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

    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: DOI: Reference:

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

To appear in:

International Journal of Cardiology

Received date: Revised date: Accepted date:

9 April 2017 11 July 2017 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

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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 2. Doctoral School for Medicine and Life Sciences, Hasselt University, Diepenbeek, Belgium

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

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University, Diepenbeek, Belgium

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

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Foundation – Flanders (FWO, grant-number: 1127917N). Pieter Martens, Petra Nijst, and 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: [email protected]

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ACCEPTED MANUSCRIPT ABSTRACT Aims: Guidelines advocate down-titration of loop diuretics in chronic heart failure (CHF) when patients have

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or how routine diagnostic tests might help steering this process.

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

Methods and Results:

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

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without any clinical sign of volume overload were prospectively included to undergo loop diuretic down-titration. All patients underwent a similar pre-down-titration evaluation consisting of a dyspnea

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scoring, physical examination, transthoracic echocardiography (diastolic function, right ventricular function, cardiac filling pressures and valvular disease), blood sample (serum creatinine, plasma NTpro-BNP and neurohormones). Loop diuretic maintenance dose was subsequently reduced by 50% or

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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 patients exhibiting down-titration failure, this occurred within the first week. Physical examination, transthoracic echocardiography and laboratory analysis had limited predictive capability to detect

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patients with down-titration success/failure (positive likelihood-ratios below 1.5, or area under the 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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ACCEPTED MANUSCRIPT 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

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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 between loop diuretic use and adverse outcome has been shown. However this relation remains biased as higher doses of loop diuretics are used in sicker patients (3). As of 2016, the European

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Society of Cardiology Guidelines on the treatment of heart failure endorse the practice of downtitrating loop diuretics in stable heart failure patients (4). Indeed, it is recommended to reduce loop

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diuretic dose in stable patients without clear signs of volume overload. However, limited data are 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

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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

METHODS

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heart patients, and reports on the utility of routine diagnostics to guide this process.

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Study population and recruitment 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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ACCEPTED MANUSCRIPT 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

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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 study-specific consultation if the referring physician confirmed euvolemia on clinical examination. Patients received full written and oral information regarding the study protocol. After obtaining written

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informed consent, patients underwent collection of baseline data obtained by one investigator (PM). History taking and physical examination was performed with the collection of baseline demographics,

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medication use, functional status as New York Heart Association (NYHA) functional class, Visual 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-

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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 modified Simpson’s biplane method was used to calculate ejection fraction. Transmitral pulsed-wave Doppler signal was used to determine diastolic function with measurement of E wave, A wave and E-

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wave deceleration time. Continuous wave Doppler signal from a regurgitate tricuspid valve signal was 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, Liège, 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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ACCEPTED MANUSCRIPT 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

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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 after 3, 7, 30 days and 180 days to evaluate the presence of congestive symptoms and weight changes. In any case of weight gain >1.5 kg, the patient was instructed to restore the original

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maintenance dose. All patients were given an emergency contact number if symptoms of AHF were to occur. The study complies with the Declaration of Helsinki and the study protocol was approved by the

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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 absence of weight gain >1.5 kg at 30 days after down-titration. Secondary end-points included the

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

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

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 student’s t-test and Mann-Whitney U test were used as indicated for comparison between groups. Categorical variables are expressed as percentages and compared with Fisher’s 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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ACCEPTED MANUSCRIPT 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

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

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RESULTS

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Study population

During the study period, 548 patients from the outpatient clinic who took a daily maintenance dose of loop diuretics and qualified with a diagnosis of heart failure were screened for study inclusion.

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Ninety-two patients had a recent hospital admission for AHF and were excluded, 52 others had changes in the maintenance dose of loop diuretics, 2 had changes in neurohumoral blocker therapy,

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20 had received cardiac resynchronization therapy within 3 months, 60 presented with clinical signs of 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

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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 population of 50 patients. Baseline characteristics are presented in Table 1. The median maintenance

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

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(312-1,630 ng/L).

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 (figure 1). Between the 30

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day of follow-up and 180

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day of follow-up no additional patients

experienced significant weight change leading to late down-titration failure. Therefore the downtitration 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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ACCEPTED MANUSCRIPT 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,

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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 reflected in figure 2. Of these 12 patients, 75% (n=9) exhibited a weight gain the first 72-hours after stopping the diuretic. Reinstitution of the original diuretic dose resulted in 6 out of 12 patients again

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dropping their weight change below the predefined 1.5kg threshold by day 7. At day 7 a total of 3 (6%) patients reported worsening of their NYHA-class from NYHA 1 to NYHA 2. The remaining 47 patients

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(94%) did not exhibit a change in their NYHA-class at day 7. At 30 days follow-up, 7 additional patients 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

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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 the down-titration success group reported improvement of 1 NYHA-class, no patients reported worsening of their NYHA-class. In the down-titration failure group 6 patients reported improvement of

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

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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ACCEPTED MANUSCRIPT 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,

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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 success versus failure.

