title: 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: findings from the I-PRESERVE trial.
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.
  
  
  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.
authors.affiliation: VA Medical Center and University of Minnesota, Minneapolis, MN 55417, USA. anand001@umn.edu
authors.forename: Inder S
authors.initials: IS
authors.lastname: Anand
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Rector
authors.forename: John G
authors.initials: JG
authors.lastname: Cleland
authors.forename: Michael
authors.initials: M
authors.lastname: Kuskowski
authors.forename: Robert S
authors.initials: RS
authors.lastname: McKelvie
authors.forename: Hans
authors.initials: H
authors.lastname: Persson
authors.forename: John J
authors.initials: JJ
authors.lastname: McMurray
authors.forename: Michael R
authors.initials: MR
authors.lastname: Zile
authors.forename: Michel
authors.initials: M
authors.lastname: Komajda
authors.forename: Barry M
authors.initials: BM
authors.lastname: Massie
authors.forename: Peter E
authors.initials: PE
authors.lastname: Carson
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D047228:Angiotensin II Type 1 Receptor Blockers / Q000627:therapeutic use*; D015415:Biomarkers / Q000097:blood; D001713:Biphenyl Compounds / Q000627:therapeutic use*; D004311:Double-Blind Method; D005260:Female; D006333:Heart Failure / Q000188:drug therapy* / Q000401:mortality / Q000503:physiopathology*; D006760:Hospitalization; D006801:Humans; D000077405:Irbesartan; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D020097:Natriuretic Peptide, Brain / Q000097:blood*; D010446:Peptide Fragments / Q000097:blood*; D011237:Predictive Value of Tests; D011379:Prognosis; D013318:Stroke Volume / Q000502:physiology*; D015996:Survival Rate; D013777:Tetrazoles / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D015415:Biomarkers; D001713:Biphenyl Compounds; D010446:Peptide Fragments; D013777:Tetrazoles; C109794:pro-brain natriuretic peptide (1-76); D020097:Natriuretic Peptide, Brain; D000077405:Irbesartan