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Loop Diuretic Efficiency: A Metric of Diuretic Responsiveness with
Prognostic Importance in Acute Decompensated Heart Failure
Testani et al: Diuretic Efficiency
Jeffrey M. Testani, MD, MTR1,2; Meredith A. Brisco, MD, MSCE3; Jeffrey M. Turner, MD1;
Erica S. Spatz, MD, MHS1; Lavanya Bellumkonda, MD1;
Chirag R. Parikh, MD, PhD1,2; W. H. Wilson Tang, MD4
1Department of Internal Medicine, and 2Program of Applied Translational Research, Yale
University School of Medicine, New Haven, CT. 3Department of Medicine, Cardiovascular
Division, Medical University of South Carolina, Charleston, SC. 4Section of Heart Failure and
Cardiac Transplantation, the Cleveland Clinic, Cleveland, OH
Correspondence to Jeffrey M. Testani, MD, MTR Yale University 60 Temple Street, Suite 6C New Haven, CT 06510 Tel: (215) 459-3709 Fax: (203) 746-8373 Email: [email protected]
DOI: 10.1161/CIRCHEARTFAILURE.113.000895
Journal Subject Codes: [10] Cardio-renal physiology/ pathophysiology; [110] Congestive;
[118] Cardiovascular Pharmacology
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Abstract
Background—Rather than the absolute dose of diuretic or urine output, the primary signal of
interest when evaluating diuretic responsiveness is the efficiency with which the kidneys can
produce urine after a given dose of diuretic. As a result, we hypothesized that a metric of diuretic
efficiency (DE) would capture distinct prognostic information beyond that of raw fluid output or
diuretic dose.
Methods and Results—We independently analyzed two cohorts: 1) consecutive admissions at
the University of Pennsylvania (Penn) with a primary discharge diagnosis of HF (n=657) and 2)
patients in the ESCAPE dataset (n=390). DE was estimated as the net fluid output produced per
40 mg of furosemide equivalents, then dichotomized into high vs. low DE based on the median
value. There was only a moderate correlation between DE and both the IV diuretic dose and net
fluid output (r2 0.26 for all comparisons), indicating that the diuretic efficiency was describing
unique information. With the exception of metrics of renal function and pre-admission diuretic
therapy, traditional baseline characteristics including right heart catheterization variables were
not consistently associated with DE. Low DE was associated with worsened survival even after
adjusting for in-hospital diuretic dose, fluid output, in addition to baseline characteristics (Penn
HR=1.36, 95% CI 1.04-1.78, p=0.02; ESCAPE HR= 2.86, 95% CI 1.53-5.36, p=0.001.
Conclusions—Although in need of validation in less selected populations, low diuretic
efficiency during decongestive therapy portends poorer long-term outcomes above and beyond
traditional prognostic factors in patients hospitalized with decompensated heart failure.
Key Words: diuretic efficiency, diuretic resistance, diuretics, acute heart failure
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Acute decompensated heart failure (ADHF) is predominantly a disease of fluid overload.1, 2 As
such, the primary therapeutic objective of most ADHF hospitalizations is fluid removal, with the
mainstay of therapy being intravenous loop diuretics.1, 3 It has been suggested that resistance to
loop diuretics is an adverse prognostic indicator, and several authors have described a steep
dose-response relationship between the amount of loop diuretic administered and adverse
outcomes.3-5 However, the dose of loop diuretic prescribed captures much more than simply the
amount of diuretic resistance since dose selection is influenced by factors such as perceived
disease severity, degree of congestion, and the physician’s individual practices regarding diuretic
dosing. In fact, some studies have actually found a lack of survival disadvantage or even a
survival benefit associated with higher loop diuretic doses after accounting for these potential
confounding factors; illustrating that diuretic dose is not an ideal surrogate for diuretic
resistance.6-9
Fundamental to the assessment of diuretic responsiveness is determining how well the
diuretic can actually facilitate augmentation of urine production. As such, the amount of urine
produced is really only valid in context of the dose of diuretic given. For example, the loop
diuretic dose in a patient who has a goal fluid loss of 500 mL will often be significantly less than
a patient who has a goal fluid loss of >3L. However, if both patients required 200 mg of
intravenous furosemide to reach their goal, the patient that produced only 500 mL of urine would
have much greater diuretic resistance than the patient that produced 3L despite the identical
diuretic dose. The reciprocal analogy can be drawn with patients producing similar fluid output
with different doses of diuretic. As a result, the primary signal of interest in diuretic
responsiveness is really the efficiency with which the diuretic can facilitate urine production, not
the absolute dose of diuretic or the absolute production of urine. As such, we hypothesized that a
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metric of diuretic efficiency, defined as the net fluid lost per mg of loop diuretic during an
ADHF hospitalization, would capture distinct prognostic and potentially mechanistic information
from that of raw fluid output or diuretic dose. Accordingly, we sought to investigate the
association between diuretic efficiency and clinical variables and outcomes in two independent
cohorts of ADHF.
Methods
Given that decongestion strategies vary substantially across institutions and by the composition
of the patient population, two distinct cohorts of ADHF patients were analyzed separately. The
first represents a single center retrospective cohort of consecutively admitted patients to the
Hospital of the University of Pennsylvania (Penn Cohort) with which detailed information about
diuretic administration was collected. The concept was subsequently validated in a second
independent cohort, the prospective multicenter Evaluation Study of Congestive Heart Failure
and Pulmonary Artery Catheterization Effectiveness (ESCAPE) trial. Details of both cohorts are
as follows:
Penn Cohort:
We reviewed the charts of all patients with a primary discharge diagnosis of congestive heart
failure who had been admitted to non-interventional cardiology and internal medicine services at
the Hospital of the University of Pennsylvania within the years of 2004 to 2009. Inclusion
required a B-type natriuretic peptide (BNP) level of > 100 pg/mL within 24 hours of admission,
receipt of intravenous loop diuretics, and availability of data on fluid intake and output during
the hospitalization. In order to focus primarily on the physiology and timing of decongestion,
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patients with a length of stay 2 days (who likely underwent limited decongestion) and patients
with length of stay > 14 days (who likely had either atypical degrees of congestion or non-
diuresis-related problems driving the length of stay) were excluded from the cohort. Patients
receiving renal replacement therapy were also excluded. In the event of multiple hospitalizations
for a single patient, only the first admission meeting the above inclusion criteria was retained.
Please see Supplementary Figure 1A for additional details on patient selection. All-cause
mortality was determined via the Social Security Death Index and status was ascertained 2.5
years after discharge of the last patient in the dataset.10 The median time from discharge to
ascertainment of all-cause mortality was 5.1 years (interquartile range 3.7-6.3 years).
ESCAPE Cohort:
The ESCAPE Trial was a National Heart, Lung and Blood Institute sponsored, randomized,
multicenter trial of therapy guided by pulmonary artery catheter vs. clinical assessment in
hospitalized patients with ADHF. Methods and results have been published previously.11, 12
Briefly, 433 patients were enrolled at 26 sites from January 2000 to November 2003. Inclusion
criteria included an ejection fraction of 30% or less, systolic blood pressure of 125 mmHg or
less, hospitalization for HF within the preceding year, treatment during the preceding month with
more than 160 mg of furosemide equivalents daily, and at least 1 sign and 1 symptom of
congestion. Exclusion criteria included an admission creatinine level >3.5 mg/dL. Patients were
randomized to therapy guided by clinical assessment alone vs. pulmonary artery catheter and
clinical assessment. Treatment goals were resolution of the signs and symptoms of congestion
and investigators were encouraged to “avoid progressive renal dysfunction or symptomatic
systemic hypotension.” Patients in the ESCAPE population that did not have data available to
calculate net urine output (n=19) and patients that did not have data available on peak loop
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diuretic dose (n=24) were not included in the current analysis. All-cause mortality was
determined 180 days after randomization.
