You are on page 1of 9

Clinical Research in Cardiology

https://doi.org/10.1007/s00392-019-01521-y

ORIGINAL PAPER

Diuretic treatment in high‑risk acute decompensation of advanced


chronic heart failure—bolus intermittent vs. continuous infusion
of furosemide: a randomized controlled trial
Simone Frea1 · Stefano Pidello1 · Alessandra Volpe1 · Federico Giovanni Canavosio1 · Alessandro Galluzzo1 ·
Virginia Bovolo1 · Antonio Camarda1 · Pier Giorgio Golzio1 · Fabrizio D’Ascenzo1 · Serena Bergerone1 ·
Mauro Rinaldi1 · Fiorenzo Gaita1

Received: 3 April 2019 / Accepted: 26 June 2019


© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Abstract
Background  Diuretic resistance is a common issue in patients with acute decompensation of advanced chronic heart failure
(ACHF). The aim of this trial was to compare boluses and continuous infusion of furosemide in a selected population of
patients with ACHF and high risk for diuretic resistance.
Methods  In this single-centre, double-blind, double-dummy, randomized trial, we enrolled 80 patients admitted for acute
decompensation of ACHF (NYHA IV, EF ≤ 30%) with criteria of high risk for diuretic resistance (SBP ≤ 110 mmHg, wet
score ≥ 12/18, and sodium ≤ 135 mMol/L). Patients were assigned in a 1:1 ratio to receive furosemide by bolus every 12 h
or by continuous infusion. Diuretic treatment and dummy treatment were prepared by a nurse unassigned to patients’ care.
The study treatment was continued for up to 72 h. Coprimary endpoints were total urinary output and freedom from conges-
tion at 72 h.
Results  80 patients were enrolled with 40 patients in each treatment arm. Mean daily furosemide was 216 mg in continu-
ous-infusion arm and 195 mg in the bolus intermittent arm. Freedom from congestion (defined as jugular venous pressure
of < 8 cm, with no orthopnea and with trace peripheral edema or no edema) occurred more in the continuous infusion than
in the bolus arm (48% vs. 25%, p = 0.04), while total urinary output after 72 h was 8612 ± 2984 ml in the bolus arm and
10,020 ± 3032 ml in the continuous arm (p = 0.04). Treatment failure occurred less in the continuous-infusion group (15%
vs. 38%, p = 0.02), while there was no significant difference between groups in the incidence of worsening of renal function.
Conclusion  Among patients with acute decompensation of ACHF and high risk of diuretic resistance, continuous infusion
of intravenous furosemide was associated with better decongestion.
DRAIN trial  ClinicalTrials.gov number NCT03592836.

Electronic supplementary material  The online version of this


article (https​://doi.org/10.1007/s0039​2-019-01521​-y) contains
supplementary material, which is available to authorized users.

* Simone Frea
frea.simone@gmail.com
1
Division of Cardiology, Cardiovascular and Thoracic
Department, Città della Salute e della Scienza University
Hospital of Turin, Corso Bramante 88, 10126 Turin, Italy

13
Vol.:(0123456789)
Clinical Research in Cardiology

Graphic abstract

Keywords  Diuretic resistance · Advanced heart failure · Furosemide · Bolus intermittent · Continuous infusion

Introduction infusion over bolus intermittent in refractory congestive


heart failure, though the study was focused on the effect
Diuretic resistance is common in advanced chronic heart of hypertonic saline solution infusion. Assessing the best
failure (ACHF) and an established prognostic factor [1, modality of diuretic administration in patients with high
2]. It determines a shift to the right of the dose–response risk of diuretic resistance is of particular interest, as this
curve of diuretics and often a blunted maximal response. Its is a very challenging setting. The aim of this study was to
mechanisms include reduced renal blood flow and perfusion compare boluses and continuous infusion of furosemide in
pressure, hypoproteinemia, the presence of uremic anions a selected population of patients with acute decompensa-
in patients with underlying chronic kidney disease (CKD) tion of ACHF with high risk of diuretic resistance.
which limits the achievement of appropriate concentrations
of diuretics at their site of action, distal tubular adaptation,
and many others. Established risk factors of diuretic resist-
ance are hypotension, hyponatremia, severe renal dysfunc- Methods
tion, severe heart failure, and daily need of high-dose diu-
retic [3]. Study participants
Despite decades of clinical experience with furosemide,
prospective data to guide its use are sparse and controver- The DRAIN (Diuretic Response in Advanced heart fail-
sies exist about the best modality of administration [4, ure: bolus intermittent vs. continuous INfusion) trial was a
5]. The largest prospective double-blind randomized trial prospective single-centre double-blind parallel-group rand-
comparing continuous infusion and intermittent boluses in omized clinical trial that screened all consecutive patients
acute decompensated heart failure is the DOSE study [6]. admitted for acute decompensation of ACHF in the Inten-
In this trial on 308 patients, no significant differences were sive Cardiac Care Unit of Cardiology Division of Città della
found when diuretic therapy was administered by bolus Salute e della Scienza University Hospital in Turin. Patients
as compared with continuous infusion. A recent meta- were enrolled from May 2013 to December 2016. The
analysis found continuous infusion superior to boluses 90 day follow-up after the index hospitalization ended on
administration in terms of weight reduction, total urine December 2017 and the study was completed. The study was
output, and brain natriuretic peptide reduction [7]. There is approved by the institutional review board, and all patients
poor evidence comparing these two modalities of admin- provided written informed consent. No funding was received
istration in patients with high risk of diuretic resistance. to conduct this study. The trial was registered in ClinicalTri-
Licata et al. suggested a beneficial effect of continuous als.gov with number NCT03592836 on July 2018.

