Abstract
Aims
The outpatient diuretic dose is a marker of diuretic resistance and prognosis in chronic heart failure (HF). Still, the impact 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 examination, 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 predictors 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 pressure (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 analysis. 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). Survival 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 preadmission 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
Introduction
Acute heart failure (HF) is one of the leading causes of hospitalization worldwide and carries a high risk of mortality and rehospitalization. 1 , 2 Most of the symptoms related to acute HF are caused by congestion, and loop diuretics represent the mainstay of its treatment. 3 However, not every patient responds well to diuretics; symptoms and signs of congestion may persist even with increasing diuretic dose, which has been called diuretic resistance (DR). Although our understanding of the pathophysiology behind DR is limited, it is thought to result from a complex interplay between cardiac and renal dysfunction, and specific renal adaptation, such as neurohormonal activation and nephron remodelling. 4 , 5 , 6 Moreover, there is no standardized and generally accepted definition of DR, although poor diuretic efficiency (DE) has been associated with increased mortality and HF readmission. 7 , 8 , 9 , 10 , 11 These studies have defined DE as weight loss, net fluid loss, or urine output per 40 mg of furosemide or equivalent. It appears, however, that the correlation between weight and net fluid loss is modest and that the latter systematically overestimates weight loss. 12 Additionally, these measures can be complex in daily clinical practice and require several days from admission. In chronic HF, a high diuretic dose is a marker of DR and adverse outcomes. 13 , 14 , 15 , 16 Nevertheless, the impact of the outpatient dose before admission on DE in acute HF is not fully known.
The study aimed to investigate the predictors of low DE in acute HF, focusing on the diuretic dose before admission and the association between the different DR criteria and the long‐term prognosis.
Methods
The design of the ‘REsistance to DIuretic in Heart Failure [REDIHF] registry’ was described in a previous report. 17 It is an observational and prospective study, which analyses different aspects of DR in patients admitted for HF. All patients admitted for acute HF in the Cardiology Department of the Hospital del Mar (between July 2017 and April 2018) and Hospital Universitario 12 de Octubre (from May 2018 to July 2019) were screened for eligibility. The inclusion criteria were age > 18 years, an N‐terminal pro‐brain natriuretic peptide (NT‐proBNP) > 600 or >1000 pg/mL in atrial fibrillation, the need for intravenous diuretic treatment, and at least one criterion of congestion on admission (jugular ingurgitation, lung crackles, ascites, oedema of the lower limbs, or pleural effusion on chest X‐ray or lung ultrasound). Patients on renal replacement therapy, under intravenous diuretic treatment for >72 h before the screening, admitted to the intensive care unit, and those unable to understand and sign the informed consent were excluded. One physician of the investigation team reviewed the patients admitted to the Cardiology Department every day except on weekends and offered to participate to those who met the inclusion criteria. Every patient gave written informed consent. The study was approved by the hospital's ethics committees and complied with the Declaration of Helsinki and the Declaration of Istanbul.
Past medical history, previous medical treatment, physical examination, blood test with NT‐proBNP, and electrocardiography and echocardiography data were collected at admission. The diuretic dose and the rest of the medical treatment were left to the discretion of treating physicians. On the fifth day of admission, we evaluated decongestion by physical examination, hemoconcentration, change in NT‐proBNP, and lung ultrasound with a pocket device (VScan, GE Healthcare, Boston, MA, USA). Decongestion was defined by physical examination as the absence of jugular ingurgitation, lung crackles, ascites, and oedema of the lower limbs. Hemoconcentration was assessed as the increase of the haemoglobin level. A decrease of >30% of NT‐proBNP level was considered decongestion. Lastly, decongestion was defined as the lack of pleural effusion or B‐lines in the 28 spaces assessed by lung ultrasound.
Furthermore, on the fifth day, we assessed DE with the weight loss or urine output from admission per unit of 40 mg furosemide or equivalent and visual analogue scale of dyspnoea (0–10) and urinary sodium. The latter was measured before the morning bolus of furosemide. Worsening renal function was defined as an increase in serum creatinine ≥ 0.3 mg/dL during hospitalization. An on‐site visit with blood and urine tests was made 2 months after enrolment. 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.
Statistical analysis
Discrete variables were expressed as a proportion, and continuous variables as a mean ± standard deviation or median [interquartile range]. Comparisons were made 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.