The relative diuretic efficiency in each patient was determined as the fluid output per mg
of loop diuretic received (expressed as mL of net fluid output per 40 mg of furosemide
equivalents). Forty milligrams of furosemide equivalents was chosen as a reference since this is
a dose reported to produce near maximal rate of instantaneous natriuresis in a healthy volunteer
naive to diuretics.13 For the Penn cohort, where detailed information on diuretic administration
was available, diuretic efficiency was calculated using the cumulative in-hospital net fluid output
divided by the cumulative in-hospital amount of intravenous (IV) loop diuretic received
(Cumulative diuretic efficiency). For the ESCAPE cohort, only maximum loop diuretic dose
received in a 24 hour period was available, thus diuretic efficiency was calculated using the
average daily fluid output divided by the peak IV loop diuretic (Peak diuretic efficiency). Given
the desire to compare effect sizes across variables and between cohorts, the median values for
diuretic efficiency [Penn cohort median 480 (interquartile range 195-1024) mL net fluid
output/40 mg furosemide equivalents; ESCAPE cohort median 148 (interquartile range 61-283)
mL net fluid output/40 mg furosemide equivalents] was primarily employed. To allow direct
comparison between the cohorts, the primary analyses were repeated using Peak diuretic
efficiency in the Penn cohort calculated using the median from the ESCAPE cohort. Estimated
glomerular filtration rate (eGFR) was calculated using the four variable Modified Diet and Renal
Disease equation.14 Worsening renal function (WRF) was defined as a 20% decrease in eGFR
at any time during the hospitalization, unless otherwise specified.15-20 Loop diuretic doses were
converted to furosemide equivalents with 1 mg bumetanide = 20 mg torsemide = 80 mg
furosemide for oral diuretics, and 1 mg bumetanide = 20 mg torsemide = 40 mg furosemide for
) ) ) ) ) ) ) lololololololoopopopopopopop dididididididiururururururureteteteteteteticicicicicicic rrrrrrreeeeee
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intravenous diuretics.21, 22 The study was approved or determined to qualify as exempt from
Institutional Review Board review by the Hospital of the University of Pennsylvania and Yale
University Institutional Review Boards.
Statistical Analysis:
Values reported are mean ± SD, median (quartile 1 - quartile 4) and percentile. Independent
Student’s t test or the Wilcoxon Rank Sum test was used to compare continuous variables
between two groups of patients. The chi-square test was used to evaluate associations between
categorical variables. Correlation coefficients reported are Spearman’s rho and are reported as r2
values. The independent association between renal variables associated with diuretic efficiency
was determined using logistic regression. Proportional hazards modeling was used to evaluate
time-to-event associations with all-cause mortality. Candidate covariates entered in the model
were baseline characteristics with less than 10% missing values and a univariate association with
all-cause mortality at p 0.2. In the Penn cohort these variables consisted of age, race, diabetes,
ischemic heart failure etiology, presence of edema, digoxin use, outpatient loop diuretic dose,
thiazide diuretic use, heart rate, systolic blood pressure, B-type natriuretic peptide, serum
sodium, hemoglobin, eGFR, and blood urea nitrogen. In the ESCAPE cohort these variables
were age, hypertension, ischemic heart failure etiology, presence of edema, jugular venous
distension, baseline beta blocker use, baseline angiotensin converting enzyme or receptor blocker
use, pre-admission loop diuretic dose, thiazide diuretic use, systolic blood pressure, serum
sodium, eGFR, blood urea nitrogen and hemoglobin. In-hospital or discharge variables with a
theoretical basis for confounding were forced into subsequent models regardless of univariate
association with mortality. Models were built using backward elimination (likelihood ratio test)
where all covariates with a p<0.2 were retained.23 Survival curves were plotted for patients with
ociiatatatatatatatededededededed wwwwwwwititititititith h hhhhh dididididididiuuuuuuu
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the 4 combinations of diuretic efficiency above or below the median and diuretic dose above or
below the median for both cohorts. The x axis was terminated when the number at risk was
<10% and statistical significance was determined using the log rank test. Statistical analysis was
performed with IBM SPSS Statistics version 20.0 (IBM Corp., Armonk, NY) and statistical
significance was defined as 2-tailed p<0.05 for all analyses except for tests for interaction, where
p<0.1 was considered significant.
Results
Baseline characteristics of the two cohorts are presented in Table 1. There was a broad range of
diuretic efficiency represented in the cohorts (Figure 1). There was only a moderate correlation
between diuretic efficiency and the IV diuretic dose (Penn r2=0.12, ESCAPE r2= 0.21) or net
fluid output (Penn r2= 0.26, ESCAPE r2= 0.21, Supplementary Figure 2). The direct correlation
between diuretic dose and net fluid output was also moderate (Penn r2=0.27, ESCAPE r2= 0.14).
In line with the requirement for baseline high dose loop diuretic use for enrollment into the
ESCAPE trial, loop diuretic doses were generally higher and diuretic efficiency was lower in the
ESCAPE population (Table 1).
Baseline and in-hospital factors associated with low diuretic efficiency:
Characteristics of patients with diuretic efficiency above or below the median value (below the
median hence forth referred to as “low diuretic efficiency”) are reported in Table 1. As expected
from the nature of the dichotomization, the net urine output was significantly less and doses of
loop diuretics greater in patients with low diuretic efficiency (Table 2). However, patients with
low diuretic efficiency were not universally given high doses of loop diuretics (32.5% had
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diuretic doses below the median in the Penn cohort and 32.9% in the ESCAPE cohort). Both the
baseline and discharge loop diuretic doses were greater in patients with low in-hospital diuretic
efficiency (Table 1).
Non-diuretic baseline differences between patients with and without low diuretic
efficiency, including right heart catheterization variables and physical examination findings,
were small and generally not statistically significant across both cohorts (Table 1). The only
non-diuretic baseline characteristics associated with diuretic efficiency in both ESCAPE and
Penn cohorts were blood urea nitrogen and eGFR (Table 1). Interestingly, the correlation was
small between eGFR and diuretic dose (Penn r2=0.05, p<0.001; ESCAPE r2=0.0, p=0.76), net
fluid output (Penn r2=0.0, p=0.35; ESCAPE r2=0.03, p=0.002), and diuretic efficiency (Penn r2=
0.02, p<0.001; ESCAPE r2=0.04, p<0.001) (Figure 2). In a multivariable model incorporating
both eGFR and baseline BUN, only BUN remained significantly associated with low diuretic
efficiency (Penn cohort OR=1.14 per 10 increase in BUN, p=0.009; ESCAPE cohort OR=1.19
per 10 increase in BUN, p=0.005). In ESCAPE there was no difference in diuretic efficiency
based on randomization to a pulmonary artery catheter (PAC) guided treatment strategy (p=0.72)
or treatment with a pulmonary artery catheter (p=0.19). However, amongst patients randomized
to care guided by clinical assessment alone, there was a higher rate of crossover to PAC use in
patients with low diuretic efficiency (OR=3.5, p=0.014). The use of dobutamine and length of
stay was greater with low diuretic efficiency in the ESCAPE cohort but not the Penn cohort
(Table 2). Similar findings were noted in the Penn cohort when using the Peak diuretic
efficiency definition from the ESCAE cohort (Supplementary Tables 1 and 2).
