Journal Pre-proof

Rates of In-hospital Decongestion and Association with Mortality and

Cardiovascular Outcomes among Patients admitted for Acute Heart
Failure

Wendy McCallum MD MS , Hocine Tighiouart MS ,

Jeffrey M. Testani MD, MTR , Matthew Griffin MD ,
Marvin A. Konstam MD , James E. Udelson MD ,
Mark J. Sarnak MD, MS

PII: S0002-9343(22)00332-1
DOI: https://doi.org/10.1016/j.amjmed.2022.04.003
Reference: AJM 16743

To appear in: The American Journal of Medicine

Received date: 20 March 2022

Accepted date: 4 April 2022

Please cite this article as: Wendy McCallum MD MS , Hocine Tighiouart MS ,

Jeffrey M. Testani MD, MTR , Matthew Griffin MD , Marvin A. Konstam MD ,
James E. Udelson MD , Mark J. Sarnak MD, MS , Rates of In-hospital Decongestion and Asso-
ciation with Mortality and Cardiovascular Outcomes among Patients admitted for Acute Heart Failure,
The American Journal of Medicine (2022), doi: https://doi.org/10.1016/j.amjmed.2022.04.003

This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition
of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of
record. This version will undergo additional copyediting, typesetting and review before it is published
in its final form, but we are providing this version to give early visibility of the article. Please note that,
during the production process, errors may be discovered which could affect the content, and all legal
disclaimers that apply to the journal pertain.

© 2022 Published by Elsevier Inc.

Rates of In-hospital Decongestion and Association with Mortality and Cardiovascular
Outcomes among Patients admitted for Acute Heart Failure

Brief Title: Rate of Decongestion and Cardiovascular Outcomes

Authors

Wendy McCallum MD MSa, Hocine Tighiouart MSb, Jeffrey M. Testani MD MTRc, Matthew
Griffin MDc, Marvin A. Konstam MDd, James E. Udelson MDd, Mark J. Sarnak MD MSa
a
Division of Nephrology, Tufts Medical Center, Boston, Massachusetts
b
Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, Boston,
Massachusetts; Tufts Clinical and Translational Science Institute, Tufts University, Boston,
Massachusetts
c
Division of Cardiovascular Medicine, Yale School of Medicine, New Haven, Connecticut
d
Division of Cardiology and the CardioVascular Center, Tufts Medical Center, Boston,
Massachusetts

Funding Sources: KL2 (TR002545-04)

Relationships with Industry:

JMT reports grants and/or personal fees from 3ive labs, Bayer, Boehringer Ingelheim, Bristol
Myers Squibb, Astra Zeneca, Novartis, Cardionomic, MagentaMed, Reprieve inc., FIRE1, W.L.
Gore, Sanofi, Sequana Medical, Otsuka, Abbott, Merck, Windtree Therapeutics, Lexicon
pharmaceuticals, Precardia, Relypsa, Regeneron, BD, Edwards life sciences, and Lilly. In
addition, JMT has a patent Treatment of diuretic resistance issued to Yale and Corvidia
Therapeutics Inc, a patent Methods for measuring renalase issued to Yale, and a patent
Treatment of diuretic resistance pending with Reprieve inc. MJS sits on the Steering Committee
for Akebia with funds payed to Tufts Medical Center. JEU received grant support from Otsuka.
MAK is the chair for the DSMB for BMS, and receives grant support from Otsuka and SC
Pharma.

Authors Contributions: Study design: WM, HT, MJS; data acquisition: MAK, JEU; statistical
analysis: HT; data interpretation, manuscript preparation and editing: WM, HT, MJS, JMT, MG,
MAK, JEU; supervision: MJS.

Address for Correspondence:

Wendy McCallum, MD MS
Box 391, Division of Nephrology
Tufts Medical Center
800 Washington Street
Boston, MA 02111
Fax: 617-636-8329
Email: wmccallum@tuftsmedicalcenter.org

1
Abstract

Background: Decongestion is an important goal in the management of acute heart failure.

Whether the rate of decongestion is associated with mortality and cardiovascular outcomes is
unknown.

Methods: Using data from 4,133 patients from the Efficacy of Vasopressin Antagonism in Heart
Failure Outcome Study With Tolvaptan (EVEREST) trial, we used multivariable Cox regression
models to evaluate the association between rates of in-hospital change in assessments of volume
overload, including b-type natriuretic peptide (BNP), N-terminal pro b-type natriuretic peptide
(NT-proBNP), as well as change in hemoconcentration, with risk of all-cause mortality and a
composite outcome of cardiovascular mortality or heart failure hospitalization.

Results: More rapid rates of in-hospital decongestion were associated with decreased risk of
mortality and the composite outcome over a median 10-month follow-up. In reference to the
quartile of slowest decline, the quartile with the fastest BNP and NT-proBNP decline had lower
hazards of mortality (HR=0.43 [0.31, 0.59] and HR=0.27 [0.19, 0.40], respectively) and
composite outcome (HR=0.49 [0.39, 0.60] and HR=0.54 [0.42, 0.71], respectively). In reference
to the quartile of slowest increase, the quartile with the fastest hematocrit increase had lower
hazards of mortality (HR=0.77 [0.62, 0.95]) and composite outcome (HR=0.75 [0.64, 0.88]).
Results were also consistent when models were repeated using propensity-score matching.

Conclusions: Faster rates of decongestion are associated with reduced risk of mortality and a
composite of cardiovascular mortality and heart failure hospitalization. It remains unknown
whether more rapid decongestion provides cardiovascular benefit or whether it serves as a proxy
for less treatment resistant heart failure.

Keywords: decongestion, hemoconcentration, cardiorenal, mortality, acute heart failure

2
Abbreviations
eGFR = estimated glomerular filtration rate
BNP = b-type natriuretic peptide
NT-proBNP = N-terminal prohormone of b-type natriuretic peptide
EVEREST = Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with
Tolvaptan
ACEI = angiotensin-converting enzyme inhibitor
ARB = angiotensin II receptor blocker
MRA = mineralocorticoid receptor antagonist

Clinical Significance:

 For patients with heart failure with reduced ejection fraction admitted for acute heart

failure, we observed that more rapid decongestion is associated with reduced risk of

mortality and subsequent acute heart failure hospitalizations.

 Faster rates of decongestion are not associated with cardiovascular harm and can serve as

a proxy for less treatment-resistant heart failure and better prognosis.

3
Introduction

Heart failure carries a significant burden, with more than an estimated 1.1 million hospital

admissions for acute heart failure annually in the United States.1 Most hospitalizations for acute

heart failure are prompted by signs and symptoms of congestion, or volume overload. Clinical

congestion has been shown to be a risk factor for mortality and cardiovascular outcomes, with

greater degree of congestion at the time of admission being associated with higher risk of

mortality and poor cardiovascular outcomes2,3 as well as with short-term and longer-term

declines in kidney function.4–6

Successful fluid removal, or decongestion, as evidenced by improvement in clinical signs and

symptoms or by hemoconcentration is associated with decreased risk of mortality.7,8 Therefore,

decongestion remains one of the priorities of management for acute heart failure hospitalizations.

However, it remains controversial as to how rapidly to decongest; some clinicians may slow

volume removal due to concerns that faster rates of decongestion may outpace plasma refill

rates. Very little literature exists regarding mortality and cardiovascular outcomes related to the

rate of decongestion, leading to lack of consensus in clinical practice as to how quickly or slowly

to decongest patients with acute heart failure. Using data from the Efficacy of Vasopressin

Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST) trial, we sought to

investigate the relation between rate of decline in biomarkers of volume overload and rate of

increase in biomarkers of hemoconcentration with mortality and cardiovascular outcomes.

Methods

Study Population

The EVEREST trial was a multi-center randomized controlled trial that investigated the

use of the vasopressin V2 receptor blocker tolvaptan in patients with acute heart failure 9. It

4
enrolled patients with reduced left ventricular ejection fraction (≤40%) who had evidence of

congestion based upon ≥2 clinical signs or symptoms, and were <48 hours into the

hospitalization. Patients were randomized to either 30 mg of tolvaptan or placebo, in addition to

their standard medical therapy. Participants in EVEREST provided informed consent at the time

of enrollment; the present study was deemed exempt by the Tufts Health Sciences Institutional

Review Board.

Exposure

Rate of Change in Volume Overload

Volume overload was assessed by biomarkers including b-type natriuretic peptide (BNP) and N-

terminal prohormone of b-type natriuretic peptide (NT-proBNP), and by clinical signs and

symptoms. For administrative reasons, some centers collected BNP while others collected NT-

proBNP. Measurements were collected at the time of randomization and at pre-determined

intervals during the hospitalization (Day 3, Day 7 and day of discharge, unless discharged

sooner). Criteria for discharge were determined by the physician-investigators, who evaluated

clinical signs and symptoms of volume overload at the time of randomization into the trial and

then daily. These included a standardized 4-point graded scale for pedal edema (absent/trace,

slight, moderate, marked), jugular venous distention (≤6 cm, 6-9cm, 10-15cm, >15cm), rales

(none, bases, up to <50%, to >50%) and orthopnea (none, seldom, frequent, continuous) which

were incorporated into a single congestion score with range from 0 to 12. While there is yet to

be a validated and widely accepted standardized score for grading volume overload based on

physical exam, this scale is a modification of a previously published congestion score10 and

comprises the findings believed to be most specific to volume overload. 11 For all three measures

5
of volume overload, linear mixed models with a random intercept and slope were used to derive

the in-hospital slope per week. Given the non-normal distribution of BNP and NT-proBNP,

linear mixed models were fitted to log-transformed BNP and NT-proBNP, and then back

transformed to the percent change for ease of interpretation. Hazard ratios were assessed per

each standard deviation faster slope of decline in each biomarker.

