Cardiovascular biomarkers in patients with acute decompensated heart failure randomized to sacubitril-valsartan or enalapril in the PIONEER-HF trial

Abstract

Aims: Circulating high-sensitivity cardiac troponin (hsTn) and soluble ST2 (sST2) reflect myocardial stress in patients with heart failure (HF). Production of cyclic guanosine 3'5' monophosphate (cGMP) in response to activation of natriuretic peptide receptors reduces cardiac afterload and preload. We assessed the effects of sacubitril/valsartan on these biomarkers in patients with reduced ejection fraction and acute decompensated HF (ADHF).

Methods and results: PIONEER-HF was a randomized, double-blind trial of sacubitril/valsartan vs. enalapril in hospitalized patients with ADHF following haemodynamic stabilization. We measured circulating hsTnT, sST2, and urinary cGMP at baseline, 1, 2 (sST2, cGMP), 4, and 8 weeks (n = 694 with all baseline biomarkers). Ratios of geometric means (timepoint/baseline) were determined and compared as a ratio for sacubitril/valsartan vs. enalapril. Compared with enalapril, sacubitril/valsartan led to a significantly greater decline in hsTnT and sST2. This effect emerged as early as 1 week for sST2 and was significant for both at 4 weeks with a 16% greater reduction in hsTnT (P < 0.001) and 9% greater reduction in sST2 (P = 0.0033). Serial urinary cGMP increased with sacubitril/valsartan compared with enalapril (P < 0.001, 1 week). The significant differences between treatment groups for each biomarker were sustained at 8 weeks. In an exploratory multivariable-adjusted analysis of cardiovascular death or HF-rehospitalization, the concentrations of hsTnT, sST2 at week 1 were significantly associated with subsequent outcome.

Conclusion: Biomarkers of myocardial stress are elevated in patients with ADHF and associated with outcome. Compared with enalapril, sacubitril/valsartan reduces myocardial injury and haemodynamic stress as reflected by biomarkers, with an onset that is apparent within 1-4 weeks.

Clinical trials registration: NCT02554890 clinical.trials.gov.

Keywords: Acute heart failure; Biomarkers; Troponin.

© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology.

Figures

Figure 1

Ratio of the geometric mean concentration of hsTnT (A) and sST2 (B) at baseline (BL) and each subsequent timepoint compared with the baseline value and stratified by randomized treatment group with associated 95% confidence intervals. The reported P-values are for the comparison between changes with sacubitril/valsartan vs. enalapril.

Figure 2

Ratio of the geometric mean concentration of urinary cyclic guanosine 3′5′ monophosphate at each timepoint compared with baseline and stratified by randomized treatment group with associated 95% confidence intervals. The reported P-values are for the comparison between changes with sacubitril/valsartan vs. enalapril.

Figure 3

Kaplan–Meier-estimated rates at week 8 of cardiovascular death and rehospitalization for heart failure (84 events) with sacubitril/valsartan or enalapril using an intention-to-treat analysis stratified by baseline hsTnT, sST2, and NT-proBNP concentration ≥ median (high) vs.

Take home figure

Relative effect of sacubitril/valsartan vs. enalapril on hsTnT, sST2 and NT-proBNP calculated from the ratio of the geometric means from baseline to week 8 for each biomarker.