Interaction between loop diuretic-associated mortality and blood urea nitrogen concentration in chronic heart failure

J Am Coll Cardiol. 2011 Jul 19;58(4):375-82. doi: 10.1016/j.jacc.2011.01.052.


Objectives: 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aged
  • Blood Urea Nitrogen
  • Dose-Response Relationship, Drug
  • Female
  • Heart Failure / blood*
  • Heart Failure / drug therapy
  • Heart Failure / mortality*
  • Humans
  • Male
  • Middle Aged
  • Sodium Potassium Chloride Symporter Inhibitors / adverse effects*
  • Treatment Outcome


  • Sodium Potassium Chloride Symporter Inhibitors