Rate of Change in Hemoconcentration

Biomarkers of hemoconcentration included change in hematocrit, albumin, and total protein over

the duration of the hospitalization. These biomarkers were measured at the time of

randomization, and at pre-determined intervals as described above. Linear mixed models were

used to derive the in-hospital slope of hematocrit, albumin and total protein per week. Hazard

ratios were assessed per each standard deviation faster slope of increase in each biomarker.

Outcomes

The primary outcomes of interest were all-cause mortality and a composite endpoint of

cardiovascular mortality or first rehospitalization for heart failure, consistent with the original

pre-specified co-primary endpoints of EVEREST. 9 All events were adjudicated by a blinded

clinical events committee.

Covariates

Several covariates were selected for analysis as potential confounding variables,

including demographic characteristics (age, sex, race, body mass index [BMI]), cardiac

characteristics (NYHA class, ejection fraction, ischemic etiology), baseline medication

6
(angiotensin-converting enzyme inhibitors [ACEI] or angiotensin II receptor blockers [ARB],

mineralicorticoid receptor antagonists [MRA]), as well as randomization arm (tolvaptan or

placebo). The baseline eGFR was included as an adjustment variable in the final model, given its

potential association with the exposure variable as well as the outcome variable. Models were

also adjusted for each respective baseline measure of congestion (i.e. baseline BNP for models

examining BNP slope).

Statistical Analysis

Values are presented as mean (SD), or median [IQR] for non-normal distributions.

Differences in the baseline characteristics of patients were examined using analysis of variance

and Kruskal-Wallis tests, and by χ2 and Fisher’s exact tests, as appropriate.

Cox proportional hazards regression models were used to evaluate the association

between slope of decongestion with the outcome of all-cause mortality and composite outcome

of cardiovascular mortality or heart failure rehospitalization. In order to separate temporality

between exposure (slope of decongestion) and outcomes, the day of hospital discharge was used

as time zero for the time at risk for each outcome. Patients were censored at the end-of-trial date

(February 3, 2006), or the date of last contact. Multivariable models were used with adjustment

for covariates at baseline—in other words, from the perspective of the in-hospital treating

clinician, asking the question of whether rate of decongestion is a risk factor for mortality or

cardiovascular outcomes, taking into consideration a patient’s clinical characteristics at the time

of admission.

Several sensitivity analyses were performed in order to attempt isolation of the slope of

decongestion as a risk factor. First, models were repeated incorporating adjustments for

7
covariates at the time of discharge, including the biomarker of interest at the time of discharge,

as opposed to baseline. Second, we created a propensity score using the baseline characteristics

as listed above as well as the baseline diuretic dose, weight and additional baseline labs including

sodium, albumin, total protein, eGFR, hematocrit (for models examing BNP), baseline quartile

of BNP or NT-proBNP (for models examing hematocrit). Using this propensity score, each

patient from the quartile of most rapid BNP decline and most rapid hematocrit increase were

matched with the nearest propensity score-matched patient from the other three quartiles with a

prespecified greedy algorithm. Models using the matched cohorts were fitted using unadjusted

Cox proportional hazards regression.

Results

Baseline Patient Characteristics

Baseline characteristics by quartiles of slope of BNP are presented in Table 1, and by

quartiles of slope of hematocrit in Supplementary Table S1. Overall, 68% had an ischemic

etiology to their cardiomyopathy, 37% had diabetes and median [25th, 75th] baseline eGFR was

57 [43, 74] ml/min/1.73 m2. Those with the most rapid decongestion had slightly higher median

(IQR) starting eGFR compared to least rapid (eGFR of 63 [49, 78] vs 54 [40, 72] ml/min/1.73m2,

respectively), with faster mean (SD) rates of in-hospital decline in eGFR (-2.2 [4.0] vs -0.5 [4.0]

ml/min/1.73m2 per week, respectively) but there was no difference in the median discharge

eGFR (57 [42, 72] vs 55 [40, 72] ml/min/1.73m2, respectively). Most patients were taking either

an ACEI or an ARB (86%), without significant difference in use among those with more rapid

rates of decongestion in comparison to those with slower rates. Those with the least rapid rates of

decongestion (Quartile 1) tended to have evidence of the greatest volume overload, with higher

8
baseline BNP. A similar pattern was observed when examining the other exposures of volume

overload (Supplemental Table S2), with distributions of slopes of decongestion shown in

Supplemental Figure S1. When examining the exposures of hemoconcentration, those in Quartile

1 with the least rapid rates of decongestion tended to have higher baseline levels of hematocrit,

albumin, or total protein (Supplemental Table S2).

Outcomes

Slope of Decline in Volume Overload and Outcomes

All-cause Mortality

In continuous models, each standard deviation more negative slope in BNP per week was

associated with lower hazard for mortality (HR=0.71 [95% CI of 0.65, 0.78]). There was a

graded relation between rates of decline in BNP and all-cause mortality, with greater number of

events among those in Quartile 1 (least rapid decongestion), and fewer among those with more

rapid rates of BNP decline (Figure 1). In reference to the quartile with the slowest decline in

BNP, quartiles with more rapid decline were associated with lower hazards of mortality (Table

2) and higher survival probabilities (Figure 2, Panel A). In regards to NT-proBNP and

congestion score, similar patterns were observed (Table 2 and Figure 2).

Composite of Cardiovascular Mortality and Heart Failure Hospitalization

In continuous models, each standard deviation more negative slope in BNP per week was

associated with lower hazard for the composite outcome (HR=0.76 [95% CI of 0.71, 0.82]).

There was a graded relation between rate of decline in BNP and the composite outcome, with

greater number of events among those in Quartile 1 (least rapid decongestion), and fewer among

9
those with more rapid rates of BNP decline (Figure 1). In reference to the quartile with the

slowest decline in BNP, quartiles with more rapid decline were associated with lower hazards of

the composite outcome (Table 2) and higher probabilities of composite outcome-free survival

(Figure 3, Panel A). Results were consistent for NT-proBNP (Table 2, Figure 3). In terms of

congestion score, associations followed a similar pattern, but did not reach statistical significance

in quartile models (Table 2).

Slope of Increase in Hemoconcentration and Outcomes

All-cause Mortality

In continuous models, there was no clear association between more positive slope in

hematocrit per week (i.e. faster rise in hematocrit) with either increased or decreased hazard of

mortality (HR=0.98 [95% CI of 0.91, 1.06]). In reference to the quartile with the slowest increase

in hematocrit, quartiles with more rapid increase were associated with lower hazards of mortality

(Table 3) and higher survival probabilities (Figure 2, Panel B). In regards to albumin and total,

similar patterns were observed (Table 3 and Figure 2).

Composite of Cardiovascular Death and Heart Failure Hospitalization

In continuous models, each standard deviation more positive slope in hematocrit per

week was associated with lower hazard for the composite outcome (HR=0.92 [95% CI of 0.86,

0.97]). In reference to the quartile with the slowest increase in hematocrit, quartiles with more

rapid increase were associated with lower hazards of the composite outcome (Table 3) and

higher probabilities of composite outcome-free survival (Figure 3, Panel A). Results were

consistent for albumin and total protein (Table 3, Figure 3).

10
Sensitivity Analyses

Adjustment for Discharge Biomarker Level

When models were adjusted for covariates at the time of discharge, including the

biomarker of interest at discharge, associations for BNP and NT-proBNP remained consistent

(Supplemental Table S3). There was no association between rates of decrease in congestion

score with either outcome, however. In terms of hemoconcentration, associations showed similar

trends, albeit no longer meeting statistical significance (Supplemental Table S4). In none of the

models was faster decongestion associated with higher risk of either outcome.

Propensity Score Matching

After propensity-score matching, patients from the quartile with the most rapid BNP

decline were well matched to those from the other three quartiles (Table S5), and similarly well

matched for hematocrit increase (Table S6). In comparison to the matched counterparts with

slower BNP decline, those with the most rapid BNP decline had a lower risk of mortality and the

composite outcome, respectively (HR=0.58 [0.41, 0.81]; HR=0.68 [0.54, 0.85], Table S7).

Associations between rates of hematocrit increase were consistent with the primary analyses,

with lower risk of all-cause mortality (HR=0.86 [0.70, 1.06]) and the composite outcome in those

with more rapid increase in hematocrit (HR=0.79 [0.68, 0.93]; Table S8).

Discussion

This study indicates that more rapid achievement of decongestion, reflected by both a

faster reduction in measures of volume overload and faster increase in hemoconcentration during

11
hospitalization for acute heart failure, is associated with lower risk of mortality and composite of

cardiovascular mortality and heart failure hospitalization during follow-up. There was a graded

association, where faster rates of decongestion were associated with decreased risk. There was

no suggestion of harm, even among the extremes of rapid decongestion or in multiple sensitivity

analyses.

