Value of routine investigations to predict loop diuretic down-titration success
in stable heart failure

Pieter Martens, Frederik H. Verbrugge, Levinia Boonen, Petra Nijst,

Matthias Dupont, Wilfried Mullens

PII: S0167-5273(17)32210-6
DOI: doi:10.1016/j.ijcard.2017.10.018
Reference: IJCA 25526

To appear in: International Journal of Cardiology

Received date: 9 April 2017

Revised date: 11 July 2017
Accepted date: 4 October 2017

Please cite this article as: Martens Pieter, Verbrugge Frederik H., Boonen Levinia, Nijst
Petra, Dupont Matthias, Mullens Wilfried, Value of routine investigations to predict loop
diuretic down-titration success in stable heart failure, International Journal of Cardiology
(2017), doi:10.1016/j.ijcard.2017.10.018

This is a PDF le of an unedited manuscript that has been accepted for publication.
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 ACCEPTED MANUSCRIPT

Value of routine investigations to predict loop

diuretic down-titration success in stable heart
failure.

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Pieter Martens M.D.1,2, Frederik H. Verbrugge M.D. Ph.D.1, Levinia Boonen M.Sc.1, Petra Nijst M.D.1,2,

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Matthias Dupont M.D. 1 , Wilfried Mullens M.D. Ph.D.1,3

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1. Department of Cardiology, Ziekenhuis Oost-Limburg, Genk, Belgium
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2. Doctoral School for Medicine and Life Sciences, Hasselt University, Diepenbeek,

Belgium

3. Biomedical Research Institute, Faculty of Medicine and Life Sciences, Hasselt

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University, Diepenbeek, Belgium

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Grant Support: Pieter Martens is supported by a doctoral fellowship by the Research

Foundation Flanders (FWO, grant-number: 1127917N). Pieter Martens, Petra Nijst, and
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Wilfried Mullens are researchers for the Limburg Clinical Research Program (LCRP)

UHasselt-ZOL-Jessa, supported by the foundation Limburg Sterk Merk (LSM), Hasselt

University, Ziekenhuis Oost-Limburg and Jessa Hospital.

Corresponding author:
Wilfried Mullens, M.D., Ph.D.
Department of Cardiology, Ziekenhuis Oost-Limburg
Schiepse Bos 6, 3600 Genk, BELGIUM
Tel: +32 89 327087 | Fax: +32 89 327918 | E-mail: Wilfried.Mullens@zol.be

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ABSTRACT

Aims:

Guidelines advocate down-titration of loop diuretics in chronic heart failure (CHF) when patients have

no signs of volume overload. Limited data are available on the expected success rate of this practice

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or how routine diagnostic tests might help steering this process.

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Methods and Results:

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Fifty ambulatory CHF-patients on stable neurohumoral blocker/diuretic therapy for at least 3 months

without any clinical sign of volume overload were prospectively included to undergo loop diuretic

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down-titration. All patients underwent a similar pre-down-titration evaluation consisting of a dyspnea

scoring, physical examination, transthoracic echocardiography (diastolic function, right ventricular

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function, cardiac filling pressures and valvular disease), blood sample (serum creatinine, plasma NT-

pro-BNP and neurohormones). Loop diuretic maintenance dose was subsequently reduced by 50% or

stopped if dose was 40mg furosemide equivalents. Successful down-titration was defined as a
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persistent dose reduction after 30 days without weight increase >1.5 kg or new-onset symptoms of
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worsening heart failure. At 30-day follow-up, down-titration was successful in 62% (n=31). In 12/19
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patients exhibiting down-titration failure, this occurred within the first week. Physical examination,
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transthoracic echocardiography and laboratory analysis had limited predictive capability to detect

patients with down-titration success/failure (positive likelihood-ratios below 1.5, or area under the
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curve [AUC] non-statically different from AUC=0.5).

