Development and validation of the A-TANGO organ failure score for acute-on-chronic liver failure in global cohorts

Background and aims: Acute-on-chronic liver failure (ACLF) is characterised by multiorgan failure and high short-term mortality in hospitalised cirrhosis patients with acute decompensation (AD). While the EASL-CLIF criteria are widely used for its diagnosis and prognosis, evolving definitions of organ dysfunction and emerging therapies call for updated, tailored criteria to ensure accurate diagnosis, enable effective treatment assessment, and enhance applicability in clinical trials. The aims of the study were to develop and validate the new A-TANGO organ failure (OF) score to enhance the diagnosis of ACLF and improve its utility for assessing treatment response and risk stratification for clinical trials. Design: A retrospective analysis of prospective, observational cohort studies. Derivation cohort: 3 studies performed by the EF-CLIF consortium in Europe and Latin America (CANONIC, PREDICT, and ACLARA; n=3896). Validation cohorts: 1 from India (Ambi-spective, n=2055) and 1 from China (Catch-life, n=2568). Patients were enrolled in these studies between 2011 and 2023 and last follow-up was completed in 2023. The main outcome was to redefine thresholds of organ dysfunction and failure based on 3 subscores per organ, with subscore 3 indicating ≥15% 28-day mortality and defining OF. Results: Compared to the CLIF-C OF score, the A-TANGO OF score introduced significant changes to thresholds for diagnosing OF and included an additional ACLF grade 4, addressing the wide range of mortality in the CLIF-C OF grade 3 subgroup. The A-TANGO OF score identified a significantly higher number of OFs, increasing the diagnosis of ACLF from 24% to 36% and improving the net reclassification index by 16%. The A-TANGO OF score exhibited the same predictive accuracy for 28- and 90-day mortality. In addition, two new prognostic ACLF scores were developed (A-TANGO ACLF-WBC and ACLF-CRP score), showing strong correlations with 28-day and 90-day mortality and improved prognostic accuracy. The diagnostic and prognostic ability of the A-TANGO scores were confirmed in the validation cohorts. Conclusions: The A-TANGO OF score is a more accurate, reproducible, and comprehensive tool for diagnosing ACLF with well-maintained prognostic ability, validated in large global cohorts. The A-TANGO OF score offers a robust tool for clinical trials enabling more reliable diagnosis, reducing the required sample size and providing readily assessable clinical endpoints, such as ACLF resolution, to define treatment responses effectively. Impact and Implications The A-TANGO organ failure (OF) score provides a scientifically justified advancement in ACLF research by refining organ-specific dysfunction thresholds and introducing a new grade 4, thereby addressing limitations in current EASL-CLIF criteria and improving identification of high-risk patients. These findings are important for clinicians, researchers, and healthcare systems globally, as they increase detection of organ failure, enhance risk stratification, and allow more accurate prediction of short-term mortality in hospitalized patients with cirrhosis. The A-TANGO OF score and its associated prognostic scores (ACLF-WBC and ACLF-CRP) can be applied in clinical practice to guide treatment decisions, and serve as reliable, measurable endpoints in clinical trials evaluating emerging therapies. Although limitations such as missing data, cohort-specific recruitment differences, and historical classification criteria exist, the consistent and robust performance of the A-TANGO scores across large, multinational cohorts highlights their potential applicability and utility on a global scale.