European Heart Journal (2013) 34, 835–843 CLINICAL RESEARCH

doi:10.1093/eurheartj/ehs444 Heart failure/cardiomyopathy

Clinical course and predictive value of

congestion during hospitalization in patients
admitted for worsening signs and symptoms of
heart failure with reduced ejection fraction:

Downloaded from https://academic.oup.com/eurheartj/article/34/11/835/460424 by guest on 27 February 2021

findings from the EVEREST trial†
Andrew P. Ambrosy1, Peter S. Pang2,3, Sadiya Khan4, Marvin A. Konstam5,
Gregg C. Fonarow6, Brian Traver7, Aldo P. Maggioni8, Thomas Cook7, Karl Swedberg9,
John C. Burnett Jr10, Liliana Grinfeld11, James E. Udelson5, Faiez Zannad12, and
Mihai Gheorghiade3*, on behalf of the EVEREST trial investigators
1
Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA; 2Department of Emergency Medicine, Northwestern University Feinberg School of Medicine,
Chicago, IL, USA; 3Center for Cardiovascular Innovation, Northwestern University, Feinberg School of Medicine, 645 North Michigan Ave. Suite 1006, Chicago, IL 60601, USA;
4
Division of Cardiology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA; 5Cardiovascular Center, Tufts Medical Center, Boston,
MA, USA; 6University of California Los Angeles Medical Center, Los Angeles, CA, USA; 7University of Wisconsin, Madison, WI, USA; 8ANMCO Research Center, Florence, Italy;
9
Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; 10Mayo Clinic, Rochester, MN, USA; 11Hospital Italiano, Buenos Aires, Argentina; and 12Inserm, CIC9501,
U961, CHU, Nancy, France

Received 18 June 2012; revised 10 October 2012; accepted 28 November 2012; online publish-ahead-of-print 4 January 2013