Conclusion:

Loop diuretic down-titration is feasible in a majority of stable CHF patients in which the treating

clinician felt continuation of loops was unnecessary to sustain euvolemia. Importantly, routine

diagnostics which suggest euvolemia, have limited diagnostic impact on the post-test probability.

Keywords: loop diuretics, down-titration, congestion, and echocardiography.

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INTRODUCTION

Loop diuretics remain a cornerstone in the treatment of volume overload in heart failure. In the

setting of acute heart failure (AHF), they are used in nine out of ten patients (1). A vast amount of

literature is available on how to intensify loop diuretics or on how to combine it with other diuretics in

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AHF (2). On the contrary, surprisingly few data are available on the reverse process of down-titrating

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diuretics in patient with stable chronic heart failure. This is perhaps surprising, as a correlation

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between loop diuretic use and adverse outcome has been shown. However this relation remains

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biased as higher doses of loop diuretics are used in sicker patients (3). As of 2016, the European

Society of Cardiology Guidelines on the treatment of heart failure endorse the practice of down-

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titrating loop diuretics in stable heart failure patients (4). Indeed, it is recommended to reduce loop

diuretic dose in stable patients without clear signs of volume overload. However, limited data are
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available on the expected success rate and safety of down-titrating loop diuretics in clinical practice.

Furthermore, no data are available on the predictive capacity of clinical and technical investigations

available in routine cardiology practices to help steering the process of loop diuretic down-titration.
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This study addresses the feasibility and safety of down-titrating loop diuretics in stable heart failure
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heart patients, and reports on the utility of routine diagnostics to guide this process.
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METHODS

Study population and recruitment

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Eligible chronic heart failure patients scheduled for routine outpatient follow-up were screened

to participate in the current prospective interventional cohort study (NCT02288819). The study was

performed in the outpatient cardiology clinic of a single tertiary center (Ziekenhuis Oost-Limburg,

Genk, Belgium) between December, 2014 and February, 2016. Patients were eligible if aged 18 years

or older and had a history of chronic heart failure. Chronic heart failure was defined as either a left

ventricular ejection fraction <40%, or a previous hospitalization with a primary diagnosis of heart

failure. Exclusion criteria were: (1) a recent (<3 months) hospital admission with a primary or

secondary diagnosis of heart failure; (2) a recent (<3 months) change in the maintenance dose of loop

diuretics, beta-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, or

mineralocorticoid receptor blockers; (3) cardiac resynchronization therapy device implantation <3

months before study inclusion; (4) any clinical sign of volume overload (lung congestion, ascites, pedal

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edema equal or more than 2/3, see further for grading system); however presence of trace pedal

edema (1/4) was no exclusion criteria; (5) patients who were unable to reliably measure their weight at

home according to the treating physician.

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Baseline data collection

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Qualifying patients were directly referred after their scheduled outpatient appointment for a

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study-specific consultation if the referring physician confirmed euvolemia on clinical examination.

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Patients received full written and oral information regarding the study protocol. After obtaining written

informed consent, patients underwent collection of baseline data obtained by one investigator (PM).

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History taking and physical examination was performed with the collection of baseline demographics,

medication use, functional status as New York Heart Association (NYHA) functional class, Visual
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analogue scale (VAS) for dyspnea (supplementary figure 1), weight, heart rate, blood pressure and

presence of pedal edema. Edema was graded on a 0-3 scale (supplementary table 1). Two-

dimensional echocardiographic exam was performed (Philips Healthcare, iE33w Androver,

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Massachusetts). All reported echocardiography measurements were averaged from 3 consecutive

