Prognostic Value of Baseline Plasma Amino-Terminal Pro-Brain Natriuretic Peptide and Its Interactions With Irbesartan Treatment Effects in Patients With Heart Failure and Preserved Ejection Fraction

Abstract

Background— Plasma concentrations of natriuretic peptides (NPs) are associated with morbidity and mortality in patients with systolic heart failure (HF). However, the role of NP as a prognostic marker in patients with HF and preserved ejection fraction (HFpEF) has not been studied in a large cohort of well-characterized patients. Moreover, it is unclear whether treatments have a differential effect on morbidity and mortality across the spectrum of NP levels. Methods and Results— N-terminal pro-brain natriuretic peptide (NT-proBNP) was measured at baseline in 3480 patients in the I-PRESERVE (Irbesartan in Heart Failure with Preserved Ejection Fraction Trial). In a multivariable Cox regression model, NT-proBNP above the median of 339 pg/mL was independently associated with an increased risk of the primary end point of all-cause mortality and prespecified cardiovascular hospitalizations (adjusted hazard ratio [HR], 1.79; 95% CI, 1.56 to 2.10; P <0.001); all-cause mortality (adjusted HR, 2.04; 95% CI, 1.68 to 2.47; P <0.001); and a composite of HF events, including death due to worsening HF or sudden death or hospitalization due to worsening HF (adjusted HR, 1.77; 95% CI, 1.43 to 2.20; P <0.001). There were significant interactions between the effect of irbesartan and median split of baseline NT-proBNP for the primary outcome ( P =0.005), all-cause mortality ( P =0.05), and the HF composite outcome ( P <0.001). Use of irbesartan was associated with improved outcomes in patients with NT-proBNP below, but not above, the median. After adjusting for 20 baseline covariates, irbesartan still had a beneficial effect on the primary outcome (HR, 0.74; 95% CI, 0.60 to 90; P =0.003), all-cause mortality (HR, 0.75; 95% CI, 0.56 to 0.99; P =0.046), and HF composite outcome (HR, 0.57; 95% CI, 0.41 to 0.80; P =0.001) in patients with NT-proBNP below the median. Conclusions— The unexpected benefit of irbesartan in lower-risk patients with HFpEF in this post hoc analysis may indicate effects on early, but not later, high-risk stages of the disease. These findings question the strategy of using elevated plasma concentrations of NP as a patient selection criterion in HFpEF trials. More studies are needed to support or contest this practice. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00095238.