Aims Signs and symptoms of congestion are the most common cause for hospitalization for heart failure (HHF). The clinical
course and prognostic value of congestion during HHF has not been systemically characterized.
.....................................................................................................................................................................................
Methods A post hoc analysis was performed of the placebo group (n ¼ 2061) of the EVEREST trial, which enrolled patients within
and results 48 h of admission (median 24 h) for worsening HF with an EF ≤40% and two or more signs or symptoms of fluid over-
load [dyspnoea, oedema, or jugular venous distension (JVD)] for a median follow-up of 9.9 months. Clinician-investigators
assessed patients daily for dyspnoea, orthopnoea, fatigue, rales, pedal oedema, and JVD and rated signs and symptoms on a
standardized 4-point scale ranging from 0 to 3. A modified composite congestion score (CCS) was calculated by summing
the individual scores for orthopnoea, JVD, and pedal oedema. Endpoints were HHF, all-cause mortality (ACM), and
ACM + HHF. Multivariable Cox regression models were used to evaluate the risk of CCS at discharge on outcomes
at 30 days and for the entire follow-up period. The mean CCS obtained after initial therapy decreased from the
mean + SD of 4.07 + 1.84 and the median (25th, 75th) of 4 (3, 5) at baseline to 1.11 + 1.42 and 1 (0, 2) at discharge.
At discharge, nearly three-quarters of study participants had a CCS of 0 or 1 and fewer than 10% of patients had a
CCS .3. B-type natriuretic peptide (BNP) and amino terminal-proBNP, respectively, decreased from 734 (313,
1523) pg/mL and 4857 (2251, 9642) pg/mL at baseline to 477 (199, 1079) pg/mL, and 2834 (1218, 6075) pg/mL at dis-
charge/Day 7. A CCS at discharge was associated with increased risk (HR/point CCS, 95% CI) for a subset of endpoints
at 30 days (HHF: 1.06, 0.95–1.19; ACM: 1.34, 1.14–1.58; and ACM + HHF: 1.13, 1.03–1.25) and all outcomes for the
overall study period (HHF: 1.07, 1.01–1.14; ACM: 1.16, 1.09–1.24; and ACM + HHF 1.11, 1.06–1.17). Patients with a
CCS of 0 at discharge experienced HHF of 26.2% and ACM of 19.1% during the follow-up.
.....................................................................................................................................................................................
Conclusion Among patients admitted for worsening signs and symptoms of HF and reduced EF, congestion improves substantially
during hospitalization in response to standard therapy alone. However, patients with absent or minimal resting signs
and symptoms at discharge still experienced a high mortality and readmission rate.
-----------------------------------------------------------------------------------------------------------------------------------------------------------
†
These data were presented in part at ESC Congress 2010 in Stockholm, Sweden (citation: European Heart Journal (2010) 31 (Abstract Supplement), 15).
* Corresponding author. Tel: +1 312 695 0051, Fax: +1 312 695 1434, Email: m-gheorghiade@northwestern.edu
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2013. For permissions please email: journals.permissions@oup.com
836
Keywords Heart failure † Signs and symptoms † Hospitalization † Outcomes † Morbidity † Mortality
Introduction
Hospitalization for heart failure (HHF) account for over 1.1 million
admissions and greater than $20 billion in healthcare expenditures
each year in the USA.1,2 Signs and symptoms of congestion are the
most common cause for HHF and readmission.3 As a result, allevi-
ating clinical congestion has traditionally been one of the primary
goals of management during hospitalization.4,5 Registry data
reveal that 40% of patients are discharged despite persistent
signs and symptoms of HF with minimal decrease or even an in-
crease in body weight, suggesting failure to relieve clinical conges-
tion during index hospitalization may potentially contribute to the
high post-discharge readmission rate.6 – 8 However, the prevalence
and severity of residual congestive signs and symptoms at discharge
is likely inversely related to the length of stay, which exhibits con-
siderable geographic variation and is known to be shorter in the
USA compared with Europe.9
The Efficacy of Vasopressin Antagonism in Heart Failure:
Outcome Study with Tolvaptan (EVEREST) trial provides a
unique opportunity to systemically and longitudinally study the
natural history of congestive signs and symptoms in response to
standard therapy in a large contemporary cohort of patients hos-
pitalized for worsening HF with reduced ejection fraction (EF).
Specifically, the objectives of this analysis were: (i) to describe
the clinical course of signs and symptoms of congestion and (ii)
to evaluate the association between clinical congestion at discharge
and post-discharge morbidity and mortality.
Methods
Study overview
The study design10 and primary results11,12 of the EVEREST trial have
been previously reported. Briefly, EVEREST was a global, prospective,
randomized, double-blind, placebo-controlled trial designed to
examine the short- and long-term efficacy and safety of tolvaptan, a
vasopressin-2 receptor antagonist. Patients ≥18 years of age, hospita-
lized for worsening HF, with a left ventricular ejection fraction (LVEF)
≤40%, symptoms classified as New York Heart Association (NYHA) III
or IV, and two or more signs or symptoms of volume overload [dys-
pnoea, pitting oedema, and jugular venous distension (JVD)] at presen-
tation were enrolled within 48 h (median 24 h). Relevant exclusion
criteria included systolic blood pressure (SBP) ,90 mmHg, haemo-
dynamically significant uncorrected primary cardiac valvular disease,
serum creatinine (sCr) .3.5 mg/dL or 309.4 mmol/L, subjects current-
ly treated with haemofiltration or dialysis, or a life expectancy of ,6
months as determined by the enrolling clinician-investigator.
Background HF therapy was left to the discretion of the treating
physician, but guideline-based recommendations for optimal medical
management were included in the study protocol. EVEREST was con-
ducted in accordance with the Declaration of Helsinki, the protocol was
independently approved by the Institutional Review Board or ethics
committee at each participating centre, and written informed
A.P. Ambrosy et al.
consent was obtained from all participants. The present analysis
includes only patients randomized to the placebo group (n ¼ 2061),
since tolvaptan has previously been reported to improve dyspnoea
and decrease body weight.11
Investigator-assessed signs and symptoms of
congestion
Patients were examined daily during hospitalization by
Downloaded from https://academic.oup.com/eurheartj/article/34/11/835/460424 by guest on 27 February 2021
physician-investigators for signs and symptoms of congestion from
the time of enrolment until discharge or hospital day 7, whichever oc-
curred first. Dyspnoea, fatigue, orthopnoea, JVD, rales, and pedal
oedema were assessed on a standardized 4-point scale ranging from
0 to 3 (Table 1). A composite congestion score (CCS) was calculated
by summing the individual scores for orthopnoea, JVD, and pedal
oedema based on a precedent set by a prior study which assessed
signs and symptoms of congestion at an initial follow-up visit scheduled
between 4 and 6 weeks post-discharge.13 In addition, orthopnoea, JVD,
and pedal oedema were selected a priori in order to (i) avoid redun-
dancy regarding the severity of congestion and (ii) include a diverse
set of signs and symptoms known to have high specificity for conges-
tion.14 – 16
EVEREST endpoints
An independent and blinded adjudication committee determined the
cause of all hospitalizations and deaths reported during follow-up.
The outcomes of interest for the present analysis were HHF, all-cause
mortality (ACM), and the composite of ACM + HHF. Hospitalization
for heart failure was defined as admission that extended over a
change in calendar day and included worsening signs or symptoms of
HF resulting in the augmentation of oral medications or new adminis-
tration of intravenous HF therapies or ultrafiltration.
Statistical analysis
Patients were divided into four groups based on CCS at discharge (0, 1,
2, and 3 – 9). Baseline demographic, medical history, physical exam, and
laboratory findings were compared using Kendall’s rank correlation
test for continuous and ordered categorical variables and Pearson’s
x2 test for unordered categorical variables. The associations
between discharge CCS and HHF, ACM, and ACM + HHF were
assessed using univariate and multivariate Cox proportional-hazard
models adjusted for age, LVEF, previous HHF, SBP at enrolment,
b-type natriuretic peptide (BNP)/amino terminal-proBNP (NT-proBNP),
blood urea nitrogen (BUN), serum sodium, baseline diuretic usage, and
discharge medications (i.e. b-blockers, lipid-lowering agents, and amio-
darone). The model for adjustment was determined through a process
of backward selection with ACM as the endpoint. The least significant
candidate variables were removed until all remaining variables were
significant. Hazard ratios are presented with 95% confidence intervals.
Funding and manuscript preparation
Otsuka, Inc. (Rockville, MD, USA) provided financial and material
support for the EVEREST trial. Database management was performed
by the sponsor according to a pre-specified plan. Thomas Cook and
Brian Traver conducted all final analysis for this manuscript using
SAS version 9.1 (SAS Institute, Inc., Cary, NC, USA) and R software
Clinical course and predictive value of congestion 837

Table 1 Grading scale for investigator-assessed signs

Clinical course of congestion during
and symptoms of congestion hospitalization
There was significant improvement in the distribution of CCS from
Signs/ 0 1 2 3 baseline to discharge/Day 7 (Figure 1). The CCS decreased from a
symptoms
................................................................................ mean + SD of 4.07 + 1.84 and median (25th, 75th) of 4 (3, 5) at
Dyspnoea None Seldom Frequent Continuous baseline to 1.11 + 1.42 and 1 (0, 2) at discharge. Among patients
Orthopnoea None Seldom Frequent Continuous with a baseline CCS of 2 and 3–9, respectively, 62.5 and 88.8%
Fatigue None Seldom Frequent Continuous experienced a decrease in CCS of 2 or greater (Supplementary
JVD (cm H2O) ≤6 6– 9 10– 15 ≥15 material online, Table S1). By discharge, nearly three-quarters of
Rales None Bases To ,50% To .50% study participants had a CCS of 0 or 1 and fewer than 10% of
Oedema Absent/ Slight Moderate Marked patients had a CCS score .3. The decrease in CCS occurred con-
trace currently with a sustained body weight reduction of 22.1 (24.1,

