Author + information
- Received December 14, 2012
- Revision received April 24, 2013
- Accepted April 26, 2013
- Published online September 24, 2013.
- Stephen S. Gottlieb, MD∗∗ (, )
- Amanda Stebbins, MS†,
- Adriaan A. Voors, MD, PhD‡,
- Vic Hasselblad, PhD†,
- Justin A. Ezekowitz, MBBCh, MSc§,
- Robert M. Califf, MD‖,
- Christopher M. O'Connor, MD†,
- Randall C. Starling, MD, MPH¶ and
- Adrian F. Hernandez, MD, MHS†
- ∗University of Maryland, School of Medicine, Baltimore, Maryland
- †Duke Clinical Research Institute, Duke University Medical Center, Durham, North Carolina
- ‡University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
- §Mazankowski Alberta Heart Institute and the University of Alberta, Edmonton, Alberta, Canada
- ‖Duke Translational Medicine Institute, Duke University Medical Center, Durham, North Carolina
- ¶Cleveland Clinic, Cleveland, Ohio
- ↵∗Reprint requests and correspondence:
Dr. Stephen S. Gottlieb, University of Maryland School of Medicine, 110 South Paca Street, Baltimore, Maryland 21201.
Objectives This study sought to determine if nesiritide increases diuresis in congestive heart failure patients.
Background In the ASCEND-HF (Acute Study of Clinical Effectiveness of Nesiritide and Decompensated Heart Failure), 7,141 patients hospitalized with acute decompensated heart failure (ADHF) were randomized to receive nesiritide or placebo for 24 to 168 h, in addition to standard care. There were minimal effects of nesiritide on survival, future hospitalizations, and symptoms. However, whether or not nesiritide increases diuresis in ADHF patients is unknown.
Methods Urine output was measured in 5,864 subjects; of these, 5,320 received loop diuretics and had dose data recorded. Loop diuretics other than furosemide were converted to furosemide equivalent doses. A total of 4,881 patients had complete data. We used logistic regression models to identify the impact of nesiritide on urine output and the factors associated with high urine output.
Results Median (25th, 75th percentiles) 24-h urine output was 2,280 (1,550, 3,280) ml with nesiritide and 2,200 (1,550, 3,200) ml with placebo (p = NS). Loop diuretic dose (furosemide equivalent) was 80 (40, 140) mg with both nesiritide and placebo. Diuretic dose was a strong predictor of urine output. Other independent predictors included: male sex, greater body mass index, higher diastolic blood pressure, elevated jugular venous pressure, recent weight gain, and lower blood urea nitrogen. The addition of nesiritide did not change urine output. None of the interaction terms between nesiritide and predictors affected the urine output prediction.
Conclusions Nesiritide did not increase urine output in patients with ADHF. Higher diuretic dose was a strong predictor of higher urine output, but neurohormonal activation (as evidenced by blood urea nitrogen concentration) and lower blood pressure limited diuresis.
Nesiritide (synthetic B-type natriuretic peptide [BNP]) was approved in 2001 for symptomatic relief of acute decompensated heart failure (ADHF), presumably as a result of its vasodilatory effects. Nevertheless, the renal effects of nesiritide were of particular interest to physicians who hoped that the drug would aid in diuresing a fluid-overloaded patient who had poor or worsening renal function. At that time, preliminary data produced conflicting results about urine output, and few studies had been done in patients with chronic heart failure.
With concerns raised about the effects of nesiritide on both mortality and renal function (1,2), the ASCEND-HF (Acute Study of Clinical Effectiveness of Nesiritide and Decompensated Heart Failure) was created. The results of this large study have been previously published; the ASCEND-HF found nesiritide to have minimal effects on survival, hospitalizations, and symptoms (3). Yet, whether or not nesiritide increases diuresis in patients with heart failure remains unknown. Furthermore, the factors that predict and affect urine output in this patient population are not well-studied or understood. Knowing that the effects of nesiritide on urine output in patients with heart failure is an important clinical question, the investigators of the ASCEND-HF collected data about the acute actions of nesiritide on renal function. We used these data to assess the impact of nesiritide on urine output and to determine the factors that lead to diuresis.
The ASCEND-HF was a randomized, double-blind, placebo-controlled trial in which nesiritide was administered in addition to standard care. The details of the methodology and enrollment criteria for the ASCEND-HF have been previously published (3). The study was approved by each participating center's ethics committee or institutional review board, and all participants provided written informed consent.