Prior literature has suggested that greater degree of congestion at the time of

hospitalization for acute heart failure is associated with higher risk of cardiovascular

outcomes10,12 and kidney outcomes,5,6,13 and that lower residual congestion at the time of

discharge is associated with improved clinical outcomes.14,15 However, the rate at which to

achieve that decongestion remains controversial. Some clinicians may purposefully slow down

rapid rates of decongestion, out of concern for exceeding plasma refill and risk for intravascular

volume depletion and decreased kidney perfusion, but there has been little evidence to either

support or oppose this conventional practice. One single-center observational study found that

among 453 patients admitted for acute heart failure, compared to those who had died, those who

were still alive at 1-year following heart failure hospitalization had shown faster rates of

improvement in clinical congestion.16

Our study adds to the literature by expanding beyond assessments of decongestion based

on signs and symptoms to evaluate several domains of volume overload including changes in

natriuretic peptides, as well as measures of intravascular volume such as changes in hematocrit

and albumin and total protein. Our study’s results reveal a consistent message, showing that

among 4133 participants across multiple centers that faster rates of decongestion were associated

with improved survival and decreased risk of cardiovascular mortality and heart failure

hospitalization. Repeating these analyses based on propensity-score matching for rapid

12
decongestion, an attempt to eliminate residual confounding, demonstrated consistent results.

Furthermore, higher rates of decongestion were not associated with risk in any of the analyses.

There are two possible interpretations of these results. The first is that patients with more

advanced heart failure may have a greater degree of diuretic resistance and thereby may not have

the ability to diurese as rapidly and are inherently at greater risk of cardiovascular events. Our

adjusted and propensity score-matched analyses attempted to address this issue, with consistent

results, but residual confounding cannot be completely ruled out. Alternatively, one could argue

that more rapid decongestion is a mediating factor between the kidney’s ability to achieve

diuretic response and improved cardiac function—a pathway that remains poorly understood. We

observed partial attenuation of the relation between rate of decongestion with clinical outcomes

in several analyses after adjustment for the discharge biomarker level, rather than the baseline

level. This may suggest that discharge levels incorporate the slope and are frequently stronger

risk factors than the slope itself in epidemiological studies.14,18 We believe our primary analyses

adjusting for baseline levels are the most pertinent from a clinical standpoint when evaluating

how quickly to decongest.

There are some limitations. Rates of decongestion were not directly examined as an

intervention and thus with the observational nature of the study, there is always risk for residual

and unmeasured confounding. However, associations remained significant with adjustment for

cardiovascular characteristics and markers of degree of illness, including NYHA functional class

and systolic blood pressure, as well as with propensity-score matching models. The EVEREST

trial enrolled patients with heart failure with reduced ejection fraction, and thus it is important to

remember that these results may not be generalized beyond patients with reduced ejection

fraction and volume overload.

13
 Among patients with heart failure with reduced ejection fraction admitted for acute heart

failure, achievement of faster rates of decongestion is associated with reduced risk of mortality

as well as a composite of cardiovascular mortality and heart failure hospitalization. While it

remains unknown whether faster decongestion is causally related to improved outcomes, it is not

associated with cardiovascular harm and can serve as a proxy for less treatment-resistant heart

failure and better prognosis.

References
1. Jackson SL, Tong X, King RJ, Loustalot F, Hong Y, Ritchey MD. National Burden of
Heart Failure Events in the United States, 2006 to 2014. Circ Heart Fail.
2018;11(12):e004873. doi:10.1161/CIRCHEARTFAILURE.117.004873

2. 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(6):840-847.
doi:10.1067/mhj.2000.110933

3. Gheorghiade M, Follath F, Ponikowski P, Barsuk JH, Blair JEA, 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 JJV, Filippatos G, European Society of Cardiology, European
Society of Intensive Care Medicine. 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 Cardiology and endorsed by the European Society of
Intensive Care Medicine. Eur J Heart Fail. 2010;12(5):423-433. doi:10.1093/eurjhf/hfq045

4. Nohria A, Hasselblad V, Stebbins A, Pauly DF, Fonarow GC, Shah M, Yancy CW, Califf
RM, Stevenson LW, Hill JA. Cardiorenal interactions: insights from the ESCAPE trial. J
Am Coll Cardiol. 2008;51(13):1268-1274. doi:10.1016/j.jacc.2007.08.072

5. Mullens W, Abrahams Z, Francis GS, Sokos G, Taylor DO, Starling RC, Young JB, Tang
WHW. Importance of venous congestion for worsening of renal function in advanced
decompensated heart failure. J Am Coll Cardiol. 2009;53(7):589-596.
doi:10.1016/j.jacc.2008.05.068

6. McCallum W, Tighiouart H, Testani JM, Griffin M, Konstam MA, Udelson JE, Sarnak MJ.
Association of Volume Overload With Kidney Function Outcomes Among Patients With

14
 Heart Failure With Reduced Ejection Fraction. Kidney Int Rep. 2020;5(10):1661-1669.
doi:10.1016/j.ekir.2020.07.015

7. Rubio-Gracia J, Demissei BG, Ter Maaten JM, Cleland JG, O’Connor CM, Metra M,
Ponikowski P, Teerlink JR, Cotter G, Davison BA, Givertz MM, Bloomfield DM, Dittrich
H, Damman K, Pérez-Calvo JI, Voors AA. Prevalence, predictors and clinical outcome of
residual congestion in acute decompensated heart failure. Int J Cardiol. 2018;258:185-191.
doi:10.1016/j.ijcard.2018.01.067

8. Kociol RD, McNulty SE, Hernandez AF, Lee KL, Redfield MM, Tracy RP, Braunwald E,
O’Connor CM, Felker GM, NHLBI Heart Failure Network Steering Committee and
Investigators. Markers of decongestion, dyspnea relief, and clinical outcomes among
patients hospitalized with acute heart failure. Circ Heart Fail. 2013;6(2):240-245.
doi:10.1161/CIRCHEARTFAILURE.112.969246

9. Konstam MA, Gheorghiade M, Burnett JC, Grinfeld L, Maggioni AP, Swedberg K,

Udelson JE, Zannad F, Cook T, Ouyang J, Zimmer C, Orlandi C, Efficacy of Vasopressin
Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST) Investigators.
Effects of oral tolvaptan in patients hospitalized for worsening heart failure: the EVEREST
Outcome Trial. JAMA. 2007;297(12):1319-1331. doi:10.1001/jama.297.12.1319

10. Ambrosy AP, Pang PS, Khan S, Konstam MA, Fonarow GC, Traver B, Maggioni AP,
Cook T, Swedberg K, Burnett JC, Grinfeld L, Udelson JE, Zannad F, Gheorghiade M,
EVEREST Trial Investigators. Clinical course and predictive value of congestion during
hospitalization in patients admitted for worsening signs and symptoms of heart failure with
reduced ejection fraction: findings from the EVEREST trial. Eur Heart J. 2013;34(11):835-
843. doi:10.1093/eurheartj/ehs444

11. Thibodeau JT, Drazner MH. The Role of the Clinical Examination in Patients With Heart
Failure. JACC Heart Fail. 2018;6(7):543-551. doi:10.1016/j.jchf.2018.04.005

12. Fudim M, Parikh KS, Dunning A, DeVore AD, Mentz RJ, Schulte PJ, Armstrong PW,
Ezekowitz JA, Tang WHW, McMurray JJV, Voors AA, Drazner MH, O’Connor CM,
Hernandez AF, Patel CB. Relation of Volume Overload to Clinical Outcomes in Acute
Heart Failure (From ASCEND-HF). Am J Cardiol. 2018;122(9):1506-1512.
doi:10.1016/j.amjcard.2018.07.023

13. Testani JM, Khera AV, St John Sutton MG, Keane MG, Wiegers SE, Shannon RP,
Kirkpatrick JN. Effect of right ventricular function and venous congestion on cardiorenal
interactions during the treatment of decompensated heart failure. Am J Cardiol.
2010;105(4):511-516. doi:10.1016/j.amjcard.2009.10.020

14. Kociol RD, Horton JR, Fonarow GC, Reyes EM, Shaw LK, O’Connor CM, Felker GM,
Hernandez AF. Admission, discharge, or change in B-type natriuretic peptide and long-term
outcomes: data from Organized Program to Initiate Lifesaving Treatment in Hospitalized
Patients with Heart Failure (OPTIMIZE-HF) linked to Medicare claims. Circ Heart Fail.
2011;4(5):628-636. doi:10.1161/CIRCHEARTFAILURE.111.962290

15
15. Gargani L, Pang PS, Frassi F, Miglioranza MH, Dini FL, Landi P, Picano E. Persistent
pulmonary congestion before discharge predicts rehospitalization in heart failure: a lung
ultrasound study. Cardiovasc Ultrasound. 2015;13:40. doi:10.1186/s12947-015-0033-4

16. Oguri M, Ishii H, Takahara K, Yasuda K, Takikawa T, Sumi T, Takahashi H, Murohara T.

Efficacy of Rapid Decongestion Strategy in Patients Hospitalized for Acute Heart Failure.
Circ J. 2020;84(6):958-964. doi:10.1253/circj.CJ-19-1128