Patients were divided into three different groups depending on the preadmission dose of furosemide: de novo HF, acute decompensated heart failure (ADHF) with a previous daily dose of furosemide ≤ 80 mg, and ADHF with a previous daily dose of furosemide > 80 mg (this dose was associated with poor outcomes in chronic HF in previous studies). Baseline characteristics in both ADHF groups were compared with the de novo HF patients.
Diuretic efficiency based on weight loss and urine output was dichotomized into high vs. low based on the median value. The association between low DE and clinical characteristics at admission was assessed with a multivariate logistic regression analysis. Variables with a univariate association with low DE with a P‐value of <0.1 were included in the initial 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 diuretic doses, decongestion variables, urinary sodium, and visual 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. Receiver‐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 readmission) survival were compared using the Kaplan–Meier curves and the log‐rank test. Event‐free (death or readmission) survival was also compared between high vs. low DE based on weight loss and urine output and between urinary sodium < 50 vs. ≥50 mEq/L. A multivariate Cox regression analysis, including all the variables with P < 0.1 in the univariate analysis, was performed to identify independent predictors of event‐free (death or HF readmission) survival. Variables were removed from the model with the stepwise backward method with a cut‐off point of P < 0.05. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated for each risk factor. A P‐value < 0.05 was considered significant. The statistical analysis was performed using Stata software (V.14.0, Stata Corporation).
Results
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, mean left ventricular ejection fraction (LVEF) was 46 ± 17%, and median dose of furosemide before admission was 40 [0–80] mg (Figure 1 ). All baseline characteristics are shown in Table 1 . The median total intravenous dose of furosemide or equivalent received until the fifth day was 300 [203–415] mg. In addition, median weight loss per unit of furosemide was 0.29 [0.12–0.58] kg and median urine output per unit of furosemide was 0.78 [0.48–1.37] L. Mean hospital length of stay was 9.1 ± 5.8 days. Median follow‐up, which finished at the end of September 2020, was 26 [15–35] months. Two patients died during hospitalization and 33 in the subsequent follow‐up. Moreover, 42 patients were readmitted for HF.
Figure 1.
Outpatient daily dose of furosemide before admission.
Table 1.
Baseline characteristics
| De novo HF | ADHF–dose of furosemide ≤ 80 mg | P | ADHF–dose of furosemide > 80 mg | P | |
|---|---|---|---|---|---|
| (n = 35) | (n = 50) | (n = 20) | |||
| 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 |
| Body mass index (kg/m2) | 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 |
| Significant coronary artery disease a | 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/min/1.73 m2) | 62 ± 21 | 55 ± 21 | 0.111 | 44 ± 19 | 0.002 |
| 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 reduced 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% stenosis in a major coronary vessel.
Determinants of low diuretic efficiency
On one side, low DE based on weight loss was associated with a higher previous dose of furosemide, thiazide treatment before admission, and lower diastolic blood pressure in the univariate and multivariate analysis. On the other side, low DE based on urine output was associated with previous HF diagnosis, moderate‐to‐severe valvular heart disease, a higher previous dose of furosemide, lower systolic and diastolic blood pressure, lower haemoglobin, and lower glomerular filtration rate in the univariate analyses. Nevertheless, only previous dose of furosemide and haemoglobin at admission 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 before admission was not associated with low DE based on weight loss or urine output (Table 2 ).
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 | |
| Significant coronary artery disease a | 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 | ||
| Glomerular filtration rate at admission (mL/min/1.73 m2) | 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.
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.
Decongestion and low diuretic efficiency
Concerning DE and its effect on decongestion, low DE led to a lesser decongestion. Patients with low DE required a higher dose of furosemide, and continuous diuretic infusion was more frequent. However, both low weight loss and urine output per unit of furosemide were associated with lesser decongestion measured by NT‐proBNP, hemoconcentration, and lung ultrasound. Surprisingly, residual congestion measured by physical examination was similar between high vs. low DE. In addition, patients with low DE based on weight loss had more dyspnoea measured by the visual analogue scale and lower urinary sodium, and those with lower DE based on urine output had longer hospital length of stay (Table 3 ).