13
Clinical Research in Cardiology

Inclusion criteria were: age ≥ 18 years, all criteria for dobutamine ≥ 10 γ/kg/min) were required due to shock evolu-
ACHF as defined by Metra et al. [8] EF at admission ≤ 30% tion (development of INTERMACS ≤ 2), vasopressors were
and all the following parameters of high risk for diu- started and patients left the study protocol.
retic resistance (systolic blood pressure ≤ 110  mmHg, Thiazide diuretics were not allowed during the study proto-
serum sodium ≤ 135 mEq/L, and severe congestion (wet col. Other p.o. therapies were administered according to ESC
score ≥ 12/18; according to a modified version—the wet guidelines recommendations and were administered according
score—of a congestion grading score from Gheorghiade [10, 11]. All patients followed a water restriction of 1000 ml/
et al. [9]—see Supplementary Material). Exclusion crite- day and laid in bed up to the end of the protocol.
ria were: reversible causes of acute heart failure (such as The study treatment was continued for up to 72 h. After
acute coronary syndrome, myocarditis, acute pulmonary 72 h, all treatments were open label at the discretion of the
embolism, rhythm disorders, and severe primary organic treating physician. Patients were followed for clinical events
valve disease), cardiogenic shock at admission (defined as (overall and cardiac death, hospitalization for worsening heart
INTERMACS class ≤ 2), and eGFR (MDRD) lower than failure, urgent heart transplantation, and LVAD implantation)
15 ml/min/1.73 m2. until day 90.

Randomization and treatment assignments Clinical evaluation and laboratory tests

Patients who met inclusion/exclusion criteria were randomly At admission, clinical history (age, gender, etiology of heart
assigned in a 1:1 ratio to administration of furosemide either failure, INTERMACS class, and medications intake at home)
by intravenous bolus every 12 h or by continuous intrave- was recorded and physical examination was performed in all
nous infusion. Randomization was carried out by the use patients. Clinical examination included grading of congestion
of sequentially numbered cases prepared before starting the (according to wet score) and assessment of hypoperfusion
study by a computerized sequence. A double-blind, double- (according to the cold-modified model [12]).
dummy design was used. A nurse unassigned to patients’ An assessment of biomarkers, including creatinine, blood
care prepared a syringe pump for continuous infusion and urea nitrogen (BUN), serum neutrophil gelatinase-associated
syringes for boluses. According to the assigned treatment lipocalin (NGAL), serum and urinary electrolytes, hepatic
arm, syringes contained the assigned dose of furosemide or function (GOT/GPT and bilirubin), ammonia [13], high sensi-
a 5% glucose solution placebo. All patients received a bolus tivity Troponin T, and NT-proBNP, was performed at baseline,
of furosemide (40 or 60 mg) in the emergency department at 24, 48, and 72 h.
(length of stay < 90 min). Maximum time from admission
to diuretic treatment according to study protocol was 2 h. Echocardiogram
The dose of furosemide (low dose—120 mg/day—vs.
high dose—240 mg/day) was defined before randomization Two-dimensional transthoracic echocardiography was per-
according to the following criteria: patients with severe sys- formed at admission using Philips i33 (Philips Medical Sys-
temic congestion (wet score ≥ 14/18) and/or on daily out-of- tems, Andover, MA, USA). Left ventricular (LV) chamber
hospital oral furosemide equivalent dose ≥ 125 mg and/or on size and systo-diastolic function (with EF evaluation and E/E’
supplemental metolazone therapy on a long-term basis were ratio) were measured. Aortic and mitral regurgitation were
treated with high doses; otherwise, they were included in assessed using color Doppler. Basal right ventricular (RV)
the low-dose arm. After 48 h, the treating physician on the end-diastolic diameter and tricuspid annular plane systolic
basis of the clinical response had the option to reduce the excursion (TAPSE) were measured. Trans-tricuspid systolic
dose from 240 mg/day to 120 mg/day. gradient (TR gradient) and systolic pulmonary artery pressure
Pharmacological treatment and continuous positive air- (sPAP) were estimated by tricuspid regurgitation peak veloc-
way pressure ventilation, when indicated, were started after ity (TRV) and right atrial pressure. Right atrial pressure was
randomization. All patients underwent a prespecified phar- estimated by inferior vena cava diameter and collapse with
macological protocol. If SBP at admission was > 90 mmHg, sniff and the tricuspid E/e’ ratio and hepatic vein flow analysis
intravenous vasodilator (sodium nitroprusside) was started. in doubtful cases [14]. Finally, RV contraction pressure index
Subsequently, if SBP remained ≥ 90 mmHg without signs was calculated as TAPSE x TR gradient [15].
of hypoperfusion, vasodilator therapy was continued; oth-
erwise, it was discontinued. In patients with hypoperfusion Endpoints
(assessed by Cold Modified 2014), dopamine or dobutamine
was started. Inotropes were started in patients with cold pro- The primary endpoint was freedom from congestion at 72 h
file according to Cold Modified 2014 and titrated according (defined as jugular venous pressure of < 8 cm, with no ortho-
to clinical response. If high doses of inotropes (dopamine or pnea and with trace peripheral edema or no edema).