17. Lala A, McNulty SE, Mentz RJ, Dunlay SM, Vader JM, AbouEzzeddine OF, DeVore AD,
Khazanie P, Redfield MM, Goldsmith SR, Bart BA, Anstrom KJ, Felker GM, Hernandez
AF, Stevenson LW. Relief and Recurrence of Congestion During and After Hospitalization
for Acute Heart Failure: Insights From Diuretic Optimization Strategy Evaluation in Acute
Decompensated Heart Failure (DOSE-AHF) and Cardiorenal Rescue Study in Acute
Decompensated Heart Failure (CARESS-HF). Circ Heart Fail. 2015;8(4):741-748.
doi:10.1161/CIRCHEARTFAILURE.114.001957

18. Turin TC, Coresh J, Tonelli M, Stevens PE, de Jong PE, Farmer CKT, Matsushita K,
Hemmelgarn BR. Short-term change in kidney function and risk of end-stage renal disease.
Nephrol Dial Transplant. 2012;27(10):3835-3843. doi:10.1093/ndt/gfs263

16
Figure 1. Unadjusted event rates by quartile of slope of decline in BNP (left) and NT-proBNP (right). Event rates for both all-cause mortality and
composite of cardiovascular death and hospitalization for heart failure are highest in Quartile 1 (those with least rapid decline in marker of volume
overload) and are lowest in Quartile 4 (those with most rapid decline).
Abbreviations: BNP,b-type natriuretic peptide; NT-proBNP: N-terminal prohormone of b-type natriuretic peptide

17
Figure 2. Adjusted survival curves according to quartiles of rates of decrease in biomarkers of volume overload (a) and increase in biomarkers of
hemoconcentration (b). Quartile 1 represents the least rapid rate of decongestion and Quartile 4 represents the most rapid rate of decongestion.
Models were adjusted for age, sex, race, randomization group (tolvaptan vs placebo), body mass index, medication use (ACEI or ARB, MRA),
ejection fraction, New York Heart Association functional class, systolic blood pressure, baseline eGFR and respective baseline biomarker level.
Abbreviations: BNP, b-type natriuretic peptide; NT-proBNP: N-terminal prohormone of b-type natriuretic peptide; ACEI, angiotensin-converting
enzyme inhibitor; ARB, angiotensin II receptor blocker; MRA, mineralocorticoid receptor antagonist; eGFR, estimated glomerular filtration rate

18
Figure 3. Adjusted curves of probability free of composite outcome of CV mortality or HF hospitalization according to quartiles of rates of
decrease in biomarkers of volume overload (a) and increase in biomarkers of hemoconcentration (b). Quartile 1 represents the least rapid rate of
decongestion and Quartile 4 represents the most rapid rate of decongestion. Models were adjusted for age, sex, race, randomization group
(tolvaptan vs placebo), body mass index, medication use (ACEI or ARB, MRA), ejection fraction, New York Heart Association functional class,
systolic blood pressure, baseline eGFR and respective baseline biomarker level.
Abbreviations: CV, cardiovascular; HF, heart failure; BNP, b-type natriuretic peptide; NT-proBNP: N-terminal prohormone of b-type natriuretic
peptide; eGFR, estimated glomerular filtration rate

19
Table 1. Baseline characteristics by quartiles of slope of BNP on the log scale during hospitalization.
All Quartile 1 Quartile 2 Quartile 3 Quartile 4
(n=2419) (n=605) (n=605) (n=605) (n=604)
Least Rapid Decline Most Rapid Decline
Age 65.4 (11.4) 64.8 (11.7) 66.0 (11.5) 66.6 (11.2) 64.1 (11.1)
Female 639 (26.4) 163 (26.9) 123 (20.3) 157 (26.0) 196 (32.5)
Black 147 (6.1) 23 (3.8) 51 (8.4) 39 (6.5) 34 (5.6)
BMI, kg/m2 28.6 (5.5) 28.0 (5.4) 28.0 (5.4) 28.7 (5.2) 29.8 (5.7)
Ejection Fraction, % 28.2 (7.9) 28.1 (7.9) 25.9 (8.1) 28.3 (7.9) 30.5 (7.2)
Ischemic etiology 1611 (67.5) 444 (74.1) 370 (62.0) 414 (69.6) 383 (64.2)
Systolic Blood Pressure 121.5 (19.3) 119.2 (19.8) 118.0 (18.6) 121.5 (18.4) 127.4 (18.9)
NYHA Functional Class
Class 1 or 2 10 (0.4) 0 (0) 3 (0.5) 5 (0.8) 2 (0.3)
Class 3 1459 (60.4) 330 (54.6) 387 (64.0) 388 (64.1) 354 (58.7)
Class 4 948 (39.2) 274 (45.4) 215 (35.5) 212 (35.0) 247 (41.0)
Hypertension 1723 (71.2) 413 (68.3) 407 (67.3) 436 (72.1) 467 (77.3)
Diabetes 890 (36.8) 228 (37.7) 226 (37.4) 221 (36.5) 215 (35.6)
Smoking, current 297 (12.3) 86 (14.3) 67 (11.1) 63 (10.4) 81 (13.4)
Home Medications
ACEI or ARB 2085 (86.2) 526 (86.9) 502 (83.0) 516 (85.3) 541 (89.6)
Aldosterone antagonist 1428 (59.0) 392 (64.8) 356 (57.2) 332 (54.9) 358 (59.3)
Furosemide 2025 (83.7) 517 (85.5) 507 (83.8) 517 (85.5) 484 (80.1)
Beta Blocker 1737 (71.8) 415 (68.6) 443 (73.2) 464 (76.7) 415 (68.7)
Laboratory Results
Initial eGFR, ml/min/1.73 m2 57.5 (42.9, 74.1) 54.3 (40.3, 72.3) 54.4 (40.3, 70.8) 57.5 (42.5, 74.6) 63.3 (49.3, 78.2)
Slope of eGFR,
-1.2 (3.8) -0.5 (4.0) -0.8 (3.7) -1.4 (3.4) -2.2 (4.0)
ml/min/1.73 m2 per week
Initial BNP, pg/ml 652 (272, 1398) 1026 (433, 2007) 864 (467, 1585) 467 (239, 930) 381 (157, 1005)
Slope of BNP, % per week -22.4 (-25.1, -19.6) -16.4 (-18.5, -13.1) -21.2 (-21.9, -20.6) -23.6 (-24.4, -23.0) -27.6 (-30.4, -26.2)
Randomization Group
Tolvaptan 1197 (49.5) 296 (48.9) 285 (47.1) 313 (51.7) 303 (50.2)
Values presented as either n (%), mean ± standard deviation or median (25th, 75th interquartile range). For administrative reasons, many patients
had baseline BNP measured (n=2,419) but not all.
BMI: body mass index; NYHA: New York Heart Association; eGFR: estimated glomerular filtration rate; BNP: b-type natriuretic peptide;
ACEI:angiotensin-converting enzyme inhibitor; ARB: angiotensin II receptor blocker

