Lung ultrasound-guided therapy reduces acute decompensation events in chronic heart failure

Abstract

Objective
Pulmonary congestion is the main cause of hospital admission in patients with heart failure (HF). Lung ultrasound (LUS) is a useful tool to identify subclinical pulmonary congestion. We evaluated the usefulness of LUS in addition to physical examination (PE) in the management of outpatients with HF.

Methods
In this randomised multicentre unblinded study, patients with chronic HF and optimised medical therapy were randomised in two groups: ‘PE+LUS’ group undergoing PE and LUS and ‘PE only’ group. Diuretic therapy was modified according to LUS findings and PE, respectively. The primary endpoint was the reduction in hospitalisation rate for acute decompensated heart failure (ADHF) at 90-day follow-up. Secondary endpoints were reduction in NT-proBNP, quality-of-life test (QLT) and cardiac mortality at 90-day follow-up.

Results
A total of 244 patients with chronic HF and optimised medical therapy were enrolled and randomised in ‘PE+LUS’ group undergoing PE and LUS, and in ‘PE only’ group. Thirty-seven primary outcome events occurred. The hospitalisation for ADHF at 90 day was significantly reduced in ‘PE+LUS’ group (9.4% vs 21.4% in ‘PE only’ group; relative risk=0.44; 95% CI 0.23 to 0.84; p=0.01), with a reduction of risk for hospitalisation for ADHF by 56% (p=0.01) and a number needed to treat of 8.4 patients (95% CI 4.8 to 34.3). At day 90, NT-proBNP and QLT score were significantly reduced in ‘PE+LUS’ group, whereas in ‘PE only’ group both were increased. There were no differences in mortality between the two groups.

Conclusions
LUS-guided management reduces hospitalisation for ADHF at mid-term follow-up in outpatients with chronic HF.

Full text

1
MariniC, etal. Heart 2020;0:1–6. doi:10.1136/heartjnl-2019-316429
ORIGINAL RESEARCH
Lung ultrasound- guided therapy reduces acute
decompensation events in chronic heartfailure
Claudia Marini,1 Gabriele Fragasso,2 Leonardo Italia,1 Hamayak Sisakian ,3
Vincenzo Tufaro,1 Giacomo Ingallina ,1 Stefano Stella,1 Francesco Ancona,1
Ferdinando Loiacono,2 Pasquale Innelli,4 Marco Fabio Costantino,4
Laura Sahakyan ,3 Sirvard Gabrielyan,3 Mariam Avetisyan,3 Alberto Margonato,2,5
Eustachio Agricola1,5
Heart failure and cardiomyopathies
To cite: MariniC,
FragassoG, ItaliaL, etal.
Heart Epub ahead of
print: [please include Day
Month Year]. doi:10.1136/
heartjnl-2019-316429
►Additional material is
published online only. To view
please visit the journal online
(http:// dx. doi. org/ 10. 1136/
heartjnl- 2019- 316429).
1Cardiovascular Imaging Unit,
San Raffaele Scientific Institute,
Milan, Italy
2Heart Failure Clinic, Clinical
Cardiology, San Raffaele
Scientific Institute, Milan, Italy
3Department of Cardiology,
Yerevan State Medical
University, University Hospital 1,
Yerevan, Armenia
4SSD Imaging Cardiovascular
Department, San Carlo Hospital,
Potenza, Italy
5Vita- Salute San Raffaele
University, Milan, Italy
Correspondence to
Dr Claudia Marini, San Raffaele
Hospital, Milano 20132, Italy;
claudia. marini@ outlook. com
Received 3 January 2020
Revised 14 April 2020
Accepted 14 April 2020
© Author(s) (or their
employer(s)) 2020. No
commercial re- use. See rights
and permissions. Published
by BMJ.
ABSTRACT
Objective Pulmonary congestion is the main cause
of hospital admission in patients with heart failure
(HF). Lung ultrasound (LUS) is a useful tool to identify
subclinical pulmonary congestion. We evaluated the
usefulness of LUS in addition to physical examination
(PE) in the management of outpatients with HF.
