Surrogate markers of clinical endpoints in clinical trials of heart failure.

Clinical Snapshot

Key Findings

• P Value: P < 0.001 for LVEF correlations; P = 0.002 for natriuretic peptides and mortality

• Effect Size: LVEF showed strongest correlation with HF hospitalization (R² = 90%) and moderate correlation with mortality (R² = 59%)

• Primary Outcome: Correlation between surrogate markers and clinical endpoints (mortality and HF hospitalization)

• Nnt Or Sensitivity: Surrogate threshold effects: LVEF +6% for mortality, +2% for HF hospitalization; natriuretic peptides -34% for mortality, -30% for HF hospitalization

• Confidence Interval: Not reported in abstract

Clinical Application

Readily applicable as these surrogate markers are routinely measured in Australian cardiology practice Highly relevant to Australian practice where PBS subsidizes HF medications and TGA requires robust endpoint data. RACGP and CSANZ guidelines emphasize evidence-based HF management with hard clinical endpoints Patients with heart failure, particularly HFrEF for LVEF-based assessments

Abstract

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. METHODS: 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 (i) all-cause mortality and (ii) HF hospitalization. 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 = .002, R2 = 12%, and STE = -34%) and HF hospitalization (41 comparisons, P < .001, R2 = 32%, and STE = -30%). Changes in LVEF were moderately correlated with mortality (69 comparisons, P < .001, R2 = 59%, and STE = +6%) and strongly correlated with HF hospitalization (45 comparisons, P < .001, R2 = 90%, and 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.

References

1. 1.Wang, N., Hibbert, T., Ishak, S., Raftopulos, N., Abdo, R. M., Abhayaratna, C., Rueter, P., & Vaduganathan, M. (2026). Surrogate markers of clinical endpoints in clinical trials of heart failure. European Journal of Heart Failure. https://doi.org/10.1093/ejhf/xuag033