20
Table 2. Hazard ratios for all-cause mortality and composite cardiovascular outcome based on rates of change in measures of volume overload
Marker of Continuous Quartile 1 Quartile 2 Quartile 3 Quartile 4
Volume Least Rapid Most Rapid
Overload Decongestion Decongestion
All-cause Mortality
BNP N 2419 605 605 605 604
Per 6% decrease Event 440 160 134 92 54
per week Time 1753 373 447 472 460
Rate 25.1 42.9 30.0 19.5 11.7
Unadjusted 0.68 (0.63, 0.73) 1.00 (1.00, 1.00) 0.71 (0.56, 0.89) 0.46 (0.36, 0.60) 0.28 (0.20, 0.38)
Adjusted 0.71 (0.65, 0.78) 1.00 (1.00, 1.00) 0.70 (0.55, 0.88) 0.57 (0.43, 0.74) 0.43 (0.31, 0.59)
NT-proBNP N 1221 305 306 305 305
Per 12% decrease Event 410 171 115 85 39
per week Time 1711 334 425 454 497
Rate 24.0 51.2 27.0 18.7 7.8
Unadjusted 0.62 (0.58, 0.67) 1.00 (1.00, 1.00) 0.54 (0.42, 0.68) 0.37 (0.28, 0.48) 0.16 (0.11, 0.22)
Adjusted 0.74 (0.67, 0.82) 1.00 (1.00, 1.00) 0.66 (0.51, 0.84) 0.54 (0.41, 0.71) 0.27 (0.19, 0.40)
Congestion N 3506 876 869 888 873
Score Event 801 185 174 217 225
Per 1 point Time 3212 699 831 865 817
decrease per week Rate 24.9 26.5 20.9 25.1 27.5
Unadjusted 1.02 (0.95, 1.09) 1.00 (1.00, 1.00) 0.81 (0.66, 0.99) 0.97 (0.79, 1.18) 1.06 (0.87, 1.29)
Adjusted 0.85 (0.79, 0.92) 1.00 (1.00, 1.00) 0.84 (0.68, 1.03) 0.78 (0.63, 0.96) 0.72 (0.58, 0.89)
Composite of Cardiovascular Mortality or HF Hospitalization
BNP N 2419 605 605 605 604
Per 6% decrease Event 832 269 235 199 129
per week 1439 282 356 395 407
Time
Rate 57.8 95.2 66.1 50.4 31.7
Unadjusted 0.73 (0.69, 0.77) 1.00 (1.00, 1.00) 0.73 (0.62, 0.87) 0.57 (0.47, 0.68) 0.36 (0.29, 0.44)
Adjusted 0.76 (0.71, 0.82) 1.00 (1.00, 1.00) 0.69 (0.57, 0.82) 0.64 (0.57, 0.82) 0.49 (0.39, 0.60)
NT-proBNP N 1221 305 306 305 305
Per 12% decrease Event 644 196 189 151 108
per week 1262 234 283 345 400
Time
Rate 51.0 83.8 66.8 43.8 27.0
Unadjusted 0.71 (0.67, 0.76) 1.00 (1.00, 1.00) 0.83 (0.68, 1.01) 0.57 (0.46, 0.70) 0.36 (0.29, 0.46)
Adjusted 0.84 (0.77, 0.91) 1.00 (1.00, 1.00) 1.02 (0.83, 1.26) 0.78 (0.62, 0.99) 0.54 (0.42, 0.71)
21
Congestion N 3506 876 869 888 873
Score Event 1378 324 323 357 374
Per 1 point 2531 565 668 681 617
Time
decrease per week
Rate 54.4 57.3 48.4 52.4 60.6
Unadjusted 1.03 (0.97, 1.09) 1.00 (1.00, 1.00) 0.90 (0.77, 1.05) 0.97 (0.84, 1.13) 1.10 (0.95, 1.28)
Adjusted 0.93 (0.88, 0.99) 1.00 (1.00, 1.00) 0.91 (0.78, 1.06) 0.87 (0.74, 1.02) 0.90 (0.76, 1.07)
Cox proportional hazards regression modeling for slope of markers of volume overload during hospitalization for AHF. Time represented as total
follow-up time in years. Rate represented as per 100 person-years. Hazard ratios are interpreted per each standard deviation of slope per week
(i.e., for BNP, standard deviation of slope was 6% decrease per week), allowing for some uniformity across the different variables of rates of
change in decongestion. BNP and NT-proBNP are transformed on the log scale, enabling hazard ratios to be interpreted per percent decrease per
week. Hazard ratios for slope of congestion score (range 0 to 12, with higher score indicative of greater congestion) are per every 1 point
decrease per week.
Adjusted: Adjusted for age, sex, race, randomization group (tolvaptan vs placebo), BMI, medication use (ACEI or ARB, MRA), ejection
fraction, New York Heart Association functional class, systolic blood pressure, baseline eGFR and respective baseline biomarker level.
Abbreviations: BNP, b-type natriuretic peptide; NT-proBNP: N-terminal pro b-type natriuretic peptide; BMI, body mass index; ACEI,
angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; MRA, mineralocorticoid receptor antagonist; eGFR, estimated
glomerular filtration rate

22
Table 3. Hazard ratios for all-cause mortality and composite cardiovascular outcome based on rates of change in measures of hemoconcentration
Measures of Continuous Quartile 1 Quartile 2 Quartile 3 Quartile 4
hemoconcentration Least Rapid Most Rapid
Decongestion Decongestion
All-cause Mortality
Hematocrit N 3279 819 820 820 820
Per 1% increase per Event 747 186 183 213 165
week Time 2982 681 766 802 733
Rate 25.0 27.3 23.9 26.6 22.5
Unadjusted 1.01 (0.94, 1.09) 1.00 (1.00, 1.00) 0.89 (0.72, 1.09) 0.99 (0.82, 1.21) 0.83 (0.67, 1.02)
Adjusted 0.98 (0.91, 1.06) 1.00 (1.00, 1.00) 0.86 (0.70, 1.06) 0.86 (0.70, 1.06) 0.77 (0.62, 0.95)
Albumin N 3499 874 874 876 875
Per 0.1 g/dL Event 808 185 204 223 196
increase per Time 3208 762 836 833 778
week Rate 25.2 24.3 24.4 26.8 25.2
Unadjusted 1.01 (0.94, 1.08) 1.00 (1.00, 1.00) 1.01 (0.83, 1.24) 1.12 (0.92, 1.36) 1.03 (0.84, 1.26)
Adjusted 0.91 (0.84, 0.98) 1.00 (1.00, 1.00) 0.91 (0.74, 1.11) 0.81 (0.66, 1.00) 0.81 (0.65, 1.01)
Total Protein N 3559 889 890 890 890
Per 0.1 g/dL Event 822 185 216 221 200
increase per Time 3269 744 851 849 825
week Rate 25.1 24.9 25.4 26.0 24.2
Unadjusted 1.01 (0.94, 1.09) 1.00 (1.00, 1.00) 1.03 (0.85, 1.26) 1.06 (0.87, 1.29) 0.99 (0.81, 1.20)
Adjusted 0.95 (0.87, 1.03) 1.00 (1.00, 1.00) 0.88 (0.72, 1.08) 0.83 (0.67, 1.03) 0.78 (0.62, 0.98)
Composite of Cardiovascular Mortality or HF Hospitalization
Hematocrit N 3279 819 820 820 820
Per 1% increase per Event 1278 312 320 354 292
week Time 2356 541 596 615 605
Rate 54.2 57.7 53.7 57.5 48.3
Unadjusted 0.97 (0.92, 1.03) 1.00 (1.00, 1.00) 0.97 (0.83, 1.13) 1.05 (0.90, 1.22) 0.86 (0.73, 1.01)
Adjusted 0.92 (0.86, 0.97) 1.00 (1.00, 1.00) 0.94 (0.80, 1.10) 0.85 (0.72, 1.00) 0.75 (0.64, 0.88)
Albumin N 3499 874 874 876 875
Per 0.1 g/dL increase Event 1376 322 364 365 325
per week Time 2529 608 658 641 621
Rate 54.4 52.9 55.3 56.9 52.3
Unadjusted 0.98 (0.93, 1.03) 1.00 (1.00, 1.00) 1.06 (0.91, 1.23) 1.09 (0.94, 1.27) 0.99 (0.85, 1.15)
Adjusted 0.91 (0.85, 0.96) 1.00 (1.00, 1.00) 0.96 (0.82, 1.12) 0.85 (0.73, 1.00) 0.81 (0.69, 0.96)
Total Protein N 3559 889 890 890 890
23
Per 0.1 g/dL increase Event 1405 329 369 378 329
per week Time 2573 592 669 650 662
Rate 54.6 55.5 55.2 58.1 49.7
Unadjusted 0.97 (0.92, 1.02) 1.00 (1.00, 1.00) 1.03 (0.89, 1.20) 1.08 (0.93, 1.25) 0.93 (0.79, 1.08)
Adjusted 0.89 (0.84, 0.95) 1.00 (1.00, 1.00) 0.89 (0.76, 1.04) 0.88 (0.75, 1.04) 0.74 (0.62, 0.88)
Cox proportional hazards regression modeling for slope of markers of hemoconcentration during hospitalization for AHF. Time represented as total
follow-up time in years. Rate represented as per 100 person-years. Hazard ratios are interpreted per each standard deviation of slope per week (i.e.,
for hematocrit, standard deviation of slope per week is 1% increase in hematocrit on absolute scale), allowing for some uniformity across the
different variables of rates of change in decongestion.
Adjusted: Adjusted for age, sex, race, randomization group (tolvaptan vs placebo), BMI, medication use (ACEI or ARB, MRA), ejection fraction,
New York Heart Association functional class, systolic blood pressure, baseline eGFR and respective baseline biomarker level.
Abbreviations: BMI, body mass index; ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; MRA,
mineralocorticoid receptor antagonist; eGFR, estimated glomerular filtration rate

