ESC HEART FAILURE ORIGINAL ARTICLE ESC Heart Failure 2022; 9: 656–666 Published online 11 November 2021 in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/ehf2.13696 Dose of furosemide before admission predicts diuretic efficiency and long-term prognosis in acute heart failure Zorba Blázquez-Bermejo1,4* , Nuria Farré1,2,3 , Pedro Caravaca Perez4,5 , Marc Llagostera1, Laura Morán-Fernández4,5, Aleix Fort1, Javier de Juan Bagudá4,5 , María Dolores García-Cosio4,5 , Sonia Ruiz-Bustillo1,2,6 and Juan F. Delgado4,5,7 1 Cardiology Department, Hospital del Mar, Barcelona, Spain; 2Biomedical Research Group on Heart Disease (GREC), Hospital del Mar Medical Research Group (IMIM), Barcelona, Spain; 3Department of Medicine, Universidad Autónoma de Barcelona, Barcelona, Spain; 4Cardiology Department, Hospital Universitario 12 de Octubre, Madrid, Spain; 5CIBER de Enfermedades Cardiovasculares (CIBERCV), Barcelona, Spain; 6Department of Medicine, Universitat Pompeu Fabra, Barcelona, Spain; and 7Faculty of Medicine, Universidad Complutense de Madrid, Madrid, Spain Abstract Aims The outpatient diuretic dose is a marker of diuretic resistance and prognosis in chronic heart failure (HF). Still, the im- pact of the preadmission dose on diuretic efficiency (DE) and prognosis in acute HF is not fully known. Methods and results We conducted an observational and prospective study. All patients admitted for acute HF treated with intravenous diuretic and at least one criterion of congestion on admission were evaluated. Decongestion [physical examina- tion, hemoconcentration, N-terminal pro-brain natriuretic peptide (NT-proBNP) change, and lung ultrasound], DE (weight loss and urine output per unit of 40 mg furosemide), and urinary sodium were monitored on the fifth day of admission. DE was dichotomized into high–low based on the median value. A multivariate Cox regression analysis was conducted to find predic- tors of HF readmission or mortality. A total of 105 patients were included between July 2017 and July 2019. Mean age was 74.5 ± 12.0 years, 64.8% were male, 33.3% had de novo HF, and mean left ventricular ejection fraction was 46 ± 17%. Median follow-up was 26 [15–35] months. Low DE based on weight loss was associated with a higher previous dose of furosemide (odds ratio [OR] 1.01 [1.00–1.02]), thiazide treatment before admission (OR 9.37 [2.19–40.14]), and lower diastolic blood pres- sure (OR 0.95 [0.91–0.98]) in the multivariate regression model. Only previous dose of furosemide (OR 1.01 [1.00–1.02]) and haemoglobin at admission (OR 0.76 [0.58–0.99]) were associated with low DE based on urine output in the multivariate anal- ysis. The correlation between the previous dose of furosemide and DE based on weight loss was poor (r = 0.12; P = 0.209) and with DE based on urine output was weak to moderate (r = 0.33; P < 0.001). Low DE based on weight loss and urine output was associated with lesser decongestion measured by NT-proBNP (P = 0.011; P = 0.007), hemoconcentration (P = 0.006; P = 0.044), and lung ultrasound (P = 0.034; P = 0.029), but not by physical examination (P = 0.506; P = 0.560). Sur- vival and event-free survival in acute decompensated HF (ADHF) were lower than in de novo HF; a preadmission dose of furosemide > 80 mg in ADHF identified patients with particularly poor prognosis (log-rank < 0.001). In ADHF, the preadmis- sion dose of furosemide (hazard ratio [HR] 1.34 [1.08–1.67] per 40 mg) and NT-proBNP at admission (HR 1.03 [1.01–1.06] per 1000 pg/mL) were independently associated with mortality or HF readmission in the multivariate Cox regression analysis. Conclusions The outpatient dose of furosemide before acute HF admission predicts DE and must be taken into account when deciding on the initial diuretic dose. In ADHF, the outpatient dose of furosemide can predict long-term prognosis better than DE during hospitalization. Keywords Acute heart failure; Diuretic resistance; Prognosis Received: 18 June 2021; Revised: 21 September 2021; Accepted: 29 October 2021 *Correspondence to: Zorba Blázquez-Bermejo, Cardiology Department, Hospital del Mar, Barcelona, Spain. Tel: 0034 915868000. Email: zorba.blazquez@salud.madrid.org © 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any me- dium, provided the original work is properly cited and is not used for commercial purposes. Dose of furosemide before admission predicts diuretic efficiency and long-term prognosis in acute heart failure 657 Introduction team reviewed the patients admitted to the Cardiology De- partment every day except on weekends and offered to par- Acute heart failure (HF) is one of the leading causes of hospi- ticipate to those who met the inclusion criteria. Every patient talization worldwide and carries a high risk of mortality and gave written informed consent. The study was approved by rehospitalization.1,2 Most of the symptoms related to acute the hospital’s ethics committees and complied with the Dec- HF are caused by congestion, and loop diuretics represent laration of Helsinki and the Declaration of Istanbul. the mainstay of its treatment.3 However, not every patient Past medical history, previous medical treatment, physical responds well to diuretics; symptoms and signs of congestion examination, blood test with NT-proBNP, and electrocardiog- may persist even with increasing diuretic dose, which has raphy and echocardiography data were collected at admis- been called diuretic resistance (DR). Although our under- sion. The diuretic dose and the rest of the medical standing of the pathophysiology behind DR is limited, it is treatment were left to the discretion of treating physicians. thought to result from a complex interplay between cardiac On the fifth day of admission, we evaluated decongestion and renal dysfunction, and specific renal adaptation, such as by physical examination, hemoconcentration, change in NT- neurohormonal activation and nephron remodelling.4–6 proBNP, and lung ultrasound with a pocket device (VScan, Moreover, there is no standardized and generally accepted GE