Methods In this randomised multicentre unblinded
study, patients with chronic HF and optimised medical
therapy were randomised in two groups: ’PE+LUS’ group
undergoing PE and LUS and ’PE only’ group. Diuretic
therapy was modified according to LUS findings and PE,
respectively. The primary endpoint was the reduction
in hospitalisation rate for acute decompensated heart
failure (ADHF) at 90- day follow- up. Secondary endpoints
were reduction in NT- proBNP, quality- of- life test (QLT)
and cardiac mortality at 90- day follow- up.
Results A total of 244 patients with chronic HF and
optimised medical therapy were enrolled and randomised
in ’PE+LUS’ group undergoing PE and LUS, and in
’PE only’ group. Thirty- seven primary outcome events
occurred. The hospitalisation for ADHF at 90 day was
significantly reduced in ’PE+LUS’ group (9.4% vs 21.4%
in ’PE only’ group; relative risk=0.44; 95% CI 0.23 to
0.84; p=0.01), with a reduction of risk for hospitalisation
for ADHF by 56% (p=0.01) and a number needed to
treat of 8.4 patients (95% CI 4.8 to 34.3). At day 90,
NT- proBNP and QLT score were significantly reduced
in ’PE+LUS’ group, whereas in ’PE only’ group both
were increased. There were no differences in mortality
between the two groups.
Conclusions LUS- guided management reduces
hospitalisation for ADHF at mid- term follow- up in
outpatients with chronic HF.
INTRODUCTION
Despite significant improvements in therapies
witnessed in the last decades, the prevalence of heart
failure (HF) as well as hospitalisation rate for acute
decompensated HF (ADHF) continue to raise.1
Pulmonary congestion (PC) is the main cause of
hospital admission.2 Clinical signs of HF occur late
in the decompensation phase, even though increase
in body weight3 and intrathoracic fluid4 can be
detected at least 10 days preceding hospitalisation.
Medical history and physical examination (PE)
are a mainstay for the assessment of HF. However,
lung auscultation shows poor sensitivity and accu-
racy in detecting mild PC.5 The availability of an
additional tool to identify subclinical PC is attrac-
tive, since the ensuing treatment may prevent
hospitalisation.
Lung ultrasound (LUS) provides a semiquanti-
tative assessment of PC, identifying extravascular
lung water (EVLW) as B- lines.6–10 The latter are
significantly related with established parameters of
decompensation in outpatients with chronic HF11
and portend worse outcome in terms of hospitalisa-
tion for ADHF and death.12
We investigated the clinical impact of LUS- guided
management in outpatients with chronic HF.
METHODS
Study design
A randomised multicentre unblinded study was
designed. Patients were considered eligible if
on optimal medical therapy for HF for at least 2
months and with left ventricular ejection fraction
<45%. At the beginning of cardiology outpatient
visits at HF clinic, patients who satisfied enrolment
criteria were randomised in two parallel groups
(1:1): ‘PE+LUS’ group undergoing PE and LUS
and ‘PE only’ group. The study was approved by
local ethics committees at each centre. All patients
provided written informed consent.
PE was performed by trained physicians according
to a validated clinical assessment score.13 The quan-
tification of EVLW was graded on the lung field
height where B- lines, defined as echogenic wedge-
shaped signal, were visualised9 (details in online
supplementary appendix).
In ‘PE+LUS’ group, baseline loop diuretic dose
was modified according to physician’s judgement
based on LUS score, considering the extent of B- line
distribution (basal, middle, apical fields). There was
no fixed scheme of dose modification, rather vari-
able increments ranging from 25% to 150%, consid-
ering also vital signs, renal function and ongoing
diuretic dose. In ‘PE only’ group, diuretic therapy
was optimised according to PE, blood tests, echo-
cardiogram and chest X- ray when available. The
investigators were unblinded to group assignment
and LUS findings. Medical history, PE, therapeutic
changes, blood tests including N- terminal frag-
ment of BNP pro- hormone (NT- proBNP) and left
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2MariniC, etal. Heart 2020;0:1–6. doi:10.1136/heartjnl-2019-316429
Heart failure and cardiomyopathies
Figure 1 Enrolment of participants in the study. LUS, lung ultrasound; PE, physical examination.
ventricular dysfunction (LVD-36) questionnaire quality- of- life
test (QLT)14 were recorded at baseline and at 90- day follow- up.
