Abstract
Objectives
The purpose of this study was to investigate if 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 are associated with worsened survival.
Methods
Subjects in the Beta-Blocker Evaluation of Survival Trial receiving loop diuretics at baseline were analyzed (n=2456). 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 (HR=1.56, 95% 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 for 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).
Conclusion
The risk associated with HDLD use is strongly dependent on BUN concentrations with reduced survival in patients with elevated BUN and improved survival in patients with normal BUN. These data suggest a role for neurohormonal activation in loop diuretic associated mortality.
Keywords: Congestive heart failure, Loop diuretics, Kidney, Mortality
Introduction
In the preceding decades multiple therapies capable of prolonging life have been developed for the treatment of heart failure; however, loop diuretics have remained the primary means to control congestive symptoms.(1) Although effective in the maintenance of euvolemia, administration of loop diuretics can lead to significant neurohormonal activation.(2, 3) Given that the majority of therapeutic advances in heart failure have centered on the concept of neurohormonal antagonism, it is not surprising that there has been great interest regarding the influence of diuretics on outcomes in patients with heart failure. Indeed, numerous studies have reported a strong association between loop diuretics and worsened survival.(4–9)
Providing further complexity to the relationship between loop diuretics and adverse outcomes is the possibility that elevated filling pressures directly contribute to negative remodeling and heart failure progression.(10–13) Two recent studies have provided preliminary evidence to support the hypothesis that aggressive volume management is associated with improved outcomes, even in the setting of larger doses of loop diuretics.(14, 15) Thus, it is conceivable that a given dose of loop diuretic could contribute to either improved or worsened survival depending on the relative benefit from decongestion versus the harm from neurohormonal activation. Since there is large inter-individual variability in both heart failure phenotype and response to loop diuretics, the threshold dose for toxic effects is likely specific to each patient’s renal, cardiac, and neurohormonal physiology.
The clearance of blood urea nitrogen (BUN) is determined by both glomerular filtration rate and tubular reabsorption of urea.(16, 17) Through both direct and indirect mechanisms, neurohormonal activation leads to increased tubular urea reabsorption and decreases in glomerular filtration rate.(16, 18–20) Given that the detrimental cardiovascular effects of loop diuretics are thought secondary to renally mediated neurohormonal activation and the fact that tubular urea reabsorption parallels the kidney’s neurohormonal status, serum BUN may provide information related to the functional neurohormonal impact of high dose loop diuretics. We hypothesized that if loop diuretics are causally related to adverse outcomes via neurohormonal activation, loop diuretic associated mortality should be predominantly restricted to patients with evidence of neurohormonal activation.
Methods
The Beta-Blocker Evaluation of Survival Trial (BEST) was a National Heart, Lung and Blood Institute (NHLBI) supported randomized placebo controlled trial investigating the impact of bucindolol, a nonselective beta blocker, on all cause mortality in compensated chronic heart failure patients. The design and primary results have been previously published.(21) Briefly, 2708 patients with New York Heart Association (NYHA) functional class III or IV heart failure, a left ventricular ejection fraction of ≤ 35%, and use of an angiotensin converting enzyme inhibitor for ≥ 1 month (unless contraindicated) were randomized to bucindolol or placebo. Exclusion criteria included reversible heart failure, uncorrected primary valvular disease, decompensated heart failure, life expectancy of less than 3 years, a serum creatinine level of ≥ 3.0 mg/dL, or the use of a beta blocker within 30 days of baseline. The BEST trial was conducted and supported by the NHLBI in collaboration with the BEST study investigators. This manuscript was prepared using a limited access dataset obtained from the NHLBI and does not necessarily reflect the opinions or views of the BEST investigators or the NHLBI.
All patients with baseline loop diuretic dose ≥10 mg and a baseline BUN level were included in this analysis (N=2456). Total loop diuretic dose was converted to furosemide equivalents (i.e. 1 mg bumetanide = 20 mg torsemide = 40 mg furosemide). High dose loop diuretic use was defined, a priori, as a total daily dose of ≥160 mg of furosemide equivalents, the dose corresponding to the 75th percentile in this cohort. Glomerular filtration rate (GFR) was estimated using the four variable Modification of Diet in Renal Disease study equation.(22) The analysis is based on baseline data since that is the only time point with complete data available in the BEST dataset. This study was approved by the institutional review committee.
