title: Interaction between loop diuretic-associated mortality and blood urea nitrogen concentration in chronic heart failure.
abstract: OBJECTIVE
  The purpose of this study was to investigate whether a surrogate for renal neurohormonal activation, blood urea nitrogen (BUN), could identify patients destined to experience adverse outcomes associated with the use of high-dose loop diuretics (HDLD).
  
  
  BACKGROUND
  Loop diuretics are commonly used to control congestive symptoms in heart failure; however, these agents cause neurohormonal activation and have been associated with worsened survival.
  
  
  METHODS
  Subjects in the BEST (Beta-Blocker Evaluation of Survival Trial) receiving loop diuretics at baseline were analyzed (N = 2,456). The primary outcome was the interaction between BUN- and HDLD-associated mortality.
  
  
  RESULTS
  In the overall cohort, HDLD use (≥160 mg/day) was associated with increased mortality (hazard ratio [HR]: 1.56; 95% confidence interval [CI]: 1.35 to 1.80). However, after extensively controlling for baseline characteristics, this association did not persist (HR: 1.06; 95% CI: 0.89 to 1.25). In subjects with BUN levels above the median (21.0 mg/dl), both the unadjusted (HR: 1.59; 95% CI: 1.34 to 1.88) and adjusted (HR: 1.29; 95% CI: 1.07 to 1.60) risk of death was higher in the HDLD group. In patients with BUN levels below the median, there was no associated risk with HDLD (HR: 0.99; 95% CI: 0.75 to 1.34) and after controlling for baseline characteristics, the HDLD group had significantly improved survival (HR: 0.71; 95% CI: 0.49 to 0.96) (p interaction = 0.018).
  
  
  CONCLUSIONS
  The risk associated with HDLD use is strongly dependent on BUN concentrations with reduced survival in patients with an elevated BUN level and improved survival in patients with a normal BUN level. These data suggest a role for neurohormonal activation in loop diuretic-associated mortality.
authors.affiliation: Department of Medicine, Cardiovascular Division, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA. testani@uphs.upenn.edu
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Testani
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Cappola
authors.forename: Colleen M
authors.initials: CM
authors.lastname: Brensinger
authors.forename: Richard P
authors.initials: RP
authors.lastname: Shannon
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Kimmel
mesh_terms: D000368:Aged; D001806:Blood Urea Nitrogen; D004305:Dose-Response Relationship, Drug; D005260:Female; D006333:Heart Failure / Q000097:blood* / Q000188:drug therapy / Q000401:mortality*; D006801:Humans; D008297:Male; D008875:Middle Aged; D049994:Sodium Potassium Chloride Symporter Inhibitors / Q000009:adverse effects*; D016896:Treatment Outcome
chemical_list: D049994:Sodium Potassium Chloride Symporter Inhibitors