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cycles and assessed as recommended by the American Society of Echocardiography (5). The
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modified Simpsons biplane method was used to calculate ejection fraction. Transmitral pulsed-wave
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Doppler signal was used to determine diastolic function with measurement of E wave, A wave and E-

wave deceleration time. Continuous wave Doppler signal from a regurgitate tricuspid valve signal was
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used to measure right ventricular systolic pressure (RVSP). Vena cava width and collapsibility during

respiration was used to estimate right atrial pressure (RAP) as published previously (6). Tricuspid and

mitral valve regurgitation were classified on a 1 to 4 scale according to color Doppler flow. Venous

blood samples were obtained with the patient in the recumbent position after a 30 minutes adaptation

period. Venous samples were directly analyzed with measurement of plasma NT-proBNP (Cobas

proBNP II, Roche, Rotkreuz, Switzerland), Plasma Renine Activity (RIAZEN immunoassay, ZenTech,

Lige, Belgium), plasma aldosterone concentration (Aldosterone Maia radioimmunoassay, Adaltis,

Rome, Italy) and serum creatinine. Estimated glomerular filtration rate (eGFR), was calculated using

the Chronic Kidney Disease Epidemiology Collaboration Formula.

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Study intervention and follow-up

Subsequently, patients were instructed to follow a fixed loop diuretic tapering schedule.

Maintenance dose of loop diuretics was reduced by 50% from the next day on. If the maintenance

dose was 40 mg furosemide equivalents, loop diuretics were completely stopped, as this is the

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lowest dose in a single pill formula. To prevent accumulating volume overload, patients were

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instructed to monitor their body weight for 7 days after down-titration and were contacted by phone

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after 3, 7, 30 days and 180 days to evaluate the presence of congestive symptoms and weight

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changes. In any case of weight gain >1.5 kg, the patient was instructed to restore the original

maintenance dose. All patients were given an emergency contact number if symptoms of AHF were to

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occur. The study complies with the Declaration of Helsinki and the study protocol was approved by the

institutional committee on human research.

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Study end-points and safety
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The primary study end-point was successful down-titration of loop diuretics, defined as the
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absence of weight gain >1.5 kg at 30 days after down-titration. Secondary end-points included the

change in NYHA-class at 7, 30 days and 180 days. Mortality and readmissions with a primary
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diagnosis of AHF were prospectively registered as a safety end-point. Heart failure readmissions were
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defined as unplanned hospital admissions for symptoms of congestion and/or low output heart failure

requiring either intravenous therapy and/or increase of oral diuretics.

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Statistical analysis

Continuous variables are expressed as mean standard deviation if normally distributed or

otherwise by median (interquartile range). Normality was assessed by the Shapiro-Wilk statistic. The

students t-test and Mann-Whitney U test were used as indicated for comparison between groups.

Categorical variables are expressed as percentages and compared with Fishers exact test. Predictors

of down-titration success were screened using a univariate screen with multivariate conformation.

Univariate predictors with a p-value <0.10 were transferred to the step-forward multivariate binary

regression analysis. Sensitivity, specificity, negative predictive value, positive predictive value and

likelihood ratios of binary diagnostic tests were determined by two-by-two tables. For diagnostic tests

with a test result on a continuous scale, diagnostic characteristics were determined by receiver

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operator characteristics (ROC), reporting the area under the curve, 95% confidence interval and

asymptotic p-value. Statistical significance was always set at a 2-tailed probability level of <0.05. All

statistics were performed using IBM SPSS (version 24.0) for Windows.

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RESULTS

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Study population

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During the study period, 548 patients from the outpatient clinic who took a daily maintenance

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dose of loop diuretics and qualified with a diagnosis of heart failure were screened for study inclusion.

