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1 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, MTR 1,2 ; Meredith A. Brisco, MD, MSCE 3 ; Jeffrey M. Turner, MD 1 ; Erica S. Spatz, MD, MHS 1 ; Lavanya Bellumkonda, MD 1 ; Chirag R. Parikh, MD, PhD 1,2 ; W. H. Wilson Tang, MD 4 1 Department of Internal Medicine, and 2 Program of Applied Translational Research, Yale University School of Medicine, New Haven, CT. 3 Department of Medicine, Cardiovascular Division, Medical University of South Carolina, Charleston, SC. 4 Section 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 ns ns ns ns ns ns nsl l l l l l l at at at at at t atio io io io io io iona na na na na na nal l l l l l l Re Re Re Re Re Re Rese se se se se se sea a a a a a a f Me Me e e e e edi di di di di di dici ci ci ci ci ci c ne ne ne ne ne ne ne, , , , Ca Ca Ca Ca Ca Ca Card U a a Un n n n niv iv iv iv iversi si si i sity ty ty ty ty o o o o of f f f f South Carolina, Ch Ch Ch Ch ha arleston, SC SC SC S S . 4 4 4 Section of Hea at t t t tio io io o on, the C C Cle eve e el land nd nd nd nd Clin nic c c, C Cleve v vela a a a and nd nd nd nd, OH OH H by guest on July 14, 2018 http://circheartfailure.ahajournals.org/ Downloaded from by guest on July 14, 2018 http://circheartfailure.ahajournals.org/ Downloaded from by guest on July 14, 2018 http://circheartfailure.ahajournals.org/ Downloaded from by guest on July 14, 2018 http://circheartfailure.ahajournals.org/ Downloaded from by guest on July 14, 2018 http://circheartfailure.ahajournals.org/ Downloaded from by guest on July 14, 2018 http://circheartfailure.ahajournals.org/ Downloaded from by guest on July 14, 2018 http://circheartfailure.ahajournals.org/ Downloaded from by guest on July 14, 2018 http://circheartfailure.ahajournals.org/ Downloaded from by guest on July 14, 2018 http://circheartfailure.ahajournals.org/ Downloaded from by guest on July 14, 2018 http://circheartfailure.ahajournals.org/ Downloaded from by guest on July 14, 2018 http://circheartfailure.ahajournals.org/ Downloaded from by guest on July 14, 2018 http://circheartfailure.ahajournals.org/ Downloaded from by guest on July 14, 2018 http://circheartfailure.ahajournals.org/ Downloaded from

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1

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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APE ddddata asaaa etetetetet (n 390). DE was essssstittt mated as thehehehehe net fluid outpu

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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

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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

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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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stent cooooongngngngngesesesesstititititiononononon,, thththththe eee rarararratetetetete ooooofffff dddddeteteteteterererererioooiorararararatititititiononononon iiiiinnn nn rererererenananananal llll fufufufufuncncncncnction wfffff

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11

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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ogogognononostststicicicc iiinfnfnfnforororormmmmatatattioioioioon n n nn totototo eeeeititittheheheh r r r papapapap rarararamememememeteteteer.r.r.rr FuFuFuFFurtrtrtr hehehehermrmrmmmorororore,e,e,e dddesesespipipi

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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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ion in fully adjusted multivariable models incorporating bo h

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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.

References

1. Adams KF, Jr., Fonarow GC, Emerman CL, LeJemtel TH, Costanzo MR, Abraham WT, Berkowitz RL, Galvao M, Horton DP. Characteristics and outcomes of patients hospitalized for heart failure in the united states: Rationale, design, and preliminary observations from the first 100,000 cases in the acute decompensated heart failure national registry (adhere). Am. Heart J. 2005;149:209-216.

2. Gheorghiade M, Filippatos G, De Luca L, Burnett J. Congestion in acute heart failure syndromes: An essential target of evaluation and treatment. The American Journal of Medicine. 2006;119:S3-S10.

3. Felker GM, Mentz RJ. Diuretics and ultrafiltration in acute decompensated heart failure. J. Am. Coll. Cardiol. 2012;59:2145-2153.

4. Neuberg GW, Miller AB, O'Connor CM, Belkin RN, Carson PE, Cropp AB, Frid DJ, Nye RG, Pressler ML, Wertheimer JH, Packer M. Diuretic resistance predicts mortality in patients with advanced heart failure. Am. Heart J. 2002;144:31-38.

5. Eshaghian S, Horwich TB, Fonarow GC. Relation of loop diuretic dose to mortality in advanced heart failure. The American Journal of Cardiology. 2006;97:1759-1764.

6. Yilmaz MB, Gayat E, Salem R, Lassus J, Nikolaou M, Laribi S, Parissis J, Follath F, Peacock WF, Mebazaa A. Impact of diuretic dosing on mortality in acute heart failure using a propensity-matched analysis. European journal of heart failure. 2011;13:1244-1252.

7. Mielniczuk LM, Tsang SW, Desai AS, Nohria A, Lewis EF, Fang JC, Baughman KL, Stevenson LW, Givertz MM. The association between high-dose diuretics and clinical stability in ambulatory chronic heart failure patients. J. Card. Fail. 2008;14:388-393.