Healthcare, Boston, MA, USA). Decongestion was defined definition of DR, although poor diuretic efficiency (DE) has by physical examination as the absence of jugular ingurgita- been associated with increased mortality and HF tion, lung crackles, ascites, and oedema of the lower limbs. readmission.7–11 These studies have defined DE as weight Hemoconcentration was assessed as the increase of the loss, net fluid loss, or urine output per 40 mg of furosemide haemoglobin level. A decrease of >30% of NT-proBNP level or equivalent. It appears, however, that the correlation be- was considered decongestion. Lastly, decongestion was de- tween weight and net fluid loss is modest and that the latter fined as the lack of pleural effusion or B-lines in the 28 spaces systematically overestimates weight loss.12 Additionally, assessed by lung ultrasound. these measures can be complex in daily clinical practice and Furthermore, on the fifth day, we assessed DE with the require several days from admission. In chronic HF, a high di- weight loss or urine output from admission per unit of uretic dose is a marker of DR and adverse outcomes.13–16 40 mg furosemide or equivalent and visual analogue scale Nevertheless, the impact of the outpatient dose before ad- of dyspnoea (0–10) and urinary sodium. The latter was mea- mission on DE in acute HF is not fully known. sured before the morning bolus of furosemide. Worsening re- The study aimed to investigate the predictors of low DE in nal function was defined as an increase in serum acute HF, focusing on the diuretic dose before admission and creatinine ≥ 0.3 mg/dL during hospitalization. An on-site visit the association between the different DR criteria and the with blood and urine tests was made 2 months after enrol- long-term prognosis. ment. Subsequent follow-up was left to the discretion of the treating physician. Finally, medical reports were reviewed in all patients at the end of September 2020. Methods Statistical analysis The design of the ‘REsistance to DIuretic in Heart Failure [REDIHF] registry’ was described in a previous report.17 It is Discrete variables were expressed as a proportion, and con- an observational and prospective study, which analyses dif- tinuous variables as a mean ± standard deviation or median ferent aspects of DR in patients admitted for HF. All patients [interquartile range]. Comparisons were made using the χ 2 admitted for acute HF in the Cardiology Department of the test or exact Fisher’s test for discrete variables and Student’s Hospital del Mar (between July 2017 and April 2018) and t-test or Mann–Whitney U test for continuous variables. Hospital Universitario 12 de Octubre (from May 2018 to July Patients were divided into three different groups depend- 2019) were screened for eligibility. The inclusion criteria were ing on the preadmission dose of furosemide: de novo HF, age > 18 years, an N-terminal pro-brain natriuretic peptide acute decompensated heart failure (ADHF) with a previous (NT-proBNP) > 600 or >1000 pg/mL in atrial fibrillation, the daily dose of furosemide ≤ 80 mg, and ADHF with a previous need for intravenous diuretic treatment, and at least one cri- daily dose of furosemide > 80 mg (this dose was associated terion of congestion on admission (jugular ingurgitation, lung with poor outcomes in chronic HF in previous studies). Base- crackles, ascites, oedema of the lower limbs, or pleural effu- line characteristics in both ADHF groups were compared with sion on chest X-ray or lung ultrasound). Patients on renal re- the de novo HF patients. placement therapy, under intravenous diuretic treatment for Diuretic efficiency based on weight loss and urine output >72 h before the screening, admitted to the intensive care was dichotomized into high vs. low based on the median unit, and those unable to understand and sign the informed value. The association between low DE and clinical character- consent were excluded. One physician of the investigation istics at admission was assessed with a multivariate logistic ESC Heart Failure 2022; 9: 656–666 DOI: 10.1002/ehf2.13696 658 Z. Blázquez-Bermejo et al. regression analysis. Variables with a univariate association Figure 1 Outpatient daily dose of furosemide before admission. with low DE with a P-value of <0.1 were included in the ini- tial model. Variables were removed from the initial model with the stepwise backward method with a cut-off point of P < 0.05. Differences on the fifth day between high vs. low DE in di- uretic doses, decongestion variables, urinary sodium, and vi- sual analogue scale of dyspnoea were analysed using the χ 2 test or exact Fisher’s test for discrete variables, and Student’s t-test or Mann–Whitney U test for continuous variables. Correlations between the previous dose of furosemide and both DE variables were evaluated using Spearman’s rho. Re- ceiver-operating characteristic (ROC) curve analysis was used to assess the area under the ROC curve (AUC) of the dose of furosemide before admission to predict low DE. Regarding the prognosis, we compared patients with de novo HF, ADHF with the previous dose of furosemide ≤ 80 mg, and ADHF with the previous dose of furosemide > 80 mg. Survival and event-free (death or HF re- admission) survival were compared using the Kaplan–Meier curves and the log-rank test. Event-free (death or readmis- Determinants of low diuretic efficiency sion) survival was also compared between high vs. low DE based on weight loss and urine output and between urinary On one side, low DE based on weight loss was associated with sodium < 50 vs. ≥50 mEq/L. A multivariate Cox regression a higher previous dose of furosemide, thiazide treatment be- analysis, including all the variables with P < 0.1 in the univar- fore admission, and lower diastolic blood pressure in the uni- iate analysis, was performed to identify independent predic- variate and multivariate analysis. On the other side, low DE tors of event-free (death or HF readmission) survival. based on urine output was associated with previous HF diag- Variables were removed