13
Clinical Research in Cardiology

Secondary endpoints were: total urinary output after assigned to receive continuous intravenous furosemide and
72 h; treatment failure (defined as persistent congestion (wet 40 patients to receive bolus intermittent intravenous admin-
score ≥ 12/18) with the need of increasing diuretic treatment istration of furosemide. There were no crossovers. Seventy-
until renal replacement treatment) at 72 h; worsening renal seven patients completed the 72 h protocol. As shown in
function (defined as an absolute increase in serum creati- the diagram in Fig. 1 according to CONSORT 2010 [19],
nine > 0.3 mg/dl or > 1.5-fold from baseline) at any time three patients left the protocol before 72 h due to evolu-
from randomization to 72 h; diuretic response (defined as ∆ tion to cardiogenic shock, but were included in the analysis.
weight/40 mg furosemide [16, 17]) after 72 h; and worsen- 57 patients met criteria for high-dose furosemide, while 23
ing or persistent heart failure (defined as worsening of HF patients received low-dose furosemide.
symptoms or failure of the patient’s condition to improve Baseline characteristics are shown in Table 1. The patient
with treatment requiring the initiation, or increase in intra- population had several very high-risk features, including
venous inotropic therapy for HF and/or the implementation severe symptoms of ACHF (NYHA class IV for all with a
of mechanical circulatory or ventilator support [18]) up until mean INTERMACS class at admission of 3.7 ± 0.9), crite-
72 h and variations of NT-proBNP after 72 h. Renal replace- ria for high-risk in-hospital mortality for acute heart failure
ment treatment was indicated in patients with persistence [average SBP 98 ± 8.6 mmHg, mean EF 19.3 ± 7.7%, BUN
of congestion (wet score ≥ 12/18) and reduced response to 46.4 ± 20.6, and NT-proBNP 7820 (IQR 4508–14,302)], and
diuretic (absence of weight reduction and/or sodium excre- criteria for high-risk in-hospital diuretic resistance (serum
tion < 30 mmol/l) despite mean arterial pressure ≥ 65 mmHg sodium 129.6 ± 5.3 mmol/L and creatinine 1.8 ± 0.6 mg/dl).
and optimal medical therapy including sequential nephrone The demographic and clinical characteristics were similar
blockade. in both groups as well as medical therapy. Particularly, wet
score was similar (13.9 ± 1.2 in bolus arm vs. 13.6 ± 1.5 in
Statistics infusion arm, p = 0.32), as well as cold profile at admission
(47% in bolus arm vs. 53% in infusion arm).
This trial was designed to assess the superiority of con-
tinuous infusion over bolus infusion. A sample size of 78 Clinical outcomes
patients was required to have a 70% chance of detecting,
as significant at the 10% level, a decrease in the primary The primary endpoint of freedom from congestion after
outcome measure from 48% in the bolus group to 25% in 72 h occurred in 10 patients (25%) in the bolus arm and in
the infusion group. 19 (48%) in the infusion arm (OR 2.71, 95% CI 1.05–7.00;
Continuous variables are reported as mean (SD) and cate- p = 0.04, Fig. 2).
gorical variables as frequencies and percentages. Differences Secondary endpoints are shown in Table 2. Total uri-
in the basal characteristics and endpoints among treatment nary output after 72 h was 8612 ± 2984 ml in the bolus arm
arms were analyzed using Student’s t test for quantitative 10,020 ± 3032 ml in the continuous arm (p = 0.04). Diuretic
data (or Kruskal–Wallis non-parametric test if the variable response was higher in the infusion arm than in the bolus
did not fit the normal distribution) and the χ2 test for cat- arm (− 1 ± 0.7 vs. − 0.6 ± 0.6 kg/40 mg furosemide/72 h;
egorical data. p < 0.01). Treatment failure showed a higher incidence in the
Prespecified subgroup analyses (by renal function, bolus arm (38% vs. 15%, p = 0.02). This result was driven
haemodynamic profile, and diuretic dose) were performed. from the need to increase the dose of diuretic at the end of
The significant threshold was corrected by Bonferroni protocol, while renal replacement treatment was needed in
correction. only one patient in each arm. Change in NT-proBNP at 72 h
All data were analyzed by intention-to-treat. A two- was not significantly different between arms.
sided p value < 0.05 was considered statistically significant; Worsening heart failure after 72 h of treatment occurred
all analyses were performed with SPSS 20.0 (IBM corp., in 20 patients (25%), without any significant difference
Armonk, NY, USA). between the two groups (bolus arm 30% vs. 20% infusion
arm). Worsening renal function was similar between the
bolus arm and the infusion arm (18% vs. 18%) and between
Results the low-dose arm and the high-dose arm. Particularly, no
difference was found in the change in serum creatinine
Baseline characteristics (− 0.04 ± 0.50 vs. − 0.03 ± 0.29 mg/dl for bolus arm and
infusion arm, respectively; p = 0.91—Fig. 3) and in glomeru-
From May 2013 to December 2016, 80 patients were lar filtration rate (+ 4.92 ± 20.42 vs. + 0.86 ± 15.33 ml/min
enrolled. The 90 day follow-up and the study were com- for bolus arm and infusion arm, respectively; p = 0.32) after
pleted on December 2017. 40 patients were randomly 72 h. In addition, changes in serum sodium, BUN, BUN/