Statistical Methods
Values reported are mean ± standard deviation, median (quartile 1-quartile 3), and percentile. Independent Student’s t-test, the Mann-Whitney U test, ANOVA, or the Kruskal-Wallis test were used to compare continuous parameters. Pearson’s Chi Square was used to evaluate categorical variables. The primary outcome of the study was all cause mortality and the primary analyses focused on the associations between high dose loop diuretics and mortality in subgroups stratified by a baseline BUN level above or below the median. Cox proportional modeling was used to evaluate time to event associations with all cause mortality. In order to account for all potential confounders available in this dataset, candidate covariates for multivariable modeling were obtained by screening all baseline variables and those with a univariate association with mortality (p≤ 0.2) in the population or stratum of interest were entered in the model. Covariates were removed using backwards elimination (likelihood ratio) and variables with a conservative p<0.2 were retained.(23) Kaplan–Meier curves for death from any cause were plotted for the four combinations of groups between BUN level above or below the median and high dose diuretic use. The x axis was terminated when the remaining number at risk was <10%. Stratum specific hazard ratios were derived from proportional hazards modeling of the individual strata and the significance of the interactions was formally assessed using models incorporating terms for the main effect of high dose loop diuretic use, the main effect of the dichotomous variable of interest, and the interaction between these variables. Cox regression analyses of loop diuretic dose stratified by BUN level and their associated interaction models were subjected to 1000 bootstrap replications (with replacement) to derive p values and 95% confidence intervals for these analyses. Statistical analysis was performed with PASW Statistics version 18.0 (SPSS Inc, Chicago, Illinois) and significance defined as 2-tailed p<0.05.
Results
Baseline characteristics and results of the overall BEST trial population have been previously reported.(21) The primary endpoint of all cause mortality did not show a statistically significant difference between patients receiving bucindolol or placebo. Baseline characteristics of subjects used in the current analysis (those receiving ≥10 mg of loop diuretics with a baseline BUN level available) are presented in Table 1. In total, 27.7% of the population was on high dose loop diuretics (total daily dose ≥160 mg, n=680) at baseline and of those patients 51.8% were on 160 mg. In total 33.3% of the population died and median follow up was 721 (398–1041 days).
Table 1.
Baseline Characteristics of overall cohort and patients on high versus low dose loop diuretics or with a blood urea nitrogen level above versus below the median
| Characteristics | Overall Cohort |
High Dose Loop Diuretic | BUN Above Median | ||||
|---|---|---|---|---|---|---|---|
| n=2456 | No (n=1776) |
Yes (n=680) |
p | No (n=1236) |
Yes (n=1220) |
p | |
| Demographics | |||||||
| Age | 60.3 ± 12.4 | 60.7 ± 12.2 | 59.2 ± 12.7 | 0.006* | 56.5 ± 12.1 | 63.9 ± 11.5 | <0.001* |
| White race | 68.70% | 70.80% | 63.20% | <0.001* | 65.60% | 71.80% | 0.001* |
| Male | 77.50% | 77.20% | 78.40% | 0.529 | 73.70% | 81.30% | <0.001* |
| Past Medical History | |||||||
| Hypertension | 59.80% | 57.50% | 65.90% | <0.001* | 57.30% | 62.30% | 0.011* |
| Diabetes | 36.90% | 33.00% | 47.20% | <0.001* | 29.30% | 44.50% | <0.001* |