Ninety-two patients had a recent hospital admission for AHF and were excluded, 52 others had

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changes in the maintenance dose of loop diuretics, 2 had changes in neurohumoral blocker therapy,

20 had received cardiac resynchronization therapy within 3 months, 60 presented with clinical signs of
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congestion, and 26 could not reliably measure their weight at home. In addition, 36 patients were

withheld from study participation by their treating physician because down-titration was deemed too

risky. Finally, 210 patients could not be included because of logistic constraints (mostly because of
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presentation at the outpatient clinic when study staff was not available). Rendering a final study
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population of 50 patients. Baseline characteristics are presented in Table 1. The median maintenance

dose of loop diuretics taken by study patients at baseline was 40 mg (20-40 mg) furosemide
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equivalents. Five patients (10%) were taking furosemide, all others bumetanide (90%). The median
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plasma N-terminal of the prohormone of B-type natriuretic peptide (NT-proBNP) level was 959 ng/L

(312-1,630 ng/L).
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Downtitration success and safety

Significant weight changes leading to down-titration failure occurred in 12 patients between inclusion

and day 7. Additionally, 7 patients exhibited significant weight change between day 7 and day 30
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(figure 1). Between the 30 day of follow-up and 180 day of follow-up no additional patients

experienced significant weight change leading to late down-titration failure. Therefore the down-

titration success-rate at 30 days (and 180 days) was 62%. One male patient died during follow-up due

to an unrelated gastro-intestinal infection. During the entire follow-up no patient was hospitalized for

AHF. A univariate screen of baseline characteristics (table 1) indicated that presence of cardiac

resynchronization therapy (p=0.097), a lower VAS-dyspnea score (p=0.057) and an absence of trace

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edema (p=0.097) predicted a higher chance of down-titration success. However, only presence of

cardiac resynchronization therapy was retained in the multivariate model (HR=5.7, CI=1.6-20.5,

p=0.007).

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Short-term and long-term changes in weight and NYHA-class

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Mean weight changes of the 12-patients exhibiting >1,5kg weight change during the first week are

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reflected in figure 2. Of these 12 patients, 75% (n=9) exhibited a weight gain the first 72-hours after

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stopping the diuretic. Reinstitution of the original diuretic dose resulted in 6 out of 12 patients again

dropping their weight change below the predefined 1.5kg threshold by day 7. At day 7 a total of 3 (6%)

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patients reported worsening of their NYHA-class from NYHA 1 to NYHA 2. The remaining 47 patients

(94%) did not exhibit a change in their NYHA-class at day 7. At 30 days follow-up, 7 additional patients
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reinstituted their original maintenance dose, of whom 2 patients temporarily (3 days each) used 150%

of original loop diuretic dose. Supplementary figure 2 illustrates the mean changes in weight and

NYHA-class after categorizing patient in to down-titration failure or success at 30-days. Patients with
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down-titration failure exhibited some residual weight increase at 30 days, however at 180 days these
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patients exhibited a weight reduction in comparison to their baseline weight. At 180 days, 7 patients in
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the down-titration success group reported improvement of 1 NYHA-class, no patients reported

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worsening of their NYHA-class. In the down-titration failure group 6 patients reported improvement of

their NYHA-class and 4 reported worsening of their NYHA-class at 180 days.

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Utility of clinical and technical evaluation

Table 2 reports the diagnostic accuracy of clinical and technical evaluations performed during the

study-specific consultation to predict success of loop diuretic down-titration at 30 days. Of the test with

a binary test- result , absence of trace edema (grade <1/3) exhibited a high sensitivity. Indicating that

patients who exhibit trace edema at baseline rarely have down-titration success. However, the

likelihood ratios of binary diagnostics test outcomes were well below 2, indicating that the test results

had a poor capability to impact pre-test probability of down-titration success. Of diagnostic tests with a

continuous outcome result, no tests exhibited an area under the curve that was statistically different

from the reference line (AUC=0.5).

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DISCUSSION

This prospective interventional cohort study adds important novel information about the practice of

down-titration of loop diuretics in patients with stable heart failure. (I) in a selected patient cohort,

down-titration is feasible in majority of patients (62%), (II) A trial of loop diuretic down-titration is safe

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and does not increase the subsequent risk of AHF, (III) Routinely available clinical and technical

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diagnostic test have a limited value of identifying patients who will have loop diuretic down-titration

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success versus failure.