13
Clinical Research in Cardiology

Enrollment Assessed for eligibility (n=217)

Excluded (n=137)
Not meeting inclusion criteria (n=133)
Declined to participate (n=4)

Eligible (n=80), assessment of dose

Low dose - 120 mg/day (n=23)


High dose - 240 mg/day (n=57)

Randomized (n=80)

Allocation
Allocated to bolus intermittent (n=40) Allocated to continuous infusion (n=40)
- Low dose (n=15) - Low dose (n=8)
- High dose (n=25) - High dose (n=32)
Discontinued intervention (evolution to Discontinued intervention (evolution to
cardiogenic shock) (n=2) cardiogenic shock) (n=1)

Follow-Up
Death (n=3) Death (n=3)
LVAD implantation (n=3) LVAD implantation (n=1)
Heart transplantation (n=1) Heart transplantation (n=1)
Lost to follow-up (n=0) Lost to follow-up (n=0)

Analysis
Analysed (n=40) Analysed (n=40)
Excluded from analysis (n=0) Excluded from analysis (n=0)

Fig. 1  Flow chart of trial profile

crea, and NGAL at 72 h were not different between treat- Subgroup analysis
ment arms. At echo-Doppler after 72 h, the infusion arm
showed a lower estimated right atrial pressure (13.5 ± 4.9 A prespecified subgroup analysis testing the primary end-
vs. 16.4 ± 4.5 mmHg, p < 0.01), while other echo-Doppler point was performed, as shown in Table 3. In particular,
variables were not different between treatment arms. furosemide continuous infusion and bolus intermittent were
Within the 90 day follow-up, 6 patients died, 4 patients compared in patients with or without severe renal dysfunc-
underwent LVAD implantation, and two patients underwent tion (eGFR < 30 ml/min), in those with or without hemody-
heart transplantation. In-hospital death occurred in four namic cold profile at admission, and in high vs. low diuretic
(5%) patients. There were no differences in the rate of sin- dose group.
gle events or in the composite of death, LVAD implantation As shown in Table 4, the primary endpoint occurred less
and heart transplantation between continuous-infusion group in the continuous-infusion arm in patients with a warm pro-
and the bolus group (7 vs. 5 patients, respectively, p 0.8). file at admission (OR 0.23, 95% CI 0.06–0.81, p = 0.02).