The trial is registered at ClinicalTrials. gov (NCT03262571).
There was no patients and public involvement in the design of
our research.
The primary endpoint was hospitalisation for ADHF at 90- day
follow- up. Secondary endpoints were mortality, modifications in
NT- proBNP values and QLT score at 90- day follow- up. ADHF
failure was defined as sudden or gradual onset of signs or symp-
toms of HF.15
Statistics
We estimated that the 90- day rate of primary endpoint would
be 20%, hence the need to follow 440 patients for 3 months
to provide the study with a power of 80% to detect a relative
reduction of 50% in risk of hospitalisation for ADHF in LUS
group, at an overall two- sided alpha level of 0.05. At the third
interim analysis, scheduled at 244 enrolled patients, principal
investigators verified that prespecified stopping boundary for
overwhelming benefit had been crossed and decided to stop the
study.
Data are expressed as mean±SD, median (IQR) or percentage
when appropriate. For group comparisons, paired and unpaired
t- test, χ2 test or Fisher’s exact test and Wilcoxon matched- pairs
signed rank test were used as appropriate. The relative risk
(RR), number needed to treat (NNT) and 95% CI were defined.
Survival free from ADHF events was estimated with Kaplan-
Meier method and compared by long- rank test. According to the
interim nature of analysis, p<0.027 was considered statistically
significant to reject the null hypothesis (details in online supple-
mentary appendix).
RESULTS
From January 2011 to November 2016, 256 patients were
screened and 244 enrolled: 127 (52%) in ‘PE+LUS’ group and
117 (48%) in ‘PE only’ group (figure 1). Baseline character-
istics are shown in tables 1 and 2. All participants completed
follow- up.
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MariniC, etal. Heart 2020;0:1–6. doi:10.1136/heartjnl-2019-316429
Heart failure and cardiomyopathies
Table 1 Baseline characteristics of the overall study population,
group ‘PE+LUS’ and group ‘PE only’
Variable Overall population
Group ‘PE+LUS’
(n=127)
Group ‘PE only’
(n=117) P value
Age (years) 71.57±11.25 73.22±10.94 69.79±11.35 0.15
Male 167 (68%) 88 (69%) 79 (67%) 0.78
HF aetiology
Ischaemic 166 (68%) 68.5% (87) 67.5% (79) 0.94
Valvular 17 (6.9%) 7 (5.5%) 10 (8.5%) 0.35
Hypertensive 24 (9.8%) 16 (12.5%) 8 (6.8%) 0.13
Idiopathic 43 (17.6%) 15 (11.8%) 28 (23.9%) 0.01
Congenital 2 (0.8%) 2 (1.5%) 0 0.17
Hypertension 163 (66.8%) 86 (67.7%) 77 (65.8%) 0.75
Diabetes mellitus 78 (32%) 36 (28.3%) 42 (35.9%) 0.2
Atrial fibrillation 54 (22.1%) 27 (21.2%) 27 (23.1%) 0.53
CKD 73 (29.9%) 40 (31.5%) 33 (28.2%) 0.57
COPD 41 (16.8%) 20 (15.7%) 21 (17.9%) 0.65
CRT 26 (10.6%) 16 (12.6%) 10 (8.5%) 0.38
ICD 44 (18%) 19 (14.9%) 25 (21.3%) 0.32
NYHA class 0,31
I 10 (4.1%) 5 (3.9%) 5 (4.3%)
II 96 (39.3%) 43 (33.9%) 53 (45.3%)
III 131 (53.7%) 75 (59.1%) 56 (47.9%)
IV 7 (2.9%) 4 (3.1%) 3 (2.6%)
B- line baseline values
0 34 (26.7%)
1 32 (25.1%)
2 43 (33.8%)
3 18 (14.1%)
Positive PE 92 (37.7%) 60 (48%) 32 (26.4%) 0.006
QLT 17.35±8.83 17.95±8.89 16.69±8.75 0.26
LV EF (%) 31.47±9.09 32.16±9.64 30.73±8.43 0.22
sPAP (mm Hg) 43.49±14.84 44.6±15.63 42.27±13.91 0.28
NT- proBNP (pg/mL) 1545 (IQR 544–3433) 1559 (IQR 576–4101) 1319 (IQR 387–2818) 0.81
Creatinine (mg/dL) 1.38±0.61 1.36±0.66 1.38±0.57 0.85
CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; CRT, cardiac resynchronisation therapy; HF, heart failure;
ICD, implantable cardioverter defibrillator; LUS, lung ultrasound; LV EF, left ventricular ejection fraction; NYHA, New York Heart
Association; PE, physical examination; QLT, quality- of- life test; sPAP, systolic pulmonary artery pressure.