Downloaded from https://academic.oup.com/eurheartj/article/34/11/835/460424 by guest on 27 February 2021

JVD, jugular venous distension.
(R Development Core Team, 2005). The authors had full access to the
data, take responsibility for its integrity, and had complete control and
authority over manuscript preparation and the decision to publish.
Results
Study population
Between October 2003 and February 2006, 2061 patients were
assigned to the placebo arm of the EVEREST trial. Study partici-
pants had a mean age of 65.6 + 12.0 years, approximately three-
quarters were male, and the vast majority self-identified their
race as white. Patients had a mean EF of 27.5 + 8.2% and most
had an ischaemic aetiology of HF. Nearly 80% of participants
reported a prior history of HHF and presented with New York
Heart Association (NYHA) class III or IV symptoms. The preva-
lence of medical comorbidities was high. Patients were well-treated
with evidence-based therapies including angiotensin-converting
enzyme inhibitors/angiotensin receptor blockers, b-blockers, and
mineralocorticoid receptor antagonists.
20.8) kg. B-type natriuretic peptide and NT-proBNP, respectively,
decreased from 734 (313, 1523) pg/mL and 4857 (2251, 9642) pg/
mL at baseline to 477 (199, 1079) pg/mL and 2834 (1218,
6075) pg/mL at discharge/Day 7.
Patients with a CCS at discharge of 0 –2 and 3–9, respectively,
had the CCS of 3.81 + 1.76; 4 (2, 5) and 5.47 + 1.58; 0 (0, 1) at
baseline and 0.61 + 0.73; 6 (4, 7) and 3.86 + 1.12; 3 (3, 4) at dis-
charge/Day 7 (Table 3). Although both groups experienced com-
parable body weight reductions, patients with a discharge CCS
of 3–9 reported more signs and symptoms of HF and a substantial-
ly higher concentration of BNP and NT-proBNP at discharge/Day
7. Finally, patients with a discharge CCS of 3– 9 had worse renal
function (i.e. estimated glomerular filtration rate) both at baseline
and discharge/Day 7.
Discharge congestion score and
long-term outcomes
During a median follow-up of 9.9 months, patients with a CCS at
discharge of 0 and 3–9, respectively, experienced HHF of 26.2%
(n ¼ 233) and 34.7% (n ¼ 103) and ACM of 19.1% (n ¼ 170)
and 42.8% (n ¼ 127) (Table 4). After adjusting for potential con-
founders (Supplementary material online, Table S2), discharge
CCS was associated with an increased risk of ACM, and ACM +
HHF both at 30 days and for the overall study period (Figure 2
and Table 5). Discharge CCS was associated with HHF over the
duration of the study but not at 30 days.

Baseline characteristics by discharge

congestion
Patients with higher CCS at discharge/day 7 were more likely to
report a prior history of HHF, a higher prevalence of medical co-
morbidities (e.g. diabetes mellitus, severe chronic obstructive pul-
monary disease, and chronic kidney disease), and prior
revascularization (i.e. percutaneous coronary intervention or coron-
ary artery bypass graft) or medical device therapy (i.e. automated
implantable cardioverter-defibrillator or pacemaker) (Table 2).
They were also more likely to be classified as NYHA IV. Notably, pul-
monary rales were found to be the least prevalent in patients with a
discharge CCS of 3–9. Finally, patients with more signs and symp-
toms of congestion at discharge were found to have a lower EF
and were more likely to have a prolonged QRS duration and abnor-
mal basic laboratory (i.e. BUN and sCr) and neurohormonal profile
[i.e. BNP/NT-proBNP and arginine vasopressin (AVP)].
Discussion
To the best of our knowledge, this is the first global study to de-
scribe the clinical course and predictive value of congestive signs
and symptoms in patients hospitalized for worsening HF with
reduced EF in the context of a clinical trial with daily monitoring.
Clinical congestion improved rapidly and dramatically in response
to standard therapy with minimal or absent signs and symptoms
at discharge. Although improvements in signs and symptoms of
congestion occurred concurrently with body weight decreases,
BNP/NT-proBNP remained markedly elevated at discharge.
Clinical congestion at discharge was associated with an increased
risk of 30-day and overall ACM and ACM + HHF as well as
overall HHF. However, patients with absent or minimal signs and
symptoms of congestion at discharge still experienced a high mor-
tality and readmission rate.
838 A.P. Ambrosy et al.

Table 2 Baseline characteristics by composite congestion score at discharge/day 7

0 1 2 3– 9 P-value
...............................................................................................................................................................................
Total, n (%) 890 (45.90) 505 (26.04) 247 (12.74) 297 (15.32)
Age mean (SD) 65.3 (11.8) 65.2 (12.4) 65.5 (12.1) 66.3 (11.8) 0.413
Male, n (%) 668 (75.06) 379 (75.05) 192 (77.73) 220 (74.07) 0.902
...............................................................................................................................................................................
Race
Caucasian, n (%) 784 (88.09) 426 (84.36) 213 (86.23) 242 (81.48) 0.023
Black, n (%) 47 (5.28) 36 (7.13) 22 (8.91) 30 (10.10)
Other, n (%) 59 (6.63) 43 (8.51) 12 (4.86) 25 (8.42)
Weight (kg) mean (SD) 80.6 (17.1) 83.7 (18.0) 85.7 (21.2) 87.4 (19.6) ,0.001

Downloaded from https://academic.oup.com/eurheartj/article/34/11/835/460424 by guest on 27 February 2021