13
Clinical Research in Cardiology

Table 1  Grading congestion by Variable Score


WET score (0–18)
0 1 2 3

Dyspnoea Absent Use of one pillow Use of more than one pillow Sleeps in an
armchair or
in a seated
position
Jugular venous pressure (cm) < 8 8–10 11–15 > 16
Hepatomegaly Absent Liver edge Moderate enlargement Massive tender
enlargement
extending to
midline
Oedema None Below knee Over knee Sacral/anasarca
NT-proBNP (pg/ml) < 400 400–1500 1500–3000 > 3000
6 min walk test (m) > 300 200–300 100–200 < 100

Wet score (= sum of all items score): < 6 mild congestion, > 12/18 severe congestion

sodium rebound’, which consists of increased sodium


reabsorption after a fall in diuretic levels below the thresh-
old to maintain adequate natriuresis. These effects could
potentially obviate some known mechanisms of diuretic
resistance.
The most relevant result of our study is that a greater
diuresis in the continuous-infusion arm was associated with
a significant clinical benefit. In fact, more patients in the
continuous-infusion group achieved a complete deconges-
tion and less patients needed an increase in diuretic treat-
ment because of inadequate diuretic response. The differ-
ences between the DRAIN and the DOSE trial may be due
to key differences in the populations enrolled. The DOSE
trial’s population was not selected for resistance to diuretics,
Fig. 2  Outcomes after 72 h according to treatment arm. *p < 0.05 while the DRAIN trial was designed to enroll patients with
high risk of diuretic resistance (low BP, low serum sodium,
and low EF). In this point of view, we might have selected
Other subgroups showed a neutral result. Moreover, continu- patients more sensitive to continuous infusion because of a
ous infusion showed a lower incidence of treatment failure in higher diuretic resistance.
the high-dose group (OR 0.22, 95% CI 0.06–0.92, p = 0.03). Another main result of this study is that worsening renal
function was not associated with greater diuretic response,
greater decongestion, or high-dose diuretics. Although prior
Discussion studies suggest that continuous infusion and higher diuretic
doses are associated with worsening renal function [17], our
In this trial on a selected cohort of patients with acute result is not unexpected, since the DRAIN trial enrolled only
decompensation of ACHF and high risk for diuretic resist- patients with severe congestion. In fact, it is well established
ance, we found faster decongestion and greater diuretic that renal venous congestion leads to worsening renal func-
response without higher incidence of worsening renal func- tion and that in this setting, lowering renal vein pressure
tion when diuretic therapy was administered by continuous is expected to improve renal function rather than worsen it
infusion rather than boluses. [22]. In addition, as previously indicated, effective deconges-
The greater diuresis produced by continuous infusion tion is more important than transient worsening renal func-
is consistent with the results of prior studies [20, 21]. As tion in terms of better long-term outcomes [23, 24]. Besides,
suggested before, continuous infusion of loop diuretics may worsening or persistent heart failure was not affected by
maintain concentrations above the natriuretic threshold and treatment arm, probably because WHF did not depend only
thus provides more constant diuresis without wide swings on an effective treatment of congestion but also of hypoper-
in intravascular volume and also avoid the ‘post-diuretic fusion that is not influenced by diuretic treatment.

13
Clinical Research in Cardiology

Table 2  Baseline characteristics
Bolus intermittent (N = 40) Continuous infusion (N = 40) p value