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 and diuretic efficiency
As mentioned above, patients with low DE had a higher dose of furosemide before admission. 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). There was a moderate correlation between DE based on weight loss and DE based on urine output (r = 0.54; P < 0.001) (Supporting Information, Figure S1 ). In addition, the previous dose of furosemide showed an AUC = 0.65 to predict low DE based on weight loss and an AUC = 0.72 to predict low DE based on urine output (Supporting Information, Figure S2 ). A previous daily dose of ≥80 mg was the best cut‐off point; it had a positive predictive value of 69.2% and negative predictive value of 62.9% for low DE based on weight loss, and 76.3% and 65.6%, respectively, based on urine output.
Diuretic resistance and long‐term outcomes
Survival and event‐free (death or HF readmission) survival in ADHF were lower than in de novo HF; besides, a previous daily dose of furosemide > 80 mg in ADHF identified patients with particularly poor prognosis (log‐rank < 0.001) (Figure 2 ). Low DE based on urine output was also associated with a worse prognosis (log‐rank = 0.009). Still, the difference between high vs. low DE based on weight loss was not statistically significant (log‐rank = 0.093) (Figure 3 ). Neither was the difference between high vs. low urinary sodium (log‐rank = 0.327).
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, previous HF diagnosis, higher dose of furosemide before admission, 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 or HF readmission. However, in the multivariate analysis, only previous HF diagnosis, NT‐proBNP at admission, decrease in NT‐proBNP ≤ 30%, and DE based on weight loss were independent predictors of mortality or HF readmission. We also performed a multivariate Cox regression analysis in ADHF patients (excluding de novo HF): the dose of furosemide before admission and NT‐proBNP at admission were independently associated with mortality or HF readmission (Table 4 ).
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 | ||||
| Significant coronary artery disease a | 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 | ||||
| Glomerular filtration rate at admission (mL/min/1.73 m2) | 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 | ||
| 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 receptor antagonist; NS, not significant; NT‐proBNP, N‐terminal pro‐brain natriuretic peptide; UNa, urinary sodium.
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.
Discussion
The analysis of the REDIHF registry showed that more advanced disease, low blood pressure, renal dysfunction, anaemia, and high preadmission dose of diuretics are predictors of low DE in acute HF. Furthermore, low DE was associated with a lesser decongestion. The dose of furosemide before admission seems better to predict DE based on urine output than weight loss. Both previous outpatient dose of furosemide, NT‐proBNP levels, and DE based on weight loss were independent predictors of HF readmission or mortality.
Determinants of low diuretic efficiency
More advanced disease, low blood pressure, renal dysfunction, anaemia, and high preadmission dose of diuretics were predictors of low DE. Similar results have been seen in other studies. 6 , 7 , 8 , 10 , 11 First, renal dysfunction is common among patients hospitalized with acute HF and is an important determinant of diuretic response. 6 , 18 Diuretic exerts their effects via the kidney, relying on secretion to achieve the tubule. Renal dysfunction is associated with reduced diuretic secretion and consequently worse urinary diuretic delivery. However, defects at the level of the renal tubule are more important than reduced diuretic delivery in determining DR. 19 Second, it would appear reasonable that more advanced disease and low blood pressure predict low DE, as they are linked to chronic kidney disease and higher doses of diuretics. Third, anaemia in HF has been associated with increased severity of HF, progressive worsening of renal function, and the need for higher doses of 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 with mineralocorticoid receptor antagonists did not affect DE in our study. This is not surprising, given that in the ATHENA‐HF trial, high‐dose spironolactone use was not associated with greater congestion improvement, urine output, weight loss, or clinical outcomes. 21
Decongestion and low diuretic efficiency
Congestion evaluation is key in the therapeutic management of acute HF. Given that physical examination has some limitations in the assessment of decongestion, several biomarkers and lung ultrasound parameters have been proposed as essential tools to guide diuretic treatment. We assessed change in NT‐proBNP, hemoconcentration, and lung ultrasound, as they had shown to predict outcomes in acute HF. 22 , 23 , 24 Patients with low DE, as could be expected, had lesser decongestion measured by all these methods. Surprisingly, residual congestion measured by physical examination was similar in high vs. low DE patients. This may be because it was collected as a dichotomized variable, and there is considerable subjectivity in its measurement.