| Obstructive coronary artery disease | 48.50% | 48.60% | 48.20% | 0.874 | 42.40% | 54.50% | <0.001* |
| Physical Examination | |||||||
| Heart rate (bpm) | 82.5 ± 13.4 | 81.6 ± 13.1 | 84.8 ± 13.9 | <0.001* | 82.8 ± 13.5 | 82.2 ± 13.4 | 0.241 |
| Systolic blood pressure (mmHg) | 118.1 ± 19.5 | 119.8 ± 19.6 | 113.6 ± 18.4 | <0.001* | 121.1 ± 19.4 | 115.2 ± 19.0 | <0.001* |
| Jugular venous distention | 48.10% | 44.70% | 57.00% | <0.001* | 43.90% | 52.20% | <0.001* |
| Peripheral edema | 31.60% | 27.90% | 41.40% | <0.001* | 27.60% | 35.50% | <0.001* |
| Rales | 15.40% | 14.00% | 18.90% | 0.003* | 12.60% | 18.10% | <0.001* |
| S3 gallop | 45.90% | 42.30% | 55.60% | <0.001* | 42.90% | 48.90% | 0.003* |
| Medications (Baseline) | |||||||
| Digoxin | 92.90% | 91.90% | 95.30% | 0.004* | 92.70% | 93.00% | 0.745 |
| Vasodilators | 44.70% | 41.40% | 53.40% | <0.001* | 39.50% | 49.80% | <0.001* |
| ACE inhibitor | 91.70% | 93.30% | 87.50% | <0.001* | 92.60% | 90.80% | 0.097 |
| Bucindolol | 50.10% | 48.50% | 54.30% | 0.010* | 48.80% | 51.40% | 0.197 |
| Total loop diuretic dose | 80 (40–160) | 160 (160–240) | 60 (40–80) | <0.001* | 80 (40–120) | 80 (60–160) | <0.001* |
| Antiarrhythmic drug use | 2.70% | 2.80% | 2.60% | 0.879 | 2.10% | 3.30% | 0.071 |
| Laboratory Value | |||||||
| Hemoglobin (g/dL) | 13.9 ± 1.7 | 14.0 ± 1.6 | 13.7 ± 1.7 | <0.001* | 14.2 ± 1.5 | 13.7 ± 1.8 | <0.001* |
| Serum sodium (mmol/L) | 138.9 ± 3.4 | 139.2 ± 3.2 | 138.2 ± 3.7 | <0.001* | 139.2 ± 3.1 | 138.6 ± 3.6 | <0.001* |
| Uric acid (mg/dL) | 8.3 ± 2.4 | 7.9 ± 2.2 | 9.4 ± 2.7 | <0.001* | 7.4 ± 2.0 | 9.1 ± 2.5 | <0.001* |
| Serum creatinine (mg/dL) | 1.3 ± 0.4 | 1.2 ± 0.4 | 1.4 ± 0.5 | <0.001* | 1.0 ± 0.2 | 1.5 ± 0.4 | <0.001* |
| Glomerular filtration rate (ml/min/1.73 m2) | 64.6 ± 22.6 | 66.2 ± 22.4 | 60.4 ± 22.6 | <0.001* | 76.9 ± 20.1 | 52.5 ± 17.8 | <0.001* |
| Blood urea nitrogen (mg/dL) | 21 (16–30) | 20 (15–26) | 26 (18–40) | <0.001* | 16 (13–18) | 30 (24–41) | <0.001* |
| Norepinephrine (pg/mL) † | 441 (305–642) | 434 (298–616) | 470 (315–687) | 0.007* | 404 (283–567) | 494 (328–703) | <0.001* |
| Functional Status / Ejection Fraction | |||||||
| Ejection fraction (%) | 23 (17–29) | 24 (18–30) | 21 (16–27) | <0.001* | 24 (18–30) | 22 (17–28) | <0.001* |
| MLHF score | 71.4 ± 23.9 | 69.6 ± 23.6 | 76.1 ± 23.9 | <0.001* | 71.7 ± 23.7 | 71.1 ± 24.1 | 0.543 |
BUN: blood urea nitrogen. MLHF score: Minnesota Living with Heart Failure score. Total loop diuretic dose represents furosemide equivalents (1 mg bumetanide = 20 mg torsemide = 40 mg furosemide). High dose loop diuretic defined as total daily dose ≥160 mg of furosemide equivalents. Coronary artery disease defined as a >70% stenosis on angiography or history of percutaneous intervention or coronary artery bypass grafting.
Represents a significant p value.
Available in n=1922 subjects.
Values represent mean ± standard deviation, median (quartile 1- quartile 3), and percentile
Overall, baseline indicators of heart failure disease severity were more common in patients receiving high dose loop diuretics (Table 1). Unadjusted, high dose diuretics were associated with significantly increased incidence of all cause mortality (HR=1.56, 95% CI 1.35 to 1.80, p<0.0001). However, after controlling for confounding variables (hemoglobin, GFR, 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) the association between high dose diuretics and mortality was no longer significant (HR=1.06, 95% CI 0.89 to 1.25, p=0.52).
