Gennaro D'Amico1, Juan G Abraldes2, Paola Rebora3, Maria Grazia Valsecchi3, Guadalupe Garcia-Tsao4. 1. Gastroenterology Unit, Ospedale V. Cervello, Clinica La Maddalena, Palermo, Italy. 2. Division of Gastroenterology (Liver Unit), Department of Medicine, CEGIIR, University of Alberta, Edmonton, AB, Canada. 3. Dipartimento di Medicina e Chirurgia, Università di Milano-Bicocca, Milano, Italy. 4. Section of Digestive Diseases, Yale University School of Medicine/VA-CT Healthcare System, New Haven, CT.
Abstract
BACKGROUND AND AIMS: Prevention of decompensation is a primary therapeutic target in patients with compensated cirrhosis (CC). However, a major problem is the large sample size and long follow-up required to demonstrate a significant treatment effect because of the relatively low baseline risk. For this reason, it has been recently suggested that ordinal outcomes may be used in this area to gain power and reduce sample size. The aim of this study was to assess the applicability of ordinal outcomes in cirrhosis. APPROACH AND RESULTS: An inception cohort of 202 patients with CC (no ascites, gastrointestinal bleeding, encephalopathy, or jaundice) without esophageal varices was included, and 5-year outcome is reported. Etiology was mostly viral and alcoholic, and there were no dropouts. Ordinal outcome was set according to six grades with a previously established prognostic ordinality: grade 1 = no disease progression; grade 2 = development of varices; grade 3 = bleeding alone; grade 4 = nonbleeding single decompensation; grade 5 = more than one decompensating event; and grade 6 = death. At the 60-month time point, patients were distributed in grades 1 through 6 as follows: 129, 43, 2, 7, 5, and 16, respectively. Emulation of a clinical trial performed by dividing patients based on baseline platelet count into two groups (cutoff, 150 × 109 /L) demonstrated a statistically significant outcome difference between groups when using ordinal outcomes not detectable by binary logistic or chi-square or time-to-event analyses. Additionally, using ordinal outcomes in a hypothetical study to prevent decompensation resulted in sample-size estimates 3-to 4-fold lower than using a binary composite endpoint. CONCLUSIONS: Compared to traditional binary outcomes, the use of ordinal outcomes in trials of cirrhosis decompensation may provide more power and thus may require a smaller sample size.
BACKGROUND AND AIMS: Prevention of decompensation is a primary therapeutic target in patients with compensated cirrhosis (CC). However, a major problem is the large sample size and long follow-up required to demonstrate a significant treatment effect because of the relatively low baseline risk. For this reason, it has been recently suggested that ordinal outcomes may be used in this area to gain power and reduce sample size. The aim of this study was to assess the applicability of ordinal outcomes in cirrhosis. APPROACH AND RESULTS: An inception cohort of 202 patients with CC (no ascites, gastrointestinal bleeding, encephalopathy, or jaundice) without esophageal varices was included, and 5-year outcome is reported. Etiology was mostly viral and alcoholic, and there were no dropouts. Ordinal outcome was set according to six grades with a previously established prognostic ordinality: grade 1 = no disease progression; grade 2 = development of varices; grade 3 = bleeding alone; grade 4 = nonbleeding single decompensation; grade 5 = more than one decompensating event; and grade 6 = death. At the 60-month time point, patients were distributed in grades 1 through 6 as follows: 129, 43, 2, 7, 5, and 16, respectively. Emulation of a clinical trial performed by dividing patients based on baseline platelet count into two groups (cutoff, 150 × 109 /L) demonstrated a statistically significant outcome difference between groups when using ordinal outcomes not detectable by binary logistic or chi-square or time-to-event analyses. Additionally, using ordinal outcomes in a hypothetical study to prevent decompensation resulted in sample-size estimates 3-to 4-fold lower than using a binary composite endpoint. CONCLUSIONS: Compared to traditional binary outcomes, the use of ordinal outcomes in trials of cirrhosis decompensation may provide more power and thus may require a smaller sample size.
Authors: Sonja Lang; Anna Martin; Xinlian Zhang; Fedja Farowski; Hilmar Wisplinghoff; Maria J G T Vehreschild; Marcin Krawczyk; Angela Nowag; Anne Kretzschmar; Claus Scholz; Philipp Kasper; Christoph Roderburg; Raphael Mohr; Frank Lammert; Frank Tacke; Bernd Schnabl; Tobias Goeser; Hans-Michael Steffen; Münevver Demir Journal: Liver Int Date: 2021-05-07 Impact factor: 8.754