Impacto Del Potasio PDF

10.1161/CIRCULATIONAHA.117.
030576
Long-Term Potassium Monitoring and Dynamics in Heart Failure

and Risk of Mortality
Running Title: Núñez and Bayés-Genís et al.; Potassium Dynamics and Mortality in Heart
Failure
Julio Núñez, PhD1,2*; Antoni Bayés-Genís, PhD2,3*; Faiez Zannad, PhD4;

Patrick Rossignol, PhD4; Eduardo Núñez, MPH1; Vicent Bodí, PhD1; Gema Miñana, PhD1,2;
Enrique Santas, PhD1; Francisco J. Chorro, PhD1; Anna Mollar, PhD1,2; Arturo Carratalá, MD5;
Jorge Navarro, PhD6; Jose Luis Gorriz, PhD7; Josep Lupón, PhD2,3; Oliver Husser, PhD8;
Marco Metra, PhD9; and Juan Sanchis, PhD1,2
*Both authors contributed similarly in the present study
1
Cardiology Department, Hospital Clínico Universitario de Valencia, INCLIVA, Departamento
de Medicina, Universitat de València, Valencia, Spain; 2CIBER in Cardiovascular Diseases
Downloaded from http://circ.ahajournals.org/ by guest on October 12, 2017
(CIBERCV), Madrid, Spain; 3Heart Institute, Hospital Universitari Germans Trias i Pujol,
Badalona, Spain & Department of Medicine, Autonomous University of Barcelona, Barcelona,
Spain; 4Inserm, Centre d’Investigation Clinique Plurithématique 1433, Inserm U1116, U111616, Un
16 Univ
Université
iver
iv ersi
er s té
de Lorraine, CHRU de Nancy, F-CRIN INI-CRCT, Nancy, France; 5Biochemist Biochemistrytry Department.
Deppar
artm
tment.
tm
Hospital Clínico Universitario de Valencia, INCLIVA, Valencia, Spain; 6Hospit Hospital
ital C
it Clínico
líniico
Universitario, Universitat de València, INCLIVA, Valencia, Spain, CIBERESP; 7Nephrology
Department, Hospital Clínico Universitario, INCLIVA, Department of Medicine, Universitat de
V
Va
València,
lèènc
ncia, Vaalencia, Spain; 8Klinik für Herz-
Valencia, Herzz- und Kreislauferkrankungen,
Kreislauferkraank n ungen, Deutsches
Herzzent ntru
nt
Herzzentrum rum M
ru ünchen, Technical Universityy Munich,, Munich,
München, Munnicch, Germany;
G rmany;
Ge y 9Cardiology
y; Cardiology,gyy,
Department
Department off Me Medi
Medical
dica
di call an
ca andd Su
Surg
Surgical
rgic
rgi al Specialties,
Speciialties
es, Radiological
Radi
Ra d olog
di log
ogical
all Sciences
Scien
encess and
and Public
Publ
Pu b icc Health,
Healtlth,
lt h,
University
Uniiversity ooff B
Brescia,
resccia
ia, It
Ita
Italy
al y
aly
Address for Correspondence:

Julio Núñez, MD, PhD
Servicio de Cardiología
Hospital Clínico Universitario de Valencia
Avda. Blasco Ibáñez 17
46010 Valencia, Spain
Tel: +34652856689
Fax: +34963862658
Email: yulnunez@gmail.com
1
10.1161/CIRCULATIONAHA.117.030576
Abstract
Background—The prognostic value of long-term potassium monitoring and dynamics in heart