Dose of furosemide before admission and diuretic efficiency
Loop diuretic agents inhibit NaCl reabsorption in the thick ascending limb, thereby increasing the luminal NaCl concentration in fluid entering the distal convoluted tubule. However, chronic diuretic treatment increases the capacity of the distal nephron to reabsorb delivered NaCl, leading to a decline in natriuresis (‘braking phenomenon’). 25 In our study, the previous outpatient dose of furosemide helped predict low DE in acute HF, especially with regard to DE based on urine output. In fact, the latter had a weak to moderate correlation with the previous dose of furosemide. This supports the current recommendation of treating patients on an ambulatory diuretic regimen with at least the pre‐existing oral dose administered intravenously. 3 Furthermore, the DOSE‐AHF trial demonstrated that high loop diuretic dose (2.5 usual home dose) compared with low dose (equal to home dose) resulted in higher dyspnoea relief, weight loss, and net fluid loss. 26 Worsening renal function occurred more in the high‐dose arm. However, subsequent analyses showed that an initial rise in plasma creatinine was associated with better, rather than worse, long‐term clinical outcomes. 27 Therefore, the outpatient dose of furosemide before admission and renal function should be critical when deciding on the initial diuretic dose in acute HF.
Diuretic resistance and long‐term outcomes
Several post hoc analyses from different clinical trials in acute HF have shown that poor DE is associated with HF readmission and mortality. 7 , 8 , 11 Our results also showed this association in a real‐world population with acute HF, that is, older patients, those with preserved LVEF, or those with several comorbidities. However, an even more important finding was the usefulness of the outpatient dose of furosemide before admission to predict long‐term outcomes. In this sense, it should be noted that its ability to predict HF readmission or mortality in ADHF was independent of DE during hospitalization. Moreover, it is easily obtained and available in all patients at admission, so its usefulness in clinical practice is assured. A daily dose of furosemide > 80 mg was associated with poor outcomes in chronic HF in previous studies. 13 , 14 , 28 , 29 It was a good cut‐off point at admission to predict mortality or HF rehospitalization in our study. Moreover, it should be noted that for each extra 40 mg of furosemide, we observed a 34% increased risk of events. This was also observed in a post hoc analysis from the DOSE trial that showed that previous furosemide dose ≥ 120 mg in ADHF was associated with increased risk of HF readmission or death at 60 days. 30
Limitations
Several limitations of this study are worth noting. First, the small sample size was the main limitation. In spite of this, however, patients were rigorously evaluated during hospitalization, and different methods to assess diuretic response and congestion were used. Thus, we consider that the present study provides important information about DR in acute HF. Second, contrary to other studies, lower urinary sodium was not associated with worse outcomes. This was probably because it was measured before loop‐diuretic administration. Recent studies have shown the prognostic value of spot urinary sodium after diuretic administration. 31 , 32 In fact, we recently 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 variable. Therefore, we did not assess the degree of congestion 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 and that the latter systematically overestimates weight loss. 12 This is probably explained by inaccuracies in fluid intake determination and errors in the estimation of insensible water loss. Fifth, even though the dose of loop and thiazide diuretics was collected, the pathophysiology of diuretic response is complex and multifactorial; this makes difficult to exclude confounding factors such as diuretic effect from other drugs, medical interactions, and, given its dynamic nature, variations in DR during hospitalization. Sixth, follow‐up after the 2 month visit was telematic. However, we had access to medical reports in all patients and no patient was lost to follow‐up. Finally, even though the COVID‐19 pandemic has collapsed the health care system and caused the deaths of thousands of people in our country, no patient died from COVID‐19 during the study period.
Conclusions
More advanced disease, low blood pressure, renal dysfunction, anaemia, and higher preadmission dose of diuretics predict low DE during hospitalization. Outpatient dose of furosemide and renal function must be taken into account when deciding on the initial diuretic dose in acute HF. Furthermore, low DE is associated with a lesser decongestion measured by NT‐proBNP, hemoconcentration, and lung ultrasound. Concerning prognosis, de novo HF patients have fewer events during follow‐up. In ADHF, the outpatient dose of furosemide before admission can predict long‐term prognosis better than DE during hospitalization.
Conflict of interest
None of the authors have any conflicts of interest to disclose.
Funding
None.
Supporting information
Figure S1: Correlation between previous dose of furosemide and DE based on weight loss (A) or DE based on urine output (B). Correlation between DE based on weight loss and based on urine output (C).
Figure S2: ROC curve of dose of furosemide before admission to predict low diuretic efficiency based on weight loss (A) and urine output (B).