24
Table S1. Baseline characteristics by quartiles of slope of hematocrit change during hospitalization.
All Quartile 1 Quartile 2 Quartile 3 Quartile 4
(n=3279) (n=819) (n=820) (n=820) (n=820)
Least Rapid Increase Most Rapid Increase
Age 65.5 (11.5) 65.1 (11.2) 65.5 (12.0) 66.0 (11.4) 64.1 (11.1)
Female 825 (25.2) 211 (25.8) 196 (23.9) 220 (26.8) 198 (24.2)
Black 211 (6.4) 37 (4.5) 51 (6.2) 78 (9.5) 45 (5.5)
BMI, kg/m2 28.6 (5.5) 28.6 (5.4) 28.5 (5.5) 28.5 (5.6) 28.8 (5.4)
Ejection Fraction, % 27.7 (7.9) 29.0 (7.6) 27.2 (8.1) 26.6 (7.9) 28.1 (7.8)
Ischemic etiology 2152 (66.5) 585 (71.9) 534 (65.6) 510 (63.4) 523 (65.1)
Systolic Blood Pressure 120.8 (19.5) 121.5 (19.2) 120.2 (19.1) 119.9 (20.0) 121.7 (19.6)
NYHA Functional Class
Class 1 or 2 16 (0.5) 0 (0.0) 7 (0.9) 4 (0.5) 5 (0.6)
Class 3 1961 (59.8) 470 (57.4) 516 (62.9) 516 (63.0) 459 (56.0)
Class 4 1300 (39.7) 349 (42.6) 297 (36.2) 299 (36.5) 355 (43.4)
Hypertension 2324 (70.9) 593 (72.4) 572 (69.8) 589 (71.8) 570 (69.5)
Diabetes 1241 (37.9) 298 (36.4) 316 (38.5) 338 (41.2) 289 (35.2)
Smoking, current 407 (12.4) 110 (13.5) 106 (12.9) 89 (10.9) 102 (12.5)
Medications
ACEI or ARB 2801 (85.4) 713 (87.1) 700 (85.4) 699 (85.2) 689 (84.0)
Aldosterone antagonist 1884 (57.5) 491 (60.0) 448 (54.6) 445 (54.3) 500 (61.0)
Furosemide 2730 (83.3) 696 (85.0) 673 (82.1) 684 (83.4) 677 (82.6)
Beta Blocker 2338 (71.3) 572 (69.8) 583 (71.1) 609 (74.3) 574 (70.0)
Laboratory Results
Initial eGFR, ml/min/1.73 m2 57.5 (42.4, 74.8) 57.1 (42.1, 74.4) 57.7 (43.7, 73.9) 55.5 (41.0, 74.9) 59.5 (43.5, 75.7)
Slope of eGFR,
-1.3 (3.7) -0.2 (4.4) -1.3 (3.0) -1.7 (2.9) -2.0 (4.2)
ml/min/1.73 m2 per week
Initial hematocrit, % 42.1 (5.8) 44.4 (5.7) 43.2 (5.1) 40.0 (5.2) 40.8 (5.9)
Slope of hematocrit, % per week 0.7 (1.0) -0.5 (0.7) 0.5 (0.1) 0.9 (0.1) 1.9 (0.8)
Randomization Group
Tolvaptan 1626 (49.6) 369 (45.1) 371 (45.2) 450 (54.9) 436 (53.2)
Values presented as either n (%), mean ± standard deviation or median (25th, 75th interquartile range). Slope of hematocrit derived using linear
mixed models and represented on the absolute scale.
BMI: body mass index; NYHA: New York Heart Association; eGFR: estimated glomerular filtration rate; BNP: b-type natriuretic peptide;
ACEI:angiotensin-converting enzyme inhibitor; ARB: angiotensin II receptor blocker

25
Table S2. Number of patients with available biomarker data in each exposure with baseline biomarkers and mean slopes of change
Biomarker Baseline Quartile 1 Quartile 2 Quartile 3 Quartile 4
Biomarker Level Slowest Decongestion Fastest Decongestion
BNP
N 2419 605 605 605 604
Baseline BNP, pg/ml 652 (272, 1398) 1026 (433, 2007) 864 (467, 1585) 467 (239, 930) 381 (157, 1005)
Slope of change* -22.1 (6.2) -14.7 (5.6) -21.2 (0.8) -23.7 (0.8) -28.9 (4.0)
NT-proBNP
N 1221 305 306 305 305
Baseline NT-proBNP, pg/ml 4312 (2007, 8428) 8923 (4974, 17119) 5492 (3105, 8340) 3160 (1630, 5620) 2091 (844, 4497)
Slope of change* -36.3 (11.9) -20.9 (9.2) -34.1 (2.1) -40.5 (1.9) -49.8 (5.3)
Congestion Score
N 3506 876 869 888 873
Baseline Congestion Score 5.11 (2.07) 4.23 (2.17) 4.20 (1.80) 5.16 (1.53) 6.84 (1.51)
Slope of change -3.5 (1.46) -1.67 (0.64) -3.01 (1.80) -3.95 (0.28) -5.36 (0.81)
Hematocrit
N 3279 819 820 820 820
Baseline hematocrit, % 42.1 (5.8) 44.4 (5.7) 43.2 (5.1) 40.0 (5.2) 40.8 (5.9)
Slope of change 0.7 (1.00) -0.5 (0.7) 0.5 (0.2) 0.9 (0.1) 1.9 (0.8)
Albumin
N 3499 874 874 876 875
Baseline Albumin, g/dL 3.76 (0.52) 4.06 (0.50) 3.90 (0.40) 3.63 (0.45) 3.47 (0.53)
Slope of change 0.08 (0.10) -0.04 (0.08) 0.06 (0.02) 0.11 (0.02) 0.21 (0.06)
Total Protein
N 3559 889 890 890 890
Baseline total protein, g/dL 7.07 (0.72) 7.55 (0.72) 7.25 (0.52) 6.86 (0.54) 6.62 (0.69)
Slope of change 0.24 (0.16) 0.04 (0.11) 0.20 (0.02) 0.28 (0.02) 0.43 (0.10)
Values presented as either mean (standard deviation) or median (interquartile range). Linear mixed models were used to derive
slopes for each exposure variable on the absolute scale, with the exception of BNP and NT-proBNP.
*Values of BNP and NT-proBNP were log-transformed given the non-linear distribution and slopes presented as a percent change
BNP, b-type natriuretic peptide; NT-proBNP: N-terminal pro b-type natriuretic peptide

26
Table S3. Hazard ratios for all-cause mortality and composite cardiovascular outcome based on rates of change in measures of volume overload,
adjusting for discharge covariates including the discharge biomarker level
Marker of Continuous Quartile 1 Quartile 2 Quartile 3 Quartile 4
Volume Least rapid Most rapid
Overload decongestion decongestion
All-cause mortality
BNP N 2381 597 594 594 596
Per 6% decrease Event 434 158 132 91 53
per week Time 1715 365 436 462 452
Rate 25.3 43.3 30.3 19.7 11.7
Unadjusted 0.68 (0.63, 0.74) 1.00 (1.00, 1.00) 0.71 (0.56, 0.89) 0.46 (0.36, 0.60) 0.27 (0.20, 0.37)
Adjusted 0.84 (0.74, 0.95) 1.00 (1.00, 1.00) 0.76 (0.60, 0.98) 0.85 (0.62, 1.17) 0.77 (0.52, 1.15)
NT-proBNP N 1209 300 302 304 303
Per 12% decrease Event 406 169 113 85 39
per week Time 1694 328 420 453 493
Rate 24.0 51.5 26.9 18.8 7.9
Unadjusted 0.62 (0.58, 0.67) 1.00 (1.00, 1.00) 0.53 (0.42, 0.67) 0.37 (0.28, 0.48) 0.16 (0.11, 0.22)
Adjusted 0.88 (0.77, 1.01) 1.00 (1.00, 1.00) 0.65 (0.50, 0.85) 0.56 (0.40, 0.78) 0.30 (0.18, 0.48)
Congestion N 3487 870 865 881 871
Score Event 793 183 173 213 224
Per 1 point Time 3190 693 824 858 816
decrease per week Rate 24.9 26.4 21.0 24.8 27.5
Unadjusted 1.02 (0.95, 1.09) 1.00 (1.00, 1.00) 0.81 (0.66, 1.00) 0.96 (0.79, 1.17) 1.06 (0.87, 1.29)
Adjusted 1.00 (0.93, 1.08) 1.00 (1.00, 1.00) 0.90 (0.73, 1.11) 0.93 (0.76, 1.13) 1.04 (0.85, 1.27)
Composite of Cardiovascular mortality or HF hospitalization
BNP N 2381 597 594 594 596
Per 6% decrease Event 820 266 231 195 128
per week
Time 1409 275 348 387 399
Rate 58.2 96.6 66.4 50.4 32.1
Unadjusted 0.73 (0.69, 0.77) 1.00 (1.00, 1.00) 0.73 (0.61, 0.87) 0.56 (0.47, 0.68) 0.36 (0.29, 0.44)
Adjusted 0.84 (0.77, 0.92) 1.00 (1.00, 1.00) 0.74 (0.61, 0.89) 0.80 (0.63, 1.00) 0.67 (0.50, 0.88)
NT-proBNP N 1209 300 302 304 303
Per 12% decrease Event 635 193 185 151 106
per week
Time 1254 231 281 343 400
Rate 50.6 83.7 65.8 44.1 26.5
Unadjusted 0.71 (0.66, 0.76) 1.00 (1.00, 1.00) 0.82 (0.67, 1.00) 0.57 (0.46, 0.71) 0.36 (0.28, 0.45)
27
 Adjusted 1.02 (0.90, 1.16) 1.00 (1.00, 1.00) 1.08 (0.86, 1.35) 0.95 (0.72, 1.26) 0.65 (0.46, 0.92)
Congestion N 3487 870 865 881 871
Score Event 1367 319 322 353 373
Per 1 point
Time 2514 562 661 676 615
decrease per week
Rate 54.4 56.7 48.7 52.3 60.6
Unadjusted 1.03 (0.98, 1.09) 1.00 (1.00, 1.00) 0.91 (0.78, 1.06) 0.98 (0.84, 1.14) 1.12 (0.96, 1.30)
Adjusted 1.00 (0.95, 1.06) 1.00 (1.00, 1.00) 0.96 (0.82, 1.13) 0.94 (0.81, 1.10) 1.06 (0.91, 1.24)
Cox proportional hazards regression modeling for slope of markers of volume overload during hospitalization for AHF. Time represented as
total follow-up time in years. Rate represented as per 100 person-years. Hazard ratios are interpreted per each standard deviation of slope per
week (i.e., for BNP, standard deviation of slope was 6% decrease per week), allowing for some uniformity across the different variables of rates
of change in decongestion. BNP and NT-proBNP are transformed on the log scale, enabling hazard ratios to be interpreted per percent decrease
per week. Hazard ratios for slope of congestion score (range 0 to 12, with higher score indicative of greater congestion) are per every 1 point
decrease per week.
Adjusted: Adjusted for age, sex, race, randomization group (tolvaptan vs placebo), BMI, medication use (ACEI or ARB, MRA), ejection
fraction, New York Heart Association functional class, systolic blood pressure, discharge eGFR and respective discharge biomarker level.
Abbreviations: BNP, b-type natriuretic peptide; NT-proBNP: N-terminal pro b-type natriuretic peptide; BMI, body mass index; ACEI,
angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; MRA, mineralocorticoid receptor antagonist; eGFR, estimated
glomerular filtration rate