Baseline BUN level was also strongly associated with increased mortality (HR=1.28 per 10mg/dL increase, 95% CI 1.24 to 1.33, p<0.0001) and patients with a BUN level above the median (21.0 mg/dL) had significantly increased risk of death (HR=2.30, 95% CI 1.99 to 2.66, p<0.0001). Similar to high dose loop diuretic status, a BUN level above the median was associated with multiple markers of adverse prognosis (Table 1). After controlling for confounding variables (loop diuretic dose, hemoglobin, GFR, 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) a BUN level above the median remained significantly associated with worsened survival (HR=1.30, 95% CI 1.07 to 1.57, p=0.009). A BUN level above the median was significantly associated with high dose loop diuretic use (OR=2.1, p<0.0001). Regardless of high dose loop diuretic status, an elevated BUN was associated with increased mortality; however, in patients on high dose loop diuretics an elevated BUN (HR=3.09, 95% CI 2.31 to 4.14, p<0.0001) had significantly greater risk than patients not receiving high dose diuretics (HR=1.94, 95% CI 1.63 to 2.30, p<0.0001).
In analyses stratified by BUN, patients with BUN levels above the median continued to have a highly significant increase in mortality associated with high dose vs. low dose loop diuretic use (HR=1.59, 95% CI 1.34 to 1.88, p<0.0001) (N events=537) (Figure 1). Characteristics of the 4 patients groups presented in Figure 1 can be found in Table 2. In patients with a BUN level below the median, however, the univariate association between mortality and high dose diuretic use was no longer present (HR=0.99, 95% CI 0.75 to 1.34, p=0.99) (N events=282, p interaction=0.008) (Figure 1). Controlling for confounding variables (serum sodium, GFR, serum uric acid, hemoglobin, systolic blood pressure, left ventricular ejection fraction, Minnesota Living with Heart Failure score, age, medication use, physical exam findings, history of diabetes, coronary artery disease and hypertension) the association between high dose loop diuretics and mortality remained significant (HR=1.29, 95% CI 1.07 to 1.60, p=0.012) in patients with a BUN level above the median. However, after controlling for confounding variables in patients with a BUN level below the median (GFR, serum uric acid, hemoglobin, systolic blood pressure, left ventricular ejection fraction, Minnesota Living with Heart Failure score, age, baseline medication use, physical exam findings, sex, history of diabetes, coronary artery disease and hypertension), a significant inverse association between mortality and high dose loop diuretic use emerged (HR=0.71, 95% CI 0.49 to 0.96, p=0.042). The adjusted interaction term remained significant (p=0.018, Figure 2). Coefficients for all variables in the final interaction model can be found in supplemental Table 1. Similar analyses stratified by volume overload physical examination findings or alternative variables associated with mortality did not yield any significant differences in hazard ratios and all interaction terms were nonsignificant (Table 3). We were unable to detect any interaction effect on high dose loop diuretic associated mortality with respect to race (p interaction=0.353) or gender (p interaction=0.807).
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.
Table 2.
Baseline characteristics the four combinations of groups between BUN level above or below the median and high vs. low dose loop diuretic use.
