Introduction

Direct oral anticoagulants (DOACs), particularly rivaroxaban and apixaban, are increasingly utilized to manage thromboembolic conditions due to their favorable efficacy and safety profiles. However, gastrointestinal bleeding (GIB) remains a significant concern associated with these medications, particularly considering pharmacogenetic variations among populations. This study aims to evaluate the frequency and identify risk factors associated with GIB in patients using rivaroxaban and apixaban in a Mexican healthcare setting.

Aims & Methods

This retrospective observational study analyzed data from January 2018 to December 2023 at the Centro Médico Nacional 20 de Noviembre, Mexico City. The cohort consisted of 278 patients: 136 on DOAC therapy (rivaroxaban or apixaban) and 142 controls without anticoagulation. Clinical data, demographic characteristics, comorbidities, and concomitant medications were systematically reviewed. Statistical methods employed included chi-square tests, Student's t-tests, and logistic regression analysis to assess the risk factors and association between anticoagulant type and incidence of GIB.

Results

The study population had a mean age of 67.36 ± 15.05 years, with an equal gender distribution (52.9% male). Rivaroxaban was significantly linked to increased GIB-related hospitalizations compared to controls (OR 1.29, 95% CI: 1.10–1.52, p < 0.001), while apixaban showed no statistically significant increase. NSAID co-administration dramatically raised the risk of GIB in rivaroxaban users (OR 16.1, 95% CI: 1.22–212.6, p = 0.03). Patients treated with DOACs experienced more hospitalizations (average 0.49 ± 0.80) and longer hospital stays (2.19 ± 3.54 days) compared to controls (0.30 ± 0.62 hospitalizations, 0.99 ± 2.68 days, respectively). Mortality rates were not significantly different between groups.

Conclusion

Rivaroxaban and apixaban present similar overall risks of gastrointestinal bleeding, although rivaroxaban is associated with higher hospitalization rates. Concomitant NSAID use substantially elevates the risk in patients on rivaroxaban. This underscores the necessity of individualized anticoagulant management strategies, especially in populations with distinct genetic and clinical characteristics, such as the Mexican demographic.

References

1. Lopes RD, Guimarães PO, Kolls BJ, et al. Gastrointestinal bleeding with novel oral anticoagulants: A systematic review and meta-analysis. BMJ. 2015;350:h1857.
2. Ruff CT, Giugliano RP, Braunwald E, et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet. 2014;383(9921):955-962.
3. Granger CB, Alexander JH, McMurray JJV, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365:981-992.

Introduction

The eosinophilic esophagitis (EoE) endoscopic reference score (EREFS) is the validated scoring system for endoscopic findings of EoE. EREFS findings are currently scored cumulatively and correlate modestly with histological disease activity (HDA), symptoms, and adaptive behaviors. However, inflammatory and fibrotic findings may reflect different aspects of EoE, but this has never been evaluated.

Aims & Methods

We investigated the correlation of EREFS inflammatory and fibrotic subscores with HDA, symptoms and adaptive behaviors. In three tertiary referral centres for EoE, consecutive adults (>18 years) undergoing upper endoscopy for suspected or follow up EoE were prospectively enrolled. EREFS was scored as follows: edema 0-1; rings 0-3; exudates 0-2; furrows 0-2; stricture 0-1. The EREFS inflammatory sub-score (EREFS-i) combined the scores of edema, exudates and furrows. The EREFS fibrotic sub-score (EREFS-f) combined the scores of moderate-severe rings (score ≥2) and stricture. Subsequently, at least six esophageal biopsies were collected to assess HDA based on peak eosinophil count/high-power field (PEC/HPF) (active EoE PEC ≥15/HPF; EoE in remission: PEC<15/HPF). Symptoms were assessed using the dysphagia symptoms questionnaire (DSQ). Adaptive behaviors were assessed using the Pisa EoE Adaptation Questionnaire v1.0 (PiEAQ) [reference 1]. Clinical characteristics were recorded. Kruskal-Wallis Rank Sum Test and Pearson’s Chi-squared were used for comparisons. ROC curve analysis was used to calculate the diagnostic accuracy (AUC). Spearman’s test and linear regression models were used to assess relationships between variables. Significance threshold was p<0.05.