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Diuretic strategy, relief of congestion, and worsening renal function:
Overall, the in-hospital treatment approach/outcomes for patients with or without low diuretic
efficiency appeared to differ somewhat between cohorts. In both cohorts, low diuretic efficiency
resulted in escalation of diuretic strategies such as higher doses of loop diuretics, greater use of
adjuvant thiazide diuretics, and initiation of a loop diuretic infusion (diuretic infusion usage
available only in the Penn cohort). In patients with low diuretic efficiency the maximum 24 hour
loop diuretic dose was 4.0 times the baseline dose in the Penn cohort whereas in the ESCAPE
cohort there was a 2.6 fold increase in maximum furosemide equivalents over the pre-admission
dose. In ESCAPE, low diuretic efficiency was associated with what appeared to be less
complete decongestion. This was evidenced by higher right atrial and pulmonary capillary
wedge pressure and discharge physical examination findings consistent with continued volume
overload compared to patients with preserved diuretic efficiency (Table 2). Interestingly, despite
discharge with persistent congestion, the rate of deterioration in renal function was no different
between patients with or without low diuretic efficiency (Table 2). In the Penn cohort,
significant differences in the degree of decongestion were not apparent as discharge physical
examination findings were not different between groups (Table 2). However, the rate of
worsening renal function was substantially greater in the low diuretic efficiency group (Table 2).
Overall the above findings were also noted in the Penn cohort when using the Peak diuretic
efficiency definition from the ESCAPE cohort (Supplementary Tables 1 and 2).
Diuretic efficiency and prognosis:
In the Penn cohort, a total of 346 patients (52.7%) died over a median follow up of 3.2 years
(1.2-5.2 years) and in the ESCAPE cohort, a total of 75 patients (19.2%) died over a median
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follow up of 179 days (129-180). Consistent with prior literature, a loop diuretic dose above the
median was associated with significantly reduced survival in both Penn and ESCAPE cohorts
(Table 3 and Supplementary Table 3). However, net fluid output below the median was not
associated with survival in either cohort (Table 3). The same lack of association was found for
the continuous net fluid output variables, even after accounting for length of stay (p 0.18 for
both cohorts). Despite the lack of mortality information related to net fluid output, low diuretic
efficiency was associated with substantially worsened survival (Table 3). In line with the limited
correlation between net fluid output, IV loop diuretic dose, and diuretic efficiency, this mortality
disadvantage with low diuretic efficiency appeared to be relatively independent from the
absolute dose of diuretic or amount of fluid lost (Table 3). After adjustment for baseline
characteristics, only diuretic efficiency remained significantly associated with mortality in both
cohorts (Table 3). These findings were also noted in the Penn cohort when using the Peak
diuretic efficiency definition from the ESCAPE cohort (Table 3). There was a trend toward a
stronger association between low diuretic resistance and mortality in patients with reduced
compared to preserved ejection fraction, however this did not reach statistical significance
(Supplementary Table 4). The unadjusted risk for mortality in patients with low diuretic
efficiency receiving doses of loop diuretics above or below the median is depicted in Figure 3A
and 3B. The risk of death associated with low diuretic efficiency was also present in patients
who did not receive high doses of IV loop diuretic (dose below the median) in both Penn
(adjusted for baseline characteristics HR=1.85 95% CI 1.28-2.27, p=0.001, p interaction=0.053,
Figure 3A) and ESCAPE cohorts (adjusted for baseline characteristics HR=4.08, 95% CI 1.70-
9.82, p=0.002, p interaction=0.53, Figure 3B). In both cohorts, patients that received low doses
of loop diuretic and had preserved diuretic efficiency had substantially better survival than the
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remainder of the groups (Figure 3). After extensive adjustment for baseline characteristics in
addition to in-hospital and discharge related variables (length of stay, use of milrinone,
dobutamine, adjuvant thiazide use, worsening renal function, hemoconcentration, discharge
physical examination findings and discharge medications) the association between diuretic
efficiency and mortality remained in both the Penn cohort (HR=1.46, 95% CI 1.15-1.86,
p=0.002) and the ESCAPE cohort (HR 3.57, 95% CI 1.46-8.73, p=0.005)
Discussion
In the current analysis we found that in the setting of ADHF the efficiency with which loop
diuretics induce diuresis is strongly and independently associated with survival. Notably,
diuretic efficiency was only modestly correlated with diuretic dose and net urine output, but
provided distinct prognostic information to either parameter. Furthermore, despite the strong
association between diuretic efficiency and mortality, baseline disease severity indicators such as
right heart catheterization variables, vital signs, and physical examination findings were
remarkably similar between groups. Although the simple metric of diuretic efficiency presented
in this analysis is not without shortcomings, it does provide an easily calculated metric that
strongly associates with mortality and may have advantage over diuretic dose or fluid output in
describing diuretic resistance.
The previously reported association between high doses of loop diuretics and mortality,
in conjunction with known direct adverse cardio-renal effects of loop diuretics, raised the
possibility that high dose diuretics were directly causing adverse outcomes.24-26 However, a
confounding factor is that sicker patients generally receive higher doses of diuretics. Supporting
efficicicicicicicienenenenenenencycycycycycycy wwwwwwwititititititithh hhhhh w
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this notion, previous studies have reported that a wide range of disease severity indicators are
generally worse in patients receiving high doses of diuretics.4, 6, 7, 27, 28 Furthermore, after
extensive multivariable adjustment or propensity matching, several investigators found no
association or even a survival advantage associated with the use of high doses of loop diuretics.6-
9 Although not formally testing high vs. low absolute doses, the Diuretic Optimization Strategies
Evaluation (DOSE) trial randomized patients to high vs. low intensification of their home
diuretics (although the low intensification group still received >120 mg/day of IV furosemide)
and found no difference in outcomes between groups.29 Moreover, in the recent Cardiorenal
Rescue Study in Acute Decompensated Heart Failure (CARRESS-HF) trial, patients treated with
aggressive dosing of diuretics had similar outcomes to those treated primarily with
ultrafiltration.30 In the current analysis we found that: 1) diuretic dose did not retain independent
prognostic information in fully adjusted multivariable models incorporating both loop diuretic
dose and diuretic efficiency and 2) low diuretic efficiency had an equal, if not worse, prognosis
in patients receiving lower doses of loop diuretics. These data add to a growing literature
arguing that the bulk of the association between in-hospital high dose loop diuretics and
mortality is unlikely to be cause and effect.
