Advancing methods for fair outcome comparisons in clinical trials: Application to empagliflozin in heart failure using the win ratio

Heart failure is a long-term condition where the heart cannot pump blood as well as it should. This affects millions of people worldwide, causing symptoms such as breathlessness, fatigue, and frequent hospital stays. Many new treatments are tested in clinical trials, and it is important that these trials use the best possible methods to assess whether treatments work.

In clinical trials, researchers often look at patient outcomes such as survival or whether patients need to be hospitalised. To make these comparisons fair, we usually adjust for differences in patient characteristics such as age, sex, or other health conditions. This process is called covariate adjustment. A newer approach called the win ratio is increasingly being used in heart failure studies. The win ratio compares patients across several outcomes in order of importance—for example, survival is considered more important than hospitalisation. This approach can give a fuller picture of treatment effects, but it is not yet clear how best to combine it with covariate adjustment.

This analysis will explore different ways to apply covariate adjustment when using the win ratio. To do this, we will use two approaches. First, we will run computer-based simulations to test different strategies, such as stratification (grouping patients by certain characteristics), other statistical methods (mathematical models), and using risk scores that summarise patient risk factors. Second, we will apply these approaches to data from the EMPEROR-Preserved trial.

The EMPEROR-Preserved trial studied a medicine called empagliflozin. Empagliflozin belongs to a group of medicines known as sodium-glucose cotransporter-2 (SGLT2) inhibitors. These medicines were first developed to lower blood sugar in people with type 2 diabetes (high blood sugar). They work by helping the kidneys remove excess glucose (sugar) and sodium (salt) from the body through urine. In heart failure, removing this extra fluid and salt can reduce strain on the heart, lower the chance of fluid build-up in the lungs, and decrease hospitalisations. Because of these effects, empagliflozin has been shown to benefit patients with heart failure even if they do not have diabetes.

Our research is methodological in nature, meaning we will focus on improving the statistical tools used to analyse clinical trials. We will not re-test how effective the medicine itself is. Instead, our goal is to compare different approaches for analysing outcomes so that future trials can be designed and interpreted more reliably. By doing this, we hope to support better decision-making for both researchers and doctors, which will ultimately benefit patients living with heart failure.