General characteristics
 Age (years) 58.7 ± 10.3 63.0 ± 13.1 0.11
 Male sex—no. (%) 35 (88) 37 (93) 0.71
 Ischemic etiology—no. (%) 22 (55) 25 (63) 0.65
 EF (%) 19.2 ± 6.4 19.4 ± 9.0 0.91
 ACE-I or ARB—no. (%) 15 (38) 21 (53) 0.26
 MRA—no. (%) 32 (80) 30 (75) 0.79
 β-blockers—no. (%) 38 (95) 34 (85) 0.26
 Thiazides—no. (%) 22 (55) 21 (53) 0.99
 Daily furosemide (mg/die) 242.2 ± 176.9 198.6 ± 188.0 0.29
Clinical, laboratory and echo-Doppler characteristics at admission
 Systolic blood pressure (mmHg) 97.0 ± 8.6 99.0 ± 8.6 0.30
 Heart rate (bpm) 83.0 ± 15.3 81.7 ± 17.5 0.72
 INTERMACS profile (n/7) 3.6 ± 0.9 3.7 ± 0.9 0.62
 Composite congestion score—no. (%) 13.9 ± 1.2 13.6 ± 1.5 0.32
Cold profile at admission—no. (%) 19 (47) 21 (53) 0.82
Sodium (mmol/L) 130.7 ± 5.4 129.3 ± 5.2 0.23
Creatinine (mg/dl) 1.8 ± 0.6 1.7 ± 0.7 0.49
eGFR (MDRD) (ml/min/1.73 m2) 45.9 ± 16.9 52.1 ± 33.2 0.30
BUN (mg/dl) 45.8 ± 22.5 46.9 ± 30.8 0.86
BUN/crea 56.6 ± 19.0 59.7 ± 22.2 0.50
NGAL (μg/L) 324.7 ± 193.2 213.8 ± 148.6 0.12
Ammonia (μg/dl) 131.8 ± 42.2 118.8 ± 69.7 0.32
Bilirubin (mg/dl) 1.57 ± 0.82 1.65 ± 1.08 0.71
NT-proBNP (pg/ml) 6250 (4303–11,820) 10,101 (4575–19,359) 0.39
EF (%) 19.2 ± 6.4 19.4 ± 9.0 0.91
E/E’ 19.9 ± 7.6 19.7 ± 6.6 0.90
TAPSE (mm) 12.8 ± 2.7 13.4 ± 3.9 0.43
eRAP (mmHg) 18.5 ± 3.5 19.6 ± 2.4 0.23
Use of medication from randomization through 72 h—no. (%)
High-dose furosemide (240 mg die)—no. (%) 32 (80) 25 (63) 0.14
Inotropic agent (DA or DBT ≥ 5 μg/kg/min) 5 (13) 4 (10) 0.7
Vasodilator 34 (85) 36 (90) 0.52

EF left ventricular ejection fraction, ACE-I ACE inhibitors, ARB angiotensin receptor blockers, MRA mineralocorticoid receptor antagonist,
eGFR estimated glomerular filtration rate, BUN blood urea nitrogen, NGAL neutrophil gelatinase-associated lipocalin, TAPSE tricuspid annular
plane systolic excursion, eRAP estimated right atrial pressure, DA dopamine, DBT dobutamine

Subgroup analysis interestingly suggests that continu- Limitations


ous infusion of furosemide may be more effective than
intermittent boluses in patients without severe renal dys- There are several limitations of this study. First, though
function and in those without cold profile. Though a ben- we enrolled a highly selected population of heart failure
efit of continuous infusion in patients with severe chronic patients, our sample size is fairly modest. In particular,
kidney disease was reported [25], possible explanations the study was not powered to conduct a proper subgroup
of these findings are that in those patients, both the pre- analysis. Second, though this was a randomized trial, an
existent renal dysfunction and renal hypoperfusion may uneven distribution of furosemide dosages occurred in both
have blunted the diuretic response and the potential dif- intervention groups. Third, the efficacy of diuretic treat-
ference between the two treatment arms. ment may depend not only on the route of administration,

13
Clinical Research in Cardiology

but also on different degrees of congestion, on right heart


function and diuretic responsiveness, which cannot be easily
adjusted a priori and even with randomization. Fourth, since
we enrolled advanced heart failure patients with high risk
of diuretic resistance, our findings may not be applicable
to patients with less severe heart failure. Finally, thiazides,
an established and effective treatment in diuretic resistance
[26], were not allowed during protocol. Since the synergic
effect of thiazides and loop diuretics depends on the achieve-
ment of natriuretic threshold of both drugs, time and modal-
ity of administration could be critical [27] and could point
out different results. The efficacy of different administration
modalities of loop diuretic associated with the enhanced diu-
retic effect of thiazides should be evaluated in another trial
Fig. 3  Evolution of creatinine with time according to treatment arm on heart failure patients with diuretic resistance.