Results

121 patients were included. 58% had active EoE, 42% were in histological remission. Baseline clinical data are reported in Table 1. The EREFS total score had modest AUC for predicting HDA (0.68) and did not show significant correlation with DSQ and PiEAQ. In contrast, EREFS-i had AUC of 0.73, with 88.2% sensitivity and 51.4% specificity for predicting HDA, being significantly more accurate compared to the EREFS-f (p<0.001; Figure 1). There was a significant correlation between EREFS-i and PEC/HPF with Spearman’s Rho=0.5 (p<0.001), with linear regression showing that an increase of 1 point of any inflammatory feature corresponded to an increase of 12 eosinophils/HPF (p<0.0001). In contrast, EREFS-f correlated significantly with the use of adaptive behaviors assessed with PiEAQ [Spearman’s Rho of 0.6 (p<0.001); Figure 2], with linear regression showing that an increase of 1 point of any fibrotic feature corresponded to an increase of one adaptive behavior (p=0.001). EREFS, EREFS-i, and EREFS-f had nonsignificant negative correlation with DSQ (p>0.05 for all).

Conclusion

We confirmed that, while total EREFS provides a global assessment of endoscopic disease severity, it lacks correlation with histological and clinical disease activity. However, we demonstrated that EREFS-i correlates significantly with PEC and predicts PEC/HPF and that EREFS-f correlates significantly with the use of adaptive behaviors assessed with PiEAQ, which represent known clinical markers of disease activity. Neither EREFS-i nor EREFS-f correlated significantly with DSQ. In conclusion, we showed that, compared to the total EREFS, EREFS sub-scores improve the correlation between endoscopy findings with histology and clinical disease activity markers. Applied to clinical practice, our results represent another step towards precision medicine in the setting of EoE.

References

[reference 1] Visaggi P, Del Corso G, Solinas I, Ovidi F, Adamo G, Dulmin I, Baiano Svizzero F, Bellini M, Savarino EV, de Bortoli N. Adaptive Behaviors, Esophageal Anxiety, and Hypervigilance Modify the Association Between Dysphagia Perception and Histological Disease Activity in Eosinophilic Esophagitis. Am J Gastroenterol. 2024 Dec 30. doi: 10.14309/ajg.0000000000003272. Epub ahead of print. PMID: 39787341.

Disclosure

Speaker or consultancy for Apogee Therapeutics, Dr Falk Pharma, Malesci, JB Pharmaceuticals, Sanofi

Introduction

Acute cholecystitis (AC) is a relatively frequent complication of ERCP with placement of self-expandable metal stents (SEMS) for distal malignant biliary obstruction (DMBO). SEMS design seems irrelevant, whereas neoplastic Cystic duct infiltration (CDI) has been claimed to be the most important independent predictor. However, data regarding incidence and risk factors are scant.

Aims & Methods

The primary aim of this study was to evaluate the incidence and risk factors of AC following ERCP with SEMS placement in patients with DMBO clustered according to the presence or absence of CDI evaluated by EUS.
This is a single tertiary center prospective study conducted between Feb-2024 and Jan-2025. All consecutive patients candidate to EUS and ERCP for characterization and endoscopic treatment of DMBO treated with a partially covered SEMS were included in the study (ClinicalTrials.gov identifier NCT04813055).
Two independent endosonographers blindly assessed the presence of CDI and other morphological risk factors (such as cholelithiasis or cholecystitis) at EUS.
Two independent endoscopists estimated CD coverage by the SEMS and other risk factors (such as gallbladder cannulation and contrast opacification) at ERCP.
Clinical outcomes were evaluated by one independent assessor during admission, at 30 days and then every 60 days.
The primary outcome was the onset of AC among patients with and without CDI. Risk factors for AC were evaluated through multivariate logistic regression model.

