [ 27 ] scores were calculated. Patients were managed under uniform criteria for GI bleeding diagnosis and specific treatment, which were performed following standards of care recommended by international consensus [ 28 ]. Since different sources of GI bleeding were evaluated, specific etiology management and treatment were not considered for evaluation. Transfusion of units of packed red cells was administered when hemoglobin levels were below 7 g/dl. During in-hospital stay, any unfavorable event that underwent active therapy following GI bleeding resolution was considered a complication: infection, edematous-ascitic decompensation (i.e. ascites, hydrothorax, anasarca, and pleural effusion), HRS (according to ICA-AKI criteria [ 29 ]), overt HE (according to West-Haven criteria [ 30 ]), ACLF (classified using the European Association for the Study of the Liver-Chronic Liver Failure (EASL-CLIF) criteria [ 31 ]) and liver-related death. Follow-up and clinical outcomes measures Patients were followed until their last clinical visit, OLT, or death. The primary outcome measure was 30 and 90-days liver-related mortality. Secondary outcomes included in-hospital complications and rates of rebleeding and 30-days readmission with further decompensation. Rebleeding includes failure to control bleeding and/or early bleeding within the first 7 days of the index bleeding event. The latter was defined by a sudden clinical deterioration associated with acute GI bleeding (as previously described for the index bleeding event). Further decompensation was defined as any of the specific PH-driven events that occurred following initial discharge from the index bleeding event and required in-hospital readmission, i.e., AVB, overt HE, edematous-ascitic decompensation (i.e., ascites, hydrothorax, anasarca, and pleural effusion), HRS or spontaneous bacterial peritonitis (SBP). Ethical considerations The confidentiality of the collected data was upheld. The study was approved by the local Ethics Committees and conducted in accordance with the Declaration of Helsinki. Statistical methods Categorical variables are presented as absolute (n) and relative (%) frequencies, with Fisher's exact or Pearson's chi-square tests used for comparisons. Continuous variables were assessed for normality using Shapiro-Wilk or Kolmogorov-Smirnov tests, along with kurtosis, skewness, and histograms. Data are reported as mean ± SD if normal, or median [IQR] if not, and compared using appropriate tests. Kaplan-Meier curves estimated time-dependent incidences, compared via log-rank tests. Hazard ratios were obtained from univariate Cox regressions, and independent predictors identified with a backward stepwise Cox model. Prediction accuracy was measured by AUROC, optimized with the Youden Index. Analyses were performed using IBM® SPSS® STATISTICS v25.0., with significance set at p < 0.05. Declarations Author contributions statement Andreia Guimarães and Dalila Costa conceived and designed the study ( Conceptualization, Methodology ). Josimar Cassamá was responsible for data collection and analysis ( Data Curation, Formal Analysis ). Tânia Carvalho, José Damasceno, Joana Neves, and Ângela Rodrigues contributed to the critical review of the manuscript ( Writing – Review & Editing ). Dalila Costa also contributed to the critical review of the study ( Writing – Review & Editing ). All authors read and approved the final version of the manuscript. Additional information All authors have declared no conflict of interest Data availability Data is provided within the manuscript or supplementary information files References Blachier, M., Leleu, H., Peck-Radosavljevic, M., Valla, D. C. & Roudot-Thoraval, F. The burden of liver disease in Europe: A review of available epidemiological data. J. Hepatol. 53 , 593–608 (2013). D’Amico, G., Garcia-Tsao, G. & Pagliaro, L. Natural history and prognostic indicators of survival in cirrhosis: A systematic review of 118 studies. J. Hepatol. 44 , 217–231 (2006). Garcia-Tsao, G., Friedman, S., Iredale, J. & Pinzani, M. 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Development and validation of prognostic model to predict mortality among cirrhotic patients with acute variceal bleeding: A retrospective study. J. Gastroenterol. Hepatol. Open. 5 , 658–663 (2021). Mohammad, A. N., Morsy, K. H. & Ali, M. A. Variceal bleeding in cirrhotic patients: What is the best prognostic score? Turkish J. Gastroenterol. 27 , 464–469 (2016). Mandal, A. K. et al. Factors Predicting Mortality of Variceal Bleeding in Liver Cirrhosis. J. Nepal. Med. Association . 56 , 493–496 (2018). Tables Table 1 to 5 are available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files Table15.docx SupplementaryMaterial.