Dyspnoea, n (%) 780 (89.04) 464 (92.80) 228 (95.00) 269 (93.08) 0.001
Systolic BP mean (SD) 121.1 (19.1) 120.5 (19.2) 118.9 (19.9) 118.7 (19.9) 0.013
Diastolic BP mean (SD) 72.9 (12.2) 73.1 (12.2) 73.0 (13.1) 71.4 (13.2) 0.208
Heart rate mean (SD) 79.3 (15.5) 78.7 (15.1) 81.8 (16.0) 81.2 (16.5) 0.053
NYHA class ,0.001
III, n (%) 575 (65.49) 302 (60.40) 116 (48.13) 127 (43.94)
IV, n (%) 292 (33.26) 197 (39.40) 125 (51.87) 162 (56.06)
JVD ≥10 cm, n (%) 152 (17.39) 155 (31.12) 75 (31.25) 126 (43.90) ,0.001
Heart murmur, n (%) 507 (57.81) 313 (62.60) 133 (55.19) 171 (59.17) 0.726
Rales, n (%) 742 (84.51) 401 (80.20) 202 (83.82) 220 (76.39) 0.006
Pedal oedema, n (%) 669 (76.20) 386 (77.20) 204 (84.65) 257 (88.93) ,0.001
Ejection fraction mean (SD) 28.1 (7.9) 27.5 (8.1) 26.5 (8.2) 27.2 (8.2) 0.012
Serum BUN mean (SD) 27.1 (12.0) 29.7 (16.9) 32.4 (19.7) 35.9 (20.1) ,0.001
Serum creatinine mean (SD) 1.3 (0.4) 1.4 (0.5) 1.5 (1.0) 1.5 (0.6) ,0.001
Serum sodium mean (SD) 140.1 (4.7) 140.0 (4.1) 139.1 (4.6) 138.5 (4.9) ,0.001
Arginine vasopressin mean (SD) 5.6 (5.3) 5.2 (3.6) 5.4 (4.9) 6.5 (5.8) 0.020
Serum BNP mediana (IQR) 599.2 (1246.6) 683.1 (1406.7) 826.0 (1762.0) 1193.9 (2370.7) ,0.001
Serum NT-proBNP mediana (IQR) 4145.2 (7589.1) 4244.4 (8107.5) 5456.1 (11250.0) 6385.4 (12007.5) 0.002
QRS ≥120 ms n (%) 441 (51.88) 266 (54.96) 135 (56.49) 164 (58.16) 0.040
Previous hospitalization for HF n (%) 672 (75.68) 399 (79.32) 197 (80.41) 249 (84.12) 0.002
CAD, n (%) 625 (70.30) 353 (69.90) 165 (66.80) 221 (74.66) 0.603
Previous MI, n (%) 456 (51.24) 252 (50.00) 118 (47.77) 168 (56.57) 0.532
Hypertension, n (%) 618 (69.44) 368 (72.87) 170 (68.83) 221 (74.41) 0.173
Hypercholesterolaemia, n (%) 412 (46.50) 221 (43.94) 130 (53.06) 154 (51.85) 0.089
Mitral valve disease, n (%) 254 (28.54) 172 (34.06) 79 (32.11) 104 (35.02) 0.018
Atrial fibrillation on admission, n (%) 234 (26.38) 118 (23.37) 67 (27.13) 93 (31.31) 0.307
Diabetes, n (%) 295 (33.15) 194 (38.42) 105 (42.51) 135 (45.45) ,0.001
Chronic kidney disease, n (%) 189 (21.24) 140 (27.72) 76 (30.89) 108 (36.36) ,0.001
Severe COPD, n (%) 65 (7.30) 45 (8.91) 36 (14.57) 42 (14.14) ,0.001
Peripheral vascular disease, n (%) 172 (19.35) 114 (22.57) 65 (26.42) 79 (26.78) 0.002
PTCA, n (%) 134 (15.06) 91 (18.02) 46 (18.62) 58 (19.53) 0.035
Previous CABG, n (%) 166 (18.65) 108 (21.39) 52 (21.05) 82 (27.61) 0.004
No AICD no pacemaker, n (%) 697 (78.31) 391 (77.43) 174 (70.45) 205 (69.02) 0.001
Pacemaker, n (%) 122 (13.71) 81 (16.04) 57 (23.08) 66 (22.22) ,0.001
AICD, n (%) 108 (12.13) 58 (11.49) 38 (15.38) 60 (20.20) 0.003