Although the long term mortality associated with diuretic efficiency was consistent
across cohorts, the short-term renal and decongestive outcomes were not. In the Penn cohort,
there was a strong signal for worsening in renal function in patients with low diuretic efficiency,
but a limited signal for differences in the degree of decongestion achieved as suggested by
similar discharge physical examination findings. In ESCAPE, the reciprocal was found with no
differences in renal outcomes but substantial persistent volume overload by right heart
catheterization variables and multiple physical examination findings. Interestingly, the relative
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augmentation in diuretic dose over the baseline dose was larger in the Penn cohort (4 fold) than
the ESCAPE cohort (2.6 fold). A common clinical dilemma when diuresing a diuretic resistant
patient is that additional decongestion often comes at the expense of deterioration in renal
function. Notably, the ESCAPE trial protocol specifically called for therapy to be adjusted to
achieve stable or improving renal function by discharge. Although interesting observations, the
clinical profile of patients enrolled in ESCAPE was substantially different from Penn and the
fidelity of the available data is not sufficient to allow speculation that differences in treatment
decisions caused the discordant renal and decongestive outcomes between cohorts. However, the
discordant findings between the Penn and ESCAPE cohorts, with respect to degree of discharge
congestion, does indicate that low diuretic efficiency may not always translate into an inevitable
inability to decongest a patient.
It is widely known that renal function is an important determinate of diuretic
responsiveness. Thus, it was somewhat surprising that a strong relationship between eGFR and
diuretic dose, net fluid output, or diuretic efficiency was not identified. However, multiple facets
of renal physiology contribute to diuretic resistance, only one of which is captured by GFR. In
the setting of a severely depressed GFR, it has been well described that diuretic responsiveness is
impaired.13 However, this relationship is primarily pharmacokinetic and the result of reduced
tubular drug delivery rather than true resistance since the relationship between tubular diuretic
concentrations and natriuresis is unchanged in chronic kidney disease.13, 31 Primarily a result of
the fact that loop diuretics are avidly bound to albumin, glomerular filtration is actually a minor
pathway in which loop diuretics are delivered to their tubular sight of action.13 Rather, active
secretion by the proximal tubular cells, a process which is dependent on renal blood flow, is
primarily responsible for diuretic delivery to the site of action. However, in the setting of heart
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failure the normal relationship between GFR and renal blood flow can be uncoupled by a
substantial increase in filtration fraction, weakening the pharmacokinetic relationship between
GFR and drug delivery in heart failure. Perhaps more importantly, it is thought that the primary
source of variability in response to a loop diuretic in patients with heart failure is actually
pharmacodynamics.31 Notably, multiple processes which are distinct from GFR or drug delivery
such as diuretic breaking, distal tubular structural remodeling, and renal neurohormonal
activation can all cause increased tubular sodium reabsorption even in the setting of normal
diuretic delivery.13 Although diuretic efficiency appeared to correlate slightly better than
diuretic dose or net fluid output, the relationship remained weak. Notably, a very low eGFR did
not exclude the possibility of preserved diuretic efficiency nor did a normal eGFR exclude the
possibility of poor diuretic efficiency. Although there are clearly substantial limitations in the
assessment of renal function estimated with creatinine based metrics in the setting of acute heart
failure, but these results provide further support that renal function is not the dominant factor
driving diuretic efficiency in heart failure. Rather, it is the complex interplay between cardiac
function, renal function, and volume status that ultimately determines diuretic responsiveness.
Limitations:
Given the post hoc nature of this study, the limitations of retrospective analyses apply, residual
confounding cannot be excluded, and causality is impossible to determine. Although the
definition of diuretic efficiency used in the current analyses provides substantially more
physiologic information than use of diuretic dose or net fluid output alone, it is not a perfect
measure of diuretic resistance. The sigmoidal shape of the dose response relationship of loop
diuretics with both threshold and plateau natriuretic portion limits any linear parameter of
diuretic resistance unless it is assured that all patients are on the same portion of the dose
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response curve. Given that only 33 patients in the Penn cohort and 17 patients in the ESCAPE
cohort received peak loop diuretic doses less than 40 mg (a dose which produces maximal
instantaneous natriuresis in a healthy volunteer) suggests that, in the majority of patients, only
through reduced diuretic efficiency was the renal threshold not met. However, patients that
received diuretic doses that put them on the plateau portion of the dose response curve likely had
an underestimation of their diuretic efficiency. Additionally, patients that received an adjuvant
thiazide diuretic likely had a significant alteration in their loop diuretic efficiency. However,
these changes in loop diuretic efficiency induced by non-loop diuretics is not accounted for in
these analyses potentially biasing the results. Furthermore, diuretic resistance is really only
relevant in patients with volume overload and the fidelity with which volume overload can be
defined on a population level is limited. As such, it is probable that some patients may have had
low diuretic efficiency in response to a dose of diuretic which was in fact appropriate given that
they were not volume overloaded (i.e., a patient admitted primarily due to fluid redistribution
rather than total body overload). However, the majority of these limitations would be expected
to influence associations with loop diuretic dose or raw fluid output as a metric of diuretic
resistance more so than diuretic efficiency. The use of creatinine based metrics for assessment of
renal function in the likely non-steady state scenario of acute decompensated heart failure is a
significant limitation and thus descriptions of static and dynamic associations with renal function
should be considered hypothesis generating. Although validating the diuretic resistance concept
in the multicenter ESCAPE population adds value, the ESCAPE trial was not designed to study
diuretic efficiency, the trial required high doses of baseline loop diuretic for inclusion, and
cumulative loop diuretic exposure was not collected requiring the use of 24 hour peak diuretic
dose to estimate diuretic efficiency. Furthermore, both the ESCAPE and Penn cohorts employed
etic resistance isisisiisii
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relatively selective inclusion criteria. As a result, the reported observations may not apply to less
selected populations and thus are in need of validation. Additionally, patients with a length of
stay of one or two days were excluded from the Penn cohort. This is potentially an important
source of bias as these patients may have responded particularly briskly to diuretics permitting
early discharge. These factors significantly limit the certainty of generalizability of our findings
and as a result the observations reported in this manuscript should be interpreted as hypothesis
generating and require validation in unselected cohorts.
Conclusion:
Low diuretic efficiency during decongestive therapy portends poorer long-term outcomes above
and beyond traditional prognostic factors in patients hospitalized with decompensated heart
failure. In light of the central role for loop diuretics in the management of volume overload in
HF, additional research is required to validate these findings in less selected populations, to
develop more precise metrics of diuretic efficiency, and to determine if therapeutic strategies
which improve diuretic efficiency can positively impact outcomes.
Acknowledgements
This manuscript was prepared using ESCAPE research materials obtained from the NHLBI
Biologic Specimen and Data Repository Information Coordinating Center and does not
necessarily reflect the opinions or views of the ESCAPE study investigators or the NHLBI.
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Sources of Funding
NIH Grants, 1K23HL114868, L30HL115790 (JT) and K24DK090203 (CP): The funding source
had no role in study design, data collection, analysis or interpretation.
Disclosures
None.
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d d d d d dd ouououououououtctctctctctctcomomomomomomomeseseseseseses ooooooof f f f f f f ppppppple, dddddddesesesesesesesigigigigigigignnnnn,nn aaaaaaandndndndndndnd ppppppp
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25. Francis GS, Siegel RM, Goldsmith SR, Olivari MT, Levine TB, Cohn JN. Acute vasoconstrictor response to intravenous furosemide in patients with chronic congestive heart failure. Activation of the neurohumoral axis. Ann. Intern. Med. 1985;103:1-6.
26. McCurley JM, Hanlon SU, Wei SK, Wedam EF, Michalski M, Haigney MC. Furosemide and the progression of left ventricular dysfunction in experimental heart failure. J. Am. Coll. Cardiol. 2004;44:1301-1307.