Table 3  Subgroup analysis by primary endpoint (freedom from decongestion at 72 h)


Subgroup Bolus intermittent Continuous OR (95% CI)* p value**
events/N (%) infusion events/N
(%)
Renal function
eGFR (MDRD) < 30 ml/min 2/10 (20) 4/11 (36) 0.46 (0.05–3.4) 0.46
eGFR (MDRD) ≥ 30 ml/min 8/30 (27) 15/29 (52) 0.35 (0.11–1.0) 0.05
Haemodinamic profile
Cold profile 5/16 (31) 7/18 (39) 0.72 (0.16–3.1) 0.66
Warm profile 5/24 (21) 12/22 (55) 0.23 (0.06–0.81) 0.02
Diuretic dose
Low dose (furosemide 120 2/8 (25) 9/15 (60) 0.24 (0.03–1.6) 0.14
mg/die)
High dose (furosemide 240 8/32 (25) 10/25 (40) 0.51 (0.16–1.6) 0.24
mg/die)

Bold stands for significant (p < 0.05)


*OR: bolus/infusion
**Significant p < 0.02 (Bonferroni correction)

Table 4  Endpoints
Bolus intermittent (N = 40) Continuous infusion (N = 40) p value OR (95% CI)*

Primary endpoint at 72 h


 Freedom from congestion—N (%) 10 (25) 19 (48) 0.04 2.71 (1.05–7.00)
Secondary endpoints at 72 h
 Total urinary output (ml) 8612 ± 2984 10,020 ± 3032 0.04 1.2 (1.03–1.4)**
 Treatment failure—N (%) 15 (38) 6 (15) 0.02 0.29 (0.10; 0.87)
  Increase in diuretic dose—N (%) 15 (38) 6 (15) 0.02 0.29 (0.10; 0.87)
  Ultrafiltration—N (%) 1 (3) 1 (3) > 0.99 1
 Worsening renal function—N (%) 7 (18) 7 (18) > 0.99 1
 Worsening or persistent heart 12 (30) 8 (20) 0.44 0.59 (0.18; 1.83)
failure—N (%)
 Diuretic response (∆ weight − 0.6 ± 0.6 − 1.0 ± 0.7 < 0.01 0.41 (0.17–0.87)
kg/40 mg furosemide)
  ∆NT-proBNP (pg/ml) − 307 (IQR − 2830 to 3749) − 738 (IQR − 5564 to 1739) 0.42 1.00 (0.98–1.02)

Bold stands for significant (p < 0.05)


