Utilizing NT-proBNP for Eligibility and Enrichment in Trials in HFpEF, HFmrEF, and HFrEF

The purpose of this study was to assess the association between N-terminal pro-B-type natriuretic peptide (NT-proBNP) and cardiovascular (CV) versus non-CV events and between NT-proBNP and potential treatment effects in heart failure (HF) with preserved, mid-range, and reduced ejection fraction (HFpEF, HFmrEF, and HFrEF, respectively) and clinically relevant subgroups.

Optimizing patient eligibility criteria in HF trials requires biomarkers that enrich for CV but not for non-CV events and select patients most likely to respond to the tested intervention.

In the Swedish HF registry population stratified by EF category, we used Kaplan-Meier curves to estimate unadjusted CV and non-CV risks (mortality or hospitalization); Poisson regressions to calculate crude event rates of CV and non-CV events according to NT-proBNP levels; and Cox regressions to calculate the adjusted hazard ratios for HF therapies according to NT-proBNP ≤ or > median.

In a cohort of 15,849 patients (23% HFpEF, 21% HFmrEF, 56% HFrEF), median NT-proBNP was 2,037, 2,192, and 3,141 pg/ml, respectively. With increasing NT-proBNP, CV event rates increased more steeply than non-CV rates (range 20 to 160 and 30 to 100 per 100 patient-years in HFpEF; 20 to 130 and 20 to 100 in HFmrEF; and 20 to 110 and 20 to 50 in HFrEF, respectively). The CV-to-non-CV ratio increased with increasing NT-proBNP in HFpEF and HFrEF, but only in the lower range in HFmrEF. The association between treatments (e.g., angiotensin-converting enzyme-inhibitor, angiotensin II receptor blockers, and beta-blockers) and outcomes was consistent in NT-proBNP ≤ and > median.

In HF trial design in different EF categories, NT-proBNP may be a useful tool for eligibility and enrichment for CV events, but its role in predicting a potential treatment response remains unclear.