Surrogate markers of clinical endpoints in clinical trials of heart failure

Abstract Background and aims We aimed to determine whether treatment-related changes in surrogate markers predict longer-term therapeutic effects on all-cause mortality and heart failure (HF) hospitalization in randomized trials of HF. Method Systematic literature search included randomized trials of interventions in patients with HF until October 2024. Random-effects meta-regression models with inverse variance weighting were calculated between fifteen surrogate markers and the clinical endpoints of 1) all-cause mortality and 2) HF hospitalisation. The degree of heterogeneity of each model explained by the surrogate marker was determined with R2. Surrogate threshold effects (STEs) were also calculated. Results Ninety-six randomized trials with median follow-up 12 months were included, enrolling a total of 120,304 patients with HF. Treatment related changes in natriuretic peptides (NPs) were weakly correlated with all-cause mortality (64 comparisons, p=0.002, R2=12%, STE=-34%) and HF hospitalization (41 comparisons, p0.001, R2=34%, STE=-30%). Changes in LVEF were moderately correlated with mortality (69 comparisons, p0.001, R2=59%, STE=+6%) and strongly correlated with HF hospitalization (45 comparisons, p0.001, R2=90%, STE=+2%), although this finding was only observed in trials of HFrEF. LV end-diastolic diameter was correlated with HF hospitalization but not mortality. Other echocardiographic markers were not predictive of clinical endpoints. Treatment related changes in patient reported outcomes and exercise capacity were either weakly correlated with clinical outcomes or derived from small clinical trials. Conclusion In HF trials, most surrogate markers, including NPs and echocardiographic measures were only weakly or moderately correlated with treatment effects on all-cause mortality. There is insufficient evidence to support the use of a single biomarker or echocardiographic measure in regulatory trials of HF.