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6383294","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":442005839,"identity":"54f3b72f-5e6c-4a1e-87fa-b3d9020e0ae7","order_by":0,"name":"Andreia Guimarães","email":"data:image/png;base64,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","orcid":"","institution":"Unidade Local de Saúde de Braga","correspondingAuthor":true,"prefix":"","firstName":"Andreia","middleName":"","lastName":"Guimarães","suffix":""},{"id":442005840,"identity":"45dfbb8c-38cd-4640-83d2-b9280afde6bd","order_by":1,"name":"Josimar Cassamá","email":"","orcid":"","institution":"Unidade Local de Saúde de Tâmega e Sousa","correspondingAuthor":false,"prefix":"","firstName":"Josimar","middleName":"","lastName":"Cassamá","suffix":""},{"id":442005841,"identity":"9778278a-8415-4016-bb77-392fb5dfce1d","order_by":2,"name":"Tânia Carvalho","email":"","orcid":"","institution":"Unidade Local de Saúde de Braga","correspondingAuthor":false,"prefix":"","firstName":"Tânia","middleName":"","lastName":"Carvalho","suffix":""},{"id":442005842,"identity":"899227e6-a867-4790-b450-ecadeaab14a9","order_by":3,"name":"José Damasceno","email":"","orcid":"","institution":"Unidade Local de Saúde de Braga","correspondingAuthor":false,"prefix":"","firstName":"José","middleName":"","lastName":"Damasceno","suffix":""},{"id":442005843,"identity":"5ed6c29d-1f91-4b07-bd0c-df4bd8adb16d","order_by":4,"name":"Joana Neves","email":"","orcid":"","institution":"Unidade Local de Saúde de Braga","correspondingAuthor":false,"prefix":"","firstName":"Joana","middleName":"","lastName":"Neves","suffix":""},{"id":442005844,"identity":"c7e826f2-35f3-4286-8687-a1a25108e572","order_by":5,"name":"Ângela Rodrigues","email":"","orcid":"","institution":"Unidade Local de Saúde de Braga","correspondingAuthor":false,"prefix":"","firstName":"Ângela","middleName":"","lastName":"Rodrigues","suffix":""},{"id":442005845,"identity":"d92b0e37-2e4b-4ba9-a293-fbae77852764","order_by":6,"name":"Dalila Costa","email":"","orcid":"","institution":"Unidade Local de Saúde de Braga","correspondingAuthor":false,"prefix":"","firstName":"Dalila","middleName":"","lastName":"Costa","suffix":""}],"badges":[],"createdAt":"2025-04-05 17:23:11","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6383294/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6383294/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":80712797,"identity":"b9b02fe7-1dd2-4737-bec8-8e3f931708b7","added_by":"auto","created_at":"2025-04-16 09:19:47","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":20513,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eGroups of patients (NVBG and AVBG).\u003c/strong\u003e AVBG, acute variceal gastrointestinal bleeding group; LGE, lower gastrointestinal endoscopy; MWS, Mallory-Weiss syndrome; NVBG, non-variceal gastrointestinal bleeding group; PUD, peptic ulcer disease; UGE, upper gastrointestinal endoscopy.\u003c/p\u003e\n\u003cp\u003e*Others include Dieulafoy’s lesion, portal hypertensive gastropathy, diverticular hemorrhage, gastric polyps, and colorectal polyps.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-6383294/v1/9820e1942cf7b1abe6030c15.png"},{"id":80712798,"identity":"29d39231-101b-40f2-8fa3-6c55bee07e01","added_by":"auto","created_at":"2025-04-16 09:19:47","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":33822,"visible":true,"origin":"","legend":"\u003cp\u003eOutcomes incidences. Hazard rates of rebleeding (A) and decompensation (B) and survival rates of 30-day (C) and 90-day (D) liver-related death in both groups were obtained from Kaplan-Meier estimates and compared using the log-rank test (\u003cem\u003ep\u003c/em\u003e-value \u0026lt;0.05). In Figure 3D, the survival rate at day 90 was 83.3% in the NVBG and 91.3% in the AVBG.\u003c/p\u003e\n\u003cp\u003eAVBG, acute variceal bleeding group; NVBG, non-variceal bleeding group.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-6383294/v1/105e3e7d4b2f57464593b09d.png"},{"id":80715108,"identity":"b53a5b18-5470-42c2-92ad-e9979b556334","added_by":"auto","created_at":"2025-04-16 09:43:49","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":647381,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6383294/v1/98e71032-4584-4622-850a-e38b78397135.pdf"},{"id":80712799,"identity":"b6ea0932-7b77-46dd-9152-130b66562de3","added_by":"auto","created_at":"2025-04-16 09:19:47","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":34614,"visible":true,"origin":"","legend":"","description":"","filename":"Table15.docx","url":"https://assets-eu.researchsquare.com/files/rs-6383294/v1/13c490ee723020050bede98c.docx"},{"id":80714077,"identity":"cf492bc2-2249-4479-8a29-de6de9d1b10d","added_by":"auto","created_at":"2025-04-16 09:27:47","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":358732,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryMaterial.docx","url":"https://assets-eu.researchsquare.com/files/rs-6383294/v1/8e0b8c6a2c4bce6aad68c9f7.