a
Not all patients had BNP and NT-proBNP measured. Of the 2061 placebo patients, 1481 had BNP measurements, 722 had NT-proBNP, and 261 had both measured at baseline.
CCS, composite congestion score; SD, standard deviation; BP, blood pressure; NYHA, New York Heart Association; JVD, jugular venous distension; BUN, blood urea nitrogen;
BNP, b-type natriuretic peptide; NT-proBNP, amino terminal proBNP; CAD, coronary artery disease; MI, myocardial infarction; COPD, chronic obstructive pulmonary disease;
PTCA, percutaneous transluminal coronary angioplasty; CABG, coronary artery bypass graft; AICD, automated implantable cardioverter-defibrillator.
Clinical course and predictive value of congestion
Figure 1 Distribution (%) of composite congestion score at
baseline and discharge/day 7.
Clinical course of congestive signs and
symptoms
It is notable that moderate-to-severe signs and symptoms of con-
gestion were present at baseline assessment, which occurred up to
48 h after admission, well after the timeframe traditionally ascribed
to the very acute phase. Previous research has demonstrated that
with early initiation of standard therapy dyspnoea measured in a
seated and upright position improved substantially within 6 h of
initial presentation.17 This finding suggests that initial therapy may
have been delayed in the EVEREST trial due to diagnostic uncer-
tainty, or, alternatively, dyspnoea may resolve more rapidly and im-
provement in other congestive signs (e.g. JVP and pedal oedema)
and symptoms (e.g. orthopnoea) may lag behind temporally. In
contrast, by discharge close to 85% of patients enrolled in the
EVEREST trial were found to have minimal or no signs or symp-
toms of congestion. Traditionally, relieving dyspnoea has been
the primary endpoint for short-term efficacy in pivotal clinical
trials in HF.18 The observation that standard therapy rapidly and
dramatically improved clinical congestion suggests that it may be
difficult for novel therapies to ‘beat’ placebo.
A more unexpected outcome is the finding that pulmonary rales
were the least prevalent among patients with the highest CCS. This
seemingly paradoxical finding may be at least partially explained by
a bias towards right-sided HF signs (i.e. JVD and pedal oedema) in
defining CCS and the fact that the prevalence of pulmonary rales
may not accurately reflect the severity.
Dissociation between clinical and
haemodynamic congestion
It should be emphasized that although patients experienced
improvements in congestive signs and symptoms concomitantly
with a sustained reduction in body weight, BNP/NT-proBNP
decreased but remained markedly elevated at discharge. Concep-
tually, volume overload has been subdivided into ‘clinical’ and
839
‘haemodynamic’ congestion.3,9,19 Clinical congestion manifests as
signs and symptoms of volume overload (e.g. dyspnoea, orthop-
noea, JVD, etc.), while haemodynamic congestion has been
defined as elevated cardiac filling pressures with or without clinical
congestion. Haemodynamic congestion may be present days or
weeks prior to admission for AHFS and resolution during hospital-
ization may be delayed or incomplete despite aggressive diuresis.
The finding that BNP/NT-proBNP remained significantly elevated
despite improvements in signs and symptoms of congestion high-
lights the disassociation between clinical and haemodynamic con-
gestion. Persistent haemodynamic congestion is thought to
contribute to the pathophysiological progression of HF, suggesting
Downloaded from https://academic.oup.com/eurheartj/article/34/11/835/460424 by guest on 27 February 2021
that alleviating signs and symptoms without correcting underlying
subclinical haemodynamic abnormalities may be insufficient. This
hypothesis is further supported by the fact that higher natriuretic
peptide concentration has been shown to be one of the strongest
predictors of morbidity and mortality both at discharge20 and at
1-week post-discharge.21
Distinguishing between responders and
non-responders
A number of clinically interesting findings emerged when patients
were subdivided into ‘responders’ (i.e. CCS 0–2) and ‘non-
responders’, or perhaps more accurately ‘partial responders’ (i.e.
CCS 3–9), at discharge. First, in interpreting these data it should
be reiterated that the majority of patients enrolled in the
EVEREST trial responded rapidly and dramatically in response to
standard therapy alone and only 15% of patients were dis-
charged with a CCS ≥3. However, it is notable that although
responders and non-responders had clinically, although not nu-
merically, comparable signs and symptoms of congestion at base-
line (e.g. dyspnoea) there were substantial between-group
differences in neurohormonal markers of haemodynamic conges-
tion (i.e. BNP/NT-proBNP and AVP) and more subtle discrepan-
cies in renal function parameters (i.e. sCr and BUN).
In contrast, at discharge, by definition, responders exhibited
minimal or no signs and symptoms of HF while non-responders
manifested signs and symptoms similar in severity to responders
at baseline. Baseline renal impairment and worsening renal function
during hospitalization are markers of more severe HF requiring
high-dose diuretic therapy to maintain fluid homoeostasis,
perhaps at least partially explaining the disparity in congestion
relief observed in the present analysis.22,23 However, it is difficult
to hypothesize whether diuresis was impeded or intentionally
limited in non-responders by renal dysfunction.
Treating beyond resting signs and
symptoms of congestion
It has been previously established the congestive signs and symp-
toms are associated with increased morbidity and mortality at
initial presentation,24following index hospitalization,13 and in the
ambulatory setting.25 The present analysis found clinical congestion
at discharge to be predictive of post-discharge mortality and rehos-
pitalization for HF. This finding is clinically relevant since signs and
symptoms of congestion are the most common cause for HHF and
readmission, an important therapeutic target of inpatient
840 A.P. Ambrosy et al.

Table 3 Select clinical and laboratory variables at baseline and discharge/day 7 by discharge composite congestion
score

Discharge CCS 0– 2 Discharge CCS 3– 9

............................................................... ...............................................................
Baseline Discharge/Day 7 Baseline Discharge/Day 7
...............................................................................................................................................................................
CCS 3.81 + 1.76; 4 (2, 5) 0.61 + 0.73; 0 (0, 1) 5.47 + 1.58; 6 (4, 7) 3.86 + 1.12; 3 (3, 4)
Dyspnoea 2.17 + 0.59; 2 (2, 3) 0.84 + 0.67; 1 (0, 1) 2.34 + 0.61; 2 (2, 3) 1.57 + 0.79; 2 (1, 2)
Orthopnoea 1.36 + 0.99; 1 (0, 2) 0.21 + 0.46; 0 (0, 0) 1.95 + 0.96; 2 (2, 3) 1.44 + 0.99; 1 (1, 2)
Fatigue 2.06 + 0.78; 2 (2, 3) 1.04 + 0.82; 1 (0, 2) 2.33 + 0.73; 2 (2, 3) 1.70 + 0.90; 2 (1, 2)
Rales 1.09 + 0.68; 1 (1, 1) 0.19 + 0.43; 0 (0, 0) 1.03 + 0.75; 1 (1, 1) 0.54 + 0.66; 0 (0, 1)
Pedal oedema 1.46 + 1.01; 2 (1, 2) 0.17 + 0.43; 0 (0, 0) 2.17 + 1.02; 3 (2, 3) 1.45 + 0.99; 2 (1, 2)

Downloaded from https://academic.oup.com/eurheartj/article/34/11/835/460424 by guest on 27 February 2021

