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

BACKGROUND & AIMS: Acute-on-chronic liver failure (ACLF) is characterised by multiorgan failure and high short-term mortality in hospitalised patients with acute decompensation of cirrhosis. Although the EASL-CLIF criteria are widely used for diagnosis and prognostication, evolving definitions of organ dysfunction and emerging therapies require updated, tailored criteria to improve diagnostic accuracy, treatment assessment, and applicability in clinical trials. We aimed to develop and validate the A-TANGO organ failure (OF) score to refine ACLF diagnosis and enhance its utility for treatment response evaluation and risk stratification.

METHODS: We performed a retrospective analysis of prospective observational cohorts. The derivation cohort comprised three EF-CLIF consortium studies conducted in Europe and Latin America (CANONIC, PREDICT, ACLARA; n = 3,896). Validation cohorts included one study from India (Ambi-spective study n = 2,055) and one from China (CATCH-LIFE; n = 2,568). Patients were enrolled between 2011 and 2023, with follow-up completed in 2023. The primary objective was to redefine thresholds for organ dysfunction and failure using three subscores per organ, with subscore 3 corresponding to ≥15% 28-day mortality and defining organ failure.

RESULTS: Compared with the CLIF-C OF score, the A-TANGO OF score introduced revised thresholds for organ failure and added an ACLF grade 4 to address the wide mortality variation within CLIF-C OF grade 3. A-TANGO identified more organ failures, increasing ACLF diagnosis from 24% to 36% and improving the net reclassification index by 16%, while maintaining similar predictive accuracy for 28- and 90-day mortality. Two additional prognostic models (A-TANGO ACLF-WBC and A-TANGO ACLF-CRP) demonstrated strong associations with 28- and 90-day mortality and improved prognostic performance. Findings were confirmed in external validation cohorts.

CONCLUSIONS: The A-TANGO OF score is a reproducible and comprehensive tool for ACLF diagnosis with preserved prognostic performance, validated across large international cohorts. It provides a robust framework for clinical trials by enabling more accurate diagnosis, reducing required sample sizes, and offering clinically meaningful endpoints such as ACLF resolution for treatment response assessment.

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 enable 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.