A total of 7,141 patients were randomized, and 7,007 patients received the study drug. In 5,864 of these patients, 24-h urine output was measured. Subjects with urine output greater than the 99th percentile (>7,700 ml) were excluded from these analyses because of suspicion that the data might be incorrect. To assure accurate assessment of urine volume, we excluded the countries that reported less than 60% of these measurements (Australia, Canada, Germany, New Zealand, and Sweden). A sensitivity analysis, including all patients, yielded the same independent predictors of urine output.
A total of 5,320 patients received loop diuretics and had dose data recorded; of these, 80% received intravenous furosemide. For the purpose of this analysis, other loop diuretics were converted to “furosemide equivalent doses.” A dose of 40 mg of intravenous furosemide was considered equivalent to 20 mg of both intravenous and oral torsemide, 1 mg of both intravenous and oral bumetanide, and 80 mg of oral furosemide.
Factors that might impact urine output were analyzed by generalized linear modeling. A total of 4,881 patients had complete data and comprise the sample reported in these analyses.
All pre-specified discrete variables are reported as frequencies and counts. Median and the 25th and 75th percentiles are reported for continuous factors. Normality is tested using the Kolmogorov-Smirnov statistic. All continuous variables reported in Table 1 were found to be non-normally distributed. The p values reported in Table 2 are generated from the Wilcoxon rank sum test and report a non-parametric p value. Generalized linear modeling was generated to assess the pre-specified factors' relationship to outcomes. Pre-specified baseline factors are reported in Table 1. Modeling assumptions were verified and residual plots were generated between potential predictors and outcomes. Transformations were used when necessary. The log transformation was used for urine output, blood urea nitrogen (BUN), and diuretic dose. The stepwise procedure with inclusion level set to <0.05 was used to attain the significant predictors of outcome. We generated the main effect for each variable on outcome and interaction between the main effects and treatment. No adjustments for multiple comparisons were made. All statistical computations were generated using SAS version 9.0 software (SAS Institute Inc., Cary, North Carolina).
Of the 5,864 subjects with urine output measurements, 66% were male, 52% were classified as white, 15% as black, and 28% as Asian. The median (25th, 75th percentile) age was 66 (56, 76) years. Body mass index (BMI) was 27.4 (23.7, 32.5) kg/m2, systolic blood pressure was 123 (110, 140) mm Hg, diastolic blood pressure was 75 (67, 84) mm Hg, and heart rate was 82 (72, 95) beats/min. The ejection fraction was 30% (20%, 36%) in the 4,562 subjects in whom it was assessed.
Recent weight gain was reported in 65% of subjects, 63% reported dyspnea at rest, 37% reported dyspnea on minimal exertion, 72% had a history of hypertension, 35% had a history of myocardial infarction, and 42% had diabetes mellitus. Baseline creatinine was 1.2 (1.0, 1.6) mg/dl and BUN was 25 (18, 38) mg/dl. B-type natriuretic peptide was measured in 2,181 subjects and was 990 (543, 1,825) pg/ml, whereas NT pro-BNP was 4,460 (2,051, 9,030) pg/ml in 3,211 subjects.
Baseline characteristics of patients divided by urine output above and below the median value of 2,250 ml are shown in Table 2. After 24 h, BUN increased 0.0 (−3.0, 4.0) mg/dl in the low urine output group and 1.4 (−2.0, 5.5) mg/dl in the high urine output (p < 0.0001). Urine output in the first 24 h correlated with the improvement in dyspnea, with a Spearman's rank correlation coefficient of 0.123 (p < 0.0001).
Predictors of urine output
The results of the stepwise modeling of factors that predicted urine output (including all parameters listed in Table 1) are shown in Table 3. The statistically significant predictors are shown. Diuretic dose was a strong predictor of urine output. A doubling of the log diuretic dose was independently associated with a 7% increase in the log urine output. The relatively modest increase in urine output may have been the result of the higher doses needed in patients with worse renal function (Fig. 1) for similar urine output (Table 4). The relationship between furosemide dose and urine output is demonstrated in Figure 2. There was a correlation between log urine output and log dose, with a Spearman's rank correlation coefficient of 0.154 (p < 0.0001). Also predictive of increased urine output were male sex, higher BMI, higher diastolic blood pressure, the presence of elevated jugular venous pressure, recent weight gain, and a lower BUN.
