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

Abstract

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.

Figure 1

Kaplan–Meier plots for total survival grouped by serum blood urea nitrogen and high dose loop diuretic use. BUN; blood urea nitrogen. High and low BUN represent values above and below the median respectively.

Figure 2

Survival plots for total survival grouped by serum blood urea nitrogen and high dose loop diuretic use after adjustment for potential confounders. Survival plots are adjusted for hemoglobin, serum creatinine, BUN, serum sodium, serum uric acid, systolic blood pressure, left ventricular ejection fraction, Minnesota Living with Heart Failure score, age, physical examination findings, baseline medication use, diabetes, hypertension, and coronary artery disease.