8. Testani JM, Cappola TP, Brensinger CM, Shannon RP, Kimmel SE. Interaction between loop diuretic-associated mortality and blood urea nitrogen concentration in chronic heart failure. J. Am. Coll. Cardiol. 2011;58:375-382.

9. Nunez J, Nunez E, Minana G, Bodi V, Fonarow GC, Bertomeu-Gonzalez V, Palau P, Merlos P, Ventura S, Chorro FJ, Llacer P, Sanchis J. Differential mortality association of loop diuretic dosage according to blood urea nitrogen and carbohydrate antigen 125 following a hospitalization for acute heart failure. European journal of heart failure. 2012;14:974-984.

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19

10. Quinn J, Kramer N, McDermott D. Validation of the social security death index (ssdi): An important readily-available outcomes database for researchers. West J Emerg Med. 2008;9:6-8.

11. Shah MR, O'Connor CM, Sopko G, Hasselblad V, Califf RM, Stevenson LW. Evaluation study of congestive heart failure and pulmonary artery catheterization effectiveness (escape): Design and rationale. Am. Heart J. 2001;141:528-535.

12. Binanay C, Califf RM, Hasselblad V, O'Connor CM, Shah MR, Sopko G, Stevenson LW, Francis GS, Leier CV, Miller LW, Investigators E, Coordinators ES. Evaluation study of congestive heart failure and pulmonary artery catheterization effectiveness: The escape trial. JAMA : the journal of the American Medical Association. 2005;294:1625-1633.

13. Brenner BM, Rector FC. Brenner & rector's the kidney. Philadelphia: Saunders Elsevier; 2008.

14. Levey AS, Coresh J, Greene T, Stevens LA, Zhang YL, Hendriksen S, Kusek JW, Van Lente F, Chronic Kidney Disease Epidemiology C. Using standardized serum creatinine values in the modification of diet in renal disease study equation for estimating glomerular filtration rate. Ann. Intern. Med. 2006;145:247-254.

15. Testani JM, McCauley BD, Kimmel SE, Shannon RP. Characteristics of patients with improvement or worsening in renal function during treatment of acute decompensated heart failure. Am. J. Cardiol. 2010;106:1763-1769.

16. Testani JM, McCauley BD, Chen J, Shumski M, Shannon RP. Worsening renal function defined as an absolute increase in serum creatinine is a biased metric for the study of cardio-renal interactions. Cardiology. 2010;116:206-212.

17. Testani JM, Kimmel SE, Dries DL, Coca SG. Prognostic importance of early worsening renal function after initiation of angiotensin-converting enzyme inhibitor therapy in patients with cardiac dysfunction. Circulation. Heart failure. 2011;4:685-691.

18. Testani JM, Coca SG, McCauley BD, Shannon RP, Kimmel SE. Impact of changes in blood pressure during the treatment of acute decompensated heart failure on renal and clinical outcomes. European journal of heart failure. 2011;13:877-884.

19. Testani JM, Chen J, McCauley BD, Kimmel SE, Shannon RP. Potential effects of aggressive decongestion during the treatment of decompensated heart failure on renal function and survival. Circulation. 2010;122:265-272.

20. Testani JM, Cappola TP, McCauley BD, Chen J, Shen J, Shannon RP, Kimmel SE. Impact of worsening renal function during the treatment of decompensated heart failure on changes in renal function during subsequent hospitalization. Am. Heart J. 2011;161:944-949.

21. Brater DC, Day B, Burdette A, Anderson S. Bumetanide and furosemide in heart failure. Kidney Int. 1984;26:183-189.

22. Vargo DL, Kramer WG, Black PK, Smith WB, Serpas T, Brater DC. Bioavailability, pharmacokinetics, and pharmacodynamics of torsemide and furosemide in patients with congestive heart failure. Clin. Pharmacol. Ther. 1995;57:601-609.

23. Mickey RM, Greenland S. The impact of confounder selection criteria on effect estimation. Am. J. Epidemiol. 1989;129:125-137.

24. Francis GS, Benedict C, Johnstone DE, Kirlin PC, Nicklas J, Liang CS, Kubo SH, Rudin-Toretsky E, Yusuf S. Comparison of neuroendocrine activation in patients with left ventricular dysfunction with and without congestive heart failure. A substudy of the studies of left ventricular dysfunction (solvd). Circulation. 1990;82:1724-1729.

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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

%

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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*

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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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26

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

ananelel AA))) anandd ESESESCACAC PEEPE ccohohorortt (P(P( ananelel BB)))

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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:

  http://circheartfailure.ahajournals.org//subscriptions/

is online at: Circulation: Heart Failure Information about subscribing to Subscriptions: 

http://www.lww.com/reprints Information about reprints can be found online at: Reprints:

  document. Permissions and Rights Question and Answer process is available in the

click Request Permissions in the middle column of the Web page under Services. Further information about thisEditorial Office. Once the online version of the published article for which permission is being requested is located,

can be obtained via RightsLink, a service of the Copyright Clearance Center, not theCirculation: Heart Failure Requests for permissions to reproduce figures, tables, or portions of articles originally published inPermissions:

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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

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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.

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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

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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.

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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

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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

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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.

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Figures:

Supplementary Figure 1: Consort diagram for the Penn Cohort

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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

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Supplementary Figure 3: Scatterplots of loop diuretic dose and net fluid output in the Penn (Panel

A) and ESCAPE cohorts (Panel B)

A

B

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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