The increased log urine output in men (12% more than in women) was associated with 7% higher log diuretic doses; however, male sex predicted increased urine output, even after controlling for BMI and diuretic dose. Similarly, larger people (determined by BMI) received higher doses of diuretics. Patients with higher BUN concentrations received more diuretics (Fig. 1), but they had less urine output (Table 4). A doubling in the log of the BUN was associated with a 6% decrease in log urine output.
Diastolic blood pressure also predicted urine output. Patients with lower pressures had less urine output, despite higher diuretic doses. For a 5-U increase in diastolic blood pressure, there was a 2% increase in log urine output. Patients with evidence of fluid retention (those with reported weight gain from baseline and those with elevated jugular venous pressures) also received higher diuretic doses and had more diuresis.
Effects of nesiritide
The 24-h urine output was 2,280 (1,550, 3,280) ml for patients who received nesiritide and 2,200 (1,550, 3,200) ml for those who received placebo (p = NS). The dose of loop diuretic was 80 (40, 140) mg in both patients receiving nesiritide and patients receiving placebo (p = NS). Because it was important to determine if nesiritide increased urine output in some subgroups, we modeled the proven predictors with the addition of nesiritide. As shown in Table 5, nesiritide did not increase the urine output after adjustment for all independent predictors of urine output.
Unadjusted comparison of urine output with nesiritide and placebo in various subgroups is shown in Table 4. There is no difference between the treatments regarding subgroups of blood pressure, weight gain, jugular venous pressure, sex, and age. Subjects with a creatinine or BUN above the median had a small statistically significant increase with nesiritide. In hopes of defining subgroups that may benefit from nesiritide, we further assessed factors that might interact with nesiritide by looking at interaction terms between nesiritide and the independent predictors of urine output in the final model. None of these interaction terms affected the prediction of urine output.
The ASCEND-HF showed no evidence that nesiritide increases urine output in patients with ADHF. Furthermore, we could find no subgroup in which nesiritide increased urine output. Although there was a slight increase in patients with worse renal function, this increase was not independent of the factors that predicted urine output. The interaction terms between treatment and BUN, creatinine, and estimated glomerular filtration rate (eGFR) were not significant. We also found no evidence to support the hypothesis that the use of nesiritide may decrease the amount of diuretics needed for diuresis (4,5). Although this may be surprising to those who believe that nesiritide increases urine output, this finding is consistent with previous data.
Previous studies that have found nesiritide to have an effect on sodium and urine output have not studied the ADHF patient population. In a randomized, blinded, crossover study comparing placebo and nesiritide, there was no effect on urine output in patients receiving loop diuretics (6). Rather, increased urine output with physiological or usual pharmacological doses of BNP has only been proven in normal individuals (7,8). Interestingly, there is also evidence that when nesiritide is given after cardiac surgery it increases urine output (9). If this is true, then the acute nature of the depressed urine output in these patients could explain why they respond differently than patients with chronic heart failure. Although the ASCEND-HF evaluated patients with ADHF, most had chronic disease that could have affected the renal results.
Heart failure patients may respond differently to nesiritide than healthy individuals. For example, vascular effects of BNP differ between patients with and without heart failure (10). Similarly, a differential response to nesiritide on urinary sodium excretion was seen in one study, with heart failure patients having a urinary sodium excretion of 27 μmol/min as compared with 190 μmol/min in subjects without heart failure (11). It is also possible that neurohormonal activation limits the efficacy of natriuretic peptides. Multiple neurohormonal systems affect urine output, and the impact of natriuretic peptides has been shown to be modified by the renin-angiotensin-aldosterone (12) and sympathetic nervous systems (13). There is also a decreased response in high output failure that is associated with neurohormonal activation (14).
The concentration of nesiritide may also affect the urine output. In a small study, doses higher than those presently recommended seemed to induce a natriuresis (15). However, such doses also have greater hemodynamic effect, which has led to the use of the lower doses than those studied in the ASCEND-HF.
Predictors of urine output
In patients hospitalized for ADHF, diuresis is often a chief goal of therapy. Although the relationship between fluid loss and dyspnea improvement was statistically significant, the correlation was not strong. Furthermore, increased urine output was associated with increased BUN, indicating evidence of increased neurohormonal activation. These findings suggest that the cause of decompensation is multifactorial and is usually not simply fluid retention. Nevertheless, understanding the factors that lead to diuresis is important because many patients do present with fluid overload.