27. Peacock WF, Costanzo MR, De Marco T, Lopatin M, Wynne J, Mills RM, Emerman CL, Committee ASA, Investigators. Impact of intravenous loop diuretics on outcomes of patients hospitalized with acute decompensated heart failure: Insights from the adhere registry. Cardiology. 2009;113:12-19.
28. Hasselblad V, Gattis Stough W, Shah MR, Lokhnygina Y, O'Connor CM, Califf RM, Adams KF, Jr. Relation between dose of loop diuretics and outcomes in a heart failure population: Results of the escape trial. European journal of heart failure : journal of the Working Group on Heart Failure of the European Society of Cardiology. 2007;9:1064-1069.
29. Felker GM, Lee KL, Bull DA, Redfield MM, Stevenson LW, Goldsmith SR, LeWinter MM, Deswal A, Rouleau JL, Ofili EO, Anstrom KJ, Hernandez AF, McNulty SE, Velazquez EJ, Kfoury AG, Chen HH, Givertz MM, Semigran MJ, Bart BA, Mascette AM, Braunwald E, O'Connor CM. Diuretic strategies in patients with acute decompensated heart failure. N. Engl. J. Med. 2011;364:797-805.
30. Bart BA, Goldsmith SR, Lee KL, Givertz MM, O'Connor CM, Bull DA, Redfield MM, Deswal A, Rouleau JL, LeWinter MM, Ofili EO, Stevenson LW, Semigran MJ, Felker GM, Chen HH, Hernandez AF, Anstrom KJ, McNulty SE, Velazquez EJ, Ibarra JC, Mascette AM, Braunwald E. Ultrafiltration in decompensated heart failure with cardiorenal syndrome. N. Engl. J. Med. 2012;367:2296-2304.
31. Brater DC, Seiwell R, Anderson S, Burdette A, Dehmer GJ, Chennavasin P. Absorption and disposition of furosemide in congestive heart failure. Kidney Int. 1982;22:171-176.
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Table 1. Patient characteristics of the Penn and ESCAPE cohorts grouped by diuretic efficiency
Penn Cohort ESCAPE Cohort Diuretic Efficiency Diuretic Efficiency
Characteristic Low (n=329) High (n=328) p-value Low
(n=195) High
(n=195) p-
value Demographics
Age (y) 64.3 ± 15.0 61.3 ± 15.8 0.014* 56.8 ± 14.6 55.2 ± 13.0 0.26 Black race 65% 64% 0.78 36% 46% 0.040* Male 51% 62% 0.008* 77% 73% 0.29
Medical History Hypertension 75% 71% 0.16 48% 45% 0.54 Diabetes 49% 36% 0.002* 34% 34% 0.94 Ischemic etiology 26% 26% 0.91 54% 47% 0.16 Ejection fraction
40% 36% 31% 0.19 0% 0% N/A Admission Physical Exam
Heart rate (beats/min) 88.6 ± 20.6 90.2 ± 19.4 0.31 81.5 ± 14.9 82.4 ± 15.0 0.54 Systolic blood pressure (mmHg) 135 ± 34 136 ± 33 0.82 104 ± 17 108 ± 16 0.005* Jugular venous distention ( 12 cm water) 61% 61% 0.87 53% 53% 0.96 Edema > 1+ 47% 46% 0.79 38% 34% 0.36 Hepatojugular reflux 21% 24% 0.36 78% 82% 0.24
Cardiac Function Ejection fraction (%) 30 (15-45) 23 (15-42) 0.028* 20 (15-21) 20 (15-25) 0.088
Laboratory Values Serum sodium (mEq/L) 138 ± 5 139 ± 4 0.028* 136 ± 5 137 ± 4 0.15 B-type natriuretic peptide (pg/mL)
1454 (748-2771)
1285 (692-2312) 0.049*
593 (264-1285)
557 (209-1142) 0.421
eGFR (mL/min/1.73m2) 55.4 ± 29.3 61.9 ± 26.2 0.003* 55.6 ± 27.4 59.1 ± 23.4 0.028* BUN (mg/dL) 33.7 ± 24.2 26.8 ± 20.5 <0.001* 38.6 ± 25.4 31.6 ± 18.9 0.002* Hemoglobin (g/dL) 11.8 ± 2.1 12.4 ± 2.1 <0.001* 12.9 ± 5.3 12.5 ± 1.8 0.41
Right Heart Catheterization Variables † Right atrial pressure (mmHg) 13.4 ± 7.8 10.2 ± 5.8 0.010* 14.1 ± 9.0 13.6 ± 10.4 0.69 Pulmonary capillary wedge pressure (mmHg) 23.8 ± 8.5 23.5 ± 8.3 0.85 26.0 ± 9.4 23.8 ± 8.8 0.19 Cardiac index (L/min/m2) 2.1 ± 0.7 2.1 ± 0.6 0.95 2.0 ± 0.6 2.0 ± 0.6 0.54
Systemic vascular resistance (dyn·s/cm5) 1538 ± 582 1622 ± 618 0.43 1428 ± 753 1474 ± 897 0.71
%
0%0%0%0%0%0%0%
min) 88.6 ± 20.6 90.2 ± 19.4 0.31 81.5 ± 14.9 2
) 135 ± 34 136 ± 33 0.82 104 ± 17
c
47% 46% 0 79 38%
mimimimimin)n)n)n)n) 8888.66 666 ± 20.6 90.2 ± 19.444 0.311111 81.5 ± 14.9 82
) 133355 ±± 334 11333633 ±±± 33 0.822 11111000400 ±± 111117
cm 6661%1%1% 6661%1%1% 000.878787 535353%%%4747474747%%%%% 46464646%%%% 00000 797979799 333338%8%8%8%8%
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Medications (Admission) Beta blocker 69% 74% 0.18 63% 60% 0.51 ACE inhibitor or ARB 60% 68% 0.025* 90% 90% 0.87 Digoxin 24% 28% 0.25 73% 71% 0.65 Aldosterone antagonist 17% 18% 0.68 33% 34% 0.91 Loop diuretic dose (mg) 80 (20-160) 40 (0-80) <0.001*
220 (140-320) 160 (80-320) 0.003*
Thiazide diuretic 15% 10% 0.046* 13% 13% 0.98 Medications (Discharge)
Beta blocker 82% 87% 0.055 52% 60% 0.15 ACE inhibitor or ARB 70% 87% <0.001* 83% 88% 0.14 Digoxin 25% 26% 0.77 72% 80% 0.097 Aldosterone antagonist 23% 23% 0.90 49% 54% 0.27 Loop diuretic dose (mg) 80 (40-160) 80 (40-100) <0.001* 120 (60-240) 100 (60-160) 0.035*
Thiazide diuretic 15% 5% <0.001* 14% 10% 0.27
eGFR: Estimated glomerular filtration rate, BUN: Blood urea nitrogen, ACE: Angiotensin converting
enzyme inhibitor, ARB: Angiotensin receptor blocker. Diuretic efficiency was calculated as the
cumulative mL of net fluid output divided by the cumulative loop diuretic dose (per 40 mg of furosemide
equivalent) during the hospitalization in the Penn cohort. In the ESCAPE cohort where cumulative
diuretic dose was unavailable, diuretic efficiency was estimated using the peak dose of loop diuretic
administered in 24 hours (per 40 mg furosemide equivalents). Diuretic efficiency was then dichotomized
about the median to define high vs. low diuretic efficiency. * Significant p value. † Data available in
n=139 patients in the Penn cohort and in n=192 patients in the ESCAPE cohort.