*OR: infusion/bolus
**OR per 1000 ml increase

13
Clinical Research in Cardiology

Conclusion for levosimendan in the context of traditional treatment. Giomale


Ital Cardiol 10:422–433
12. Frea S, Pidello S, Canavosio FG et al (2015) Clinical assessment
In conclusion, among patients with acute decompensation of of hypoperfusion in acute heart failure: evergreen or antique? Circ
advanced heart failure with high risk of diuretic resistance, J 79:398–405
continuous infusion of intravenous furosemide compared 13. Frea S, Bovolo V, Pidello S, Canavosio FG, Botta M, Bergerone
S, Gaita F (2015) Clinical and prognostic role of ammonia in
with intermittent boluses was associated with better decon- advanced decompensated heart failure. The cardio-abdominal
gestion without worsening renal function. syndrome? Int J Cardiol 15(195):53–60
14. Frea S, Centofanti P, Pidello S, Giordana F, Bovolo V, Baronetto
Compliance with ethical standards  A, Franco B, Cingolani MM, Attisani M, Morello M, Bergerone
S, Rinaldi M, Gaita F (2018) Noninvasive assessment of hemody-
namic status in Heart-Ware left ventricular assist device patients:
Conflict of interest  The author declares that they have no competing
validation of an echocardiographic approach.JACC Cardiovasc
interests.
Imaging. https​://doi.org/10.1016/j.jcmg.2018.01.026
15. Frea S, Pidello S, Bovolo V, Iacovino C, Franco E, Pinneri F, Gal-
luzzo A, Volpe A, Visconti M, Peirone A, Morello M, Bergerone
References S, Gaita F (2016) Prognostic incremental role of right ventricular
function in acute decompensation of advanced chronic heart fail-
ure. Eur J Heart Fail 18(5):564–572
1. Neuberg GW, Miller AB, O’Connor CM, Belkin RN, Carson PE,
16. Valente M, Voors A, Damman K et al (2014) Diuretic response
Cropp AB, Frid DJ, Nye RG, Pressler ML, Wertheimer JH, Packer
in acute heart failure: clinical characteristics and prognostic sig-
M (2002) Diuretic resistance predicts mortality in patients with
nificance. Eur Heart J 35:1284–1293
advanced heart failure. Am Heart J 144:31–38
17. Matsue Y, Ter Maaten JM, Suzuki M, Goldsmith SR et al (2017)
2. Testani JM, Brisco MA, Turner JM, Spatz ES, Bellumkonda L,
Early treatment with tolvaptan improves diuretic response in
Parikh CR et al (2014) Loop diuretic efficiency: a metric of diu-
acute heart failure with renal dysfunction. Clin Res Cardiol
retic responsiveness with prognostic importance in acute decom-
106(10):802–812
pensated heart failure. Circ Heart Fail 7(2):261–270
18. Bekfani T, Westphal F, Schulze PC (2018) Therapeutic options in
3. Ellison DH, Felker GM (2017) Diuretic treatment in heart failure.
advanced heart failure. Clin Res Cardiol 107(2):114–119
N Engl J Med 377:1964–1975
19. Schulz KF, Altman DG, Moher D, For the CONSORT Group
4. Thomson MR, Nappi JM, Dunn SP, Hollis IB, Rodgers JE, Van
(2010) CONSORT statement: updated guidelines for reporting
Bakel AB (2010) Continuous versus intermittent infusion of
parallel group randomised trials. BMJ 340:c332
furosemide in acute decompensated heart failure. J Card Fail
20. Llorens P, Miró O, Herrero P et al (2014) Clinical effects and
16:188–193
safety of different strategies for administering intravenous diuret-
5. Allen LA, Turer AT, DeWald T et al (2010) Continuous versus
ics in acutely decompensated heart failure: a randomised clinical
bolus dosing of furosemide for patients hospitalized for heart fail-
trial. Emerg Med J 31:706–713
ure. Am J Cardiol 105(12):1794–1797
21. Ng KT, Yap JLL (2018) Continuous infusion vs. intermittent bolus
6. Felker GM, Lee KL, Bull DA, Redfield MM, Stevenson LW, Gold-
injection of furosemide in acute decompensated heart failure: sys-
smith SR et al (2011) Diuretic strategies in patients with acute
tematic review and meta-analysis of randomised controlled trials.
decompensated heart failure. N Engl J Med 364:797–805
Anaesthesia 73(2):238–247
7. Kuriyama A, Urushidani S (2019) Continuous versus intermit-
22. Mullens W, Abrahams Z, Francis GS et al (2009) Importance of
tent administration of furosemide in acute decompensated heart
venous congestion for worsening of renal function in advanced
failure: a systematic review and meta-analysis. Heart Fail Rev
decompensated heart failure. J Am Coll Cardiol 53:589–596
24(1):31–39
23. Metra M, Davison B, Bettari L, Sun H, Edwards C, Lazzarini V,
8. Metra M, Ponikowski P, Dickstein K et  al (2007) Advanced
Piovanelli B, Carubelli V, Bugatti S, Lombardi C, Cotter G, Dei
chronic heart failure: a position statement from the study group
Cas L (2012) Is worsening renal function an ominous prognostic
on advanced heart failure of the heart failure association of the
sign in patients with acute heart failure? The role of congestion
ESC. Eur J Heart Fail 9:684–694
and its interaction with renal function. Circ Heart Fail 5(1):54–62
9. Gheorghiade M, Follath F, Ponikowski P et al (2010) European
24. Brisco MA, Zile MR, Hanberg JS et  al (2016) Relevance of
society of cardiology; European society of intensive care medi-
changes in serum creatinine during a heart failure trial of decon-
cine. Assessing and grading congestion in acute heart failure: a
gestive strategies: insights from the DOSE trial. J Card Fail.
scientific statement from the acute heart failure committee of the
22:753–760
heart failure association of the European society of cardiology and
25. Sanjay S, Ra Annigeri, Seshadri R et al (2008) The comparison
endorsed by the European society of intensive care medicine. Eur
of the diuretic and natriuretic efficacy of continuous and bolus
J Heart Fail 12:423–433
intravenous furosemide in patients with chronic kidney disease.
10. ESC Scientific Document Group (2016) ESC Guidelines for the
Nephrology 13(3):247–250
diagnosis and treatment of acute and chronic heart failure: the task
26. Ng T, Konopka E, Hyderi AF et  al (2013) Comparison of
force for the diagnosis and treatment of acute and chronic heart
bumetanide- and metolazone-based diuretic regimens to furo-
failure of the European society of cardiology (ESC). Eur Heart J
semide in acute heart failure. J Cardiovasc Pharmacol Ther
37:2129–2200
18:345–356
11. Ambrosio G, Di Lenarda A, Fedele F, Gabrielli D, Metra M, Oliva
27. Sica D (2003) Metolazone and its role in edema management.
F, Perna G, Senni M, De Maria R (2009) Inotrope therapy in acute
CHF 9:100–105
heart failure: a critical review of clinical and scientific evidence

13

You might also like