failure (HF) has not been characterized completely. We sought to determine the association
between serum potassium values collected at follow-up with all-cause mortality in a prospective
and consecutive cohort of patients discharged from a previous acute HF admission.
Methods—Serum potassium was measured at every physician-patient encounter, including
hospital admissions and ambulatory settings. The multivariable-adjusted association of serum
potassium with mortality was assessed using comprehensive state-of-the-art regression methods
that can accommodate time-dependent exposure modeling.
Results—The study sample included 2164 patients with a total of 16,116 potassium
observations. Mean potassium at discharge was 4.3±0.48 mEq/L. Hypokalemia (<3.5 mEq/L),
normokalemia (3.5 to 5.0 mEq/L), and hyperkalemia (>5 mEq/L) were observed at the index
admission in 77 (3.6%), 1965 (90.8%), and 122 (5.6%) patients, respectively. At a median
follow-up of 2.8 years (range=0.03-12.8 years), 1090 patients died (50.4%). On a continuous
scale, the multivariable-adjusted association of potassium values and mortality revealed a non-
linear association (U-shaped) with higher risk at both ends of its distribution (omnibus p-
value 0.001). Likewise, the adjusted hazard ratios (HRs) for hypokalemia and hyperkalemia
value=0.001). hyperk
r alemia –
normokalemia as reference - were 2.35 (95% confidence interval [CI]:1.40-3.93; p=0.001) p==0.
0 0001) aand
nd
1.55 (95% CI:1.11-2.16; p=0.011), respectively (omnibus p-value=0.0003). Furthermore, Furtheherm
he rmor
rm orre,
e
dynamic changes in potassium were independently associated with substantial differences in
mortality risk. Potassium normalization was independently associated with lower mortality risk
(p=0.001).
p=0.001). )
Conclusions—Either
Concclulusi
s on
si ns—Eith ther modeled continuously or categorically, serum
caateegorically, seruum po potassium
otassium levels during
long-term
ngg-term monitoring
ong monnit ng were
itorrin r independently
weere in
nde
depe
pend
pe n en
nd t y associated
ntl assooci
c at
ateed wi
with
th mmortality
o ta
ortallity iin ppatients
n pa tien
ents
en ts with
i h HF.
wit HF.
Likewise,
Like
kew
ke persistence
ence ooff abno
wise, persisten abnormal
normal potassium
no assium levels
potas leveelss was linked
wa linkeked to
ke o hhigher
ighe
her ri
risk death
sk of de
deaath ccompared
ompaared
with
th ppatients
h pa who
tients w h m
ho maintained returned
aiintaineed or returne normal
o mall values.
ned to nor
or valu
values
lu e.
es
Key Words: potassium; mortality; heart fail

failure; failure,
lure; acute heart fail hyperkalemia,
i ure, hyperkale hypokalemia,
l miia, hypokalemia
i ,
longitudinal cohort study
2
Clinical Perspective
What is new?
x This study evaluated the prognostic implications of long-term longitudinal monitoring
and dynamics of serum potassium in a prospective and consecutive cohort of patients
following a hospitalization for acute heart failure.
x On a continuous scale, the follow-up trajectory of serum potassium levels independently
predicted mortality through a U-shaped association, with higher risk at both ends of the
distribution, and the same was true for potassium categories.
x Potassium changes were associated with substantial differences in mortality risk;
accordingly, transitioning from hypo/hyperkalemia to normokalemia was independently

associated with lower risk.
x Potassium normalization from hypo/hyperkalemia was the most prevalentt cchange
hang
hangee
ng
documented in our cohort.
att are
What are
re tthe
he clini
niical implications?
clinical
x These fi
ffindings
ndd ngss support
ndin sup
uppo
poort the
the need
nee
e d for clos
ose mo
close m niito
tori
ring
monitoringng ooff seru
se
erum
serumm ppotassium
otaass
ssiu
ium
ium after
a terr an eepisode
af piso
pi sode
so
of acutee dec
ecom
mpensat
ated heart ffailure.
at
decompensated aiilure.
x In aaddition,
ddit
ddi io
it ionn, they
the
heyy suggest
sugg
su ggges
estt that
that ma
ain
inta
taain
inin
i g serum
in
maintaining seru
seruum po
pota
tass
tassiu
ss ium
potassium m levels
levvels
le ls within
wit
ithi
hinn normal
hi norm
normal
a range
al ran
ange
ge
may bbe considered
id d a therapeutic
th ti target.
t t
3
The risk of mortality after hospitalization for acute heart failure (HF) remains high.1-3 The most
recent European data (ESC-HF pilot study) show that patients hospitalized with HF had 12-
month all-cause mortality rates of 17%.4 Common risk scores only include a one-time (or
baseline) assessment, neglecting important changes in risk over time,5,6 which are especially
common after an episode of acutely decompensated HF.1-6
Serum potassium disturbances are frequent in patients with HF and, to some extent,
associated with common comorbidities and usage of treatments such as diuretic therapy,
potassium supplements, and renin-angiotensin-aldosterone system (RAAS) blockers, including