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Table 2. In hospital variables of the Penn and ESCAPE cohorts grouped by diuretic efficiency
Penn Cohort ESCAPE Cohort Diuretic Efficiency Diuretic Efficiency
Characteristic Low (n=329) High (n=328) p-value Low (n=195) High (n=195) p-value Diuresis Related Variables
Cumulative IV loop diuretic dose (mg) 460 (200-950) 200 (80-340) <0.001* -- -- -- Average daily IV loop dose (mg/day) 80 (40-138) 35 (18-63) <0.001* -- -- -- Peak IV loop diuretic dose in 24 hours (mg) 160 (80-260) 80 (40-124) <0.001*
320 (180-480) 160 (80-280) <0.001*
Continuous diuretic infusion 8% 2% 0.001* -- -- -- Adjuvant thiazide diuretic 22% 9% <0.001* 34% 25% 0.034* Time receiving IV diuretic (% of hospitalization) 69.6 ± 23.1 61.0 ± 25.7 <0.001* -- -- -- Net fluid loss (L) 2.7 (-0.04-5.9) 5.7 (3.2-9.0) <0.001* 3.6 (1.0-6.9) 5.6 (3.1-10.4) <0.001* Fluid intake (L) 7.2 (4.7-11.8) 6.6 (4.2-10.0) 0.090 -- -- -- Fluid output (L) 10.0 (5.9-16.2) 12.5 (7.8-20.2) <0.001* -- -- -- Average net daily fluid loss (L) 0.5 (-0.1-0.9) 1.0 (0.7-1.5) <0.001* 0.5 (0.2-0.9) 1.4 (0.9-1.9) <0.001* Diuretic efficiency (mL fluid output/40 mg furosemide equivalents) 198 (-8.9-347)
1024 (698-1760) N/A -- -- --
Estimated peak dose diuretic efficiency (mL fluid output/40 mg furosemide equivalents) 92.3 (-3.4-174)
148456 (296-724) <0.001* 60 (22-104) 281 (194-552) <0.001*
In-hospital inotropes Milrinone 14% 16% 0.69 20% 14% 0.13 Dobutamine 2% 1% 0.47 36% 21% 0.001*
In-Hospital Maximum Change in Laboratory Variables eGFR (%) -18.8 ± 15.8 -13.0 ± 13.3 <0.001* -- -- -- Worsening renal function 42% 28% <0.001* -- -- -- Blood urea nitrogen (%) 49.4 ± 55.6 33.5 ± 44.0 <0.001* -- -- -- Bicarbonate (%) 20.7 ± 17.2 23.2 ± 51.3 0.86 -- -- --
Admission to Discharge Change in Laboratory Variables eGFR (%) -1.7 ± 26.6 4.9 ± 25.2 <0.001* 0.2 ± 33.2 0.1 ± 25.8 0.97 Worsening renal function 22% 11% <0.001* 24% 20% 0.29 Blood urea nitrogen (%) 29.9 ± 54.5 15.9 ± 48.1 <0.001* 22.3 ± 61.4 23.0 ± 55.3 0.91 Bicarbonate (%) 11.1 ± 17.7 14.1 ± 52.7 0.95 -- -- -- Sodium (%) -0.6 ± 3.3 -1.1 ± 4.8 0.43 -1.1 ± 3.2 -1.0 ± 2.8 0.69
Hospital Course . Length of stay (days) 6 (4-9) 5 (4-8) 0.099 9 (6-14) 6 (4-8) <0.001*
Discharge Physical Examination Jugular venous distention ( 8 cm H2O) 19% 21% 0.563 39% 29% 0.035*
001 3.6 (1.0 666.090909090909090 0 00000 -------- 001**** -------------
fluid loss
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Edema > 1+ 17% 15% 0.38 7% 2% 0.032* Hepatojugular reflux 4% 4% 0.97 22% 16% 0.11 Rales -- -- -- 14% 4% <0.001* Ascites -- -- -- 6% 2% 0.034*
Right Heart Catheterization Variables at Removal † Right atrial pressure (mmHg) -- -- -- 11.5 ± 8.5 7.4 ± 4.1 <0.001* Pulmonary capillary wedge pressure (mmHg) -- -- -- 18.7 ± 7.6 15.5 ± 7.0 0.027*
Cardiac index (L/min/m2) -- -- -- 2.3 ± 0.7 2.4 ± 0.6 0.52
Systemic vascular resistance (dyn·s/cm5) -- -- -- 1081 ± 489 1135 ± 446 0.48
eGFR: Estimated glomerular filtration rate. * Significant p value. † Data available in n=166.
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Table 3. Risk of death associated with loop diuretic dose, net fluid output, and diuretic efficiency in
the Penn and ESCAPE cohorts
Univariable Multivariable Multivariable with
Adjustment for Baseline Characteristics
HR (95% CI) p Value HR (95% CI) P Value HR (95% CI) P Value
Penn Cohort (Cumulative
diuretic efficiency)
Loop diuretic† 1.56 (1.26-1.93) <0.001* 1.36 (1.05-1.76) 0.021* 1.24 (0.94-1.64) 0.13 Net fluid output† 1.01 (0.82-1.25) 0.93 1.04 (0.80-1.34) 0.78 0.96 (0.74-1.26) 0.78 Diuretic efficiency† 1.64 (1.32-2.03) <0.001* 1.51 (1.17-1.95) 0.002* 1.36 (1.04-1.78) 0.023*
Penn Cohort (Peak diuretic
efficiency)
Loop diuretic† 1.56 (1.26-1.93) <0.001* 1.41 (1.11-1.79) 0.005* 1.25 (0.97-1.62) 0.073 Net fluid output† 1.01 (0.82-1.25) 0.93 1.08 (0.84-1.39) 0.54 0.96 (0.74-1.25) 0.78 Diuretic efficiency† 1.70 (1.38-2.11) <0.001* 1.67 (1.31-2.18) <0.001* 1.39 (1.08-1.77) 0.007*
ESCAPE Cohort (Peak diuretic
efficiency)
Loop diuretic† 2.46 (1.54-3.94) <0.001* 1.68 (0.98-2.88) 0.059 1.32 (0.72-2.40) 0.37 Net fluid output† 0.96 (0.61-1.51) 0.86 0.91 (0.54-1.51) 0.71 1.17 (0.66-2.09) 0.59
Diuretic efficiency† 3.98 (2.32-6.84) <0.001* 3.47 (1.97-6.24) <0.001* 2.86 (1.53-5.36) 0.001*
HR: Hazard ratio, CI: Confidence interval. †To facilitate comparison of effect sizes, hazard ratios
represent the risk for all-cause mortality associated with a value above or below the median with the HR
reflecting an exposure of diuretic dose above the median, efficiency below the median or fluid output
below the median. In the Penn cohort, variables entered in the multivariable model consisted of: age, race,
diabetes, ischemic heart failure etiology, presence of edema, digoxin use, outpatient loop diuretic dose,
thiazide diuretic use, heart rate, B-type natriuretic peptide, systolic blood pressure, serum sodium,
hemoglobin, eGFR, and blood urea nitrogen. In the ESCAPE cohort these variables were: age,
hypertension, ischemic heart failure etiology, presence of edema, jugular venous distension, baseline beta
blocker use, baseline angiotensin converting enzyme or receptor blocker use, outpatient loop diuretic
dose, thiazide diuretic use, systolic blood pressure, serum sodium, eGFR, blood urea nitrogen and
hemoglobin.