Blázquez‐Bermejo, Z. , Farré, N. , Caravaca Perez, P. , Llagostera, M. , Morán‐Fernández, L. , Fort, A. , de Juan Bagudá, J. , García‐Cosio, M. D. , Ruiz‐Bustillo, S. , and Delgado, J. F. (2022) Dose of furosemide before admission predicts diuretic efficiency and long‐term prognosis in acute heart failure. ESC Heart Failure, 9: 656–666. 10.1002/ehf2.13696.
References
- 1. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JGF, Coats AJS, Falk V, González‐Juanatey JR, Harjola VP, Jankowska EA, Jessup M, Linde C, Nihoyannopoulos P, Parissis JT, Pieske B, Riley JP, Rosano GMC, Ruilope LM, Ruschitzka F, Rutten FH, van der Meer P, ESC Scientific Document Group. 2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J 2016; 37: 2129–2200.27206819 [Google Scholar]
- 2. Adams KF, Fonarow GC, Emerman CL, LeJemtel TH, Costanzo MR, Abraham WT, Berkowitz RL, Galvao M, Horton DP. ADHERE Scientific Advisory Committee and InvestigatorsCharacteristics and outcomes of patients hospitalized for heart failure in the United States: Rationale, design, and preliminary observations from the first 100,000 cases in the Acute Decompensated Heart Failure National Registry (ADHERE). Am Heart J. 2005; 149: 209–216. [DOI] [PubMed] [Google Scholar]
- 3. Mullens W, Damman K, Harjola VP, Mebazaa A, Brunner‐la Rocca HP, Martens P, Testani JM, Tang WHW, Orso F, Rossignol P, Metra M, Filippatos G, Seferovic PM, Ruschitzka F, Coats AJ. The use of diuretics in heart failure with congestion — A position statement from the heart failure Association of the European Society of cardiology. Eur J Heart Fail 2019; 21: 137–155. [DOI] [PubMed] [Google Scholar]
- 4. Ter Maaten JM, Valente MAE, Damman K, Hillege HL, Navis G, Voors AA. Diuretic response in acute heart failure ‐ pathophysiology, evaluation, and therapy. Nat Rev Cardiol 2015; 12: 184–192. [DOI] [PubMed] [Google Scholar]
- 5. Ellison DH, Felker GM. Diuretic treatment in heart failure. N Engl J Med 2017; 377: 1964–1975. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6. Kiernan MS, Stevens SR, Tang WHW, Butler J, Anstrom KJ, Birati EY, Grodin JL, Gupta D, Margulies KB, LaRue S, Dávila‐Román VG, Hernandez AF, de Las Fuentes L, NHLBI Heart Failure Clinical Trials Network Investigators. Determinants of diuretic responsiveness and associated outcomes during acute heart failure hospitalization: An analysis from the NHLBI heart failure network clinical trials. J Card Fail 2018; 24: 428–438. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7. Ter Maaten JM, Dunning AM, Valente MAE, Damman K, Ezekowitz JA, Califf RM, Starling RC, van der Meer P, O'Connor CM, Schulte PJ, Testani JM, Hernandez AF, Tang WH, Voors AA. Diuretic response in acute heart failure ‐ An analysis from ASCEND‐HF. Am Heart J. 2015; 170: 313–321.e4. [DOI] [PubMed] [Google Scholar]
- 8. Voors AA, Davison BA, Teerlink JR, Felker GM, Cotter G, Filippatos G, Greenberg BH, Pang PS, Levin B, Hua TA, Severin T, Ponikowski P, Metra M, for the RELAX‐AHF Investigators . Diuretic response in patients with acute decompensated heart failure: Characteristics and clinical outcome ‐ an analysis from RELAX‐AHF. Eur J Heart Fail 2014; 16: 1230–1240. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9. Testani JM, Brisco MA, Turner JM, Spatz ES, Bellumkonda L, Parikh CR, Tang WHW. Loop diuretic efficiency a metric of diuretic responsiveness with prognostic importance in acute decompensated heart failure. Circ Hear Fail. 2014; 7: 261–270. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10. Aronson D, Burger AJ. Diuretic response: Clinical and hemodynamic predictors and relation to clinical outcome. J Card Fail 2016; 22: 193–200. [DOI] [PubMed] [Google Scholar]