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Comparison of clinical outcomes in cirrhotic patients presenting with acute variceal and non-variceal gastrointestinal bleeding","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eAdvanced chronic liver disease (ACLD) is the final stage of various chronic liver diseases, with high morbidity and mortality rates [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Its course transitions from compensated (cACLD) to decompensated (dACLD) states, with distinct prognoses and survival rates [\u003cspan additionalcitationids=\"CR3\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Decompensation signals the onset of liver-related complications.\u003c/p\u003e \u003cp\u003eProgression of ACLD correlates with rising hepatic venous pressure gradient (HVPG), the best predictor of first decompensation [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Portal hypertension (PH) drives this progression and causes complications like gastroesophageal varices (GEV), ascites, hepatorenal syndrome (HRS), spontaneous bacterial peritonitis (SBP), and hepatic encephalopathy (HE) [\u003cspan additionalcitationids=\"CR7\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. GEV develops at 8% per year, with rupture rates of 5\u0026ndash;15% annually and at least 20% mortality [\u003cspan additionalcitationids=\"CR10 CR11\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Nonselective beta-blockers (NSBBs) are recommended in cACLD to lower portal pressure and prevent acute decompensation [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eNon-variceal gastrointestinal bleeding (NVB) affects 20%-30% of ACLD patients, arising from PH-associated causes (PH gastropathy, gastric antral vascular ectasia [GAVE]) or unrelated causes (peptic ulcer disease [PUD], Mallory-Weiss syndrome [MWS], esophagitis) [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. MWS is linked to heavy alcohol consumption, while PUD remains relevant in due to Helicobacter pylori and NSAID use [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Carvalho et al. showed that the rate of Helicobacter pylori testing and treatment in patients with ACLD is low [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Despite medical advances, NVB mortality remains 15\u0026ndash;20% [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eObservational studies show mixed results on mortality and re-hospitalization rates between AVB and NVB in ACLD patients [\u003cspan additionalcitationids=\"CR20 CR21\" citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. The prognostic impact of bleeding etiology in ACLD remains unclear. This study aimed to compare clinical outcomes in ACLD patients with AVB and NVB and predict their clinical course.\u003c/p\u003e"},{"header":"RESULTS","content":"\u003cp\u003eCOMPARISON OF CIRRHOTIC PATIENTS WITH AVB AND NVB\u003c/p\u003e\n\u003cp\u003e\u003cspan id=\"_Toc117470320\"\u003ePatients\u0026rsquo; characteristics\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003cp\u003eDuring the study period, 176 patients with ACLD presented with acute GI bleeding, of whom 154 fulfilled the inclusion and no exclusion criteria and were finally included in this study (Supplementary material - Figure 1). Based on endoscopic findings, they were divided into NVB (n = 57) and AVB (n = 97) groups (Figure 1). Table 1 and 2 condenses patients\u0026apos; baseline characteristics, index bleeding event, and in-hospital complications.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe median age was 60 years and most patients were male (72.7%). At baseline, 75 (48.7%) patients had cACLD with 35 (46.7%) in stage 1 and 40 (53.3%) in stage 2 with GEV. Within patients with dACLD (n = 79, 51.3%), 18 (22.8%) were in stage 3, 39 (49.4%) in stage 4, and 22 (27.8%) in stage 5. The most common etiology for ACLD was alcoholic-related liver disease (61.7%). The NVB group of patients was significantly older than the AVBG group (67 \u0026plusmn; 19 vs. 55 \u0026plusmn; 19, \u0026nbsp;\u003cem\u003ep\u003c/em\u003e \u0026lt; 0.001) and had a documented higher use of antiplatelet agents (21.1% vs. 7.2%, \u003cem\u003ep\u003c/em\u003e = 0.012).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFigure 1.\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRegarding the index bleeding event, patients with NVB presented with higher MELDNa scores compared to those with AVB (18 \u0026plusmn; 12 vs. 15 \u0026plusmn; 8.5, \u003cem\u003ep\u003c/em\u003e = 0.016) and a higher rate of ascites at admission (52.6% vs. 35.1%, \u003cem\u003ep\u0026nbsp;\u003c/em\u003e= 0.033). Hematological and biochemical laboratory investigations were similar with the exception that patients with NVB had higher serum urea (76 \u0026plusmn; 55.8 vs. 54 \u0026plusmn; 42\u003cem\u003e, p\u0026nbsp;\u003c/em\u003e= 0.008) and creatinine levels (1.2 \u0026plusmn; 0.9 vs. 0.9 \u0026plusmn; 0.5\u003cem\u003e, p\u003c/em\u003e \u0026lt;0.001) compared to those with AVB.