Evaluation of diuretic efficiency of intravenous furosemide in patients with advanced heart failure in a heart failure clinic

Abstract

Introduction:

Diuretic efficiency (DE) is an independent predictor of all-cause mortality in acute heart failure (HF) at long-term follow-up. The performance of DE in advanced HF and the outpatient scenario is unclear.

Methods:

Survival function analysis on a retrospective cohort of patients with advanced HF followed at the outpatient clinic of Hospital Universitario San Ignacio (Bogotá, Colombia) between 2017 and 2021. DE was calculated as the average of total diuresis in milliliters divided by the dose of IV furosemide in milligrams for each 6-h session, considering all the sessions in which the patient received levosimendan and IV furosemide. We stratified DE in high or low using the median value of the cohort as the cutoff value. The primary outcome was a composite of all-cause mortality and HF hospitalizations during a 12-month follow-up. Kaplan–Meier curves and log-rank test were used to compare patients with high and low DE.

Results:

In all, 41 patients (66.5 ± 13.2 years old, 75.6% men) were included in the study, with a median DE of 24.5 mL/mg. In total, 20 patients were categorized as low and 21 as high DE. The composite outcome occurred more often in the high DE group (13 versus 5, log-rank test p = 0.0385); the all-cause mortality rate was 29.2% and was more frequent in the high DE group (11 versus 1, log-rank test p = 0.0026).

Conclusion:

In patients with advanced HF on intermittent inotropic therapy, a high DE efficiency is associated with a higher risk of mortality or HF hospitalization in a 12-month follow-up period.

Introduction

Acute heart failure (HF) is the leading cause of hospitalization in patients older than 65 years. It is associated with in-hospital mortality of up to 10% and a high rate of hospital readmissions, reaching 30% in the first month. Its mortality ranges between 30% and 45% per year and could exceed 50% within 5 years. ¹ Acute HF episodes are associated with visits to emergency services and hospital admission. In general, its management requires a comprehensive approach that includes education, an active search for causes of decompensation, hydro saline restriction, and the use of loop diuretics as a pillar of depletive management.^2,3

The evidence regarding the correct dosage and administration of loop diuretics in acute HF is controversial. Some observational studies suggest that high doses of loop diuretics are associated with adverse outcomes, while others found no difference. ⁴ The question of whether a poor diuretic response is associated with worse outcomes or reflects the severity of HF still has no answer; very few studies have evaluated it. The picture is less clear when we talk about patients with advanced HF or in special programs such as HF clinics, where the evidence regarding response to diuretics is summarized in small descriptive studies.^5,6

Historically, it has been suggested that resistance to diuretics indicates a poor prognosis and is associated with higher hospital readmissions and mortality. ⁴ Among the proposed definitions of diuretic resistance are (1) congestion refractory to standard diuretic therapy or (2) reduced diuresis and natriuresis with repeated doses and persistent congestion, despite increasing the diuretic dose. However, neither of these is entirely accepted.4 Likewise, multiple metrics have been proposed to evaluate the diuretic response, including (1) weight loss in kilograms per unit of 40 mg of furosemide or equivalent, (2) natriuretic response, understood as the ratio between urinary sodium and urinary furosemide concentration, or (3) the net diuresis in milliliters per mg of furosemide or furosemide equivalent, known as diuretic efficiency (DE). ⁷

DE has been retrospectively evaluated in patients hospitalized for acute HF, finding that low DE is independently associated with higher mortality from any cause.^8,9 However, there are no studies evaluating DE in patients with advanced HF or in those receiving outpatient management, where the hemodynamic factors are very different.

This study aims to describe DE in patients with advanced HF, managed with intermittent inotropy with levosimendan and intravenous loop diuretic requirement, and assess its association with mortality and hospitalization for HF at 1-year follow-up.