Table 2 Medical therapy and renal function of the study population
Variable
Group ‘PE+LUS’
(n=127)
Group ‘PE only’
(n=117) P value
Medications
β-blocker 117 (91.9%) 100 (85.5%) 0.26
ACE- I/ARB 75 (59.7%) 70 (60%) 0.97
Digoxin 24 (19.7%) 21 (18.2%) 0.83
Diuretic 98 (77.4%) 96 (82.1%) 0.52
Diuretic therapy titration
Mean diuretic dose at
baseline (mg)
73.64±119.87 91.58±132.65 0.46
Mean diuretic dose at 3
months (mg)
103.51±158.98 93.24±132.71 0.72
Renal function
Serum creatinine at
baseline (mg/dL)
1.365±0.66 1.388±0.57 0.85
Serum creatinine at 3
months (mg/dL)
1.367±0.66 1.549±0.63 0.21
ACE- I, ACE inhibitor; ARB, angiotensin receptor blocker; LUS, lung ultrasound ; PE,
physical examination.
Figure 2 Kaplan- Meier curves for hospitalisation- free survival
from ADHF in group ‘PE+LUS’ versus group ‘PE only’ patients. ADHF,
acute decompensated heart failure; LUS, lung ultrasound; PE, physical
examination.
In the ‘PE+LUS’ group, 26.8% of patients presented no
B- lines, 25.2% B- lines only in basal fields, 33.9% B- lines
extended to middle fields and 14.2% B- lines extended to apical
fields. In none of the patients pleural effusion was found.
In ‘PE+LUS’ group, 60 patients (47%) were both LUS and PE
positive, 33 patients (26%) were LUS positive and PE negative,
34 (27%) patients resulted LUS- negative. Therefore, 93 (73%)
LUS- positive patients were addressed with an increase in diuretic
therapy (mean furosemide uptitration 50.7±57.2 mg), whereas
in the remaining 34 (27%) ongoing therapy was confirmed.
At 90- day follow- up, 56% of ‘PE+LUS’ patients showed a
significant reduction in B- line extension (0.5 (IQR 0–1) vs 1
(IQR 0.75–2), p<0.001).
At 90- day follow- up, hospitalisation for ADHF occurred in 12
patients (9.4%) in ‘PE+LUS’ group and in 25 patients (21.4%)
in ‘PE only’ group (relative risk (RR)=0.44; 95% CI 0.23 to
0.84; p=0.01). As compared with ‘PE only’ group, the risk was
reduced by 56% in ‘PE+LUS’ group (p=0.01) with an NNT of
8.4 patients (95% CI 4.8 to 34.3).
The survival- free rate from hospitalisation for ADHF was
84.5% (95% CI 81.5 to 87.5) for ‘PE+LUS’ group and 79.7%
(95% CI 75.6 to 83.7) for ‘PE only’ group (log- rank 6.5,
p=0.01) (figure 2).
At 90- day follow- up in ‘PE+LUS’ group, the NT- proBNP value
was significantly reduced (p=0.026) and QLT score significantly
decreased (p=0.001) indicating an improvement in health status,
while in ‘PE only’ group, NT- proBNP value (p=0.004) and QLT
score (p<0.001) were significantly increased (figure 3A,B).