\u003c/p\u003e\n\u003cp id=\"_Toc117470321\"\u003eIn-hospital complications\u003c/p\u003e\n\u003cp\u003eDuring hospitalization, edematous-ascitic decompensation was the most frequent complication (22.7%). Both groups had similar overall complication rates; however, the NVB group had more infections (respiratory infections at 10.5%, urinary tract infections, and SBP at 26.3% vs. 9.3%) (p = 0.005). Fourteen patients (9.1%) experienced rebleeding, with no significant difference between NVB and AVB (14.0% vs. 6.2%; p = 0.102). All patients underwent endoscopy, and rescue treatments (TIPS, surgery) were unnecessary. Eleven patients (7.1%) died from liver-related complications, with death rates of 12.3% in NVB versus 4.1% in AVB (p = 0.101).\u003c/p\u003e\n\u003cp\u003eFollow-up and clinical outcomes\u003c/p\u003e\n\u003cp\u003eMedian follow-up time was 23.0 months (max 85.2). Table 2 and Figure 2 summarize data for AVB and NVB groups. Of 143 patients alive, 22 (15.4%) were readmitted within 30 days post-bleed due to dACLD decompensation, with similar rates between groups (16.0% vs. 15.1%, p=0.881; overall p=0.913, Figure 2B). Liver-related death during follow-up was 24% in NVB versus 15.1% in AVB (p=0.290). Kaplan-Meier analysis showed no significant differences in 30-day (p=0.107) or 90-day (p=0.112) mortality, although NVB trended higher (Figures 2C, 2D). Over 90 days, dACLD patients at baseline had higher liver-related mortality than cACLD (p=0.028), regardless of bleeding etiology (Supplementary Material \u0026ndash; Figure 2).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFigure 2.\u003c/strong\u003e\u003c/p\u003e\n\u003cp id=\"_Toc117470323\"\u003eCLINICAL COURSE FOLLOWING AVB AS THE FIRST OR FURTHER DECOMPENSATION\u003c/p\u003e\n\u003cp\u003e\u003cspan id=\"_Toc117470324\"\u003eConsidering the prevalence of this PH complication, the AVB group was independently evaluated (n = 97). Patients were divided according to their clinical stage before the index bleeding event as cACLD \u0026ndash; AVB as first decompensating event - \u0026nbsp;or dACL\u003c/span\u003e\u003cspan id=\"_Toc117454600\"\u003eD- AVB as further descompensatin.\u0026nbsp;\u003c/span\u003eAt admission, cACLD and dACLD patients with AVB were similar, except dACLD had lower hemoglobin (9.1 \u0026plusmn; 2.6 vs. 8.1 \u0026plusmn; 2.1, p=0.040). dACLD experienced more complications overall (29.4% vs. 58.7%, p=0.004), notably higher HE (3.9% vs. 17.4%, p=0.043), and trends toward increased edematous-ascitic decompensation, HRS, and infections (Table 3).\u003c/p\u003e\n\u003cp\u003eBoth groups had equal risks of rebleeding, 30-day readmission, and liver-related death (30 and 90 days). Kaplan-Meier estimates are in the supplementary material - Figure 3.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePredictors of mortality following\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eAVB\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThrough the multivariate analysis, MELDNa score was identified as an independent predictor of mortality within 30 (HR = 1.16, 95%CI 1.09-1.23, \u003cem\u003ep\u003c/em\u003e \u0026lt;0.001; see Table 4) and 90 days (HR = 1.18, 95%CI 1.12-1.25, \u003cem\u003ep\u003c/em\u003e \u0026lt;0.001; see Table 5) in ACLD patients following AVB event.\u003c/p\u003e\n\u003cp\u003eFor 30-day mortality, the AUC was 0.869 (95% CI 0.77\u0026ndash;0.97, p\u0026lt;0.001) with a cutoff of 23.5 (75% sensitivity, 89% specificity). For 90-day mortality, the AUC was 0.895 (95% CI 0.82\u0026ndash;0.97, p\u0026lt;0.001) with the same cutoff (76.5% sensitivity, 91.6% specificity) (Supplementary material- Figure 4).\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eAcute GI bleeding is common in patients with ACLD and is associated with poorer outcomes compared to the general population [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. Our study evaluated the clinical course of AVB and NVB in cirrhotic patients and found similar in-hospital complications between groups. However, NVB patients experienced more infection-related issues, in contrast to previous studies, which reported comparable complication rates except for a higher occurrence of acute kidney injury in variceal bleeding [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. Our NVB group were older, had worse liver function at admission\u0026mdash;evidenced by higher MELD, MELDNa scores and greater ascites prevalence\u0026mdash;which likely predisposed them to more complications, including a higher risk of SBP, ultimately contributing to the higher rate of infection-related complications.