Work

Exploring desirability of outcome ranking and generalised pairwise comparisons as endpoints in serious infections: Post hoc application with the MERINO trial

Year: 2024

Type: article

Abstract: Objectives Randomised controlled trials in serious infections typically use a single primary endpoint such as mortality. Ordinal or rank-based composite endpoints that evaluate mortality and other measures are a novel approach in clinical trials. Desirability of outcome ranking (DOOR) has been increasingly used in infectious disease trials and generalised pairwise comparisons (GPC) in cardiovascular trials. Methods We undertook a post hoc analysis of the MERINO trial, comparing piperacillin-tazobactam (PTZ) with meropenem in bloodstream infections due to ceftriaxone non-susceptible Escherichia coli and Klebsiella spp. to demonstrate and compare the DOOR and GPC approaches. The primary composite endpoint included mortality, microbiological relapse and secondary infection. A further analysis was performed by adding length of stay as a tiebreaker. We applied DOOR to evaluate the DOOR distribution, probability and conducted partial credit analyses. We applied GPC to estimate the win statistics: win ratio, win odds and net benefit. A secondary analysis with both approaches was conducted with trial participants with PTZ susceptible isolates only as recorded by a central laboratory. Results The DOOR probability was 44.3 % (95 % CI: 40.8 %, 47.9 %), indicating superiority of meropenem. Partial credit analyses demonstrated similar conclusions across different patient preferences. The win ratio, win odds and net benefit were 0.40 (95 % CI: 0.23, 0.70; p = 0.001), 0.80 (95 % CI: 0.69, 0.92; p = 0.002) and −11.3 % (95 % CI:18.7 %, −4.0 %; p = 0.003), also indicating superiority of meropenem. With the addition of length of stay, the DOOR probability was 43.7 % (95 % CI: 37.9 %, 49.6 %) and the win ratio, win odds and net benefit were 0.77 (95 % CI: 0.60, 0.99; p = 0.04), 0.78 (95 % CI: 0.62, 0.99; p = 0.04), −12.1 % (95 % CI:23.8 %, −0.3 %; p = 0.04). Superiority of meropenem was not able to be demonstrated in the secondary analysis where only patients with PTZ susceptible isolates were assessed. Conclusions Though the functionality and interpretation of DOOR and GPC differ, both approaches can enhance the overall understanding of treatment effect in survivors beyond a single endpoint such as mortality.

Source: CMI Communications

DOI: 10.1016/j.cmicom.2024.105040

Authors: Melissa J. Hardy, Patrick N.A. Harris, Mark D. Chatfield, Yin Mo, David L. Paterson