No differences in mortality rate were observed between the
groups at 90- day follow- up (table 3).
A post hoc subgroup analysis, further dividing the overall
population in negative and positive PE patients was performed.
Subgroups were not defined by characteristics known before
randomisation, and thus subgroup analyses are a non- randomised
unadjusted comparison with potential biases.
In patients with negative PE (n=152, 66 from ‘PE+LUS’
group), primary outcome occurred in 3 (4.5%) patients in
‘PE+LUS’ group and in 19 (22.1%) of the ‘PE only’ group
(RR=0.20; 95% CI 0.06 to 0.67; p=0.002). Hence, ‘PE+LUS’
patients with negative PE had an 80% risk reduction for
hospitalisation for ADHF as compared with ‘PE only’ group
(p=0.002) (table 3). At 90- day follow- up in ‘PE+LUS’ group,
the NT- proBNP value was significantly reduced (p=0.01) and
QLT score significantly decreased (p=0.02), while in ‘PE only’
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4MariniC, etal. Heart 2020;0:1–6. doi:10.1136/heartjnl-2019-316429
Heart failure and cardiomyopathies
Figure 3 NT- proBNP and QLT values at baseline and at 90- day follow- up in ‘PE+LUS’ and ‘PE only’ groups. LUS, lung ultrasound; PE, physical
examination; QLT, quality- of- life test.
Table 3 ADHF and death according to ‘PE+LUS’ group and ‘PE only’
group in the entire study population and subgroups PE positive and PE
negative
Entire population
Total=244 PE+LUS
(n=127)
PE only
(n=117)
Relative risk (95% CI) P value
Primary endpoint:
hospitalisation for ADHF
12 (9.4%) 25 (21.4%) 0.44 (0.23 to 0.84) 0.01
Secondary endpoint: death 5 (3.9%) 4 (3.4%) 1.15 (0.31 to 4.18) 0.8
Subgroup PE negative
Total=152 PE+LUS
(n=66)
PE only
(n=86)
Relative risk (95% CI) P value
Primary endpoint:
hospitalisation for ADHF
3 (4.5%) 19 (22.1%) 0.2 (0.06 to 0.67) 0.002
Secondary endpoint:
death
2 (3 %) 1 (1.2%) 2.61 (0.24 to 28.13) 0.41
Subgroup PE positive
Total=92 PE+LUS
(n=60)
PE only
(n=32)
Relative risk (95% CI) P value
Primary endpoint:
hospitalisation for ADHF
9 (14.8%) 6 (19.4%) 0.76 (0.29 to 1.95) 0.57
Secondary endpoint:
death
3 (4.9%) 3 (9.6%) 0.5 (0.11 to 2.37) 0.38
ADHF, acute decompensated heart failure; LUS, lung ultrasound; PE, physical examination.
Figure 4 NT- proBNP and QLT values at baseline and at 90- day follow- up in the subgroup of patients with negative PE. LUS, lung ultrasound; PE,
physical examination; QLT, quality- of- life test.
NT- proBNP value (p<0.001) and QLT score (p<0.001) were
significantly increased (figure 4A,B).
In patients with a positive PE (n=92, 60 from ‘PE+LUS’
group) no significant differences in hospitalisation for ADHF
between the two groups were observed (table 3). Neither signif-
icant differences in NT- proBNP at 3 months were observed
(figure 5A), while QLT scores were significantly decreased in
‘PE+LUS’ group (p=0.01) and increased in ‘PE only’ group
(p=0.02) at 3 months (figure 5B).
In these subgroups, no difference in mortality between
‘PE+LUS’ and ‘PE only’ at 90- day follow- up was observed
(table 3).
We found no safety issues in the group PE- LUS with no signifi-
cant difference in serum creatinine (p=0.5) and creatinine clear-
ance (p=0.66), while a trend of worsening of renal function
in ‘PE only’ group at 90- day follow- up was identified (further
details in online supplementary appendix).