28
Table S4. Hazard ratios for all-cause mortality and composite cardiovascular outcome based on rates of change in measures of hemoconcentration,
adjusted for discharge covariates including the discharge biomarker level
Measures of Continuous Quartile 1 Quartile 2 Quartile 3 Quartile 4
hemoconcentration Least rapid Most rapid
decongestion decongestion
All-cause mortality
Hematocrit N 3126 797 762 768 799
Per 1% increase per Event 712 182 175 196 159
week Time 2836 662 708 753 714
Rate 25.1 27.5 24.7 26.0 22.3
Unadjusted 1.01 (0.93, 1.08) 1.00 (1.00, 1.00) 0.91 (0.74, 1.12) 0.97 (0.79, 1.19) 0.81 (0.66, 1.01)
Adjusted 1.02 (0.94, 1.11) 1.00 (1.00, 1.00) 0.88 (0.71, 1.08) 0.90 (0.74, 1.11) 0.81 (0.65, 1.01)
Albumin N 3466 870 863 866 867
Per 0.1 g/dL Event 802 185 202 222 193
increase per Time 3173 756 824 823 769
week Rate 25.3 24.5 24.5 27.0 25.1
Unadjusted 1.00 (0.94, 1.08) 1.00 (1.00, 1.00) 1.01 (0.83, 1.23) 1.12 (0.92, 1.36) 1.03 (0.84, 1.26)
Adjusted 1.05 (0.98, 1.13) 1.00 (1.00, 1.00) 1.05 (0.86, 1.29) 1.05 (0.86, 1.28) 1.10 (0.89, 1.35)
Total Protein N 3557 889 889 889 890
Per 0.1 g/dL Event 822 185 216 221 200
increase per Time 3267 744 850 847 825
week Rate 25.2 24.9 25.4 26.1 24.2
Unadjusted 1.01 (0.94, 1.09) 1.00 (1.00, 1.00) 1.03 (0.85, 1.26) 1.06 (0.87, 1.29) 0.99 (0.81, 1.20)
Adjusted 1.00 (0.92, 1.07) 1.00 (1.00, 1.00) 0.96 (0.79, 1.17) 0.98 (0.80, 1.19) 0.90 (0.74, 1.11)
Composite of Cardiovascular mortality or HF hospitalization
Hematocrit N 3126 797 762 768 799
Per 1% increase per Event 1213 306 298 328 281
week Time 2251 525 555 581 589
Rate 53.9 58.3 53.7 56.4 47.7
Unadjusted 0.97 (0.91, 1.02) 1.00 (1.00, 1.00) 0.96 (0.82, 1.12) 1.02 (0.87, 1.19) 0.84 (0.72, 0.99)
Adjusted 1.00 (0.94, 1.06) 1.00 (1.00, 1.00) 0.96 (0.82, 1.13) 0.93 (0.79, 1.09) 0.87 (0.73, 1.03)
Albumin N 3466 870 863 866 867
Per 0.1 g/dL increase Event 1365 322 360 362 321
per week Time 2503 603 650 635 616
Rate 54.5 53.4 55.4 57.1 52.1
Unadjusted 0.97 (0.92, 1.03) 1.00 (1.00, 1.00) 1.05 (0.91, 1.23) 1.08 (0.93, 1.26) 0.98 (0.84, 1.14)
Adjusted 1.00 (0.95, 1.06) 1.00 (1.00, 1.00) 1.06 (0.91, 1.23) 1.01 (0.86, 1.17) 1.01 (0.86, 1.18)
29
Total Protein N 3557 889 889 889 890
Per 0.1 g/dL increase Event 1404 329 369 377 329
per week Time 2572 592 667 650 662
Rate 54.6 55.5 55.3 58.0 49.7
Unadjusted 0.97 (0.92, 1.02) 1.00 (1.00, 1.00) 1.03 (0.89, 1.20) 1.08 (0.93, 1.25) 0.93 (0.79, 1.08)
Adjusted 0.97 (0.92, 1.03) 1.00 (1.00, 1.00) 0.97 (0.84, 1.13) 1.01 (0.87, 1.17) 0.88 (0.75, 1.03)
Cox proportional hazards regression modeling for slope of markers of hemoconcentration during hospitalization for AHF. Time represented as total
follow-up time in years. Rate represented as per 100 person-years. Hazard ratios are interpreted per each standard deviation of slope per week (i.e.,
for hematocrit, standard deviation of slope per week is 1% increase in hematocrit on absolute scale), allowing for some uniformity across the
different variables of rates of change in decongestion.
Adjusted: Adjusted for age, sex, race, randomization group (tolvaptan vs placebo), BMI, medication use (ACEI or ARB, MRA), ejection fraction,
New York Heart Association functional class, systolic blood pressure, discharge eGFR and respective discharge biomarker level.
Abbreviations: BMI, body mass index; ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; MRA,
mineralocorticoid receptor antagonist; eGFR, estimated glomerular filtration rate

30
Table S5. Characteristics of patients with most rapid BNP decline and less rapid decline, before and after propensity-score matching
Before Matching After Matching
Slower Decongestion Rapid Decongestion Standardized Slower Decongestion Rapid Decongestion Standardized
(n=1815) (n=604) Difference (%) (n=596) (n=596) Difference
Quartiles 1-3 Quartile 4 Matched from Quartiles 1-3 Quartile 4 (%)
Age, years 65.8 (11.5) 64.1 (11.1) 14.9 64.7 (11.4) 64.3 (11.1) 3.7
Female 443 (24.4) 196 (32.5) -17.9 198 (33.2) 195 (32.7) 1.1
Black 113 (6.2) 34 (5.6) 2.5 30 (5.0) 33 (5.5) -2.2
2
BMI, kg/m 28.2 (5.4) 29.8 (5.7) -27.6 29.4 (5.6) 29.7 (5.7) -4.6
Baseline Weight, kg 82.1 (17.9) 85.5 (19.3) -18.2 84.4 (18.0) 85.1 (19.0) -4.1
Ischemic etiology 1228 (68.6) 383 (64.2) 9.4 387 (66.4) 381 (64.7) 3.6
Ejection fraction, % 27.4 (8.0) 30.5 (7.2) -40.3 30.1 (7.4) 30.4 (7.2) -4.2
NYHA Class 4 701 (38.6) 247 (40.9) -4.6 249 (41.8) 245 (41.1) 1.4
Hypertension 1256 (69.2) 467 (77.3) -18.4 465 (78.0) 460 (77.2) 2.0
Diabetes 675 (37.2) 215 (35.6) 3.3 208 (34.9) 213 (35.7) -1.8
Smoking
Never 644 (35.5) 241 (39.9) -9.0 240 (40.3) 239 (40.1) 0.5
Current 216 (11.9) 81 (13.4) -4.5 93 (15.6) 79 (13.3) 6.8
Former 953 (52.6) 282 (46.7) 11.8 262 (44.0) 278 (46.6) -5.2
Baseline Congestion 5.2 (2.1) 5.0 (2.0) 7.5 4.9 (2.0) 5.0 (2.0) -5.5
Score
Systolic Blood Pressure 119.6 (19.0) 127.4 (18.9) -41.5 127.4 (19.0) 128.0 (20.5) 3.4
Medications
ACEI or ARB 1544 (85.1) 541 (89.6) -13.6 536 (89.9) 533 (89.4) 1.7
MRA 1070 (59.0) 358 (59.3) -0.6 353 (59.2) 352 (59.1%) 0.3
Diuretic 1541 (84.9%) 484 (80.1%) 12.6 482 (80.9%) 479 (80.4%) 1.3
Diuretic Dose 80 (40, 160) 40 (20, 120) 26.2 80 (40, 120) 40 (20, 120) 0.1
Laboratory Results
BNP, pg/ml 762.0 (345.0, 1505.7) 381.0 (156.5, 1005.0) 1.9 424.0 (194.5, 957.5) 387.1 (159.9, -6.6
1023.5)
Hematocrit, % 41.9 (5.7) 43.1 (5.3) -20.6 43.0 (5.5) 43.0 (5.3) -1.4
Albumin, g/dL 3.7 (0.5) 3.9 (0.5) -34.5 3.9 (0.5) 3.9 (0.5) 0.6
Total protein, g/dL 7.1 (0.7) 7.2 (0.7) -23.5 7.2 (0.7) 7.2 (0.7) -3.7
Sodium, mEq/L 139.8 (4.4) 141.2 (4.2) -31.7 141.3 (4.0) 141.2 (4.2) 1.8
eGFR, ml/min/1.73 m2 57.3 (21.3) 64.3 (21.1) -33.3 63.0 (20.3) 64.1 (21.1) -5.2
Creatinine, mg/dL 1.38 (0.49) 1.21 (0.41) 37.2 1.22 (0.37) 1.22 (0.41) 1.0
Randomized to 894 (49.3) 303 (50.2) -1.8 311 (52.2) 299 (50.2) 4.0