the combination of angiotensin II receptor blockers (ARB) and neprilysin inhibitors.7 The
prognostic implications of a single measurement of serum potassium in patients with

witth chronic
chro
chr ni
ro nicc and
and
acute HF have been evaluated in previous studies with heterogeneous findings.8-10 However, to
the
he best of our knowledge, no studies have specifically addressed the long-term prognostic
significance
ign
nif
ificance off serum
seru
rum potassium
poota
tass
s iu
um monitoring
monito
mo toring and
n ddynamics
nd ynam
mic
icss in a ttruly
ruly
ruly
l lon
longitudinal
ongitu
udi
dina
nall se
na ssetting.
ttin
i g.
in
Acco
Accordingly,
cordingly, tthis
co hiis st
stud
study
dy wass ddesigned
esigned tto
o fill this
thhis gapp in knowledge
kno
n wl
w edgge by evaluating
evalluating ann unselected
ev unnselected
ed
cohort of patients discharged

dis
i ch episode
harged after an epi
isode
d of acute HF.
Methods
Study group and protocol
The data, analytic methods, and study materials will not be made available to other researchers
for purposes of reproducing the results or replicating the procedure.
We analyzed 2642 patients consecutively discharged after admission for acutely
decompensated HF between January 1, 2008, and July 1, 2016 from a single center. Diagnosis of
HF decompensation was defined as the rapid onset of symptoms and signs secondary to
4
abnormal cardiac function and the presence of objective evidence of structural or functional
abnormality of heart at rest (such as cardiomegaly, third heart sound, cardiac murmur,
abnormality of the echocardiogram or raised natriuretic peptides). The current study was
restricted to patients discharged alive from the hospital and followed long-term in an outpatient
HF clinic. After excluding 234 in-hospital deaths during index admission and 244 patients with
ambulatory follow-up elsewhere, the final study sample included 2164 patients (Supplementary
file 1). Data were collected on patient demographics, vital signs and physical examination at
presentation and discharge, medical history, laboratory tests, 12-lead electrocardiogram,

echocardiogram, and medications during the index hospital stay and in outpatient visits or
ubsequent hospitalizations for HF decompensation.