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As of 2016, the European Society Guidelines for the treatment of heart failure suggest to

down-titrate loop diuretics in patients with stable heart failure without signs of volume overload (4).

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This suggestion is mainly based on the observation that high doses of loop diuretics are associated

with harm in the setting of AHF (3). Surprisingly, only two studies have been published over the past
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two decades evaluating the feasibility of loop diuretic down-titration in chronic heart failure patients (7,

8). Grinstead et al. illustrated that only 29% of the 41 patients with heart failure who discontinued their

loop diuretic, were able to maintain this at six week follow-up (7). However, this study preceded the
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era of systematically prescribing renin-angiotensin system blockers or mineralocorticod receptor

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antagonist use. Walma et al. randomized 202 elderly patients (>65years) treated with loop diuretics to
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either loop diuretic down-titration or continuation (8). Of the 102 patients randomized to the down-
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titration group, 50 patients (49%) required reinstitution of the original loop diuretic dose. However, this

study included patients with numerous indications for loop diuretic use, with a majority receiving
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diuretics to treat hypertension. Reasons for reinstituting diuretics included occurrence of hypertension

in addition to worsening of heart failure. Furthermore this study was performed at the primary care

level and limited baseline data of the few heart failure patients enrolled were available. The current,

albeit small study, adds data about the feasibility and safety of loop diuretic down-titration in

contemporary heart failure patients. Our success-rate of 62% far exceeds the number of Grinstead

etal (29%)(7). This is not surprising as our patients were on a robust regimen of contemporary

evidence based treatments consisting of neurohormonal blockers and cardiac resynchronization

therapy. Indeed, previous implantation of cardiac resynchronization therapy was the only baseline

characteristics predicting loop diuretic down-titration success. A previous analysis has shown that

following cardiac resynchronization therapy, patients are often able to reduce the loop diuretic dose.

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Especially patients exhibiting more pronounced reverse remodeling are likely to reduce or discontinue

their maintenance dose (9).

In addition to being feasible, our study emphasis that loop diuretic down-titration with close

follow-up is safe and does not result in an increased risk for AHF if closely monitored. Few studies

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have evaluated the potential harm of discontinuing loop diuretics in stable chronic heart failure.

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Damman et al. demonstrated in 30 patients with HFrEF that a 72 hours discontinuation of the loop

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diuretic resulted in higher level of tubular dysfunction markers, yet the clinical consequence of this rise

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in tubular dysfunction markers is unknown (10). McKie on the other hand illustrated in 32 patients that

loop diuretic reduction for three weeks resulted in improvement of glomerular filtration rate (measured

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by iothalamate)(11). Importantly, up to 62% of patients tolerated loop diuretic reduction without

significant weight changes or changes in clinical status during the three week follow-up. This percent
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of down-titration success at three weeks is similar to our number, however in the study of McKie all

patients were reinstituted on their loop diuretic at the end of the three week study. In an experimental

study, four patients implanted with a hemodynamic monitoring system (Chronicle, Medtronic,
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Minneapolis) underwent withdrawal of their loop diuretic (12). Three out of 4 patients exhibited
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significant weight changes (2.9kg 4.0kg) accompanied by an increase in filling pressures

necessitating reinstitution of the loop diuretic. However one patient gained 2.5kg without any changes
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in cardiac filling pressures or symptomatic status. This indicates that in patients with pre-existing
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volume depletion discontinuing loop diuretics might induce compensatory weight changes (switch to

euvolemia) without exposing the patient to the detrimental effects of congestion. In line with this, we
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previously showed that 67% of optimally treated stable heart failure patients exhibited volume

contraction measured by direct plasma-volume analysis (13). Suggesting that many patients could use

lower doses of loop diuretics from a total-body volume perspective. However at the same time it might

suggest that weight changes may not be the optimal metric to define loop diuretic down-titration

failure.