from the model with the stepwise nosis, moderate-to-severe valvular heart disease, a higher backward method with a cut-off point of P < 0.05. Hazard ra- previous dose of furosemide, lower systolic and diastolic tios (HRs) and 95% confidence intervals (CIs) were calculated blood pressure, lower haemoglobin, and lower glomerular fil- for each risk factor. A P-value < 0.05 was considered signifi- tration rate in the univariate analyses. Nevertheless, only pre- cant. The statistical analysis was performed using Stata soft- vious dose of furosemide and haemoglobin at admission ware (V.14.0, Stata Corporation). were associated with low DE based on urine output in the multivariate regression model. It should be noted that the treatment with mineralocorticoid receptor antagonists be- fore admission was not associated with low DE based on weight loss or urine output (Table 2). Results A total of 105 patients were included between July 2017 and Decongestion and low diuretic efficiency July 2019. Mean age was 74.5 ± 12.0 years, 64.8% were male, 33.3% had de novo HF, mean left ventricular ejection fraction Concerning DE and its effect on decongestion, low DE led to (LVEF) was 46 ± 17%, and median dose of furosemide before a lesser decongestion. Patients with low DE required a admission was 40 [0–80] mg (Figure 1). All baseline character- higher dose of furosemide, and continuous diuretic infusion istics are shown in Table 1. The median total intravenous was more frequent. However, both low weight loss and dose of furosemide or equivalent received until the fifth urine output per unit of furosemide were associated with day was 300 [203–415] mg. In addition, median weight loss lesser decongestion measured by NT-proBNP, per unit of furosemide was 0.29 [0.12–0.58] kg and median hemoconcentration, and lung ultrasound. Surprisingly, resid- urine output per unit of furosemide was 0.78 [0.48–1.37] L. ual congestion measured by physical examination was simi- Mean hospital length of stay was 9.1 ± 5.8 days. Median fol- lar between high vs. low DE. In addition, patients with low low-up, which finished at the end of September 2020, was 26 DE based on weight loss had more dyspnoea measured by [15–35] months. Two patients died during hospitalization and the visual analogue scale and lower urinary sodium, and 33 in the subsequent follow-up. Moreover, 42 patients were those with lower DE based on urine output had longer hos- readmitted for HF. pital length of stay (Table 3). ESC Heart Failure 2022; 9: 656–666 DOI: 10.1002/ehf2.13696 Dose of furosemide before admission predicts diuretic efficiency and long-term prognosis in acute heart failure 659 Table 1 Baseline characteristics ADHF–dose of ADHF–dose of De novo HF furosemide ≤ 80 mg furosemide > 80 mg (n = 35) (n = 50) P (n = 20) P Age (years) 74 ± 13 75 ± 10 0.767 74 ± 14 0.951 Male sex 26 (74.3%) 31 (62.0%) 0.236 11 (55.0%) 0.143 Diabetes mellitus 11 (31.4%) 25 (50.0%) 0.088 9 (45.0%) 0.314 Arterial hypertension 27 (77.1%) 46 (92.0%) 0.064 17 (85.0%) 0.483 Dyslipidaemia 21 (60.0%) 37 (74.0%) 0.172 12 (60.0%) 1.000 2 Body mass index (kg/m ) 28.6 ± 5.1 28.9 ± 5.7 0.825 29.4 ± 4.8 0.601 Chronic kidney disease 8 (22.9%) 19 (38%) 0.140 14 (70%) 0.001 Chronic obstructive pulmonary disease 9 (25.7%) 10 (20.0%) 0.534 6 (30.0%) 0.731 Cerebrovascular disease 3 (8.6%) 5 (10.0%) 1.000 1 (5.0%) 1.000 Peripheral vascular disease 3 (8.6%) 3 (6.0%) 0.687 1 (5.0%) 1.000 a Significant coronary artery disease 8 (22.9%) 22 (44.0%) 0.045 6 (30.0%) 0.559 Moderate-to-severe valvular heart disease 7 (20.0%) 24 (48.0%) 0.008 12 (60.0%) 0.003 Atrial fibrillation 19 (54.3%) 30 (60.0%) 0.600 16 (80.0%) 0.082 LVEF (%) 46 ± 15 43 ± 18 0.320 51 ± 18 0.295 HFrEF 11 (31.4%) 24 (48.8%) 0.127 5 (25.0%) 0.614 HFmrEF 6 (17.7%) 4 (8.0%) 0.305 1 (5.0%) 0.402 HFpEF 18 (51.4%) 22 (44.0%) 0.499 14 (70.0%) 0.179 Dose of furosemide before admission (mg) 0 [0–20] 40 [40–80] <0.001 120 [120–160] <0.001 Beta-blocker before admission 16 (45.7%) 43 (86.0%) <0.001 18 (90.0%) 0.001 ACE inhibitor or ARB before admission 23 (65.7%) 27 (54.0%) 0.280 9 (45.0%) 0.134 Sacubitril/valsartan before admission 0 (0%) 6 (12%) 0.040 2 (10.0%) 0.128 MRA before admission 5 (14.3%) 14 (28.0%) 0.135 8 (40.0%) 0.031 SGLT2 inhibitor before admission 1 (2.9%) 1 (2.0%) 1.000 0 (0%) 1.000 NSAIDs before admission 1 (2.9%) 0 (0%) 0.417 0 (0%) 1.000 Haemoglobin at admission (g/dL) 12.7 ± 2.1 12.9 ± 1.9 0.583 11.8 ± 2.1 0.115 Sodium at admission (mmol/L) 141 ± 3 140 ± 4 0.267 140 ± 5 0.648 Glomerular filtration rate at admission (mL/ 62 ± 21 55 ± 21 0.111 44 ± 19 0.002 2 min/1.73 m ) GGT at admission (U/L) 72 ± 66 80 ± 75 0.651 77 ± 55 0.873 Bilirubin at admission (mg/dL) 0.8 ± 0.5 1.0 ± 0.7 0.102 1.1 ± 1.0 0.234 Albumin at admission (g/dL) 3.9 ± 0.4 3.9 ± 0.5 0.879 3.9 ± 0.5 0.829 NT-proBNP at admission (pg/mL) 3665 [2300–5801] 6000 [2667–12 091] 0.046 5605 [2328–14 540] 0.105 ACE, angiotensin-converting enzyme; ADHF, acute decompensated heart failure; ARB, angiotensin II receptor blocker; HF, heart failure; HFmrEF, heart failure with mid-range ejection fraction; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with re- duced ejection fraction; LVEF, left ventricular ejection fraction; MRA, mineralocorticoid receptor antagonist; NSAIDs, non-steroidal anti- inflammatory drugs; NT-proBNP, N-terminal pro-brain natriuretic peptide; SGLT2, sodium-glucose contransporter-2. Differences in baseline characteristics between groups: de novo HF, ADHF with previous daily dose of furosemide ≤ 80 mg, and ADHF with previous daily dose of furosemide > 80 mg. Each group of ADHF was compared with the de novo HF group. Significant coronary artery disease was defined by invasive coronary angiography as >50% stenosis of the left main stem or >70% ste- a nosis in a major coronary vessel. Dose of furosemide before admission and diuretic dictive value of 62.9% for low DE based on weight loss, and efficiency 76.3% and 65.6%, respectively, based on urine output. As mentioned above, patients with low DE had a higher dose of furosemide before