| Characteristics | Low BUN Low Loop Dose (n=972) |
High BUN Low Loop Dose (n=804) |
Low BUN High Loop Dose (n=248) |
High BUN High Loop Dose (n=432) |
|---|---|---|---|---|
| Demographics | ||||
| Age | 57.0 ± 12.2 | 65.2 ± 10.6 | 54.9 ± 11.5 | 61.6 ± 12.7 |
| White race | 67.70% | 74.60% | 57.30% | 66.70% |
| Male | 73.40% | 81.80% | 75.00% | 80.30% |
| Past Medical History | ||||
| Hypertension | 44.80% | 39.80% | 34.70% | 33.80% |
| Diabetes | 72.90% | 59.80% | 62.10% | 47.50% |
| Obstructive coronary artery disease | 42.90% | 55.50% | 40.30% | 52.80% |
| Physical Examination | ||||
| Heart rate (bpm) | 82.0 ± 13.4 | 81.0 ± 12.8 | 86.0 ± 13.6 | 84.4 ±14.1 |
| Systolic blood pressure (mm Hg) | 122.3 ± 19.8 | 116.8 ± 18.9 | 116.0 ± 17.2 | 112.2 ± 18.9 |
| Jugular venous distention | 41.60% | 48.40% | 52.80% | 59.30% |
| Peripheral edema | 25.30% | 31.00% | 36.80% | 44.00% |
| Rales | 11.50% | 17.00% | 16.60% | 20.10% |
| S3 gallop | 40.40% | 44.50% | 52.60% | 57.30% |
| Medications (baseline) | ||||
| Digoxin | 91.70% | 92.30% | 96.80% | 94.40% |
| Vasodilators | 36.50% | 47.30% | 51.20% | 54.60% |
| ACE inhibitor | 94.00% | 92.40% | 87.10% | 87.70% |
| Bucindolol | 47.90% | 49.10% | 52.00% | 55.60% |
| Total loop diuretic dose | 40 (40–80) | 40 (80–80) | 160 (160–240) | 160 (160–240) |
| Antiarrhythmic drug use | 2.10% | 3.60% | 2.40% | 2.80% |
| Laboratory Value | ||||
| Hemoglobin (g/dL) | 14.2 ± 1.5 | 13.7 ± 1.7 | 14.0 ± 1.6 | 13.5 ± 1.8 |
| Serum sodium (mmol/L) | 139.4 ± 3.0 | 139.0 ± 3.3 | 138.6 ± 3.3 | 137.9 ± 3.9 |
| Uric acid (mg/dL) | 7.2 ± 1.9 | 8.6 ± 2.2 | 8.2 ± 2.1 | 10.0 ± 2.8 |
| Serum creatinine (mg/dL) | 1.0 ± 0.2 | 1.4 ± 0.4 | 1.1 ± 0.2 | 1.6 ± 0.4 |
| Glomerular filtration rate (ml/min/1.73 m2) | 76.7 ± 20.1 | 53.6 ± 18.0 | 77.7 ± 20.1 | 50.4 ± 17.3 |
| Blood urea nitrogen (mg/dL) | 15 (13–18) | 28 (24–37) | 16 (14–19) | 34 (27–51) |
| Norepinephrine (pg/mL)* | 401 (282–552) | 494 (330–696) | 422 (286–644) | 491(324–725) |
| Functional Status / Ejection Fraction | ||||
| Left ventricular ejection fraction (%) | 24 (19–30) | 23 (17–28) | 21 (16–27) | 21 (16–26) |
| MLHF score | 70.7 ± 23.7 | 68.1 ± 23.4 | 75.7 ± 23.2 | 76.4 ± 24.4 |
BUN: blood urea nitrogen. MLHF score: Minnesota Living with Heart Failure score. Total loop diuretic dose represents furosemide equivalents (1 mg bumetanide = 20 mg torsemide = 40 mg furosemide). High dose loop diuretic defined as total daily dose ≥ 160 mg of furosemide equivalents. Coronary artery disease defined as a >70% stenosis on angiography or history of percutaneous intervention or coronary artery bypass grafting. All variables had between group differences with an uncorrected p value <0.001 with the exclusion of antiarrhythmic drug use (p=0.25), bucindolol use (p=0.55) and digoxin use (p=0.20).
Available in n=1922 subjects.
Values represent mean ± standard deviation, median (quartile 1- quartile 3), and percentile
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.
Table 3.