Finally, most diagnostic tests carried a limited capacity to significantly impact pre-test

probability (which might have been high due to selection) of the experienced physician. For binary test

results it is generally acknowledged that a likelihood of less than 2 insufficiently adds relevant

information. For continuous test results, an AUC of more than 0.85 is often regarded to as the

requirement to guide individual patient decision making. It is clear from our results that in our patient

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population the additional testing did not achieve the diagnostic requirements to impact decision

making. This is potentially explained by the targets that most of the diagnostic test actually measured.

Indeed dyspnea, RAP, RVSP, E-wave velocity, E-wave deceleration time, NT-proBNP all more closely

track with filling pressures and not automatically with volume status(14). Indeed, when filling

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pressures are high, volume overload can be a driving factor. However these test might be insufficient

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to detect subclinical volume excess without accompanying increases in filling pressures. Therefore

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overreliance on these test to help identify patients with loop diuretic down-titration success seems of

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limited value.

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Study limitations

One, only 50 from the 548 patients screened (9%) were eventually included in the study,
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which might imply selection bias. Second, the primary end-point of the study relied heavily on body

weight monitoring by the patient at home, which is perhaps less objective as in office weight

monitoring. However, in clinical practice the same constrain will occur, making our finding more
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applicable to clinical practice. Third, maintenance loop diuretic dose at study entry was relatively low,
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with the 75 percentile at 40 mg furosemide equivalents. Nevertheless even low doses of loop
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diuretics might be harmful in the patient with volume contraction.

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Conclusions
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In selected optimally treated heart failure patients (at least 3 months stable) without signs of volume

overload for, it is feasible in a majority of patients to down-titrate loop diuretics. Ambulatory short-term

weight changes can easily monitor this practice and avoids exposing patients to rebound congestion.

Routine diagnostic tests carry a limited capability to help steer this process, above and beyond the

clinical insight of the experienced physician.

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REFERENCES

1. Yancy CW, Fonarow GC. Quality of care and outcomes in acute decompensated heart failure:
The ADHERE Registry. Curr Heart Fail Rep 2004;1(3):121-128.

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congestion in heart failure. Curr Heart Fail Rep 2014;11(1):1-9.

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3. Hasselblad V, Gattis SW, Shah MR, Lokhnygina Y, O'Connor CM, Califf RM, Adams KF, Jr.
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ESCAPE trial. Eur J Heart Fail 2007;9(10):1064-1069.

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4. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ, Falk V, Gonzalez-
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Pieske B, Riley JP, Rosano GM, Ruilope LM, Ruschitzka F, Rutten FH, van der Meer P. 2016
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6. Beigel R, Cercek B, Luo H, Siegel RJ. Noninvasive evaluation of right atrial pressure. J Am Soc
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Echocardiogr 2013;26(9):1033-1042.

7. Grinstead WC, Francis MJ, Marks GF, Tawa CB, Zoghbi WA, Young JB. Discontinuation of
chronic diuretic therapy in stable congestive heart failure secondary to coronary artery disease
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or to idiopathic dilated cardiomyopathy. Am J Cardiol 1994;73(12):881-886.

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8. Walma EP, Hoes AW, van DC, Prins A, van der Does E. Withdrawal of long-term diuretic
medication in elderly patients: a double blind randomised trial. BMJ 1997;315(7106):464-468.

9. Schmidt S, Hurlimann D, Starck CT, Hindricks G, Luscher TF, Ruschitzka F, Steffel J. Treatment
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with higher dosages of heart failure medication is associated with improved outcome following
cardiac resynchronization therapy. Eur Heart J 2014;35(16):1051-1060.

10. Damman K, Ng Kam Chuen MJ, MacFadyen RJ, Lip GY, Gaze D, Collinson PO, Hillege HL, van
OW, Voors AA, van Veldhuisen DJ. Volume status and diuretic therapy in systolic heart failure
and the detection of early abnormalities in renal and tubular function. J Am Coll Cardiol
2011;57(22):2233-2241.