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Figure Legends
Figure 1. Distribution of diuretic efficiency in the Penn and ESCAPE cohorts
Figure 2. Scatterplots of eGFR and net fluid output, diuretic dose (Panel A) and diuretic
efficiency (Panel B) in the Penn Cohort (top panels) and ESCAPE cohort (bottom panels)
eGFR: Estimated glomerular filtration rate. Diuretic efficiency expressed as mL of net fluid
output per 40 mg of furosemide equivalent.
Figure 3. Kaplan-Meier survival curves grouped by diuretic efficiency and diuretic dose in
the Penn cohort (Panel A) and ESCAPE cohort (Panel B)
Loop diuretic dose and diuretic efficiency were dichotomized into high and low by the median
value in each cohort. “Low loop dose” was also defined as a loop diuretic dose above or below
the median value which was 280 mg (120-600) in the Penn cohort and 240 mg in 24 hours (120-
400) in the ESCAPE cohort.
M d
anel A) and ESCAPE cohort (Panel B)
Meier survival cuuuurvrvrvvveseseseses gggggrorororooupupuupedd bbbbby y y y y diddid uruurururetetetetticicicicic efficiency and d
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Chirag R. Parikh and W. H. Wilson TangJeffrey M. Testani, Meredith A. Brisco, Jeffrey M. Turner, Erica S. Spatz, Lavanya Bellumkonda,
Acute Decompensated Heart FailureLoop Diuretic Efficiency: A Metric of Diuretic Responsiveness with Prognostic Importance in
Print ISSN: 1941-3289. Online ISSN: 1941-3297 Copyright © 2013 American Heart Association, Inc. All rights reserved.
is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231Circulation: Heart Failure published online December 30, 2013;Circ Heart Fail.
http://circheartfailure.ahajournals.org/content/early/2013/12/30/CIRCHEARTFAILURE.113.000895World Wide Web at:
The online version of this article, along with updated information and services, is located on the
http://circheartfailure.ahajournals.org/content/suppl/2013/12/30/CIRCHEARTFAILURE.113.000895.DC1Data Supplement (unedited) at:
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SUPPLEMENTAL MATERIAL:
Tables:
Supplementary Table 1: Patient characteristics of the Penn cohort grouped by Peak diuretic efficiency:
Diuretic Efficiency
Characteristic Low (n=329) High (n=328) p-value
Demographics
Age (y) 65.8 ± 15.3 61.1 ± 15.3 <0.001*
Black race 66.5% 63.8% 0.484
Male 47.3% 61.9% <0.001*
Medical History
Hypertension 74.7% 72.0% 0.444
Diabetes 49.6% 38.2% 0.004*
Ischemic etiology 22.9% 27.4% 0.195
Ejection fraction ≥40% 34.0% 32.5% 0.692
Admission Physical Exam
Heart rate (beats/min) 90.0 ± 20.3 89.1 ± 19.8 0.555
Systolic blood pressure (mmHg) 135.1 ± 36.1 135.8 ± 31.9 0.775
Jugular venous distention (≥ 12 cm water) 59.7% 61.6% 0.697
Edema > 1+ 45.4% 47.2% 0.665
Hepatojugular reflux 22.5% 22.4% 0.989
Cardiac Function
Ejection fraction (%) 28 (15, 45) 25 (15, 45) 0.307
Laboratory Values
Serum sodium (mEq/L) 137.8 ± 5.2 138.7 ± 4.3 0.018*
B-type natriuretic peptide (pg/mL) 1529 (821, 2785) 1291 (659, 2348) 0.007*
eGFR (mL/min/1.73m2) 53.3 ± 29.2 61.8 ± 26.7 <0.001*
BUN (mg/dL) 34.3 ± 24.2 27.9 ± 21.4 0.001*
Hemoglobin (g/dL) 11.8 ± 2.0 12.3 ± 2.1 0.010*
Right atrial pressure (mmHg) 11.9 ± 7.1 11.2 ± 6.7 0.573
Pulmonary capillary wedge pressure (mmHg) 23.1 ± 8.2 23.9 ± 8.4 0.583
Cardiac index (L/min/m2) 2.1 ± 0.8 2.0 ± 0.5 0.387
Systemic vascular resistance (dyn·s/cm5) 19.0 ± 7.9 20.4 ± 7.3 0.292
Medications (Admission)
Beta blocker 67.3% 73.8% 0.077
ACE inhibitor or ARB 55.9% 68.4% 0.001*
Digoxin 22.0% 28.0% 0.092
Aldosterone antagonist 12.2% 20.0% 0.011*
Loop diuretic dose (mg) 80 (0, 160) 40 (20, 80) 0.033*
Thiazide diuretic 16.7% 10.2% 0.015*
Medications (Discharge)
Beta blocker 67.3% 73.8% 0.077
ACE inhibitor or ARB 67.7% 85.0% <0.001*
Digoxin 22.5% 26.9% 0.212
Aldosterone antagonist 15.7% 27.4% 0.001*
Loop diuretic dose (mg) 80 (40, 160) 80 (40, 160) 0.133
Thiazide diuretic 14.8% 7.1% 0.002*
eGFR: Estimated glomerular filtration rate, BUN: Blood urea nitrogen, ACE: Angiotensin converting enzyme
inhibitor, ARB: Angiotensin receptor blocker. Diuretic efficiency was calculated as the average daily net fluid loss
divided by the peak dose of loop diuretic administered in 24 hours (per 40 mg furosemide equivalents). Diuretic
efficiency was then dichotomized about the median value in the ESCAPE trial (148 ml/40 mg) to allow direct
comparison between cohorts.* Significant p value.
Supplementary Table 2: In hospital parameters of the Penn cohort grouped by Peak diuretic efficiency using
the cut point from the ESCAPE trial:
Diuretic Efficiency
Characteristic Low (n=329) High (n=328) p-value
Diuresis Related Parameters
Cumulative IV loop diuretic dose (mg) 380 (160, 830) 240 (120, 495) <0.001*
Average daily IV loop dose (mg/day) 60 (28, 114) 50 (24, 87) 0.008*
Peak IV loop diuretic dose in 24 hours (mg) 160 (80, 260) 80 (80, 160) <0.001*
Continuous diuretic infusion 9.4% 2.4% <0.001*
Adjuvant thiazide diuretic 20.1% 12.7% 0.011*
Time receiving IV diuretic (% of hospitalization) 64.9 ± 24.9 65.3 ± 24.9 0.867
Net fluid loss (L) -1.2 (-5.1, 0.5) -5.5 (-9.4, -3.1) <0.001*
Fluid intake (L) 7.9 (5.1, 13.2) 6.3 (4.1, 9.9) <0.001*
Fluid output (L) 9.7 (5.3, 16.0) 12.1 (7.5, 19.6) <0.001*
Average net daily fluid loss (L) 0.2 (0.1, 0.6) 1.0 (0.7, 1.5) <0.001*
Diuretic efficiency (mL fluid output/40mg
furosemide equivalents)
122.6 (-79.3,
255.0)
832.8 (483.1,
1497.3) <0.001*
Estimated peak dose diuretic efficiency (mL fluid
output/40 mg furosemide equivalents) 56.4 (-34.6, 110.1) 382.8 (251.1, 638.8) <0.001*
In-hospital inotropes
Milrinone 19.5% 12.3% 0.014*
Dobutamine 3.0% 0.2% 0.003*
In-Hospital Maximum Change in Laboratory Parameters
eGFR (%) 19.1 ± 16.2 14.0 ± 13.7 <0.001*
Worsening renal function 41.4% 31.1% 0.007*
Blood urea nitrogen (%) -51.8 ± 57.6 -35.3 ± 45.1 <0.001*
Bicarbonate (%) -21.0 ± 17.7 -22.6 ± 46.4 0.606
Admission to Discharge in Laboratory Parameters
eGFR (%) -0.8 ± 29.1 -2.0 ± 24.2 0.560
Worsening renal function 20.9% 13.9% 0.019*
Blood urea nitrogen (%) -30.3 ± 56.7 -18.6 ± 48.3 0.007*
Bicarbonate (%) -10.5 ± 18.2 -13.8 ± 47.5 0.299
Sodium (%) 0.9 ± 5.6 0.8 ± 3.0 0.764
Hospital Course
Length of stay (days) 7 (4, 11) 5 (4, 8) <0.001*
Discharge Physical Examination
Jugular venous distention (≥ 8 cm H2O) 19.8% 20.1% 0.942
Edema > 1+ 18.1% 15.1% 0.318
Hepatojugular reflux 3.8% 3.5% 0.898
eGFR: Estimated glomerular filtration rate. * Significant p value.