31
Tolvaptan
Values presented as either n (%), mean ± standard deviation or median (25th, 75th interquartile range). Standardized difference is the mean difference divided
by the pooled standard deviation, expressed as a percentage.
BMI: body mass index; NYHA: New York Heart Association; eGFR: estimated glomerular filtration rate; BNP: b-type natriuretic peptide; NT-proBNP: N-
terminal prohormone of b-type natriuretic peptide; ACEI:angiotensin-converting enzyme inhibitor; ARB: angiotensin II receptor blocker; MRA,
mineralocorticoid receptor antagonist

32
Table S6. Characteristics of patients with most rapid hematocrit increase and less rapid increase, before and after propensity-score matching
Before Matching After Matching
Slower Rapid Decongestion Standardized Slower Decongestion Rapid Standardized
Decongestion (n=820) Difference (%) (n=818) Decongestion Difference (%)
(n=2459) Quartile 4 Matched from (n=818)
Quartiles 1-3 Quartiles 1-3 Quartile 4
Age, years 65.5 (11.5) 65.5 (11.6) 0.0 65.5 (11.5) 65.5 (11.5) 0.0
Female 627 (25.5) 198 (24.2) 3.1 191 (23.4) 198 (24.2) -2.0
Black 166 (6.8) 45 (5.5) 5.3 51 (6.2) 45 (5.5) 3.1
BMI, kg/m2 28.5 (5.5) 28.8 (5.4) 7.3 28.7 (5.5) 28.8 (5.4)
Baseline Weight, kg 82.9 (18.6) 83.9 (18.2) -5.7 83.6 (18.5) 83.9 (18.1) -1.7
Ischemic etiology 1629 (67.0) 523 (65.1) 4.1 505 (62.7) 522 (65.1) -4.9
Ejection fraction 27.6 (8.0) 28.1 (7.8) -6.4 27.9 (8.0) 28.1 (7.8)
NYHA Class 4 945 (38.4) 355 (43.3) -9.9 351 (42.9) 353 (43.2) -0.5
Hypertension 1754 (71.3) 570 (69.5) 4.0 568 (69.4) 569 (69.6) -0.3
Diabetes 952 (38.7) 289 (35.2) 7.2 293 (35.8) 289 (35.3) 1.0
Smoking
Never 861 (35.0) 286 (34.9) 0.3 282 (34.5) 285 (34.9) -0.8
Current 305 (12.4) 102 (12.5) -0.1 91 (11.1) 102 (12.5) -4.2
Former 1291 (52.5) 431 (52.6) -0.2 444 (54.4) 430 (52.6) 3.4
Baseline Congestion Score 5.0 (2.1) 5.4 (2.1) -17.5 5.4 (2.1) 5.4 (2.1) 1.0
Systolic Blood Pressure 120.6 (19.4) 121.7 (19.6) -5.8 121.5 (19.7) 121.7 (19.6) -0.9
Medications
ACEI or ARB 2112 (85.9) 689 (84.0) 5.2 697 (85.2) 687 (84.0) 3.4
MRA 1384 (56.3) 500 (61.0) -9.5 499 (61.0) 498 (60.9) 0.3
Diuretic 2053 (83.5) 677 (82.6) 2.5 673 (82.3) 675 (82.5) -0.6
Diuretic Dose 80.0 (40.0, 160.0) 80.0 (40.0, 160.0) 1.5 80.0 (40.0, 160.0) 80.0 (40.0, 160.0) -4.5
Laboratory Results
Hematocrit 42.5 (5.7) 40.8 (5.9) 29.8 40.9 (5.4) 40.8 (5.9) 1.0
Albumin, g/dL 3.8 (0.5) 3.7 (0.5) 24.4 3.7 (0.5) 3.7 (0.5) 2.9
Total protein, g/dL 7.1 (0.7) 6.9 (0.7) 30.4 6.9 (0.7) 6.9 (0.7) -0.9
Sodium, mEq/L 139.7 (4.5) 140.1 (4.5) -8.1 140.0 (4.5) 140.0 (4.5) -0.3
eGFR, ml/min/1.73 m2 58.8 (21.8) 60.7 (22.1) -8.6 60.4 (22.3) 60.6 (22.0) -0.6
Creatinine, mg/dL 1.35 (0.47) 1.32 (0.49) 7.0 1.33 (0.47) 1.32 (0.49) 1.7
Randomized to Tolvaptan 1190 (48.4) 436 (53.2) -9.6 443 (54.2) 435 (53.2) 2.0
Values presented as either n (%), mean ± standard deviation or median (25th, 75th interquartile range). Standardized difference is the mean difference
divided by the pooled standard deviation, expressed as a percentage.
BMI: body mass index; NYHA: New York Heart Association; eGFR: estimated glomerular filtration rate; BNP: b-type natriuretic peptide; NT-proBNP: N-
terminal prohormone of b-type natriuretic peptide; ACEI:angiotensin-converting enzyme inhibitor; ARB: angiotensin II receptor blocker; MRA,
mineralocorticoid receptor antagonist

33
Table S7. Hazard ratios for all-cause mortality and composite cardiovascular outcome based on rate of BNP decline
Multivariable Model*- Before Matching Univariable Model- After PS Score Matching
Slower Slower Decongestion
Rapid Decongestion Rapid Decongestion
Decongestion Matched from
Quartile 4 Quartile 4
Quartiles 1-3 Quartiles 1-3
All-cause mortality
BNP N 1815 604 596 596
Per 6% decrease Event 386 54 90 54
per week Time 15510 5523 5239 5428
Rate 29.9 11.7 20.6 11.9
HR (95% CI) Ref 0.54 (0.40, 0.72) Ref 0.58 (0.41, 0.81)
Composite of Cardiovascular mortality or HF hospitalization
BNP N 1815 604 596 596
Per 6% decrease Event 703 129 176 129
per week
Time 12393 4789 4342 4784
Rate 68.1 31.7 48.6 32.4
HR (95% CI) Ref 0.63 (0.52, 0.76) Ref 0.68 (0.54, 0.85)
Cox proportional hazards regression models were fitted to assess the association between more rapid rate of BNP decline in
comparison to slower decline during hospitalization for AHF with all-cause mortality and composite of CV mortality or HF
hospitalization. A propensity score was developed to match patients from the quartile with the most rapid rate of BNP decline
(“Rapid Decongestion”) to the three quartiles with slower rates (“Slower Decongestion”). Time represented as total follow-up
time in years. Rate represented as per 100 person-years.
* Adjusted for age, sex, race, randomization group (tolvaptan vs placebo), BMI, medication use (ACEI or ARB, MRA), ejection
fraction, New York Heart Association functional class, systolic blood pressure, baseline eGFR and baseline BNP.
Abbreviations: PS: propensity score; BNP: b-type natriuretic peptide; HF: heart failure; BMI: body mass index; eGFR: estimated
glomerular filtration rate; ACEI: angiotensin-converting enzyme inhibitor; ARB: angiotensin II receptor blocker; MRA:
mineralicorticoid receptor blocker

34
Table S8. Hazard ratios for all-cause mortality and composite cardiovascular outcome based on rate of hematocrit decline
Multivariable Models*- Before Matching Univariable Model- After PS Matching
Slower Slower Decongestion
Rapid Decongestion Rapid Decongestion
Decongestion Matched from Quartiles
Quartile 4 Quartile 4
Quartiles 1-3 1-3
All-cause Mortality
Hematocrit N 2459 820 818 818
Per 1% decrease Event 582 165 199 165
per week Time 26992 8797 9195 8771
Rate 25.9 11.7 26.0 22.6
HR (95% CI) Ref 0.84 (0.71, 1.01) Ref 0.86 (0.70, 1.06)
Composite of Cardiovascular Mortality or HF Hospitalization
Hematocrit N 2459 820 818 818
Per 1% decrease Event 986 292 347 291
per week
Time 21023 7255 6848 7234
Rate 56.3 48.3 60.8 48.3
HR (95% CI) Ref 0.81 (0.71, 0.93) Ref 0.79 (0.68, 0.93)
Cox proportional hazards regression models were fitted to assess the association between more rapid rate of BNP decline in
comparison to slower decline during hospitalization for AHF with all-cause mortality and composite of CV mortality or HF
hospitalization. A Propensity score was developed to match patients from the quartile with the most rapid rate of hematocrit
increase (“Rapid Decongestion”) to the three quartiles with slower rates (“Slower Decongestion”). Time represented as total
follow-up time in years. Rate represented as per 100 person-years.
* Adjusted for age, sex, race, randomization group (tolvaptan vs placebo), BMI, medication use (ACEI or ARB, MRA), ejection
fraction, New York Heart Association functional class, systolic blood pressure, baseline eGFR and baseline hematocrit.
Abbreviations: PS: propensity score; HF, heart failure; BMI: body mass index; eGFR: estimated glomerular filtration rate;
ACEI:angiotensin-converting enzyme inhibitor; ARB: angiotensin II receptor blocker; MRA: mineralicorticoid receptor blocker

35
Supplemental Figure S1. Distributions of slope of decongestion per week.

36