admission. The correlation between the Diuretic resistance and long-term outcomes previous dose of furosemide and DE based on weight loss was poor (r = 0.12; P = 0.209) and with DE based on urine Survival and event-free (death or HF readmission) survival in output was weak to moderate (r = 0.33; P < 0.001). There ADHF were lower than in de novo HF; besides, a previous was a moderate correlation between DE based on weight loss daily dose of furosemide > 80 mg in ADHF identified patients and DE based on urine output (r = 0.54; P < 0.001) with particularly poor prognosis (log-rank < 0.001) (Figure 2). (Supporting Information, Figure S1). In addition, the previous Low DE based on urine output was also associated with a dose of furosemide showed an AUC = 0.65 to predict low DE worse prognosis (log-rank = 0.009). Still, the difference be- based on weight loss and an AUC = 0.72 to predict low DE tween high vs. low DE based on weight loss was not statisti- based on urine output (Supporting Information, Figure S2). cally significant (log-rank = 0.093) (Figure 3). Neither was the A previous daily dose of ≥80 mg was the best cut-off point; difference between high vs. low urinary sodium (log- it had a positive predictive value of 69.2% and negative pre- rank = 0.327). ESC Heart Failure 2022; 9: 656–666 DOI: 10.1002/ehf2.13696 660 Table 2 Predictors of low diuretic efficiency Low diuretic efficiency based on weight loss Low diuretic efficiency based on urine output Univariate Multivariate Univariate Multivariate OR (95% CI)/P-value OR (95% CI)/P-value OR (95% CI)/P-value OR (95% CI)/P-value Age (years) 1.00 (0.97–1.03)/0.983 1.01 (0.98–1.05)/0.335 Male sex 0.82 (0.36–1.84)/0.625 0.55 (0.24–1.28)/0.164 Arterial hypertension 2.81 (0.82–9.63)/0.101 0.88 (0.29–2.63)/0.812 Diabetes mellitus 1.04 (0.47–2.28)/0.933 0.82 (0.37–1.81)/0.621 Dyslipidaemia 1.84 (0.79–4.28)/0.159 0.94 (0.41–2.17)/0.887 De novo heart failure 0.72 (0.32–1.66)/0.441 0.25 (0.10–0.62)/0.003 NS a Significant coronary artery disease 0.94 (0.42–2.14)/0.891 1.67 (0.72–3.86)/0.233 Moderate-to-severe valvular heart disease 1.04 (0.47–2.28)/0.933 2.71(1.18–6.22)/0.019 NS Atrial fibrillation 0.97 (0.43–2.17)/0.938 1.59 (0.70–3.62)/0.266 LVEF (%) 1.02 (1.00–1.05)/0.070 NS 1.02 (0.99–1.04)/0.207 Dose of furosemide before admission (mg) 1.01 (1.00–1.02)/0.008 1.01 (1.00–1.02)/0.021 1.02 (1.01–1.03)/0.001 1.01 (1.00–1.02)/0.005 Thiazide before admission 3.68 (1.21–11.19)/0.022 9.37 (2.19–40.14)/0.003 0.47 (0.17–1.27)/0.137 Beta-blocker before admission 0.97 (0.40–2.37)/0.953 0.92 (0.37–2.29)/0.863 ACE inhibitor or ARB before admission 1.87 (0.84–4.16)/0.127 0.48 (0.21–1.10)/0.082 NS Sacubitril/valsartan before admission 0.15 (0.02–1.32)/0.088 NS 0.37 (0.07–1.99)/0.245 MRA before admission 1.14 (0.47–2.75)/0.776 1.07 (0.44–2.61)/0.870 Systolic blood pressure at admission (mmHg) 0.98 (0.96–1.00)/0.107 0.98 (0.96–0.99)/0.02 NS Diastolic blood pressure at admission (mmHg) 0.95 (.092–0.98)/0.003 0.95 (0.91–0.98)/0.002 0.98 (0.96–1.00)/0.02 NS Heart rate at admission (b.p.m.) 1.00 (0.98–1.02)/0.855 1.00 (0.98–1.02)/0.825 Haemoglobin at admission (g/dL) 0.91 (0.75–1.11)/0.373 0.71 (0.57–0.90)/0.004 0.76 (0.58–0.99)/0.038 Sodium at admission (mmol/L) 0.95 (0.86–1.05)/0.279 0.96 (0.87–1.06)/0.425 2 Glomerular filtration rate at admission (mL/min/1.73 m ) 0.99 (0.97–1.01)/0.410 0.98 (0.96–1.00)/0.022 NS Creatinine at admission (mg/dL) 1.39 (0.71–2.72)/0.340 1.80 (0.86–3.78)/0.121 Urea at admission (mg/dL) 1.00 (0.98–1.02)/0.837 1.02 (0.99–1.04)/0.153 Albumin at admission (g/dL) 1.00 (0.96–1.05)/0.871 1.00 (0.96–1.05)/0.891 GGT at admission (U/L) 1.00 (0.99–1.01)/0.972 1.00 (0.99–1.00)/0.591 Bilirubin at admission (mg/dL) 1.09 (0.63–1.90)/0.752 1.30 (0.74–2.28)/0.368 NT-proBNP at admission (pg/mL) 1.00 (0.99–1.01)/0.646 0.99 (0.98–1.01)/0.371 ACE, angiotensin-converting enzyme; ARB, angiotensin II receptor blocker; CI, confidence interval; LVEF, left ventricular ejection fraction; MRA, mineralocorticoid receptor antagonist; NS, not significant; NT-proBNP, N-terminal pro-brain natriuretic peptide; OR, odds ratio. Association between clinical characteristics at admission and low diuretic efficiency based on weight loss and based on urine output. a Significant coronary artery disease was defined by invasive coronary angiography as >50% stenosis of the left main coronary artery or >70% stenosis in a major coronary vessel. DOI: 10.1002/ehf2.13696 ESC Heart Failure 2022; 9: 656–666 Z. Blázquez-Bermejo et al. Table 3 Differences during hospitalization between patients with low vs. high diuretic efficiency Diuretic efficiency based on weight loss Diuretic efficiency based on urine output Low diuretic efficiency High diuretic efficiency P-value Low diuretic efficiency High diuretic efficiency P-value No congestion on physical examination on the 5th day 45.8% 39.2% 0.506 40.0% 45.8% 0.560 Decrease in NT-proBNP > 30% 48.9% 74.0% 0.011 48.9% 75.5% 0.007 Change in haemoglobin on the 5th day (g/dL) 0.18 ± 1.19 0.43 ± 0.93 0.006 0.08 ± 1.15 0.38 ± 1.05 0.044 Increase in haemoglobin on the 5th day 44.9% 70.0% 0.012 54.2% 63.3% 0.363 Lack of B-lines in lung ultrasound on the 5th day 26.8% 48.9% 0.034 25.0% 47.8% 0.029 UNa on the 5th day (mEq/L) 51 ± 30 67 ± 33 0.019 60 ± 33 60 ± 35 0.982 UNa on the 5th day <50 mEq/L 50.0% 34.8% 0.154 40.5% 44.2% 0.729 VAS of dyspnoea on the 5th day (0–10) 2.6 ± 2.6 1.6 ± 2.0 0.035 2.2 ± 2.4 1.5 ± 2.1 0.154 Cumulative dose of furosemide on the 5th day (mg) 330 [220–480] 240 [200–340] 0.029 400 [320–540] 220 [170–260] <0.001 Dose of furosemide in the 1st day (mg) 100 [60–145] 80 [60–120] 0.272 120 [80–160] 80 [60–80] <0.001 Dose of furosemide in the 2nd day (mg) 80 [60–160] 60 [60–120] 0.025 120 [80–160] 60 [40–70] <0.001 Dose of furosemide in the 3rd day (mg) 80 [40–120] 60 [40–80] 0.006 80 [55–120] 40 [40–60] <0.001 Dose of furosemide in the 4th day (mg) 40 [28–83] 40 [20–60] 0.446 60 [40–120] 40 [0–60] <0.001 Peak intravenous furosemide dose in 24 h (mg) 120 [80–160] 80 [60–140] 0.065 155 [100–180] 80 [60–95] <0.001 