Stratified analyses and interaction effects for additional dichotomous variables
| Characteristics | HR for High Dose Loop Diuretic† |
||||
|---|---|---|---|---|---|
| Low Risk |
p | High Risk |
p | P Interaction |
|
| Demographics | |||||
| Age | 1.77 | <0.001* | 1.52 | <0.001* | 0.274 |
| Physical Examination | |||||
| Systolic blood pressure | 1.62 | <0.001* | 1.41 | <0.001* | 0.884 |
| Jugular venous distention | 1.47 | 0.001* | 1.54 | <0.001* | 0.717 |
| Peripheral edema | 1.42 | <0.001* | 1.62 | <0.001* | 0.393 |
| Rales | 1.54 | <0.001* | 1.54 | 0.008* | 0.917 |
| S3 gallop | 1.55 | <0.001* | 1.50 | <0.001* | 0.869 |
| Functional Status / Ejection Fraction | |||||
| Left ventricular ejection fraction | 1.71 | <0.001* | 1.38 | 0.001* | 0.163 |
| MLHF score | 1.61 | <0.001* | 1.53 | <0.001* | 0.724 |
| Laboratory Value | |||||
| Hemoglobin | 1.51 | <0.001* | 1.53 | <0.001* | 0.934 |
| Serum sodium | 1.44 | 0.003* | 1.62 | <0.001* | 0.376 |
| Uric acid | 1.36 | 0.018* | 1.45 | <0.001* | 0.648 |
| Glomerular filtration rate | 1.25 | 0.085 | 1.59 | <0.001* | 0.130 |
HR: Hazard ratio. MLHF score: Minnesota Living with Heart Failure score. High dose loop diuretic defined as total daily dose ≥ 160 mg of furosemide equivalents. Continuous variables are dichotomized by the median values and physical examination findings represent presence or absence of the finding.
Represents a significant p value.
Represents HR for high dose loop diuretic use with analysis stratified by the dichotomous characteristic in the low or high risk category.
Despite the above noted differences in mortality, left ventricular ejection fraction (p=0.43), Minnesota Living with Heart Failure score (p=0.74), jugular venous distention (p=0.10), edema (p=0.07), pulmonary rales (p=0.26), presence of S3 gallop (p=0.24), and baseline medication use (p≥0.17 for all medications) were similar in patients receiving high dose loop diuretics, regardless if BUN levels were above or below the median. Moreover, median loop diuretic doses were also similar (160 (160–240 mg) for both groups, p=0.63). Supporting the concept of neurohormonal activation, patients on high dose loop diuretics had significantly higher plasma norepinephrine levels (available in 81%) if baseline BUN levels were above the median compared to those with BUN levels below the median [491(324, 725 pg/mL) vs. 422 (286, 644 pg/mL), p=0.005]. Similarly, in patients receiving high dose diuretics, serum uric acid was higher (10.0 ± 2.8 vs. 8.3 ± 2.1 mg/dL, p<0.0001) and serum sodium was lower (138 ± 3.9 vs. 139 ± 3.3 mEq/L, p=0.007) in those with BUN above median.
Discussion
The principal finding of this study is the strong interaction between serum BUN level and the mortality risk associated with high dose loop diuretic use. In the overall population high dose loop diuretics had a significant unadjusted association with worsened survival; however, after extensively controlling for baseline confounders this association was no longer present. Most importantly, in patients with a BUN level above the median, the use of high dose diuretics was associated with significantly increased mortality, an association which persisted after controlling for baseline characteristics. In contrast, patients with a BUN level below the median had a significant association between high dose loop diuretic use and improved survival in multivariable analysis. These results suggest that serum BUN, a variable that parallels neurohormonal activation in the kidney, may identify patient populations that are at risk of experiencing adverse neurohormonal effects from high dose loop diuretics.
In the kidney, the macula densa serves a key role in the regulation of renin secretion via the monitoring of tubular sodium chloride content.(24) Sodium chloride entry into these cells is facilitated by the sodium/potassium/2-chloride cotransporter, the primary target of loop diuretics. As a result, loop diuretic administration leads to increased renin release and the neurohormonal cascade that follows.(24–26) This loop diuretic induced neurohormonal activation has been documented both acutely and chronically in humans and loop diuretics have been associated with adverse outcomes in a number of studies.(2–9) Additionally, in experimentally induced heart failure, administration of loop diuretics leads to a more rapid progression of left ventricular dysfunction.(27) However, the multiple redundant feedback loops governing renal blood flow, glomerular filtration rate, and renal neurohormonal status makes the response to any given dose of loop diuretic a highly individualized phenomenon.(28, 29) This was illustrated in a study where the same dose of loop diuretic was given to a group of heart failure patients.(29) Interestingly, plasma renin activity and aldosterone concentration increased in some subjects yet decreased in others. Moreover, neither hormonal change correlated with the volume of diuresis, which varied more than 20 fold amongst subjects.