- 11. Valente MAE, Voors AA, Damman K, van Veldhuisen DJ, Massie BM, O'Connor CM, Metra M, Ponikowski P, Teerlink JR, Cotter G, Davison B, Cleland JGF, Givertz MM, Bloomfield DM, Fiuzat M, Dittrich HC, Hillege HL. Diuretic response in acute heart failure: Clinical characteristics and prognostic significance. Eur Heart J 2014; 35: 1284–1293. [DOI] [PubMed] [Google Scholar]
- 12. Testani JM, Brisco MA, Kociol RD, Jacoby D, Bellumkonda L, Parikh CR, Coca SG, Tang WHW. Substantial discrepancy between fluid and weight loss during acute decompensated heart failure treatment. Am J Med 2015; 128: 776–783.e4. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13. Damman K, Kjekshus J, Wikstrand J, Cleland JGF, Komajda M, Wedel H, Waagstein F, McMurray JJV. Loop diuretics, renal function and clinical outcome in patients with heart failure and reduced ejection fraction. Eur J Heart Fail 2016; 18: 328–336. [DOI] [PubMed] [Google Scholar]
- 14. Martins J, Lourenço P, Araújo JP, Mascarenhas J, Lopes R, Azevedo A, Bettencourt P. Prognostic implications of diuretic dose in chronic heart failure. J Cardiovasc Pharmacol Ther 2011; 16: 185–191. [DOI] [PubMed] [Google Scholar]
- 15. Kapelios CJ, Bonou Μ, Malliaras K, Athanasiadi E, Vakrou S, Skouloudi M, Masoura C, Barbetseas J. Association of loop diuretics use and dose with outcomes in outpatients with heart failure: A systematic review and meta‐analysis of observational studies involving 96,959 patients. Heart Fail Rev 2020. 10.1007/s10741-020-09995-z [DOI] [PubMed] [Google Scholar]
- 16. Eshaghian S, Horwich TB, Fonarow GC. Relation of loop diuretic dose to mortality in advanced heart failure. Am J Cardiol 2006; 97: 1759–1764. [DOI] [PubMed] [Google Scholar]
- 17. Blázquez‐Bermejo Z, Farré N, Llagostera M, Caravaca Perez P, Morán‐Fernández L, Fort A, De‐Juan J, Ruiz S, Delgado JF. The development of chronic diuretic resistance can be predicted during a heartfailure hospitalization. Results from the REDIHF registry. PLoS One. 2020; 15: e0240098. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18. Heywood JT, Fonarow GC, Costanzo MR, Mathur VS, Wigneswaran JR, Wynne J. High prevalence of renal dysfunction and its impact on outcome in 118,465 patients hospitalized with acute decompensated heart failure: A report from the ADHERE database. J Card Fail 2007; 13: 422–430. [DOI] [PubMed] [Google Scholar]
- 19. ter Maaten JM, Rao VS, Hanberg JS, Perry Wilson F, Bellumkonda L, Assefa M, Sam Broughton J, D'Ambrosi J, Wilson Tang WH, Damman K, Voors AA, Ellison DH, Testani JM. Renal tubular resistance is the primary driver for loop diuretic resistance in acute heart failure. Eur J Heart Fail 2017; 19: 1014–1022. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20. Silverberg DS, Wexler D, Iaina A, Steinbruch S, Wollman Y, Schwartz D. Anemia, chronic renal disease and congestive heart failure ‐ the cardio renal anemia syndrome: The need for cooperation between cardiologists and nephrologists. Int Urol Nephrol 2006; 38: 295–310. [DOI] [PubMed] [Google Scholar]
- 21. Butler J, Anstrom KJ, Felker GM, Givertz MM, Kalogeropoulos AP, Konstam MA, Mann DL, Margulies KB, McNulty SE, Mentz RJ, Redfield MM, Tang WHW, Whellan DJ, Shah M, Desvigne‐Nickens P, Hernandez AF, Braunwald E, for the National Heart Lung and Blood Institute Heart Failure Clinical Research Network . Efficacy and safety of spironolactone in acute heart failure. JAMA Cardiol 2017; 2: 950–958. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22. Bettencourt P, Azevedo A, Pimenta J, Friões F, Ferreira S, Ferreira A. N‐terminal‐pro‐brain natriuretic peptide predicts outcome after hospital discharge in heart failure patients. Circulation 2004; 110: 2168–2174. [DOI] [PubMed] [Google Scholar]
