The win ratio was motivated by the Finkelstein–Schoenfeld (FS) test, with the aim of providing an estimate of the treatment effect (the win ratio) and confidence interval, in addition to a P-value. The general principle behind both the Finkelstein-Schoenfeld test and the win ratio is that they are both methods for examining composite endpoints in clinical trials. Win ratio can be considered as a popular name for the Finkelstein-Schoenfeld test. See my previous post "Finkelstein-Schoenfeld Method, Win Ratio, and Hodges-Lehman Estimates - Statistical Methods Based on All Paired Comparisons". In practice, we may see the terms "Win Ratio test" and "Finkelstein-Schoenfeld test" interchangeably.
Win Ratio is defined differently than hazard ratio in survival analysis, however, both Win Ratio and Hazard Ratio are important statistical measures used in clinical trials to assess treatment outcomes and compare different treatments. However, they have distinct interpretations and applications, making them suitable for different types of clinical trial data and research questions. Here are comparison table for Win Ratio and Hazard Ratio:
For win-ratio and hazard ratio comparison, please see the article by Ferreira et al "Use of the Win Ratio in Cardiovascular Trials".
Win Ratio approach has been used to re-analyze the clinical trials with a composite endpoint (either the primary efficacy or secondary efficacy endpoint). There is a table in Redfors et al 2020 paper that summarized the re-analysis results using the Win Ratio approach. We recently published a paper in Annals of American Thoracic Society "A Novel Approach to Clinical Change Endpoints: A Win Ratio Analysis of the INCREASE Trial" where the Win Ratio approach was used to analyze the secondary efficacy endpoint of clinical worsening events.
This past week, Biotech company, Bridgebio Pharma announced their phase III study of acoramidis in transthyretin amyloid cardiomyopathy, or ATTR-CM. One of the primary efficacy endpoint is a composite endpoint - a hierarchical combination of 1) all-cause mortality, 2) cumulative frequency of cardiovascular-related hospitalization, 3) change from baseline in NT-proBNP, and 4) change from baseline in 6MWT over a 30-month fixed treatment duration. According to clinicaltrials.gov, the composite endpoint is analyzed using the following approach:
The win ratio test requires a pairwise comparison (each subject in the treatment group is compared with each subject in the placebo (control) group). The number of pairs is the sample size (n) for the treatment group times the sample size (m) for the placebo group, i.e., n x m pairs. The win ratio test results are largely dependent on the rules or algorithms in determining the win/loss/tie for each individual pair. Therefore, the rules and algorithm need to be pre-specified. For the prospective clinical trials, these rules and algorithms need to be pre-specified in the statistical analysis plan (SAP) and the SAP needs to be submitted to FDA for review to avoid the potential biases or potential impression of biases.
References:
|
Metric |
Win
Ratio |
Hazard
Ratio |
|
Definition |
Ratio of treatment
success in the experimental group to the control group |
Compares the risk of
an event occurring in the treatment group to the control group over time |
|
Clinical trial design |
Usually fixed-duration
studies |
Both fixed-duration
studies and event-driven studies |
|
Endpoint |
Composite endpoint,
all events are considered |
Composite endpoint,
usually time to the first event |
|
Interpretation |
Great than 1:
Experimental treatment has higher success rate than control group Equal to 1: Both
groups have the same success rate<br> Less than 1:
Experimental treatment has lower success rate than control group |
Greater than 1: Higher
risk of event in treatment group<br> Equal to 1: Equal risk
of event in both groups<br> Less than 1: Lower
risk of event in treatment group |
|
Application |
Non-inferiority or
superiority trials to assess treatment efficacy |
Survival analysis with
time-to-event outcomes (e.g., overall survival, progression-free survival) |
|
Focus |
Treatment success
rates |
Risk of an event over
time |
|
Type of Data |
Binary or categorical
data |
Time-to-event data |
For win-ratio and hazard ratio comparison, please see the article by Ferreira et al "Use of the Win Ratio in Cardiovascular Trials".
Win Ratio approach has been used to re-analyze the clinical trials with a composite endpoint (either the primary efficacy or secondary efficacy endpoint). There is a table in Redfors et al 2020 paper that summarized the re-analysis results using the Win Ratio approach. We recently published a paper in Annals of American Thoracic Society "A Novel Approach to Clinical Change Endpoints: A Win Ratio Analysis of the INCREASE Trial" where the Win Ratio approach was used to analyze the secondary efficacy endpoint of clinical worsening events.
Win Ratio approach has also been prespecified as the primary analysis method to analyze the clinical trials with composite endpoints. A table in Redfors et al 2020 paper summarized seven different trials including ATTR-ACT, Chart-1, and TAVR-UNLOAD trials where the Win Ratio approach was listed as the primary analysis method.
This past week, Biotech company, Bridgebio Pharma announced their phase III study of acoramidis in transthyretin amyloid cardiomyopathy, or ATTR-CM. One of the primary efficacy endpoint is a composite endpoint - a hierarchical combination of 1) all-cause mortality, 2) cumulative frequency of cardiovascular-related hospitalization, 3) change from baseline in NT-proBNP, and 4) change from baseline in 6MWT over a 30-month fixed treatment duration. According to clinicaltrials.gov, the composite endpoint is analyzed using the following approach:
Each subject will be compared to every other subject within a stratum over outcomes of all-cause mortality (death due to any cause), cumulative frequency of cardiovascular-related hospitalizations (number of times a subject is hospitalized for cardiovascular-related causes), change from baseline in NT-proBNP, and change from baseline in the total distance walked in 6 minutes (distance in meters).In the company's presentation slides, results for the primary endpoint and secondary endpoints are listed. The win ratio is listed as 1.8, which indicates 80% more wins in acoramidis treatment group than in the placebo group.
The hierarchical approach with the Finkelstein-Schoenfeld test will be applied and the test recognizes the greater importance of the mortality endpoint. Scores are transformed to -1, 0, +1. The alternative hypothesis is a subject in the acoramidis treatment group will have a greater score than a subject in the placebo group.
The win ratio test requires a pairwise comparison (each subject in the treatment group is compared with each subject in the placebo (control) group). The number of pairs is the sample size (n) for the treatment group times the sample size (m) for the placebo group, i.e., n x m pairs. The win ratio test results are largely dependent on the rules or algorithms in determining the win/loss/tie for each individual pair. Therefore, the rules and algorithm need to be pre-specified. For the prospective clinical trials, these rules and algorithms need to be pre-specified in the statistical analysis plan (SAP) and the SAP needs to be submitted to FDA for review to avoid the potential biases or potential impression of biases.
References:
- Pocock et al (2012) The win ratio: a new approach to the analysis of composite endpoints in clinical trials based on clinical priorities.
- Redfors et al, 2020 The win ratio approach for composite endpoints: practical guidance based on previous experience
- Ferreira et al (2020) Use of the Win Ratio in Cardiovascular Trials
- Maurer et al (2018) Tafamidis Treatment for Patients with Transthyretin Amyloid Cardiomyopathy
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