11. McKie PM, Schirger JA, Benike SL, Harstad LK, Chen HH. The effects of dose reduction of
furosemide on glomerular filtration rate in stable systolic heart failure. JACC Heart Fail
2014;2(6):675-677.

12. Braunschweig F, Linde C, Eriksson MJ, Hofman-Bang C, Ryden L. Continuous haemodynamic

monitoring during withdrawal of diuretics in patients with congestive heart failure. Eur Heart J
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14. Thibodeau JT, Jenny BE, Maduka JO, Divanji PH, Ayers CR, Araj F, Amin AA, Morlend RM,
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TABLES

Table 1. Baseline characteristics of the study population (n=50)

Parameter Value

Age (years) 73 (61-78)

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Male/female gender 60/40%

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New York Heart Association functional class (I/II) 52/48%

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Visual analogue scale for dyspnea (/100) 25 18

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Trace pedal edema 6%

In-office body weight (kg) 79 17

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Body mass index (kg/m) 29 5

Heart rate (bpm) 69 11

Systolic blood pressure (mmHg) 118 20

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Diastolic blood pressure (mmHg) 68 14

Time since heart failure diagnosis (years) 4 (2-7)

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Proportion HFrEF / HFpEF 92% / 8%

Left ventricular ejection fraction (%) if HFrEF 38 9

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Left ventricular ejection fraction (%) if HFpEF 56 3

Ischemic heart disease 44%

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Atrial fibrillation 48%

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Diabetes 18%

Estimated glomerular filtration rate (mL/min/1.73m) 54 21

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Cardiac resynchronization therapy 66%

Implantable cardioverter-defibrillator 40%

Angiotensin-converting enzyme inhibitor use 62%

Angiotensin receptor blocker use 18%

Beta-blocker use 88%

Mineralocorticoid receptor antagonist use 60%

Digoxin use 12%

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Table 2. Diagnostic capability to predict loop-diuretic down-titration success.

Binary test results

Parameter Sensitivity Specificity NPV PPV Likelihood
Ratio
Clinical parameters

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Absence of trace 97% 11% 67% 64% 1.09

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Peripheral edema
Echocardiographic parameters

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Absence of mitral 74% 16% 27% 59% 0.88
regurgitation >

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Absence of
tricuspid 84% 11% 29% 61% 0.94
regurgitation >

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Absence of
estimated 75% 25% 40% 60% 1
RAP>5mmHg
Absence of RV-
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dysfunction 87% 42% 67% 71% 1.5
(TAPSE>17mm)

Continuous test results

Asymptotic
Parameter Area 95% CI
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significance
Clinical parameters
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% of target dose RAS-blocker 0.556 0.531 0.385 0.727

% of target dose BB-blocker 0.506 0.946 0.336 0.676
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% of target dose MRA 0.524 0.785 0.350 0.699

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VAS-dyspnea scale 0.522 0.795 0.347 0.697

Laboratory parameters
Glomerular filtration rate 0.495 0.953 0.309 0.681
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NT-proBNP 0.515 0.868 0.340 0.691

Plasma aldosterone concentration 0.593 0.281 0.422 0.764
Plasma renin activity 0.395 0.250 0.221 0.569
Echocardiographic parameters
E-wave velocity 0.628 0.131 0.469 0.788
E-wave deceleration time 0.576 0.374 0.414 0.737
Right ventricular systolic pressure 0.454 0.669 0.247 0.662

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FIGURES

Figure 1: failure rate on 7, 30 and 180 days.

T
IP
R
SC
NU
MA
D
P TE
CE

* one patient died between 30-days and 180-days.

AC

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Figure 2: Short-term weight changes

T
R IP
SC
NU
MA
D
TE

Bold N; indicate the numbers of patients exhibiting more than >1,5kg weight gain that

day.
P
CE
AC

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