\u003c/p\u003e \u003cp\u003eThere were no significant differences in rebleeding rates between groups, a finding that contrasts with studies reporting higher rates in AVB [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. In our cohort, rebleeding occurred in 14% of NVB patients, possibly due to older age and antiplatelet use. However, the heterogeneity of sources of GI bleeding in this group hinders any conclusions. The rebleeding rates for AVB have been reported to range from 19\u0026ndash;30% [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e], whereas we found a much lower rate. Silva et al. previosly reported a rebleeding rate of 8.6% in a portuguese cohort, in line with our findings [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. Adherence to guideline-based therapy with somatostatin analogs and effective endoscopic treatment may have improved clinical outcomes [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e, \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThirty-day readmission rates for further decompensation were similar between NVB and AVB groups. While some studies report readmission rates up to 7.8% [\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e, \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e], differences in patient selection may explain the higher rates in our cohort. In contrast, Ebhohon et al. observed a 30-day readmission rate of 31.4% in patients with underlying ACLD and prior liver-related hospitalization [\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e]. One study that included 746 chirrotic patients identified NVB as a risk factor for readmission 3 months after first decompensation. Non-variceal GI bleeding like portal hypertensive gastropathy and peptic ulcer disease in cirrhosis patients was difficult to control compared to varix bleeding due to limitations in the use of direct endoscopy therapy and poor wound healing due to decreased gastrointestinal mucosal flow [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. This can cause recurrent acute or chronic GI bleeding, induce additional hepatic insults than other tolerable and adjustable events of AD, and lead to readmission after the first decompensation.\u003c/p\u003e \u003cp\u003eLiver-related mortality was comparable between groups, although there was a trend for a higher mortality rate in the NVB group (33.3% in the NVB group vs. 18.6% in the AVB group), a finding that contrasts with recent research where AVB patients exhibited higher mortality rates [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e]. This discrepancy may be explained by the fact that in previous studies AVB patients had more severe presentations upon admission, whereas in our cohort, NVB patients had worse liver function. This suggest that mortality may be more closely related to liver function than to the type of bleeding event. Indeed, regardless of the etiology of the index bleeding event, patients with prior decompensated cirrhosis had higher liver-related mortality rates throughout the 90-day follow-up. Nevertheless, both our study and recent research report lower mortality rates than those historically documented for AVB (33.5%) [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. This decline may be at least partially attributed to advancements in the management of advanced chronic liver disease (ACLD), particularly in the acute care of gastrointestinal bleeding in the emergency setting, where the combined use of endoscopic and pharmacological therapies may have contributed to improved patient survival.\u003c/p\u003e \u003cp\u003eWe also examined outcomes following AVB as either a first or further decompensating event, observing higher in-hospital complication rates in patients with further decompensation (significantly higher rates of HE, but also a tendency to higher edematous-ascitic decompensation, HRS, and infections), despite comparable survival (30 and 90 days), 30-day readmission and rebleeding rate. In our cohort, both groups were very similar at baseline, including MELD scores at admission (median 14). The similarities extend to all clinical and analytical data evaluated at admission, except for hemoglobin levels, whose means were lower in the dACLD. Current studies suggested that the severity of the underlying liver disease and the acute bleeding episode have been demonstrated as poor prognostic factors of acute GI bleeding [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e], which is alluded to by our findings. So, complications might be simply explained by the fact that dACLD patients have baseline worse liver function, being rational to think that their prognosis might be worse. Despite the Baveno VII consensus determined and established that the transition from compensated to decompensated cirrhosis leads to increased mortality risk and that further decompensation in cirrhosis is a prognostic stage linked with even higher mortality than first decompensation [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e], these results were not supported by our study. On one hand, previous studies did not singly evaluate AVB as the index decompensating event, and it is known that patients with bleeding alone have better outcomes [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. On the other hand, our survival analysis might be different with a longer follow-up.