JVD 0.99 + 0.81; 1 (0, 1) 0.23 + 0.47; 0 (0, 0) 1.37 + 0.85; 1 (1, 2) 0.97 + 0.77; 1 (0, 1)
△Weight (kg) — 22.20 (24.05, 20.90) — 22.00 (24.50, 20.40)
SBP (mmHg) 120 (105, 130) 113 (102, 125) 115 (104, 130) 110 (100, 125)
DBP (mmHg) 70 (63, 80) 70 (60, 80) 70 (61, 80) 69 (60, 78)
HR (b.p.m.) 78 (68, 88) 72 (65, 80) 78 (69, 92) 76 (70, 86)
BNP (pg/mL) 658 (275, 1352) 423 (180, 915) 1194 (522, 2390) 929 (385, 1764)
NT-proBNP (pg/mL) 4340 (1942, 8439) 2581 (1135, 5221) 6217 (2800, 11389) 4437 (2096, 10058)
BUN (mg/dL) 25 (19, 33) 28 (21, 39) 30 (23, 46) 31 (22, 48)
sCr (mg/dL) 1.2 (1.0, 1.5) 1.2 (1.0, 1.6) 1.3 (1.1, 1.7) 1.3 (1.1, 1.7)
eGFR (mL/min) 60.1 (45.1, 74.4) 58.5 (43.7, 73.3) 53.60 (39.6, 68.6) 56.10 (38.4, 71.7)
Na+ (mEq/L) 140 (137, 142) 139 (136, 142) 139 (136, 141) 139 (135, 141)
AVP (pg/mL) 2.8 (2.8, 7.1) 2.8 (2.8, 6.0) 2.8 (4.1, 8.4) 2.8 (2.8, 7.4)

All values are expressed as a mean + SD and/or a median and an IQR (25th, 75th).
CCS, composite congestion score; SD, standard deviation; IQR, inter-quartile range; JVD, jugular venous distension; SBP, systolic blood pressure; DBP, diastolic blood pressure;
HR, heart rate; BNP, B-type natriuretic peptide; NT-proBNP, amino terminal-proBNP; BUN, blood urea nitrogen; sCr, serum creatinine; AVP, arginine vasopressin.

Table 4 Outcomes (n, %) by composite congestion score at discharge

Discharge CCS Overalla

............................................................................................................
0 1 2 3 –9
...............................................................................................................................................................................
Total (n) 890 505 247 297 2061
HHF 233, 26.2% 176, 34.9% 86, 34.8% 103, 34.7% 629, 30.5%
ACM 170, 19.1% 125, 24.8% 62, 25.1% 127, 42.8% 543, 26.4%
ACM + HHF 317, 35.6% 231, 45.7% 113, 45.8% 177, 60.0% 912, 44.3%

a
Includes patients who died during hospitalization prior to discharge.
CCS, composite congestion score; HHF, hospitalization for heart failure; ACM, all-cause mortality.