subsequent
Left ventricular ejection fraction (LVEF) was assessed by echocardiography (Agilent
Sonos 5500-Philips and ie33-Philips) during the index hospitalization in all patients. Treatment
with
h angiotensin
angiotenssin
n converting
con
o ve
v rttin
ingg en
enzy
zyme
zyme inh
enzyme nhibitorss (A
inhibitors (ACCEI)), ARB,
(ACEI), ARB,
B beta-blockers,
betta-
a bl
b oc
ocke
k rss, mi
mine
nera
ner lo
oco
ort
rtic
iccoi
mineralocorticoidoid
eceept
p or antag
receptor gon
onisstss (MR
antagonists M A)), diuretics, aanticoagulants,
(MRA), nticoaagulaants,
s, and
and other
oth
ther ttherapeutic
herape
peuttic
tic strategi
giess w
gi
strategies ere
were
ndividualized following
individualized follo
l wiing established guide
d lines during the study
guidelines d period.
Potassium measurements
Serum potassium was measured by indirect potentiometry using an ion-selective electrode. The
first measurement was assessed at discharge with further measurements taken during routine
clinical visits and subsequent hospitalizations. Using standard cut-off points, three groups were
created (K-3C): hypokalemia (<3.5 mEq/L), normokalemia (3.5 to 5.0 mEq/L), and
hyperkalemia (>5 mEq/L). In addition, a 7-category variable (K-3Cch) was created to include the
following changes in K-3C among two consecutive observations of the same patient (i.e., using
the previous observation as reference): 1) normokalemia-to-normokalemia, 2) normokalemia-to-
5
hypokalemia, 3) normokalemia-to-hyperkalemia, 4) hypokalemia-to-hypokalemia, 5)
hypokalemia-to-normokalemia/hyperkalemia, 6) hyperkalemia-to-hyperkalemia, and 7)
hyperkalemia-to-normokalemia/hypokalemia.
Post-discharge follow-up
Patients who died during index admission and those with no further follow-up were excluded
from this analysis. For the remaining cohort, patient follow-up continued until death or cardiac
transplant. After the index hospitalization, potassium measurements were made under the clinical
settings of a new hospitalization (34.7%) or as an outpatient visit (65.3%). The number of visits
with a serum potassium measurement, including index admission, was 16,116, and ranged from
2 to 78, with a median of 5. The chronological distribution of the number of measu

sure
reme
rement
mentss wa
nt
measurements was:
14,088 (87.4%) during the first year; 15,495 (96.1%) during the first two years; 15,877 (98.5%)
by three yyears;
ears; and 16,077 (99.8%) by five years.
Surv
rviival outcome
rv
Survival outco
ome
All-
-ca
c use mort
All-cause rttal
alitty w
mortality ass sele
was ected as thee m
selected ain endpoint.
main endpo
poin
nt. Secondary
Sec
econndary
y endpoints
endppoint
nts included
nt includded
cardiovascul
lar, HF
cardiovascular, F-related, and sudd
HF-related, d en ddeath.
sudden eath
h. Ca
C use of death was categorized followi
Cause ing the
following
classification used by the American Heart Association. Deaths of cardiovascular etiology
included sudden death, progressive HF death, deaths attributable to other cardiovascular causes
(such as myocardial infarction, stroke, etc.), and unknown cause of death. Sudden death was
defined as the event that occurred unexpectedly in an otherwise stable patient, and progressive
HF death when it occurred in the setting of progressive clinical deterioration of HF symptoms
with no other apparent cause.11 Information regarding patients’ survival status was ascertained at
each hospitalization, during office visits, or through a review of electronic medical records.
Investigators in charge of endpoint adjudication were blinded to medical information, including
6
serum potassium status. This study conforms to the principles outlined in the Declaration of
Helsinki and was approved by an institutional review committee.
Statistical analysis
Continuous variables are expressed as mean ± standard deviation (SD) or median (interquartile
range [IQR]). Discrete variables are presented as percentages. Baseline characteristics among
hypokalemia, normokalemia, and hyperkalemia were compared by ANOVA, Kruskall–Wallis, or
chi-squared tests as appropriate.
Multilevel survival analysis.

Multilevel survival analysis was used to combine the longitudinal (repeated-measures) and
urvival (time-to-event endpoint) aspects of the data. We fit a two-level model wi