\u003c/p\u003e \u003cp\u003eD'Amico et al. identified MELD and Child-Pugh scores as long-term survival predictors in decompensated cirrhosis, with similar prognostic value [\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e]. Durand et al. suggested MELD's advantage lies in its objective biological variables, less prone to subjective judgment or external influence than ascites and HE [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e]. In our population, MELDNa effectively predicted 30- and 90-day mortality with an optimal cut-off of 23.5, aligning with recent studies, though with different cut-offs (Acharya et al. used 32.14 [\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e]). While some studies [\u003cspan additionalcitationids=\"CR48\" citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e] suggest age, bilirubin, and systolic blood pressure as mortality predictors, our model found no significant results. Recalibrating MELDNa with additional variables could improve its accuracy in predicting mortality in cirrhotic patients with AVB.\u003c/p\u003e \u003cp\u003eOur study is limited by its retrospective design, single-center inclusion, and small sample size, which may hinder detection of subtle differences and introduce bias. While not fully representative, our center serves a diverse population across a large region. This is the first study comparing GI bleeding etiologies in ACLD, offering a novel perspective. It generates hypotheses for future large-scale research to better understand ACLD, acute GI bleeding, and their clinical outcomes.\u003c/p\u003e \u003cp\u003eIn summary, our study suggests that the etiology of GI bleeding may not significantly influence the clinical course of cirrhotic patients, as key outcomes were similar between AVB and NVB. However, AVB as a further decompensating event was associated with higher in-hospital complication rates, though survival remained comparable. Additionally, MELDNa proved to be a reliable predictor of mortality in cirrhotic patients following AVB. Future research should explore enhanced predictive models incorporating additional variables to further optimize clinical management.\u003c/p\u003e"},{"header":"MATERIALS/PATIENTS AND METHODS","content":"\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eStudy design and sample selection\u003c/h2\u003e \u003cp\u003eWe performed a retrospective, observational, single-center study in patients with ACLD admitted with acute GI bleeding at the Gastroenterology Department that underwent emergency upper and/or lower GI endoscopy, between january 2016 to january 2022. ACLD was diagnosed based on clinical, biochemical, imaging, and/or histological criteria. Acute GI bleeding was any clinical evidence of hematemesis, melena, rectal hemorrhage, or/and hematochezia. Patients with previous transjugular intrahepatic portosystemic shunt placement; orthotopic liver transplantation (OLT); hepatocellular carcinoma; occlusive portal vein thrombosis; non-cirrhotic portal hypertension; anemia without clinical evidence of an acute GI bleeding event; significant cardiovascular, pulmonary disease or chronic kidney disease requiring renal replacement therapy were excluded.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eDefinitions and variables\u003c/h2\u003e \u003cp\u003eThe first acute GI bleeding in the study period was classified as the index bleeding event. Baseline patient characteristics were registered: gender, age at admission, cirrhosis etiology, current medication use (beta-blockers, antiplatelet agents, and anticoagulation), presence of GEV, previous AVB, variceal bleeding prophylaxis (primary vs. secondary) and clinical stage of cirrhosis. Patients were classified according to the recently defined clinical stages, adapted from Baveno VII and D\u0026rsquo;Amico \u003cem\u003eet al\u003c/em\u003e [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. cACLD was divided into 2 stages (S1 or S2), based on the absence or presence of clinical sginificant PH (CSPH). CSPH was defined by the presence of varices or by transient elastography (TE) +/- platelet count. dACLD was characterized by the development of at least one decompensating event, i.e., clinically overt ascites, variceal bleeding, and clinically overt HE. Since the prognostic weight of covert HE remains to be defined, it was not considered in this cohort. Patients with dACLD were sub-classified into 