Two main factors appeared to affect the ability of patients to diurese: 1) the dose of diuretic administered; and 2) sicker patients are more refractory to diuresis. Not surprisingly, diuresis increased when larger doses were administered. The dose of diuretics was not randomized and thus characteristics that were associated with higher diuretic doses were not randomly distributed and often also predicted urine output. Many factors can affect the dose given, but the present study suggests that it is not merely refractoriness of diuretics that causes larger doses to be given, but rather that it is the physician's reluctance to give higher doses that may limit adequate diuresis.
Larger patients, men, and those who had more fluid overload (having elevated jugular venous pressure or recent weight gain) received higher doses of diuretics and urinated more. From the data collected, it is impossible to know if these patients needed more diuresis and were therefore more aggressively diuresed, or if the physician's subjective factors had influenced the dosing. Although these factors are associated with diuretic dose, they were also independently associated with urine output. Regardless of these factors, the finding that higher doses of diuretics were used and that there was more urine output in patients with a higher BMI suggests that larger size (which was also associated with men) causes physicians to be more comfortable with prescribing higher doses of diuretics.
There does not appear to be neurohormonal reasons why women should have less diuresis. Indeed, sex differences in neurohormonal response to endothelin would be expected to lead to more urine output in women (16). Similarly, testosterone activates the renin angiotensin system, so that one might expect men to have decreased urine output (17). As a result, the differences between men and women are more likely to be related to diuretic doses or renal function.
The second main cause of decreased diuresis, suggested by our study, is expected; sicker patients are more refractory to diuresis. Renal dysfunction, as assessed by eGFR and BUN concentrations, was associated with less urine output despite higher diuretic doses. Yet, interestingly, BUN was more predictive than eGFR, perhaps because BUN reflects both renal function and avidity for urine retention. An increased BUN/creatinine ratio reflects neurohormonal activation, with associated elevations in plasma renin activity, arginine vasopressin, and endothelin concentrations (18,19). Increases in BUN probably reflect neurohormonal activation more than any fall in glomerular filtration rate (20), and BUN plus the BUN/creatinine ratio are more prognostic than creatinine (18,20–22). Even the association of loop diuretics and mortality may be related to the elevated BUN in patients receiving higher doses of loop diuretics, again suggesting that the elevated BUN reflects neurohormonal activation (23). Although renal dysfunction is undoubtedly important, the fact that BUN independently predicts urine output suggests that the physiology leading to an elevated BUN is also important.
Despite receiving higher doses of diuretics, those patients with a lower diastolic blood pressure had less urine output. This may reflect the severity of their heart failure, but it also may be related to renal perfusion pressure, as renal perfusion pressure affects natriuresis induced by natriuretic peptides (24). Similarly, after renal transplantation, higher nocturnal blood pressure was associated with increased urine output (25).
By examining data from the ASCEND-HF, we found that urine output was most strongly related to diuretic dose, suggesting that physicians can often increase diuresis simply by increasing the diuretics. Nevertheless, neurohormonal activation (as evidenced by BUN concentration) and lower blood pressure limit diuresis. Nesiritide did not lead to increased urine output in patients with ADHF. As a result, new interventions are needed for patients who are refractory to conventional diuretics.
This work was supported internally by the Duke Clinical Research Institute. The ASCEND-HF trial was supported by Scios, Inc. Dr. Gottlieb is a consultant with Gambro and Otsuka; and has received research grant support from Johnson and Johnson. Dr. Voors received consultants fees and/or research grants from Alere, Anexon, Bayer, Cardio3Biosciences, Celladon, Merck/MSD, Novartis, Servier, Torrent, Travena, and Vifor. Justin Ezekowitz is a consultant with Johnson and Johnson. Dr. Califf is a consultant to Bayer, Bristol-Meyers Squibb Foundation, CV Sight LLC, Daiichi-Sankyo, Eli Lilly & Company, Gambro, Heart.org, Janssen R&D LLC, Johnson and Johnson, Kowa, Novartis, Pfizer, Regeneron, Roche and Scios; and has received research grant support from Bristol-Myers Squibb Foundation, Novartis, Amylin, Merck, Schering-Plough Research Institute, Scios, Johnson and Johnson, and Eli Lilly and Company. Dr. O'Connor, is a consultant with Johnson and Johnson. Dr. Hernandez is a consultant to Johnson and Johnson, and Corthera. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. John Teerlink, MD, served as Guest Editor for this paper.
- Abbreviations and Acronyms
- acute decompensated heart failure
- body mass index
- B-type natriuretic peptide
- blood urea nitrogen
- estimated glomerular filtration rate
- Received December 14, 2012.
- Revision received April 24, 2013.
- Accepted April 26, 2013.
- American College of Cardiology Foundation
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