Supplementary Table 3: Univariate and multivariate associations with mortality in the Penn and ESCAPE
cohorts
Penn Cohort
Univariate HR (95% CI) P Value Final model HR (95% CI) P Value
Loop diuretic 1.6 (1.3-1.9) <0.001 Loop diuretic 1.2 (0.9-1.6) 0.132
Net fluid output 1.0 (0.8-1.2) 0.929 Net fluid output 1.0 (0.7-1.2) 0.78
Diuretic efficiency 1.6 (1.3-2.0) <0.001 Diuretic
efficiency 1.4 (1.0-1.8) 0.023
Age (years) 1.03 (1.02-1.04) <0.001 Age (per 10
years) 1.4 (1.2-1.5) <0.001
Heart rate (per 10 BPM) 0.90 (0.86-0.95) <0.001
Systolic blood pressure
(per 10 mmHg) 0.90 (0.87-0.93) <0.001
Systolic blood
pressure (per 10
mmHg)
0.92 (0.88-0.96) <0.001
Loop dose at baseline
(per 100 mg) 1.1 (1.05-1.2) <0.001
Serum sodium (per 5
meq/l) 0.79 (0.71-0.88) <0.001
Serum sodium
(per 5 meq/l) 0.89 (0.79-1.0) 0.071
Hemoglobin (g/dl) 0.89 (0.85-0.94) <0.001
Log B-type natriuretic
peptide (pg/ml) 1.8 (1.3-2.4) <0.001
eGFR (per 10
ml/min/1.73m2)
0.89 (0.85-0.92) <0.001
Blood urea nitrogen
(per 10 mg/dl) 1.2 (1.2-1.2) <0.001
Blood urea
nitrogen (per 10
mg/dl)
1.1 (1.1-1.2) <0.001
Black race 0.79 (0.64-0.98) 0.034 Race 1.3 (1.0-1.7) 0.043
Diabetes 1.2 (0.97-1.5) 0.093
Ischemic etiology for
HF 1.4 (1.1-1.8) 0.002
Baseline edema 1.4 (1.1-1.7) 0.004
Baseline digoxin use 1.4 (1.1-1.7) 0.008 Digoxin use 1.4 (1.1-1.8) 0.011
Baseline thiazide
diuretic use 1.5 (1.1-2.0) 0.01
Thiazide
diuretic use 1.3 (0.92-1.7) 0.143
ESCAPE Cohort
Univariate HR (95% CI) P Value Final model HR (95% CI) P Value
Loop diuretic 2.5 (1.5-3.9) <0.001 Loop diuretic 1.3 (0.7-2.4) 0.366
Net fluid output 1.0 (0.6-1.5) 0.86 Net fluid output 1.2 (0.7-2.1) 0.59
Diuretic efficiency 4.0 (2.3-6.8) <0.001 Diuretic
efficiency 2.9 (1.5-5.4) 0.001
Age (per 10 years) 1.3 (1.1- 1.5) 0.012 Age (per 10
years) 1.2 (0.94-1.5) 0.158
Systolic blood pressure
(per 10 mmHg) 0.88 (0.76-1.0) 0.08
Loop dose at baseline
(per 100 mg) 1.2 (1.1-1.3) <0.001
Loop dose at
baseline (per
100 mg)
1.2 (1.0-1.3) 0.018
Serum sodium (per 5
meq/l) 0.67 (0.54-0.83) <0.001
Serum sodium
(per 5 meq/l) 0.80 (0.62-1.00) 0.096
Hemoglobin (per 1 g/dl) 1.04 (1.00-1.08) 0.043 Hemoglobin
(per 1 g/dl) 1.04 (1.00-1.07) 0.041
eGFR (per 10
ml/min/1.73m2)
0.79 (0.70-0.88) <0.001
Blood urea nitrogen
(per 10 mg/dl) 1.3 (1.2-1.4) <0.001
Blood urea
nitrogen (per 10
mg/dl)
1.2 (1.1-1.3) <0.001
Hypertension 0.70 (0.44-1.1) 0.124 Hypertension 0.58 (0.34-0.98) 0.043
Ischemic etiology for
HF 2.1 (1.3-3.4) 0.003
Ischemic
etiology for HF 1.54 (0.86-2.7) 0.143
Baseline beta blocker 0.67 (0.42-1.0) 0.079 Baseline beta
blocker 0.60 (0.36-0.99) 0.046
Baseline ACE or ARB 0.43 (0.24-0.78) 0.006
Baseline thiazide
diuretic use 1.9 (1.1-3.3) 0.027
Baseline jugular venous
distension 1.5 (0.9-2.4) 0.088
Baseline edema 1.9 (1.2-3.0) 0.006
Supplementary Table 4: Association between diuretic efficiency and mortality in patients with and without
preserved ejection fraction in the Penn cohort.
Patients with: HR (95% CI) p Value p interaction
Ejection Fraction <40% 1.8 (1.4-2.4) <0.001*
0.245 Ejection Fraction ≥40% 1.4 (1.0-2.0) 0.074
Ejection Fraction <50% 1.8 (1.4-2.3) <0.001*
0.255 Ejection Fraction ≥50% 1.3 (0.9-2.1) 0.209
HR: Hazard ratio, CI: Confidence interval. Hazard ratios represent cumulative diuretic efficiencies below
compared to above the median value.
Figures:
Supplementary Figure 1: Consort diagram for the Penn Cohort
Supplementary Figure 2: Scatterplots of diuretic efficiency, loop diuretic dose, and net fluid output
in the Penn (Panel A) and ESCAPE cohorts (Panel B)
A
B
Supplementary Figure 3: Scatterplots of loop diuretic dose and net fluid output in the Penn (Panel
A) and ESCAPE cohorts (Panel B)
A
B
Supplementary Figure 4: Kaplan-Meier survival curves grouped by quartiles of diuretic efficiency
in the Penn cohort (Panel A) and ESCAPE cohort (Panel B)
A
B