3 additional stages: S3: history of acute variceal bleeding; S4: first non-bleeding decompensation (i.e., ascites); S5: further decompensation as defined by either (i) ascites plus bleeding, (ii) refractory ascites according to International Ascites Club criteria [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e], (iii) hepatorenal syndrome, or (iv) spontaneous bacterial peritonitis (defined as an absolute neutrophil count\u0026thinsp;\u0026gt;\u0026thinsp;250 cells/mm\u003csup\u003e3\u003c/sup\u003e on paracentesis [SBP]). At the index bleeding event, clinical and analytical data were registered. Child-Pugh [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e], MELD [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e], MELDNa [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e], and CLIF-AD [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e] scores were calculated. Patients were managed under uniform criteria for GI bleeding diagnosis and specific treatment, which were performed following standards of care recommended by international consensus [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. Since different sources of GI bleeding were evaluated, specific etiology management and treatment were not considered for evaluation. Transfusion of units of packed red cells was administered when hemoglobin levels were below 7 g/dl.\u003c/p\u003e \u003cp\u003eDuring in-hospital stay, any unfavorable event that underwent active therapy following GI bleeding resolution was considered a complication: infection, edematous-ascitic decompensation (i.e. ascites, hydrothorax, anasarca, and pleural effusion), HRS (according to ICA-AKI criteria [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]), overt HE (according to West-Haven criteria [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]), ACLF (classified using the European Association for the Study of the Liver-Chronic Liver Failure (EASL-CLIF) criteria [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]) and liver-related death.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eFollow-up and clinical outcomes measures\u003c/h2\u003e \u003cp\u003ePatients were followed until their last clinical visit, OLT, or death. The primary outcome measure was 30 and 90-days liver-related mortality. Secondary outcomes included in-hospital complications and rates of rebleeding and 30-days readmission with further decompensation. Rebleeding includes failure to control bleeding and/or early bleeding within the first 7 days of the index bleeding event. The latter was defined by a sudden clinical deterioration associated with acute GI bleeding (as previously described for the index bleeding event).\u003c/p\u003e \u003cp\u003eFurther decompensation was defined as any of the specific PH-driven events that occurred following initial discharge from the index bleeding event and required in-hospital readmission, i.e., AVB, overt HE, edematous-ascitic decompensation (i.e., ascites, hydrothorax, anasarca, and pleural effusion), HRS or spontaneous bacterial peritonitis (SBP).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eEthical considerations\u003c/h2\u003e \u003cp\u003eThe confidentiality of the collected data was upheld. The study was approved by the local Ethics Committees and conducted in accordance with the Declaration of Helsinki.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eStatistical methods\u003c/h2\u003e \u003cp\u003eCategorical variables are presented as absolute (n) and relative (%) frequencies, with Fisher's exact or Pearson's chi-square tests used for comparisons. Continuous variables were assessed for normality using Shapiro-Wilk or Kolmogorov-Smirnov tests, along with kurtosis, skewness, and histograms. Data are reported as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD if normal, or median [IQR] if not, and compared using appropriate tests. Kaplan-Meier curves estimated time-dependent incidences, compared via log-rank tests. Hazard ratios were obtained from univariate Cox regressions, and independent predictors identified with a backward stepwise Cox model. Prediction accuracy was measured by AUROC, optimized with the Youden Index. Analyses were performed using IBM\u0026reg; SPSS\u0026reg; STATISTICS v25.0., with significance set at p\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/p\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor contributions statement\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAndreia Guimar\u0026atilde;es and Dalila Costa conceived and designed the study (\u003cem\u003eConceptualization, Methodology\u003c/em\u003e). Josimar Cassam\u0026aacute; was responsible for data collection and analysis (\u003cem\u003eData Curation, Formal Analysis\u003c/em\u003e). T\u0026acirc;nia Carvalho, Jos\u0026eacute; Damasceno, Joana Neves, and \u0026Acirc;ngela