Much like creatinine, urea is freely filtered through the glomerulus. However, urea undergoes substantial tubular reabsorption.(24) This tubular reabsorption of urea is highly dependent on neurohormonal activation through both direct effects on the distal nephron and indirect effects of decreased renal blood flow and increased proximal tubular solute and water reabsorption.(16, 18–20) Given that loop diuretic induced neurohormonal activation is primarily a renally mediated process, it is biologically plausible that a renal marker of neurohormonal activation, such as clearance of BUN, would parallel the adverse effects of loop diuretics.
Patients with more severe degrees of heart failure generally receive larger doses of loop diuretics and logically confounding by indication has been suggested to account for the association between loop diuretic dose and mortality.(30) The strong, qualitative interaction between BUN, a surrogate for neurohormonal activation, and the effect of loop diuretics on outcomes argues against confounding by indication as the sole mechanism behind these observations. The possibility that confounding by indication is only operative in high risk individuals, potentially explaining the above noted interaction, also appears to be unlikely given that there were no significant interactions when the cohort was dichotomized into high and low risk groups with numerous other variables. Moreover, the finding that a protective effect of high dose loop diuretics was found in patients without elevated BUN levels also provides evidence against confounding by indication as the primary mechanism linking loop diuretics and mortality.
If these data are replicated, formal clinical investigation may be warranted to evaluate volume management strategies based on serum BUN concentrations or other more direct markers of renal neurohormonal activation. Additionally, novel methods of decongestion such as intermittent ultrafiltration or the use of natriuretic doses of potassium sparing diuretics may allow both minimization of loop diuretic doses and the maintenance of euvolemia. The development of more reliable methods of intravascular volume assessment may also provide an improved risk/benefit ratio for loop diuretics by avoiding occult hypervolemia and hypovolemia.
Limitations
Given the post hoc nature of this study the limitations of retrospective analyses apply. Uncontrolled confounding cannot be excluded. Although the inclusion of patients with a serum creatinine up to 3.0 mg/dL was permitted in the trial, the median creatinine value was 1.2 mg/dL with approximately 80% of patients having a creatinine ≤ 1.5 mg/dL. As a result, these findings likely do not apply to a population with more advanced intrinsic renal insufficiency since the reduced glomerular filtration of urea may overwhelm neurohormone related urea clearance in determining serum BUN levels. In addition to the rate of clearance, urea production can be influenced by factors such as protein catabolism and diet, introducing additional noise and potential bias into the assessment of neurohormonal activation with BUN. Additionally, treating physicians were not blinded to the serum BUN concentrations and may have modified treatment based on these values. BUN levels are probably not static over time and serial data points might yield further information and address additional hypotheses. The analysis of norepinephrine levels was limited by missing values in approximately 19% of the study population. The BEST trial required a New York Heart Association class of III or IV for enrollment and thus these results may not be applicable to populations with less severe heart failure symptoms. Unlike the other large scale beta-blocker clinical trials, bucindolol was not found to have a statistically significant impact on all cause mortality. Although this may have been secondary to a lack of efficacy of bucindolol, it is also possible the BEST patient population was somehow different than other beta-blocker trial populations, making it important to validate our findings in additional cohorts.
Conclusions
The association between high doses of loop diuretics and increased mortality in this study was largely dependent on the presence of an elevated BUN level, a surrogate for neurohormonal activation. In patients with elevated BUN levels, higher mortality was noted with the use of high dose loop diuretics. However, in patients with lower serum BUN levels high dose diuretic use was actually associated with improved survival. These data suggest that the worsened survival associated with loop diuretics may be mediated by neurohormonal activation. Further research is necessary to validate these findings and investigate diuretic dosing strategies that can both minimize neurohormonal activation and maintain optimal volume control.
Supplementary Material
Acknowledgments
Funding Sources: NIH Grant 5T32HL007843-15
Abbreviations
- GFR
Glomerular Filtration Rate
- BUN
Blood Urea Nitrogen
- BEST
Beta-Blocker Evaluation of Survival Trial
- NHLBI
National Heart, Lung and Blood Institute
- NYHA
New York Heart Association
Footnotes
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