Methods

A study of survival functions was carried out in a retrospective cohort evaluating patients with advanced HF under follow-up at the HF clinic of Hospital Universitario San Ignacio in Bogota, Colombia, between November 2017 and December 2021. We included patients older than 18 years in the day hospital program receiving management with intermittent inotropy with levosimendan according to the LION-HEART protocol ¹⁰ and who received an intravenous loop diuretic in at least one session. Patients on renal replacement therapy were excluded.

Patients were identified from the electronic records of the HF clinic, and the information on each patient was obtained from the medical records that were systematically filled out. The information was extracted using a standardized form, including demographic variables, functional capacity, initial congestive signs, Charlson Comorbidity Index (CCI), pharmacological management, and use of implantable devices. In addition, for each of the six sessions contemplated in the LION-HEART protocol, the following data were obtained ¹⁰ : vital signs at the beginning, initial weight, creatinine, natriuretic peptides, diuresis during the session, and dose of intravenous furosemide applied. Each patient was followed up for 12 months for the outcomes of hospitalization for HF and death.

Definitions

Advanced HF was defined according to the criteria proposed by the European Society of Cardiology in 2018. ¹¹ The LION-HEART protocol consists of an intravenous infusion of levosimendan at 0.2 µg/kg/min for 6 h, every 2 weeks for 12 weeks. ¹⁰ In addition, patients receive intravenous furosemide in each session, according to the criteria of the treating cardiologist, based on congestive signs and symptoms. The administered dose is usually equal to or doubles the outpatient dose; however, it is possible that patients did not receive intravenous furosemide in some sessions.

The DE was calculated as the ratio of diuresis in milliliters (mL) divided by the dose of intravenous furosemide in milligrams (mg) for each session. For the final analysis, an average of DE of the different sessions was made. Only the sessions in which the patients received treatment with intravenous levosimendan and furosemide were considered. For our study, the quantified total diuresis was obtained during the 6 h of surveillance in the day hospital. Based on the study published by Testani et al., ⁸ DE was stratified as high or low, taking the median of our cohort as the cutoff point.

We evaluated the composite outcome of hospitalization, readmission for HF, or death from any cause. Hospitalization due to HF was defined as hospital admission or emergency room stay for more than 12 h, attributed to signs and/or symptoms of decompensated HF, including at least one of the following: dyspnea, orthopnea, paroxysmal nocturnal dyspnea, edema, pulmonary rales, jugular vein engorgement, third heart sound, or radiologic evidence of pulmonary edema. Readmission due to HF was defined as hospital admission or emergency room visit 30 days after discharge, attributable to at least one previously described sign and/or symptom of decompensated HF.

Statistical methods and sample calculation

Demographic, clinical, and therapeutic variables and the outcomes were compared for both groups. For qualitative variables, Fisher’s test or chi-square test was applied. Mann–Whitney t or U tests was applied for quantitative variables, depending on whether or not the normal distribution assumption was met using the Shapiro–Wilk test. Survival function graphs were generated comparing patients with high DE and low DE through a Kaplan–Meier curve and the log-rank test statistic. A composite outcome of all-cause mortality, hospitalization, or readmission for HF at 1-year follow-up from day hospital admission was used as the outcome of interest. Statistical analyses were performed in Stata 16 (Stata Statistical Software: Release 15: StataCorp LP, College Station, TX, USA).

Results

In all, 41 patients met the inclusion criteria. The average age was 66.5 ± 13.2 years, and most patients were men (75.6%). The most frequent etiology of HF was ischemic, followed by chagasic, and idiopathic (Table 1). Most patients had a high comorbidity burden with a score greater than three on the CCI. The mean of left ventricular ejection fraction (LVEF) was 22 ± 7.1%. There was no significant difference between groups at baseline in congestive signs, functional class, creatinine, natriuretic peptides, frequency of implantable device use, or drug therapy, except for angiotensin receptor neprilysin inhibitor (ARNI) use, which was higher in the low DE group (95% versus 61.9%, p = 0.01). Table 1 describes the demographic and clinical characteristics of the cohort divided into patients with low and high DE.

Table 1.

Baseline characteristics according to DE.