management, and a major determinant of discharge decision- Limitations

making.4,5 However, despite the clinical importance of targeting
signs and symptoms during hospitalization, patients with absent
or minimal signs and symptoms of congestion experienced a post-
discharge event rate comparable in magnitude to the overall
cohort. This finding raises the hypothesis that treating beyond
resolution of resting signs and symptoms of congestion may
mediate improvements in post-discharge outcomes.26,27 Further
research is necessary to prospectively validate the clinical utility
of targeting provocative manoeuvres including an assessment of
orthopnoea and completion of a 6-minute walk test and circulating
biomarkers such as BNP/NT-proBNP in patients hospitalized for
heart failure.
There are several limitations of the data. First, this study was per-
formed post hoc and is subject to the potential biases inherent to
exploratory analyses of observational data. Nonetheless, signs
and symptoms were assessed daily by clinician-investigators using
a standardized scoring scale and events were adjudicated by a
blinded, independent events committee. Secondly, the study
protocol required two or more signs or symptoms of volume
overload (dyspnoea, pitting oedema, or JVD) at presentation,
which have may have selected for patients with a higher prevalence
and greater severity of congestive signs and symptoms. However,
enrolment was permitted up to 48 h (median 24 h) after admis-
sion and patients likely had already received diuretic therapy. Thus,
Clinical course and predictive value of congestion
Figure 2 Cumulative incidence of (A) hospitalization for heart failure, (B) all-cause mortality, and (C) all-cause mortality + hospitalization for
heart failure by composite congestion score at discharge/day 7.
it is conceivable that baseline signs and symptoms of congestion
may have been even more severe had patients been enrolled
closer to the time of presentation or alternatively patients may
have been more refractory to diuretic therapy. In addition, patients
with a baseline SBP ,90 mmHg, haemodynamically significant un-
corrected primary cardiac valvular disease, and a sCr concentra-
tion .3.5 mg/dL (or currently receiving haemofiltration, or
dialysis) were excluded, greatly limiting the applicability of this
study’s major findings to low output states and patients with
primary valvular pathology or severe renal impairment. Finally,
these data were collected in the context of a clinical trial with spe-
cific inclusion and exclusion criteria and patients were well-treated
841
Downloaded from https://academic.oup.com/eurheartj/article/34/11/835/460424 by guest on 27 February 2021
with background evidenced-based therapies and had pre-specified
post-discharge follow-up, potentially restricting the generalizability
of this analysis.
Conclusion
In a trial, congestive signs and symptoms improved rapidly and sub-
stantially in response to standard therapy alone, suggesting it may
be difficult for investigational treatments to alleviate clinical con-
gestion beyond that seen with standard therapy alone (i.e.
placebo). Notably, there is a disassociation between relief of
signs and symptoms of volume overload and subclinical
842
Table 5 Hazard ratio (95% confidence interval) per
point of composite congestion score at discharge/day 7
30-day Overall
................................................................................
HHF 1.06 (0.95, 1.19) 1.07 (1.01, 1.14)
ACM 1.34 (1.14, 1.58) 1.16 (1.09, 1.24)
ACM + HHF 1.13 (1.03, 1.25) 1.11 (1.06, 1.17)
Note: Adjusted for age, LVEF, previous HHF, systolic blood pressure (SBP) at
enrolment, serum B-type natriuretic peptide (BNP) or NT-proBNP, blood urea
nitrogen (BUN), serum sodium, baseline diuretic usage, and beta-blocker,
hyperlipidaemic agents, and amiodarone utilization at discharge.
CCS, composite congestion score; HR, hazard ratio; CI, confidence interval; HHF,
hospitalization for heart failure; ACM, all-cause mortality.
haemodynamic congestion (i.e. elevated natriuretic peptide).
Although clinical congestion at discharge was directly associated
with subsequent mortality and readmission, absent or minimal
signs and symptoms of congestion did not portend a good
post-discharge prognosis, raising the hypothesis that clinical ‘de-
congestion’ may be insufficient. Accordingly, assessing and
grading congestion during hospitalization and pre-discharge
should move beyond a basic bedside determination of resting
signs and symptoms in favor of a more comprehensive evaluation,
incorporating dynamic maneuvers (i.e. orthopnea, 6-minute walk
test, etc.) and hemodynamic biomarkers (i.e. BNP/NT-proBNP),
in order to guide therapy and discharge decision making.9
Supplementary material
Supplementary material is available at European Heart Journal
online.
Funding
Otsuka Inc. (Rockville, Maryland, USA) provided financial and material
support for the EVEREST trial.
Conflict of interest: P.S.P. is or has been a consultant for Astellas,
Bayer, EKR Therapeutics, J & J, the Medicines Company, Medtronic,
Novartis, Otsuka, Palatin Technologies, PDL BioPharma, Pericor Ther-
apeutics, SigmaTau, Solvay Pharmaceuticals, Trevena. He has received
honoraria from Alere, Beckman-Coulter, BiogenIdec, Corthera, Ikaria,
Nile Therapeutics, Momentum Research, Overcome. He has received
research support from Abbott, Merck and PDL BioPharma. He has
received travel support from MyLife. He has received equipment
support from Sonosite. G.C.F. reports receiving research support
from Medtronic (Modest), Gambro (Significant), and Novartis (Signifi-
cant). B.T. has received compensation through a contract between
Otsuka and the University of Wisconsin. T.C. has received research
grants and honoraria from Otsuka. M.G. is a consultant for and/or
has received research support from Abbott Labs, Astellas, AstraZe-
neca, Bayer Schering PharmaAG, CorThera, Inc., Cytokinetics, Inc.,
DebioPharm SA, ErrekappaTerapeutici (Milan, Italy), Glaxo Smith
Kline, JNJ, Medtronic, Novartis Pharma AG, Otsuka, Sigma Tau,
Solvay Pharmaceuticals, and Pericor Therapeutics. Dr. Marvin A.
Konstam has been a consultant for and/or received research support
from Merck, Amgen, Otsuka, Johnson and Johnson, Novartis, and Car-
diokine. The other authors declare no conflicts of interest.
A.P. Ambrosy et al.
References
1. Roger VL, Go AS, Lloyd-Jones DM, Benjamin EJ, Berry JD, Borden WB,
Bravata DM, Dai S, Ford ES, Fox CS, Fullerton HJ, Gillespie C, Hailpern SM,
Heit JA, Howard VJ, Kissela BM, Kittner SJ, Lackland DT, Lichtman JH,
Lisabeth LD, Makuc DM, Marcus GM, Marelli A, Matchar DB, Moy CS,
Mozaffarian D, Mussolino ME, Nichol G, Paynter NP, Soliman EZ, Sorlie PD,
Sotoodehnia N, Turan TN, Virani SS, Wong ND, Woo D, Turner MB. Heart
disease and stroke statistics—2012 update: a report from the American Heart As-
sociation. Circulation 2012;125:e2 –e220.