Intravenous furosemide during >48 h 72.0% 72.5% 0.951 84.0% 59.2% 0.006 Continuous diuretic infusion 20.0% 5.9% 0.041 30.0% 0.0% <0.001 Cumulative dose of hydrochlorothiazide on the 5th day (mg) 20 ± 40 18 ± 28 0.747 23 ± 40 14 ± 27 0.171 Worsening renal function 52.0% 34.0% 0.069 52.0% 33.3% 0.062 In-hospital inotropes or vasopressors 4.0% 9.8% 0.436 6.0% 8.2% 0.715 Length of stay (days) 9.4 ± 5.8 8.4 ± 4.7 0.319 9.9 ± 6.0 7.8 ± 4.1 0.039 NT-proBNP, N-terminal pro-brain natriuretic peptide; UNa, urinary sodium; VAS, visual analogue scale. Dose of furosemide before admission predicts diuretic efficiency and long-term prognosis in acute heart failure DOI: 10.1002/ehf2.13696 ESC Heart Failure 2022; 9: 656–666 661 662 Z. Blázquez-Bermejo et al. Figure 2 Outcomes in de novo HF and ADHF based on preadmission dose of furosemide. Survival (A) and event-free (death or HF readmission) survival (B) were compared between de novo HF, ADHF with preadmission dose of furosemide ≤ 80 mg, and ADHF with preadmission dose of furosemide > 80 mg. Figure 3 Event-free (death or HF readmission) survival in low vs. high diuretic efficiency based on weight loss (A) and based on urine output (B). In the univariate Cox regression analysis, dyslipidaemia, admission and NT-proBNP at admission were independently previous HF diagnosis, higher dose of furosemide before ad- associated with mortality or HF readmission (Table 4). mission, lower glomerular filtration rate at admission, higher NT-proBNP at admission, decrease in NT-proBNP ≤ 30%, lower increase in haemoglobin, and lower DE based on both weight loss and urine output were associated with mortality Discussion or HF readmission. However, in the multivariate analysis, only previous HF diagnosis, NT-proBNP at admission, decrease in The analysis of the REDIHF registry showed that more ad- NT-proBNP ≤ 30%, and DE based on weight loss were inde- vanced disease, low blood pressure, renal dysfunction, anae- pendent predictors of mortality or HF readmission. We also mia, and high preadmission dose of diuretics are predictors of performed a multivariate Cox regression analysis in ADHF pa- low DE in acute HF. Furthermore, low DE was associated with tients (excluding de novo HF): the dose of furosemide before a lesser decongestion. The dose of furosemide before admis- ESC Heart Failure 2022; 9: 656–666 DOI: 10.1002/ehf2.13696 Table 4 Univariate and multivariate Cox regression analysis for mortality or HF readmission in the whole cohort and in ADHF cohort All patients (n = 105) Acute decompensated heart failure (n = 70) Univariate Multivariate Univariate Multivariate HR (95% CI) P-value HR (95% CI) P-value HR (95% CI) P-value HR (95% CI) P-value Age (years) 1.00 (0.98–1.03) 0.814 0.99 (0.96–1.02) 0.504 Male sex 0.99 (0.57–1,71) 0.982 1.37 (0.75–2.52) 0.305 Arterial hypertension 1.03 (0.49–2.19) 0.934 0.72 (0.30–1.70) 0.446 Diabetes mellitus 1.20 (0.71–2.05) 0.483 1.15 (0.64–2.05) 0.639 Dyslipidaemia 2.02 (1.09–3.77) 0.026 NS 1.55 (0.80–3.01) 0.192 De novo heart failure 0.33 (0.16–0.65) 0.001 0.38 (0.18–0.79) 0.010 Atrial fibrillation 1.36 (0.78–2.36) 0.275 1.23 (0.66–2.28) 0.519 a Significant coronary artery disease 1.07 (0.61–1.87) 0.806 1.13 (0.63–2.05) 0.683 LVEF < 40% 1.42 (0.83–2.41) 0.191 1.34 (0.75–2.39) 0.326 Beta-blocker before admission 1.06 (0.58–1.96) 0.829 0.47 (0.22–1.02) 0.055 NS ACE inhibitor or ARB before admission 0.88 (0.52–1.48) 0.622 1.08 (0.60–1.93) 0.799 Sacubitril/valsartan before admission 1.59 (0.68–3.73) 0.282 1.12 (0.48–2.65) 0.793 MRA before admission 1.18 (0.66–2.11) 0.578 1.01 (0.55–1.89) 0.966 Dose of furosemide before admission (per 40 mg) 1.44 (1.21–1.71) <0.001 NS 1.33 (1.08–1.65) 0.007 1.34 (1.08–1.67) 0.009 Thiazide before admission 0.98 (0.50–1.95) 0.964 1.15 (0.51–2.57) 0.737 Systolic blood pressure at admission (mmHg) 0.99 (0.98–1.01) 0.592 0.99 (0.98–1.01) 0.334 Heart rate at admission (b.p.m.) 0.99 (0.98–1.01) 0.700 1.00 (0.98–1.01) 0.871 Haemoglobin at admission (g/dL) 0.89 (0.78–1.02) 0.087 NS 0.88 (0.76–1.02) 0.081 Sodium at admission (mmol/L) 1.01 (0.94–1.08) 0.737 1.02 (0.95–1.10) 0.559 2 Glomerular filtration rate at admission (mL/min/1.73 m ) 0.98 (0.97–1.00) 0.018 NS 0.99 (0.98–1.01) 0.192 Creatinine at admission (mg/dL) 1.64 (1.11–2.42) 0.013 NS 1.61 (1.01–2.56) 0.047 NS Albumin at admission (g/dL) 0.88 (0.50–1.56) 0.662 0.75 (0.42–1.37) 0.350 GGT at admission (U/L) 1.00 (0.99–1.01) 0.128 1.00 (1.00–1.01) 0.804 Bilirubin at admission (mg/dL) 1.28 (0.89–1.85) 0.181 0.87 (0.57–1.34) 0.534 NT-proBNP at admission (per 1000 pg/mL) 1.04 (1.02–1.07) <0.001 1.08 (1.04–1.12) <0.001 1.03 (1.01–1.06) 0.004 1.03 (1.01–1.06) 0.004 Urine output per unit of furosemide (per 100 mL/40 mg) 0.93 (0.88–0.98) 0.007 NS 0.96 (0.91–1.02) 0.153 Weight loss per unit of furosemide (per 100 g/40 mg) 0.94 (0.89–1.00) 0.038 0.91 (0.85–0.98) 0.009 0.93 (0.86–1.00) 0.054 NS UNa on the 5th day (mEq/L) 1.00 (0.99–1.01) 0.795 1.00 (0.99–1.01) 0.774 Decrease in NT-proBNP > 30% 0.52 (0.30–0.89) 0.016 0.45 (0.25–0.83) 0.010 0.69 (0.38–1.27) 0.232 Dose of furosemide before admission predicts diuretic efficiency and long-term prognosis in acute heart failure Change in haemoglobin on the 5th day (g/dL) 0.78 (0.63–0.97) 0.026 NS 0.82 (0.65–1.04) 0.102 Lack of B-lines in lung ultrasound on the 5th day 0.67 (0.37–1.22) 0.193 0.72 (0.38–1.39) 0.333 ACE, angiotensin-converting enzyme; ARB, angiotensin II receptor blocker; CI, confidence interval; HR, hazard ratio; LVEF, left ventricular ejection fraction; MRA, mineralocorticoid re- ceptor antagonist; NS, not significant; NT-proBNP, N-terminal pro-brain natriuretic peptide; UNa, urinary sodium. a Significant coronary artery disease was defined by invasive coronary angiography as >50% stenosis of the left main coronary artery or >70% stenosis in a major coronary vessel. DOI: 10.1002/ehf2.13696 ESC Heart Failure 2022; 9: 656–666 663 664 Z. Blázquez-Bermejo et al. sion seems better to predict DE based on urine output than Dose of furosemide before admission and diuretic weight loss. Both previous