- 23. Breidthardt T, Weidmann ZM, Twerenbold R, Gantenbein C, Stallone F, Rentsch K, Rubini Gimenez M, Kozhuharov N, Sabti Z, Breitenbücher D, Wildi K, Puelacher C, Honegger U, Wagener M, Schumacher C, Hillinger P, Osswald S, Mueller C. Impact of haemoconcentration during acute heart failure therapy on mortality and its relationship with worsening renal function. Eur J Heart Fail 2017; 19: 226–236. [DOI] [PubMed] [Google Scholar]
- 24. Gargani L, Pang PS, Frassi F, Miglioranza MH, Dini FL, Landi P, Picano E. Persistent pulmonary congestion before discharge predicts rehospitalization in heart failure: A lung ultrasound study. Cardiovasc Ultrasound 2015; 13: 40. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25. Felker GM, Ellison DH, Mullens W, Cox ZL, Testani JM. Diuretic therapy for patients with heart failure: JACC state‐of‐the‐art review. J Am Coll Cardiol 2020; 75: 1178–1195. [DOI] [PubMed] [Google Scholar]
- 26. Felker GM, Lee KL, Bull DA, Redfield MM, Stevenson LW, Goldsmith SR, LeWinter M, Deswal A, Rouleau JL, Ofili EO, Anstrom KJ, Hernandez AF, McNulty S, Velazquez EJ, Kfoury AG, Chen HH, Givertz MM, Semigran MJ, Bart BA, Mascette AM, Braunwald E, O'Connor CM, NHLBI Heart Failure Clinical Research Network. Diuretic strategies in patients with acute decompensated heart failure. N Engl J Med 2011; 364: 797–805. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27. Brisco MA, Zile MR, Hanberg JS, Wilson FP, Parikh CR, Coca SG, Tang WHW, Testani JM. Relevance of changes in serum creatinine during a heart failure trial of decongestive strategies: Insights from the DOSE trial. J Card Fail 2016; 22: 753–760. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28. Kapelios CJ, Kaldara E, Ntalianis A, Sousonis V, Repasos E, Sfakianaki T, Vakrou S, Pantsios C, Nanas JN, Terrovitis JV. High furosemide dose has detrimental effects on survival of patients with stable heart failure. Hell J Cardiol. 2015; 56: 154–159. [PubMed] [Google Scholar]
- 29. Trullàs J‐C, Casado J, Morales‐Rull J‐L, Formiga F, Conde‐Martel A, Quirós R, Epelde F, González‐Franco Á, Manzano L, Montero‐Pérez‐Barquero M. Prevalence and outcome of diuretic resistance in heart failure. Intern Emerg Med 2019; 14: 529–537. [DOI] [PubMed] [Google Scholar]
- 30. Shah RV, McNulty S, O’Connor CM, Felker GM, Braunwald E, Givertz MM. Effect of admission oral diuretic dose on response to continuous versus bolus intravenous diuretics in acute heart failure: An analysis from diuretic optimization strategies in acute heart failure. Am Heart J 2012; 164: 862–868. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31. Biegus J, Zymliński R, Sokolski M, Todd J, Cotter G, Metra M, Jankowska EA, Banasiak W, Ponikowski P. Serial assessment of spot urine sodium predicts effectiveness of decongestion and outcome in patients with acute heart failure. Eur J Heart Fail 2019; 21: 624–633. [DOI] [PubMed] [Google Scholar]
- 32. Tersalvi G, Dauw J, Gasperetti A, Winterton D, Cioffi GM, Scopigni F, Pedrazzini G, Mullens W. The value of urinary sodium assessment in acute heart failure. Eur Hear Journal Acute Cardiovasc Care 2020; 10: 216–223. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33. Caravaca Pérez P, Nuche J, Morán Fernández L, Lora D, Blázquez‐Bermejo Z, López‐Azor JC, de Juan Bagudá J, García‐Cosío Carmena MD, Escribano Subías P, Salguero‐Bodes R, Arribas Ynsaurriaga F, Delgado JF. Potential role of natriuretic response to furosemide stress test during acute heart failure. Circ Hear Fail. 2021; 14: e008166. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Figure S1: Correlation between previous dose of furosemide and DE based on weight loss (A) or DE based on urine output (B). Correlation between DE based on weight loss and based on urine output (C).
Figure S2: ROC curve of dose of furosemide before admission to predict low diuretic efficiency based on weight loss (A) and urine output (B).