2. Fang J, Mensah GA, Croft JB, Keenan NL. Heart failure-related hospitalization in
the U.S., 1979 to 2004. J Am Coll Cardiol 2008;52:428 – 434.
3. Gheorghiade M, Filippatos G, De Luca L, Burnett J. Congestion in acute heart
failure syndromes: an essential target of evaluation and treatment. Am J Med
2006;119 (12 Suppl 1):S3–S10.
4. Hunt SA, Abraham WT, Chin MH, Feldman AM, Francis GS, Ganiats TG,
Downloaded from https://academic.oup.com/eurheartj/article/34/11/835/460424 by guest on 27 February 2021
Jessup M, Konstam MA, Mancini DM, Michl K, Oates JA, Rahko PS, Silver MA,
Stevenson LW, Yancy CW. 2009 Focused update incorporated into the ACC/
AHA 2005 Guidelines for the Diagnosis and Management of Heart Failure in
Adults A Report of the American College of Cardiology Foundation/American
Heart Association Task Force on Practice Guidelines Developed in Collaboration
With the International Society for Heart and Lung Transplantation. J Am Coll
Cardiol 2009;53:e1 – e90.
5. Lindenfeld J, Albert NM, Boehmer JP, Collins SP, Ezekowitz JA, Givertz MM,
Katz SD, Klapholz M, Moser DK, Rogers JG, Starling RC, Stevenson WG,
Tang WH, Teerlink JR, Walsh MN. HFSA 2010 Comprehensive Heart Failure
Practice Guideline. J Card Fail 2010;16:e1 –e194.
6. Yancy CW. Current approaches to monitoring and management of heart failure.
Rev Cardiovasc Med 2006;7 (Suppl 1):S25 –S32.
7. Adams JKF, Fonarow GC, Emerman CL, LeJemtel TH, Costanzo MR,
Abraham WT, Berkowitz RL, Galvao M, Horton DP. Characteristics and out-
comes 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.
8. O’Connor CM, Stough WG, Gallup DS, Hasselblad V, Gheorghiade M. Demo-
graphics, clinical characteristics, and outcomes of patients hospitalized for decom-
pensated heart failure: observations from the IMPACT-HF registry. J Card Fail
2005;11:200 –205.
9. Gheorghiade M, Follath F, Ponikowski P, Barsuk JH, Blair JE, Cleland JG,
Dickstein K, Drazner MH, Fonarow GC, Jaarsma T, Jondeau G, Sendon JL,
Mebazaa A, Metra M, Nieminen M, Pang PS, Seferovic P, Stevenson LW, van
Veldhuisen DJ, Zannad F, Anker SD, Rhodes A, McMurray JJ, Filippatos G, Euro-
pean Society of C, European Society of Intensive Care M. Assessing and grading
congestion in acute heart failure: a scientific statement from the acute heart
failure committee of the heart failure association of the European Society of Car-
diology and endorsed by the European Society of Intensive Care Medicine. Eur J
Heart Fail 2010;12:423 –433.
10. Gheorghiade M, Orlandi C, Burnett JC, Demets D, Grinfeld L, Maggioni A,
Swedberg K, Udelson JE, Zannad F, Zimmer C, Konstam MA. Rationale and
design of the multicenter, randomized, double-blind, placebo-controlled study
to evaluate the Efficacy of Vasopressin antagonism in Heart Failure: Outcome
Study with Tolvaptan (EVEREST). J Card Fail 2005;11:260 –269.
11. Gheorghiade M, Konstam MA, Burnett JC Jr., Grinfeld L, Maggioni AP,
Swedberg K, Udelson JE, Zannad F, Cook T, Ouyang J, Zimmer C, Orlandi C.
Short-term clinical effects of tolvaptan, an oral vasopressin antagonist, in patients
hospitalized for heart failure: the EVEREST Clinical Status Trials. JAMA 2007;297:
1332 –1343.
12. Konstam MA, Gheorghiade M, Burnett JC Jr., Grinfeld L, Maggioni AP,
Swedberg K, Udelson JE, Zannad F, Cook T, Ouyang J, Zimmer C, Orlandi C.
Effects of oral tolvaptan in patients hospitalized for worsening heart failure: the
EVEREST Outcome Trial. JAMA 2007;297:1319 – 1331.
13. Lucas C, Johnson W, Hamilton MA, Fonarow GC, Woo MA, Flavell CM,
Creaser JA, Stevenson LW. Freedom from congestion predicts good survival
despite previous class IV symptoms of heart failure. Am Heart J 2000;140:840–847.
14. Wang CS, FitzGerald JM, Schulzer M, Mak E, Ayas NT. Does this dyspneic patient
in the emergency department have congestive heart failure? JAMA 2005;294:
1944 –1956.
15. Butman SM, Ewy GA, Standen JR, Kern KB, Hahn E. Bedside cardiovascular exam-
ination in patients with severe chronic heart failure: importance of rest or indu-
cible jugular venous distension. J Am Coll Cardiol 1993;22:968 –974.
16. Chakko S, Woska D, Martinez H, de Marchena E, Futterman L, Kessler KM,
Myerberg RJ. Clinical, radiographic, and hemodynamic correlations in chronic
congestive heart failure: conflicting results may lead to inappropriate care. Am J
Med 1991;90:353–359.
Clinical course and predictive value of congestion
17. Mebazaa A, Pang PS, Tavares M, Collins SP, Storrow AB, Laribi S, Andre S, Mark
Courtney D, Hasa J, Spinar J, Masip J, Frank Peacock W, Sliwa K, Gayat E,
Filippatos G, Cleland JG, Gheorghiade M. The impact of early standard therapy
on dyspnoea in patients with acute heart failure: the URGENT-dyspnoea study.
Eur Heart J 2010;31:832 – 841.
18. Gheorghiade M, Ruschitzka F. Beyond dyspnoea as an endpoint in acute heart
failure trials. Eur Heart J 2011;32:1442 –1445.
19. Gheorghiade M. Treatment of congestion in acute heart failure syndromes: im-
portance, strategies, and challenges. Introduction. Am J Med 2006;119 (12
Suppl 1):S1 –S2.
20. Allen LA, Gheorghiade M, Reid KJ, Dunlay SM, Chan PS, Hauptman PJ, Zannad F,
Konstam MA, Spertus JA. Identifying patients hospitalized with heart failure at risk
for unfavorable future quality of life. Circ Cardiovasc Qual Outcomes 2011;4:389–398.
21. Dunlay SM, Gheorghiade M, Reid KJ, Allen LA, Chan PS, Hauptman PJ, Zannad F,
Maggioni AP, Swedberg K, Konstam MA, Spertus JA. Critical elements of clinical
follow-up after hospital discharge for heart failure: insights from the EVEREST
trial. Eur J Heart Fail 2010;12:367 –374.
22. Blair JE, Pang PS, Schrier RW, Metra M, Traver B, Cook T, Campia U, Ambrosy A,
Burnett JC Jr, Grinfeld L, Maggioni AP, Swedberg K, Udelson JE, Zannad F,
843
Konstam MA, Gheorghiade M, Investigators E. Changes in renal function during
hospitalization and soon after discharge in patients admitted for worsening
heart failure in the placebo group of the EVEREST trial. Eur Heart J 2011;32:
2563–2572.
23. Ruggenenti P, Remuzzi G. Worsening kidney function in decompensated
heart failure: treat the heart, don’t mind the kidney. Eur Heart J 2011;32:
2476 –2478.
24. Nohria A, Tsang SW, Fang JC, Lewis EF, Jarcho JA, Mudge GH, Stevenson LW.
Clinical assessment identifies hemodynamic profiles that predict outcomes
in patients admitted with heart failure. J Am Coll Cardiol 2003;41:
1797 –1804.
25. Drazner MH, Rame JE, Stevenson LW, Dries DL. Prognostic importance of ele-
vated jugular venous pressure and a third heart sound in patients with heart
failure. N Engl J Med 2001;345:574 – 581.
26. Gheorghiade M, Braunwald E. A proposed model for initial assessment and man-
agement of acute heart failure syndromes. JAMA 2011;305:1702 – 1703.
Downloaded from https://academic.oup.com/eurheartj/article/34/11/835/460424 by guest on 27 February 2021
27. Gheorghiade M, Braunwald E. Hospitalizations for heart failure in the United
States—a sign of hope. JAMA 2011;306:1705 – 1706.