Assessment of Esophageal and Gastric Varices in Patients With Cirrhosis for Clinical Trials: A Centralized Blinded Evaluation System

Background and Aims: Development of varices is an important milestone in the natural history of patients with cirrhosis, and yet the data are sparse in terms of how best to assess for gastroesophageal varices as a clinical trial outcome in multicenter studies. Here we describe a centralized upper endoscopy (esophagogastroduodenoscopy [EGD]) reading process for assessing esophageal varices (EVs) and gastric varices (GVs) and to investigate inter-reader agreement between experienced endoscopists on the presence/size of varices. Methods: Patients with compensated metabolic dysfunction–associated steatohepatitis cirrhosis evaluated for inclusion in the NAVIGATE phase 2b/3 trial (NCT04365868) underwent EGD by local endoscopists, video recordings of which were centrally read by a pool of 6 qualified, trained reviewers. Two initial reviewers determined the presence/absence and size of varices, and in cases of disagreement, a third adjudicating reviewer assisted with the final determination. Agreement between the reviewers was analyzed using Cohen's kappa. Results: Structured central blinded adjudication of varices was achieved at the participating centers across the globe. Each assigned reviewer completed their review within 24 hours of assignment. Of the 1006 EGDs reviewed, 216 (21.5%) had confirmed EVs, including 115 (53.2%) small, 71 (32.9%) medium, and 30 (13.9%) large varices. GVs were identified among 20 (2.0%) EGDs. Adjudication was required in 399 (39.7%) cases, with the third reviewer confirming varices in 216 (54.1%) cases. Percent agreement between reader pairs for EVs ranged from 40.0% to 100% (kappa 0.118–1.000), and inter-reader agreement for GVs varied between 81.8% and 100% (kappa 0.000–1.000). Conclusion: Centralized review of EGD video recordings, coupled with a structured adjudication process, can be implemented in large multicenter trials to provide reliable varices assessment in metabolic dysfunction–associated steatohepatitis clinical trials.