outpatient dose of furosemide, efficiency NT-proBNP levels, and DE based on weight loss were inde- pendent predictors of HF readmission or mortality. Loop diuretic agents inhibit NaCl reabsorption in the thick as- cending limb, thereby increasing the luminal NaCl concentra- tion in fluid entering the distal convoluted tubule. However, chronic diuretic treatment increases the capacity of the distal Determinants of low diuretic efficiency nephron to reabsorb delivered NaCl, leading to a decline in natriuresis (‘braking phenomenon’).25 In our study, the previ- More advanced disease, low blood pressure, renal dysfunc- ous outpatient dose of furosemide helped predict low DE in tion, anaemia, and high preadmission dose of diuretics acute HF, especially with regard to DE based on urine output. were predictors of low DE. Similar results have been seen In fact, the latter had a weak to moderate correlation with in other studies.6–8,10,11 First, renal dysfunction is common the previous dose of furosemide. This supports the current among patients hospitalized with acute HF and is an impor- recommendation of treating patients on an ambulatory di- tant determinant of diuretic response.6,18 Diuretic exerts uretic regimen with at least the pre-existing oral dose admin- their effects via the kidney, relying on secretion to achieve istered intravenously.3 Furthermore, the DOSE-AHF trial the tubule. Renal dysfunction is associated with reduced di- demonstrated that high loop diuretic dose (2.5 usual home uretic secretion and consequently worse urinary diuretic dose) compared with low dose (equal to home dose) resulted delivery. However, defects at the level of the renal tubule in higher dyspnoea relief, weight loss, and net fluid loss.26 are more important than reduced diuretic delivery in deter- Worsening renal function occurred more in the high-dose mining DR.19 Second, it would appear reasonable that more arm. However, subsequent analyses showed that an initial advanced disease and low blood pressure predict low DE, rise in plasma creatinine was associated with better, rather as they are linked to chronic kidney disease and higher than worse, long-term clinical outcomes.27 Therefore, the doses of diuretics. Third, anaemia in HF has been associ- outpatient dose of furosemide before admission and renal ated with increased severity of HF, progressive worsening function should be critical when deciding on the initial di- of renal function, and the need for higher doses of uretic dose in acute HF. diuretics.20 Therefore, it is not surprising that anaemia was associated with low DE in our study. Finally, as will be explained below, a high outpatient dose of furosemide before admission predicts low DE. However, the treatment Diuretic resistance and long-term outcomes with mineralocorticoid receptor antagonists did not affect DE in our study. This is not surprising, given that in the Several post hoc analyses from different clinical trials in acute ATHENA-HF trial, high-dose spironolactone use was not as- HF have shown that poor DE is associated with HF readmis- sociated with greater congestion improvement, urine out- sion and mortality.7,8,11 Our results also showed this associa- put, weight loss, or clinical outcomes.21 tion in a real-world population with acute HF, that is, older patients, those with preserved LVEF, or those with several co- morbidities. However, an even more important finding was the usefulness of the outpatient dose of furosemide before Decongestion and low diuretic efficiency admission to predict long-term outcomes. In this sense, it should be noted that its ability to predict HF readmission or Congestion evaluation is key in the therapeutic management mortality in ADHF was independent of DE during hospitaliza- of acute HF. Given that physical examination has some limita- tion. Moreover, it is easily obtained and available in all pa- tions in the assessment of decongestion, several biomarkers tients at admission, so its usefulness in clinical practice is and lung ultrasound parameters have been proposed as es- assured. A daily dose of furosemide > 80 mg was associated sential tools to guide diuretic treatment. We assessed change with poor outcomes in chronic HF in previous in NT-proBNP, hemoconcentration, and lung ultrasound, as studies.13,14,28,29 It was a good cut-off point at admission to they had shown to predict outcomes in acute HF.22–24 Pa- predict mortality or HF rehospitalization in our study. More- tients with low DE, as could be expected, had lesser decon- over, it should be noted that for each extra 40 mg of furose- gestion measured by all these methods. Surprisingly, mide, we observed a 34% increased risk of events. This was residual congestion measured by physical examination was also observed in a post hoc analysis from the DOSE trial that similar in high vs. low DE patients. This may be because it showed that previous furosemide dose ≥ 120 mg in ADHF was collected as a dichotomized variable, and there is consid- was associated with increased risk of HF readmission or death erable subjectivity in its measurement. at 60 days.30 ESC Heart Failure 2022; 9: 656–666 DOI: 10.1002/ehf2.13696 Dose of furosemide before admission predicts diuretic efficiency and long-term prognosis in acute heart failure 665 Limitations Conclusions Several limitations of this study are worth noting. First, the More advanced disease, low blood pressure, renal dysfunc- small sample size was the main limitation. In spite of this, tion, anaemia, and higher preadmission dose of diuretics pre- however, patients were rigorously evaluated during hospital- dict low DE during hospitalization. Outpatient dose of ization, and different methods to assess diuretic response furosemide and renal function must be taken into account and congestion were used. Thus, we consider that the pres- when deciding on the initial diuretic dose in acute HF. Fur- ent study provides important information about DR in acute thermore, low DE is associated with a lesser decongestion HF. Second, contrary to other