Variable	Total n = 41	Low DE n = 20	High DE n = 21	p Value
Age in years, mean (SD)	66.5 (13.2)	67.2 (12.0)	65.8 (14.5)	0.732
Male gender, n (%)	31 (75.6)	15 (75.0)	16 (76.2)	0.929
Etiology, n (%)
Ischemic	29 (70.7)	14(70)	12(57.1)	0.558
Chagasic	8 (19.5)	3(15)	5(23.8)
Valvular	4 (9.7)	2(10)	2(9.52)
Post CT cardiomyopathy	2 (4.8)	1(5)	1(4.7)
Hypertensive	1 (2.4)	0	1(4.7)
Idiopathic	6 (14.6)	3(15)	3(14.2)
Charlson Index, n (%)
0–1	3 (7.3)	1 (5)	2 (9.5)	0.764
2	5 (12.1)	2 (10)	3 (14.9)
>3	33 (80.4)	17 (85)	16 (76.1)
Comorbidities, n (%)
Peripheral arterial disease	3 (7.3)	0	3 (14.2)	0.079
Cerebrovascular disease	2 (4.8)	1 (5)	1 (4.7)	0.972
COPD	13 (31.7)	7 (35)	6 (28.5)	0.658
Diabetes mellitus	14 (34.1)	8 (40)	6 (28.5)	0.440
Chronic kidney disease	18 (43.9)	8(40)	10 (47.6)	0.623
Hypothyroidism	11 (26.8)	3(15)	8 (38.1)	0.095
OSAHS	5 (12.1)	4(20)	1 (4.76)	0.136
Dyslipidemia	12 (29.2)	5(25)	7 (33.3)	0.558
Arterial hypertension	13 (31.7)	8(40)	5 (23.8)	0.265
Atrial fibrillation	18 (43.9)	9(45)	9 (42.8)	0.890
Treatment, n (%)
Furosemide	31(75.6)	17(85)	14 (66.6)	0.172
ACEi	4 (9.7)	1 (5)	3 (14.2)	0.317
ARB	1 (2.4)	0	1 (4.7)	0.323
ARNI	32 (78)	19 (95)	13 (61.9)	0.010
Beta blocker	41 (100)	20 (100)	21 (100)	–
MRA	30 (73.1)	15 (75)	15 (71.4)	0.796
Ivabradine	4 (9.7)	3 (15)	1 (4.76)	0.269
iSGLT2	31 (75.6)	17 (85)	14 (66.6)	0.172
Intravenous Fe	8 (19.5)	6 (30)	2 (9.5)	0.098
Levosimendan	41 ( 100)	20(100)	21(100)	1.000
Number of cycles
2	1 (2)	0	1 (5)	0.405
3	2 (5)	0	2 (10)
4	1 (2)	1 (5)	0
5	6 (15)	3 (15)	3 (14)
6	31 (76)	16 (80)	15 (71)
Devices, n (%)
IDC	18 (43.9)	8 (40)	10 (47.6)
CRT	10 (24.3)	4 (20)	6 (28.5)
Pacemaker	1 (2.4)	1 (5)	0
LVEF %, mean (SD)	22 (7.1)	23.4 (7.6)	20.5 (6.5)	0.200
Congestive signs, n (%)
Edema	31 (75.6)	4 (20)	27 (33.3)	0.498
Jugular engorgement	20 (48.7)	9 (45)	11 (52.3)	0.308
Hepatojugular reflux	3 (7.3)	1 (5)	2 (9.52)	0.578
Rales	14 (34.1)	7 (35)	7 (33.3)	0.910
Ascites	5 (12.1)	2 (10)	3 (14.2)	0.675
Third sound	1 (2.4)	1 (5)	0	0.300
NYHA
I	1 (2.4)	1 (5)	0	0.530
II	11 (26.8)	6 (30)	5 (23.8)
III	28 (68.2)	13 (65)	15 (71.4)
IV		0	1 (4.7)
Creatinine mg/dL, mean (SD)	1.37 (0.5)	1.24(0.4)	1.5(0.6)	0.119
Pro-BNP pg/mL, median (IQR)	3561(2263–5697)	5600 (5806)	4839(5134)	0.718
Diuresis mL, mean (SD)	1676 (894.5)	1546 (959)	1831 (833)	0.47
Basal furosemide oral dose, median (IQR)	40 (20–80)	80 (20–120)	40 (0–40)	0.018
Mean furosemide oral dose, median (IQR)*	53.3 (36.6–83.3)	78.6 (41.6–91.3)	43.3 ( 33.3–60.0)	0.036
Mean IV furosemide dose, median (IQR)*	23.3(13.3–40)	32.6(20–48.3)	16 (0–26.6)	0.012
DE, mean (SD)	26.2 (10.8)	17.5(5.4)	34.4(7.6)	<0.001