Rodrigues contributed to the critical review of the manuscript (\u003cem\u003eWriting \u0026ndash; Review \u0026amp; Editing\u003c/em\u003e). Dalila Costa also contributed to the critical review of the study (\u003cem\u003eWriting \u0026ndash; Review \u0026amp; Editing\u003c/em\u003e). All authors read and approved the final version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAdditional information\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors have declared no conflict of interest\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData is provided within the manuscript or supplementary information files\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eBlachier, M., Leleu, H., Peck-Radosavljevic, M., Valla, D. C. \u0026amp; Roudot-Thoraval, F. The burden of liver disease in Europe: A review of available epidemiological data. \u003cem\u003eJ. Hepatol.\u003c/em\u003e \u003cb\u003e53\u003c/b\u003e, 593\u0026ndash;608 (2013).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eD\u0026rsquo;Amico, G., Garcia-Tsao, G. \u0026amp; Pagliaro, L. 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Development and validation of prognostic model to predict mortality among cirrhotic patients with acute variceal bleeding: A retrospective study. \u003cem\u003eJ. Gastroenterol. Hepatol. Open.\u003c/em\u003e \u003cb\u003e5\u003c/b\u003e, 658\u0026ndash;663 (2021).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMohammad, A. N., Morsy, K. H. \u0026amp; Ali, M. A. Variceal bleeding in cirrhotic patients: What is the best prognostic score? \u003cem\u003eTurkish J. Gastroenterol.\u003c/em\u003e \u003cb\u003e27\u003c/b\u003e, 464\u0026ndash;469 (2016).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMandal, A. K. et al. Factors Predicting Mortality of Variceal Bleeding in Liver Cirrhosis. \u003cem\u003eJ. Nepal. Med. Association\u003c/em\u003e. \u003cb\u003e56\u003c/b\u003e, 493\u0026ndash;496 (2018).\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1 to 5 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"acute gastrointestinal bleeding, cirrhosis, mortality, variceal bleeding","lastPublishedDoi":"10.21203/rs.3.rs-6383294/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6383294/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eIn patients with advanced chronic liver disease, acute gastrointestinal bleeding can present as acute variceal bleeding (AVB) or non-variceal bleeding (NVB). This study aimed to compare clinical outcomes between AVB and NVB, and identify predictors of liver-related death following AVB. A retrospective, observational, single-center study including patients with acute GI bleeding from 2016 to 2022, divided into AVB and NVB groups. Outcomes included complications, rebleeding, further decompensation, and liver-related death. Survival was analyzed using Kaplan-Meier, and predictors were identified with Cox regression and ROC curves. A total of 154 patients were included. The NVB group (n\u0026thinsp;=\u0026thinsp;57) was older (67 vs. 55 years, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), had higher MELDNa scores (18 vs. 15, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.016), and more ascites at admission (52.6% vs. 35.1%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.033). There were no significant differences between groups in in-hospital mortality, complications, rebleeding, further decompensation, or liver-related death during follow-up. In AVB patients, MELDNa independently predicted liver-related death at 30 and 90 days (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). AVB, whether a first or subsequent decompensation event, showed similar 30-day readmission rates and liver-related death. Clinical outcomes were similar between AVB and NVB. In AVB patients, MELDNa was an independent predictor of short-term liver-related mortality.\u003c/p\u003e","manuscriptTitle":"Comparison of clinical outcomes in cirrhotic patients presenting with acute variceal and non-variceal gastrointestinal bleeding","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-04-16 09:19:42","doi":"10.21203/rs.3.rs-6383294/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"f4f0292a-40c1-4b30-9b4c-e76ed457b004","owner":[],"postedDate":"April 16th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":47065217,"name":"Health sciences/Gastroenterology/Gastrointestinal diseases/Liver diseases/Liver cirrhosis"},{"id":47065218,"name":"Health sciences/Gastroenterology/Gastrointestinal diseases/Liver diseases/Portal hypertension"}],"tags":[],"updatedAt":"2025-04-16T09:19:45+00:00","versionOfRecord":[],"versionCreatedAt":"2025-04-16 09:19:42","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6383294","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6383294","identity":"rs-6383294","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}