studies, lower urinary sodium measured by NT-proBNP, hemoconcentration, and lung ultra- was not associated with worse outcomes. This was probably sound. Concerning prognosis, de novo HF patients have fewer because it was measured before loop-diuretic administration. events during follow-up. In ADHF, the outpatient dose of fu- Recent studies have shown the prognostic value of spot uri- rosemide before admission can predict long-term prognosis nary sodium after diuretic administration.31,32 In fact, we re- better than DE during hospitalization. cently described that low natriuresis after a furosemide stress test identifies patients at a higher risk of inadequate diuretic response and worse outcomes.33 Third, congestion measured by physical examination was collected as a dichotomized var- Conflict of interest iable. Therefore, we did not assess the degree of congestion None of the authors have any conflicts of interest to disclose. at admission or after diuretic treatment by this method. Fourth, fluid intake and net fluid loss were not measured. We took this decision because a previous study showed that the correlation between weight and net fluid loss is modest Funding and that the latter systematically overestimates weight loss.12 None. This is probably explained by inaccuracies in fluid intake de- termination and errors in the estimation of insensible water loss. Fifth, even though the dose of loop and thiazide di- Supporting information uretics was collected, the pathophysiology of diuretic re- sponse is complex and multifactorial; this makes difficult to Additional supporting information may be found online in the exclude confounding factors such as diuretic effect from Supporting Information section at the end of the article. other drugs, medical interactions, and, given its dynamic na- ture, variations in DR during hospitalization. Sixth, follow-up Figure S1: Correlation between previous dose of furosemide after the 2 month visit was telematic. However, we had ac- and DE based on weight loss (A) or DE based on urine output cess to medical reports in all patients and no patient was lost (B). Correlation between DE based on weight loss and based to follow-up. Finally, even though the COVID-19 pandemic on urine output (C). has collapsed the health care system and caused the deaths Figure S2: ROC curve of dose of furosemide before admission of thousands of people in our country, no patient died from to predict low diuretic efficiency based on weight loss (A) and COVID-19 during the study period. urine output (B). References 1. Ponikowski P, Voors AA, Anker SD, mittee and InvestigatorsCharacteristics the heart failure Association of the Euro- Bueno H, Cleland JGF, Coats AJS, Falk and outcomes of patients hospitalized pean Society of cardiology. Eur J Heart V, González-Juanatey JR, Harjola VP, for heart failure in the United States: Ra- Fail 2019; 21: 137–155. Jankowska EA, Jessup M, Linde C, tionale, design, and preliminary observa- 4. Ter Maaten JM, Valente MAE, Damman Nihoyannopoulos P, Parissis JT, Pieske tions from the first 100,000 cases in the K, Hillege HL, Navis G, Voors AA. Di- B, Riley JP, Rosano GMC, Ruilope LM, Acute Decompensated Heart Failure Na- uretic response in acute heart failure - Ruschitzka F, Rutten FH, van der Meer tional Registry (ADHERE). Am Heart J. pathophysiology, evaluation, and ther- P, ESC Scientific Document Group. 2016 2005; 149: 209–216. apy. Nat Rev Cardiol 2015; 12: 184–192. ESC guidelines for the diagnosis and 3. Mullens W, Damman K, Harjola VP, 5. Ellison DH, Felker GM. Diuretic treat- treatment of acute and chronic heart fail- Mebazaa A, Brunner-la Rocca HP, Mar- ment in heart failure. N Engl J Med ure. Eur Heart J 2016; 37: 2129–2200. tens P, Testani JM, Tang WHW, Orso F, 2017; 377: 1964–1975. 2. Adams KF, Fonarow GC, Emerman CL, Rossignol P, Metra M, Filippatos G, 6. Kiernan MS, Stevens SR, Tang WHW, LeJemtel TH, Costanzo MR, Abraham Seferovic PM, Ruschitzka F, Coats AJ. Butler J, Anstrom KJ, Birati EY, Grodin WT, Berkowitz RL, Galvao M, Horton The use of diuretics in heart failure with JL, Gupta D, Margulies KB, LaRue S, DP. ADHERE Scientific Advisory Com- congestion — A position statement from Dávila-Román VG, Hernandez AF, de ESC Heart Failure 2022; 9: 656–666 DOI: 10.1002/ehf2.13696 666 Z. Blázquez-Bermejo et al. Las Fuentes L, NHLBI Heart Failure Clin- of observational studies involving predicts rehospitalization in heart fail- ical Trials Network Investigators. Deter- 96,959 patients. Heart Fail Rev 2020. ure: A lung ultrasound study. Cardiovasc minants of diuretic responsiveness and https://doi.org/10.1007/s10741-020- Ultrasound 2015; 13: 40. associated outcomes during acute heart 09995-z 25. Felker GM, Ellison DH, Mullens W, Cox failure hospitalization: An analysis from 16. Eshaghian S, Horwich TB, Fonarow GC. ZL, Testani JM. Diuretic therapy for pa- the NHLBI heart failure network clinical Relation of loop diuretic dose to mortal- tients with heart failure: JACC state-of- trials. J Card Fail 2018; 24: 428–438. ity in advanced heart failure. Am J the-art review. J Am Coll Cardiol 2020; 7. Ter Maaten JM, Dunning AM, Valente Cardiol 2006; 97: 1759–1764. 75: 1178–1195. MAE, Damman K, Ezekowitz JA, Califf 17. Blázquez-Bermejo Z, Farré N, Llagostera 26. Felker GM, Lee KL, Bull DA, Redfield RM, Starling RC, van der Meer P, M, Caravaca Perez P, Morán-Fernández MM, Stevenson LW, Goldsmith SR, O’Connor CM, Schulte PJ, Testani JM, L, Fort A, De-Juan J, Ruiz S, Delgado LeWinter M, Deswal A, Rouleau JL, Ofili Hernandez AF, Tang WH, Voors AA. Di- JF. The development of chronic diuretic EO, Anstrom KJ, Hernandez AF, uretic response in acute heart failure - resistance can be predicted during a McNulty S, Velazquez EJ, Kfoury AG, An analysis from ASCEND-HF. Am Heart heartfailure hospitalization. Results Chen HH, Givertz MM, Semigran MJ, J. 2015; 170: 313–321.e4. from the REDIHF registry. PLoS One. Bart BA, Mascette AM, Braunwald E, 8. Voors AA, Davison BA, Teerlink JR, 2020; 15: e0240098. O’Connor CM, NHLBI Heart Failure Felker GM, Cotter G, Filippatos G, 18. Heywood JT, Fonarow GC, Costanzo Clinical Research Network. Diuretic Greenberg BH, Pang PS, Levin B, Hua MR, Mathur VS, Wigneswaran JR, strategies in patients with acute decom- TA, Severin T, Ponikowski P, Metra M, Wynne J. High prevalence of renal dys- pensated heart failure. N Engl J Med for the RELAX-AHF Investigators. Di- function and its impact on outcome in 2011; 364: 797–805. uretic response in patients with acute 118,465 patients hospitalized with acute 27. Brisco MA, Zile MR, Hanberg JS, Wilson decompensated heart failure: Character- decompensated heart failure: A report FP, Parikh CR, Coca SG, Tang WHW, istics and clinical outcome - an analysis from the ADHERE database. J Card Fail Testani JM. Relevance of changes in se- from RELAX-AHF. Eur J Heart Fail 2007; 13: 422–430. rum creatinine during a heart failure 2014; 16: 1230–1240. 