ACEi, angiotensin-converting enzyme inhibitors; ARB, angiotensin II receptor blocker; ARNI, angiotensin-neprilysin receptor inhibitor; COPD, chronic obstructive pulmonary disease; CRT, cardiac resynchronization therapy; DE, diuretic efficiency; Fe, iron; iSGLT2, inhibitor of sodium and glucose co-transporter type 2; MRA, mineralocorticoid receptor antagonist; NYHA, New York Heart Association Functional Classification; OSAHS, obstructive sleep apnea hypopnea syndrome; SD, standard deviation.

We explored whether creatinine levels changed between the first session and the last session for each patient. We found that a statistically significant change was observed between high and low DE groups [0.03 (standard deviation, SD 0.5) versus −0.2 (SD 0.6), p = 0.003]; however, this change was not clinically significant (i.e. <0.3 mg/dL). We performed a similar approach to evaluate the change in proBNP levels, yielding a nonsignificant difference (n = 17 patients). Regarding symptomatic congestion, only one patient in each group worsened from the first session to the last session [high DE 1/21 (5%) versus low DE 1/19 (5%), p = 0.942]. In this line, 9/21 (43%) in the high DE group improved compared to 6/19 (32%) patients in the low DE group (p = 0.47).

The median ED in our cohort was 24.5 mL/mg, and this value was considered as the cutoff point, classifying 20 patients with low DE and 21 with high DE. During the 1-year follow-up, 18 events occurred: 12 patients died and 6 had hospitalizations due to HF. The composite outcome was more frequent in the high DE group compared to the low DE group (13 versus 5, p = 0.0385) (Figure 1).

Figure 1.

Composite outcome by diuretic efficiency.

When evaluating mortality from any cause separately, 12 events were observed, being more frequent in the high ED group (11 versus 1, p = 0.0026), with a mortality of 29.2% at 1 year of follow-up (Figure 2).

Figure 2.

Mortality by diuretic efficiency.

Discussion

Our study is the first to evaluate DE and its association with mortality and hospitalization in patients with advanced HF, requiring intermittent inotropy and intravenous loop diuretics, followed up in a day hospital program. We found that a high DE is associated with a higher frequency of death from any cause and hospitalization for HF.

In recent decades, it has been proposed that resistance to diuretics in patients with HF is an indicator of poor prognosis and is associated with higher rates of hospital readmissions and mortality; however, few studies evaluate the metrics of diuretic response and the evidence is conflicting (7). Based on previous studies, in our study, we used DE as a metric of diuretic resistance.^8,9 The mean DE of our cohort was 24.5 mL/mg, a much lower value than that described in other studies evaluating this metric, although these studies evaluated radically different populations than ours.