DISCUSSION
The presence of PC at PE in patients with chronic HF portends
a high risk of ADHF and death.16 LUS is an attractive tool, since
it provides a fast and low- cost bedside examination to detect
subclinical PC, overcoming the limited sensitivity and specificity
of lung auscultation.14
Prior studies have extensively demonstrated the strong
correlation between LUS and EVLW.17 Platz et al asserted that
PC is frequently detected with LUS examination in ambulatory
patients with chronic HF and associated with a worse prognosis
in terms of hospitalisation for ADHF and death.12 Similar results
have been suggested by Pellicori and colleagues, who demon-
strated that as many as 58% of 342 patients with chronic HF
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MariniC, etal. Heart 2020;0:1–6. doi:10.1136/heartjnl-2019-316429
Heart failure and cardiomyopathies
Figure 5 NT- proBNP and QLT values at baseline and at 90- day follow- up in the subgroup of patients with positive PE. LUS, lung ultrasound; PE,
physical examination; QLT, quality- of- life test.
Key messages
What is already known on this subject?
►Lung ultrasound provides a validated semiquantitative
assessment of pulmonary congestion, but it is not known
the prognostic impact on the management of patients with
chronic heart failure.
What might this study add?
►This study shows that the detection of congestion with lung
ultrasound during the ambulatory evaluation of patients
with chronic heart failure, especially in patients with no overt
signs of heart failure detected by physical examination, leads
to a reduction of hospitalisation for acute decompensated
heart failure with respect to the sole physical examination
at midterm follow- up (9.4% vs 21.4% at 90- day follow-
up, respectively, RR=0.44; 95% CI 0.23 to 0.84; p=0.01),
reducing the risk for hospitalisation by 56%.
How might this impact on clinical practice?
►Lung ultrasound is a low- cost, radiation- free and no time-
consuming method with steep learning curve. The integration
of lung ultrasound in heart failure clinics might help to
improve the treatment of heart failure targeting early signs of
decompensation.
outpatients, and 47% of subjects clinically free of congestion,
were LUS- positive.18 A recent randomised clinical trial from
Rivas- Lasarte et al showed that LUS- guided strategy significantly
improved the combined endpoint of urgent visit, hospitalisation
for ADHF and death at 6 month after an ADHF episode in 123
patients.19
Our study demonstrates that LUS improves the management
of patients with chronic HF. Indeed, LUS accuracy in detecting
subclinical PC provides the possibility to tackle an early decom-
pensation phase, reducing admissions for ADHF and HF
biomarkers and improving quality of life at 90- day follow- up.
The usefulness of LUS was also confirmed by the better trend in
renal function when therapeutic management was LUS guided.
The study has some limitations. First, the midterm follow- up
could limit the prognostic yield in predicting outcome events.
Second, the lack of blinding is a potential source of bias. Addi-
tionally, we did not use the stratified randomisation method to
control the influence of covariates. However, the two groups
of the study population were homogeneous in terms of baseline
characteristics, minimising the possible influence of covariates.
CONCLUSIONS
LUS is a low- cost, radiation- free and rapid diagnostics. The
detection of EVLW by LUS in patients with chronic HF, espe-
cially in subjects with negative PE, might help physician to opti-
mise medical treatment, preventing hospitalisation for ADHF.
Contributors EA, GF, AM: study planning, study analysis and responsible for the
overall content as guarantors. CM, GF, LI, HS, VT, GI, SS, FA, FL, PI, MFC, LS, SG, MA,
AM, EA conducted the study and performed the examinations. EA, CM, LI performed
the statistical analysis and wrote the manuscript. All authors have read and
approved the final version of the manuscript.
Funding The authors have not declared a specific grant for this research from any
funding agency in the public, commercial or not- for- profit sectors.
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in
the design, conduct, reporting or dissemination plans of this research.
Patient consent for publication Not required.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement All data relevant to the study are included in the
article and uploaded as supplementary information, and further data are available
on request.
ORCID iDs
HamayakSisakian http:// orcid. org/ 0000- 0003- 2986- 0525
GiacomoIngallina http:// orcid. org/ 0000- 0002- 4102- 6405
LauraSahakyan http:// orcid. org/ 0000- 0001- 7144- 4563
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