Win ratio analyses of piperacillin-tazobactam versus meropenem for ceftriaxone non-susceptible Escherichia coli or Klebsiella pneumoniae bloodstream infections: Post-hoc insights from the MERINO trial

Melissa Hardy; Patrick N A Harris; David L Paterson; Mark D Chatfield; Yin Mo; MERINO trial investigators

doi:10.1093/cid/ciae050

Win ratio analyses of piperacillin-tazobactam versus meropenem for ceftriaxone non-susceptible Escherichia coli or Klebsiella pneumoniae bloodstream infections: Post-hoc insights from the MERINO trial

Clin Infect Dis. 2024 Feb 2:ciae050. doi: 10.1093/cid/ciae050. Online ahead of print.

Authors

Melissa Hardy¹, Patrick N A Harris^{1

2}, David L Paterson^{1

3

4}, Mark D Chatfield¹, Yin Mo^{3

5

6

7

8}; MERINO trial investigators

Collaborators

Affiliations

¹ University of Queensland Centre for Clinical Research, Brisbane, Australia.
² Central Microbiology Laboratory, Pathology Queensland, Brisbane, Australia.
³ ADVANCE-ID, Saw Swee Hock School of Public Health, National University of Singapore, Singapore.
⁴ Infectious Diseases Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
⁵ Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
⁶ Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
⁷ Division of Infectious Diseases, University Medicine Cluster, National University Hospital, Singapore.
⁸ Yong Loo Lin School of Medicine, National University of Singapore, Singapore.

PMID: 38306577
DOI: 10.1093/cid/ciae050

Abstract

Background: Clinical trials of treatments for serious infections commonly use the primary endpoint of all-cause mortality. However, many trial participants survive their infection and this endpoint may not truly reflect important benefits and risks of therapy. The win ratio uses a hierarchical composite endpoint that can incorporate and prioritise outcome measures by relative clinical importance.

Methods: The win ratio methodology was applied post-hoc to outcomes observed in the MERINO trial, which compared piperacillin-tazobactam with meropenem. We quantified the win ratio with a primary hierarchical composite endpoint, including all-cause mortality, microbiological relapse and secondary infection. A win ratio of one would correspond to no difference between the two antibiotics, while a ratio less than one favors meropenem. Further analyses were performed to calculate the win odds and to introduce a continuous outcome variable in order to reduce ties.

Results: With the hierarchy of all-cause mortality, microbiological relapse and secondary infection, the win ratio estimate was 0.40 (95% CI: 0.22, 0.71; p=0.002), favoring meropenem over piperacillin-tazobactam. However, 73.4% of the pairs were tied due to the small proportion of events. The win odds, a modification of the win ratio accounting for ties, was 0.79 (95% CI: 0.68, 0.92). The addition of length of stay to the primary composite, greatly minimised the number of ties (4.6%) with a win ratio estimate of 0.77 (95% CI: 0.60-0.99; p=0.04).

Conclusions: The application of the win ratio methodology to the MERINO trial data illustrates its utility and feasibility for use in antimicrobial trials.

Keywords: antimicrobial resistance; bloodstream infections; composite endpoints; generalized pairwise comparisons; ordinal outcomes; randomized controlled trials; win odds; win ratio.