19. ter Maaten JM, Rao VS, Hanberg JS, trial of decongestive strategies: Insights 9. Testani JM, Brisco MA, Turner JM, Spatz Perry Wilson F, Bellumkonda L, Assefa from the DOSE trial. J Card Fail 2016; ES, Bellumkonda L, Parikh CR, Tang M, Sam Broughton J, D’Ambrosi J, 22: 753–760. WHW. Loop diuretic efficiency a metric Wilson Tang WH, Damman K, Voors AA, 28. Kapelios CJ, Kaldara E, Ntalianis A, of diuretic responsiveness with prognos- Ellison DH, Testani JM. Renal tubular re- Sousonis V, Repasos E, Sfakianaki T, tic importance in acute decompensated sistance is the primary driver for loop di- Vakrou S, Pantsios C, Nanas JN, heart failure. Circ Hear Fail. 2014; 7: uretic resistance in acute heart failure. Terrovitis JV. High furosemide dose has 261–270. Eur J Heart Fail 2017; 19: 1014–1022. detrimental effects on survival of pa- 10. Aronson D, Burger AJ. Diuretic re- 20. Silverberg DS, Wexler D, Iaina A, tients with stable heart failure. Hell J sponse: Clinical and hemodynamic pre- Steinbruch S, Wollman Y, Schwartz D. Cardiol. 2015; 56: 154–159. dictors and relation to clinical outcome. Anemia, chronic renal disease and con- 29. Trullàs J-C, Casado J, Morales-Rull J-L, J Card Fail 2016; 22: 193–200. gestive heart failure - the cardio renal Formiga F, Conde-Martel A, Quirós R, 11. Valente MAE, Voors AA, Damman K, van anemia syndrome: The need for coopera- Epelde F, González-Franco Á, Manzano Veldhuisen DJ, Massie BM, O’Connor tion between cardiologists and nephrolo- L, Montero-Pérez-Barquero M. Preva- CM, Metra M, Ponikowski P, Teerlink gists. Int Urol Nephrol 2006; 38: lence and outcome of diuretic resistance JR, Cotter G, Davison B, Cleland JGF, 295–310. in heart failure. Intern Emerg Med 2019; Givertz MM, Bloomfield DM, Fiuzat M, 21. Butler J, Anstrom KJ, Felker GM, Givertz 14: 529–537. Dittrich HC, Hillege HL. Diuretic re- MM, Kalogeropoulos AP, Konstam MA, 30. Shah RV, McNulty S, O’Connor CM, sponse in acute heart failure: Clinical Mann DL, Margulies KB, McNulty SE, Felker GM, Braunwald E, Givertz MM. characteristics and prognostic signifi- Mentz RJ, Redfield MM, Tang WHW, Effect of admission oral diuretic dose cance. Eur Heart J 2014; 35: 1284–1293. Whellan DJ, Shah M, Desvigne-Nickens on response to continuous versus bolus 12. Testani JM, Brisco MA, Kociol RD, P, Hernandez AF, Braunwald E, for the intravenous diuretics in acute heart fail- Jacoby D, Bellumkonda L, Parikh CR, National Heart Lung and Blood Institute ure: An analysis from diuretic optimiza- Coca SG, Tang WHW. Substantial dis- Heart Failure Clinical Research Net- tion strategies in acute heart failure. crepancy between fluid and weight loss work. Efficacy and safety of Am Heart J 2012; 164: 862–868. during acute decompensated heart fail- spironolactone in acute heart failure. 31. Biegus J, Zymliński R, Sokolski M, Todd ure treatment. Am J Med 2015; 128: JAMA Cardiol 2017; 2: 950–958. J, Cotter G, Metra M, Jankowska EA, 776–783.e4. 22. Bettencourt P, Azevedo A, Pimenta J, Banasiak W, Ponikowski P. Serial assess- 13. Damman K, Kjekshus J, Wikstrand J, Friões F, Ferreira S, Ferreira A. N-termi- ment of spot urine sodium predicts effec- Cleland JGF, Komajda M, Wedel H, nal-pro-brain natriuretic peptide pre- tiveness of decongestion and outcome in Waagstein F, McMurray JJV. Loop di- dicts outcome after hospital discharge patients with acute heart failure. Eur J uretics, renal function and clinical out- in heart failure patients. Circulation Heart Fail 2019; 21: 624–633. come in patients with heart failure and 2004; 110: 2168–2174. 32. Tersalvi G, Dauw J, Gasperetti A, reduced ejection fraction. Eur J Heart 23. Breidthardt T, Weidmann ZM, Winterton D, Cioffi GM, Scopigni F, Fail 2016; 18: 328–336. Twerenbold R, Gantenbein C, Stallone Pedrazzini G, Mullens W. The value of 14. Martins J, Lourenço P, Araújo JP, F, Rentsch K, Rubini Gimenez M, urinary sodium assessment in acute Mascarenhas J, Lopes R, Azevedo A, Kozhuharov N, Sabti Z, Breitenbücher heart failure. Eur Hear Journal Acute Bettencourt P. Prognostic implications of D, Wildi K, Puelacher C, Honegger U, Cardiovasc Care 2020; 10: 216–223. diuretic dose in chronic heart failure. J Wagener M, Schumacher C, Hillinger P, 33. Caravaca Pérez P, Nuche J, Morán Cardiovasc Pharmacol Ther 2011; 16: Osswald S, Mueller C. Impact of Fernández L, Lora D, Blázquez-Bermejo 185–191. haemoconcentration during acute heart Z, López-Azor JC, de Juan Bagudá J, 15. Kapelios CJ, Bonou Μ, Malliaras K, failure therapy on mortality and its rela- García-Cosío Carmena MD, Escribano Athanasiadi E, Vakrou S, Skouloudi M, tionship with worsening renal function. Subías P, Salguero-Bodes R, Arribas Masoura C, Barbetseas J. Association of Eur J Heart Fail 2017; 19: 226–236. Ynsaurriaga F, Delgado JF. Potential role loop diuretics use and dose with out- 24. Gargani L, Pang PS, Frassi F, Miglioranza of natriuretic response to furosemide comes in outpatients with heart failure: MH, Dini FL, Landi P, Picano E. Persistent stress test during acute heart failure. A systematic review and meta-analysis pulmonary congestion before discharge Circ Hear Fail. 2021; 14: e008166. ESC Heart Failure 2022; 9: 656–666 DOI: 10.1002/ehf2.13696