Results

A total of 109 patients with DMBO were included (median age 71 [IQR 62-77], female 38.5%, pancreatic adenocarcinoma 87.2%).
At EUS, prevalence of CDI was 16.5%; gallstones and sludge were present in 6.4% and 73.4% of cases.
At ERCP, where a 6-cm and 4-cm SEMS were used in 64.2% and 34% of cases, the CD was covered by the SEMS in 40.7% of the procedures.
Median follow-up was 94 [35-175] days.
Seven (6.4%) patients experienced post-ERCP pancreatitis whereas 8 (7.3%) experienced post-ERCP AC, after a median time of 6.5 [5-31] days post-procedure. AC required additional intervention in 57.1% of cases.
The rate of post-ERCP AC did not differ between patient with and without CDI, being 11.1% versus 6.6%, p=0.503.
Amongst patients with AC, ASA scores were lower while placed SEMS were longer, and the rate of CD coverage was significantly higher (87.5% versus 37%, p=0.005); the rate of CDI was higher but the difference was not significant.
At multivariate analysis, CD coverage by the SEMS was the only independent predictor of post-ERCP AC (OR[95% CI] = 13.8 [1.5-123.6].

Conclusion

In the context of SEMS placement for DMBO, post-ERCP AC is relatively more frequent than post-ERCP pancreatitis. EUS ahead of ERCP can help in predicting morphological risk factors for this event.
Coverage of the cystic duct by the SEMS appears to be the most important predictor, independent of cystic duct infiltration, potentially proposing a new high-risk group for this event, to be validated in future studies.

Introduction

The progression of Barrett’s Esophagus (BE) to malignancy is accompanied by increasing copy number alterations (CNAs). However, the timing of CNAs events during evolution remains unclear. This study leverages multi-regional, longitudinal sequencing of BE to map CAN temporal dynamics, identify key drivers of BE progression, and improve risk stratification.

Aims & Methods

Two BE cohorts were analyzed. The discovery cohort included shallow whole-genome sequencing (sWGS, 0.4X) from 777 BE samples across 88 patients, while the validation cohort included 256 BE samples from 95 patients. We refined the bioinformatics tool RASCAL¹ to improve absolute CNA analysis by automatically selecting high-quality samples. Phylogenetic trees were generated by MEDICC2² to classify CNAs along an evolutionary timeline (Figure 1). Risk scores were computed based on the probability of CNA occurrence in non-progressing vs. dysplastic BE samples. A random forest model was trained to predict dysplasia based on risk score and validated in an independent cohort.

Results

In the discovery cohort, 52.3% (260/497) of NDBE and 75.2% (124/165) of dysplastic samples were high-quality, with 16.9% (21/124) of dysplastic samples exhibiting whole genome doubling (WGD). In the validation cohort, 79.4% (181/228) of NDBE and 86.2% (25/29) of dysplasia/cancer samples were high-quality, with WGD in 24.0% (6/25) of dysplastic cases. Early-stage CNAs in non-progressing BE showed specific chromosomal gains and losses, whereas later-stage CNAs in dysplasia were more widespread and less commonly shared. Risk scoring of known drivers revealed that SMAD4 losses and CCND3/GATA4 gains were linked to dysplasia. Our model with divergent evolutionary patterns predicted dysplasia with an AUC of 0.89 (Sensitivity: 80.6%, Specificity: 95.7%) in the discovery set and AUC of 0.84 in the validation set (Sensitivity: 73.1%, Specificity: 93.9%).

Conclusion

This study maps CNA evolutionary trajectories in BE, demonstrating selective constraints in early evolution and stochastic processes in dysplastic progression. CNA-based risk scores offer a promising tool for lesion risk stratification.

References

1. Sauer C M, Eldridge M D, Vias M, et al. Absolute copy number fitting from shallow whole genome sequencing data. Biorxiv, 2021: 2021.07. 19.452658.
2. Kaufmann T L, Petkovic M, Watkins T B K, et al. MEDICC2: whole-genome doubling aware copy-number phylogenies for cancer evolution. Genome biology, 2022, 23(1): 241.