Overall, the evidence on the prognostic impact of DE in patients with HF suggests that a lower DE is associated with worse outcomes. Of note, current evidence is based only on the acute HF scenario. Testani et al. evaluated two cohorts of patients hospitalized for acute HF and defined the cutoff point for high DE based on the median of each cohort. For one of the cohorts, the median DE was 148 mL/40 mg furosemide and 480 mL/40 mg furosemide for the other. ⁸ Ferreira et al. evaluated DE in critically ill patients with acute HF associated with respiratory failure. They defined the cutoff point for high DE according to the tertiles of the sample without being clear which tertile was used. The authors considered low DE values of less than 140 mL/40 mg of furosemide. ⁹ Cox et al. ¹² included patients with acute HF who presented diuretic resistance and were randomized to an additional diuretic (i.e. metolazone, chlorothiazide, or tolvaptan). Among the evaluated outcomes, DE [i.e. urine output (mL) per 40 mg of furosemide] was assessed. The baseline mean DE was 209 (SD 134); after the intervention period, DE ranged between 217 (SD 107) and 326 (SD 213) in the three arms, and readmission rates or mortality among DE groups were not reported. Ter Maaten et al. published an interesting post-hoc analysis of the Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure trial (ASCEND-HF), in which nesiritide was evaluated in patients with acute HF. ¹³ In this analysis, the authors explored the effect of DE on clinical outcomes and its associated variables. DE was defined using a weight approach and a urine output approach. Patients with a higher DE presented a reduced risk of 30-day all-cause mortality and HF rehospitalization. The authors reported that a ‘good’ urinary DE was associated with the presence of peripheral edema, whereas a ‘poor’ urinary DE was associated with female sex, older age (>70 years), higher NYHA class, diabetes, hyperlipidemia, higher serum creatinine, and low potassium. As the authors explored urinary DE using quintiles, a median value was unavailable for comparison. Interestingly, urinary DE and DE based on weight loss were moderately correlated (p = −0.381, p < 0.001). Nesiritide presented a neutral effect on both groups.

As mentioned, multiple metrics have been proposed to evaluate the diuretic response, including weight loss in kilograms per unit of 40 mg of furosemide or equivalent. ⁷ An Italian study^14,15 included patients with acute HF and evaluated the effect of diuretic response (i.e. weight loss per 40 mg of furosemide) on the risk of death from cardiovascular cause and hospitalization due to HF during a 6-month follow-up. A low diuretic response was an independent variable associated with a higher frequency of the primary outcome. Voors et al. ¹⁶ explored DE based on weight loss in a randomized controlled trial (RCT) of serelaxin in acute HF and found a higher risk of cardiovascular death, HF hospitalization, or renal failure at a 60-day follow-up. Palazzuoli et al. ¹⁷ are currently running an RCT on the effect of high versus low doses of furosemide on the risk of cardiac death or hospitalization in patients with acute HF over 6 months. Among the secondary outcomes, diuretic response [(weight change/days of infusion)/(mean daily furosemide dosage/40 mg of furosemide)] will be evaluated.

The formula to establish DE in our study differed from former studies, as we did not use the strategy of furosemide equivalence units. This decision was made given that we only have this intravenous loop diuretic in our country and did not require equivalences. Since this is a ratio, the differences in outcomes between the high and low DE groups should not differ between the methodologies.

Furthermore, the prognostic impact of loop DE has been studied in other clinical scenarios, such as chronic kidney disease. In a retrospective cohort study that included 783 patients on oral loop diuretic with 24 h of urine collection available, Verbrugge et al. calculated DE as urine output, natriuresis, and chloruresis adjusted by loop diuretic dose. In this cohort, DE decreased from Kidney Disease Improving Global Outcomes (KDIGO) class IIIB to IV in furosemide users and from KDIGO class IV to V with all loop diuretics (p value <0.05). Low DE, defined with any of those metrics, was significantly and independently associated with a higher risk for dialysis and all-cause mortality. ¹⁸

In our study, it was striking to find a higher frequency of events in the high DE group, given that our results are different from those reported in previous studies. In the study of patients hospitalized due to acute HF, it was reported that a low DE was associated with a lower survival, ⁸ similar to what was found in the study of critical patients with acute HF and respiratory failure. ⁹ To explain these differences, we propose two hypotheses. First, patients with advanced HF who require intermittent inotropic management have more advanced renal involvement and worse perfusion status. Thus, pursuing a larger volume depletion could drive them to hypovolemia due to over-diuresis, leading to organ damage, possible electrolyte unbalance, and worse outcomes. In our study, the mean diuresis in each session was similar in both groups; however, we could not evaluate if the patients presented excessive diuresis beyond each session. Some studies suggest that the requirement for higher doses of diuretics, as expected in this group of patients, is associated with a worse prognosis.^4,8,9,19 The DE is a metric that summarizes these variables. ⁵