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

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down-titrate loop diuretics in patients with stable heart failure without signs of volume overload (4). This suggestion is mainly based on the observation that high doses of loop diuretics are associated

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with harm in the setting of AHF (3). Surprisingly, only two studies have been published over the past 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

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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 mineralocorticoïd receptor

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

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study included patients with numerous indications for loop diuretic use, with a majority receiving 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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ACCEPTED MANUSCRIPT 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

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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 diuretic resulted in higher level of tubular dysfunction markers, yet the clinical consequence of this rise in tubular dysfunction markers is unknown (10). McKie on the other hand illustrated in 32 patients that

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loop diuretic reduction for three weeks resulted in improvement of glomerular filtration rate (measured by iothalamate)(11). Importantly, up to 62% of patients tolerated loop diuretic reduction without

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significant weight changes or changes in clinical status during the three week follow-up. This percent 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

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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 significant weight changes (2.9kg – 4.0kg) accompanied by an increase in filling pressures

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

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euvolemia) without exposing the patient to the detrimental effects of congestion. In line with this, we 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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ACCEPTED MANUSCRIPT 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 not automatically with volume status(14). Indeed, when filling

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track with filling pressures and

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

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limited value.

Study limitations

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One, only 50 from the 548 patients screened (9%) were eventually included in the study, 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

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monitoring. However, in clinical practice the same constrain will occur, making our finding more

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percentile at 40 mg furosemide equivalents. Nevertheless even low doses of loop

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with the 75

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applicable to clinical practice. Third, maintenance loop diuretic dose at study entry was relatively low,

diuretics might be harmful in the patient with volume contraction.

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Conclusions

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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ACCEPTED MANUSCRIPT 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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2. Verbrugge FH, Grieten L, Mullens W. New insights into combinational drug therapy to manage 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. Relation between dose of loop diuretics and outcomes in a heart failure population: results of the 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, GonzalezJuanatey JR, Harjola VP, Jankowska EA, Jessup M, Linde C, Nihoyannopoulos P, Parissis JT, Pieske B, Riley JP, Rosano GM, Ruilope LM, Ruschitzka F, Rutten FH, van der Meer P. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC)Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J 2016.

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5. Schiller NB, Shah PM, Crawford M, DeMaria A, Devereux R, Feigenbaum H, Gutgesell H, Reichek N, Sahn D, Schnittger I, . Recommendations for quantitation of the left ventricle by twodimensional echocardiography. American Society of Echocardiography Committee on Standards, Subcommittee on Quantitation of Two-Dimensional Echocardiograms. J Am Soc Echocardiogr 1989;2(5):358-367.

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6. Beigel R, Cercek B, Luo H, Siegel RJ. Noninvasive evaluation of right atrial pressure. J Am Soc Echocardiogr 2013;26(9):1033-1042.

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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 or to idiopathic dilated cardiomyopathy. Am J Cardiol 1994;73(12):881-886. 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.

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9. Schmidt S, Hurlimann D, Starck CT, Hindricks G, Luscher TF, Ruschitzka F, Steffel J. Treatment 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 2002;23(1):59-69. 13. Nijst P, Verbrugge FH, Bertrand PB, Martens P, Dupont M, Drieskens O, Penders J, Tang WH, Mullens W. Plasma Volume Is Normal but Heterogeneously Distributed, and True Anemia Is Highly Prevalent in Patients With Stable Heart Failure. J Card Fail 2017;23(2):138-144.

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14. Thibodeau JT, Jenny BE, Maduka JO, Divanji PH, Ayers CR, Araj F, Amin AA, Morlend RM, Mammen PP, Drazner MH. Bendopnea and risk of adverse clinical outcomes in ambulatory patients with systolic heart failure. Am Heart J 2017;183:102-107.

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ACCEPTED MANUSCRIPT TABLES Table 1. Baseline characteristics of the study population (n=50) Parameter

Value 73 (61-78)

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Age (years)

60/40%

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Male/female gender

52/48%

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New York Heart Association functional class (I/II) Visual analogue scale for dyspnea (/100) Trace pedal edema

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In-office body weight (kg) Body mass index (kg/m²)

Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg)

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Time since heart failure diagnosis (years)

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Heart rate (bpm)

Proportion HFrEF / HFpEF

25 ± 18 6% 79 ± 17 29 ± 5 69 ± 11 118 ± 20 68 ± 14 4 (2-7) 92% / 8% 38 ± 9

Left ventricular ejection fraction (%) if HFpEF

56 ± 3

Atrial fibrillation Diabetes

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Ischemic heart disease

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Left ventricular ejection fraction (%) if HFrEF

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Estimated glomerular filtration rate (mL/min/1.73m²)

44% 48% 18% 54 ± 21

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

Binary test results Parameter

Sensitivity

Specificity

NPV

97%

11%

67%

PPV

64%

1.09

27%

59%

0.88

29%

61%

0.94

40%

60%

1

67%

71%

1.5

16%

Absence of tricuspid regurgitation > ¼

84%

11%

Absence of estimated RAP>5mmHg

75%

25%

Absence of RVdysfunction (TAPSE>17mm)

87%

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74%

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Absence of mitral regurgitation > ¼

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Echocardiographic parameters

42%

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Absence of trace Peripheral edema

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Clinical parameters

Likelihood Ratio

Continuous test results Asymptotic significance

95% CI

0.556

0.531

0.385 – 0.727

0.506

0.946

0.336 – 0.676

% of target dose MRA

0.524

0.785

0.350 – 0.699

VAS-dyspnea scale

0.522

0.795

0.347 – 0.697

0.495

0.953

0.309 – 0.681

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

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

% of target dose RAS-blocker

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% of target dose BB-blocker

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Clinical parameters

Area

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Parameter

Laboratory parameters

NT-proBNP

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Glomerular filtration rate

Echocardiographic parameters

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ACCEPTED MANUSCRIPT FIGURES

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

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

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Figure 2: Short-term weight changes

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day.

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

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