On the other hand, we do not rule out that a high DE reflects a higher state of congestion. Previous RCTs in patients with acute HF reported that a high DE was associated with peripheral edema, whereas a poor DE was associated with fewer signs of congestion.^13,16 Since the DE is a ratio between time-defined total diuresis and the diuretic dose, patients with a high DE would require a lower diuretic dose to achieve higher urinary volumes. In fact, a suboptimal decongestion has been associated with worse outcomes ² ; however, our follow-up strategy is based on the most recent guidelines, which suggest using clinical criteria. In fact, diuresis in both groups far exceeded of 150 mL/h threshold during the first 6 h set by current guidelines.^3,20 This theory reinforces the need to find objective decongestion criteria; pulmonary ultrasonography or impedanciometry have been proposed.^21,22

Regarding demographic characteristics, most patients in our cohort were men, with a high comorbidity burden (CCI > 3) and reduced LVEF. Regarding these baseline characteristics, we found no differences between the two groups. These data are similar to those described in the national epidemiology in the Colombian HF registry (RECOLFACA), in which 57.6% of patients were men, with a median age of 69 years; the most frequent etiology of HF was the ischemic. ²³

Concerning pharmacological management, despite being indicated in all patients, 50% of patients could tolerate quadruple therapy; it was more frequent in the low DE group compared to high DE (65% versus 33%, p = 0.191). Patients with a lower tolerance to quadruple therapy have the worst outcomes so this finding could be associated with a higher frequency of hospitalization and death in patients with high DE. However, our study illustrates real-world conditions in which patients may have a contraindication or intolerance to therapy. It should be noted that adherence to therapy recommended by management guidelines is a limitation identified worldwide. For example, in the CHAMP-HF registry published in 2018, only 22% received triple therapy (i.e. angiotensin-converting enzyme inhibitors, angiotensin-II receptor blocker or ARNI, beta-blockers, and mineralocorticoid receptor antagonist). ²⁴ On the other hand, in the recently published VICTORIA registry, which included patients hospitalized for acute HF, only 17% received triple therapy at admission, and only 28% were prescribed it at discharge; strikingly, 99% of patients were not prescribed iSGLT2 at discharge. ²⁵ Compared with these registries, the frequency of quadruple therapy management in our patients was higher than that reported in the literature, even considering that our cohort included patients with advanced HF. In addition, we found 1-year mortality of 29%, following what is described in the literature, where a poor prognosis of advanced HF is described, with 1-year mortality between 25% and 75%. ³

Limitations

The main limitation of our study is the limited sample size, which prevents adequate control of confounding variables such as age, comorbidities, renal function, and differences in pharmacological management. Prospective studies with larger samples are required to confirm our findings and evaluate the hypotheses of congestion versus volume depletion. In addition, the response to diuretics continues to be a matter of debate, so future studies should evaluate the impact of other measures such as natriuresis and imaging follow-up (i.e. pulmonary ultrasound), on outcomes. DE should be considered a variable to prioritize in these studies, considering its easy measurement and ability to allow management adjustments at the patient’s bedside. Lastly, it is necessary to standardize the way of measuring DE, particularly considering its denominator, since existing studies have used different approaches given the heterogeneity of the populations evaluated.

Conclusion

DE in patients with advanced HF may be a prognostic marker for hospitalization, readmission, and mortality. Our data suggest that a higher DE in patients with advanced HF does not imply better outcomes. Future studies should explore its utility compared to other diuretic response measures, particularly concerning prognosis and follow-up. The standardization of DE should be an objective in HF research.