survival ith
h ppatient
with atie
at ient
ient
dentification as random effects and the log (follow-up time) as a random coefficient. For the
identification
urvival portion
survival portion of the model, we used a Weibull distribution. The main exposures were: 1)
pota
assium values
potassium valu
ues (continuous),
(co
c nt
n in
nuo
u uss), hereafter
her
erea
e fter
er referr
red
e tto
referred o ass ccumulative
umul
um ulativ
ul iv
ve po
pota
ass
s ium
m (Kcu
potassium tiivee), tto
cumulative
umu
m lati o
stress
treess that is not
ot a single
singl
gle measurement
meeasurement bbut
ut the eentire
ntiire ccollection
olle
ol lect
lectio
ionn off ppotassium
otaass
ssiu
um valuess per
peer patien
patient
nt
that
hat are mode
modeled,
d led, 2)
2) K-3C categories,
K 3C categorie
K- i s, and 3)) K-3C
Cch as the temporal category cha
changes
h nges in K-3
K-3C
3C
relative to the previous observation. Regression estimates are presented as hazard ratios (HRs)
with 95% confidence intervals (CIs).
We selected explanatory variables for the multivariable regression model, with subject-
matter knowledge as the main criterion. Starting with this initial (oversaturated) model,
backward elimination was applied to exclude variables with p0.1. For our continuous exposure
(i.e., Kcumulative), we determined its appropriate functional form using the multivariable fractional
polynomial (FP) method.12 A 4-df FP of (-2 -1) was the best transformation suggested, which
relates the continuum of Kcumulative to the risk of mortality through a U-shaped curve with higher
7
risk observed at both ends. Any decision about the use of random intercept, random coefficient,
and the polynomial that best describes the functional form for Kcumulative was based on likelihood
ratio test comparisons. The type of distribution for the parametric survival function was
determined with the AIC/BIC criteria. The same set of covariates was used for the Kcumulative, K-
3C, and K-3Cch models: age (years), systolic blood pressure (mmHg), heart rate (bpm) at
baseline, LVEF (<40%, 40-DQG) at baseline, anemia using Centers for Disease
Control (CDC) criteria (0/1), estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2
(0/1), lymphocyte count <1500 x 103 FHOOVP/VHUXPVRGLXPP(T/EDVHOLQHEHWD-
blockers (0/1, baseline), logNT-proBNP (pg/mL), plasma antigen carbohydrate 125 (CA125)
>35 U/mL (0/1), NYHA class (I, II, III/IV) at baseline, Charlson Comorbidity Index
Inddex
x at
at baseline,
base
bas li
selinne,
use of potassium-modifying treatments (none, MRA, ACEI/ARB, and both) at baseline, and the
log
og of follow-up time (years). All model estimates for all-cause mortality are presented in
Supp
ppllementaryy file
pp
Supplementary f lee 2. A dy
fi ddynamic
naami
micc di
discri
rimi
m nation
o index
on
discrimination ind
ndex
x (DDI)
(DD
DDI)
I) was
was estimated
est
s im
mated
d as
as a measure
m assur
me uree of
mode
del discrimi
de
model m natioon index
mi
discrimination inndex
x in
in the setting
settin
ng of data
dat
a a with
at w th
wi h longitudinally-updated
lon
ongi
gitu
ituddinaally-uupd e-statuss.1133
p ated exposure-status.
expos
osur
os ure-
The global D
DDI
DI off the fi
ffinal
nal modell was 0.
00.802,
802,
2 revealing an excellent performance.
Multistate analysis
Using Multistate Markov model (MSM) with continuous time,14 we determined the
instantaneous transition hazards (iTH) - and their respective 95% CI - among K-3C categories.
Because the same patient can be in different states at follow-up, the summary data is presented as
patient-visits (P-Vs). These transitions were adjusted by gender, eGFR-time-varying <60
mL/min/1.73 m2 (0/1), diabetes mellitus – time-varying (0/1), and the use of potassium-
modifying treatments (none, MRA, ACEI/ARB, and both) at baseline. From all possible
transitions, we focused on the ratio of the following two: iTHr1 = [hypokalemia-to-
8
normokalemia] / [normokalemia-to-hypokalemia] as surrogate of the relative frequency of
becoming normokalemic (from a previous hypokalemic state) vs becoming hypokalemic from
previous normokalemia; and iTHr2 = [hyperkalemia-to-normokalemia] / [normokalemia-to-
hyperkalemia] as surrogate of the relative frequency of normalization from a previous
hyperkalemic state vs becoming hyperkalemic from previous normokalemia.
We set a two-sided p-value of <0.05 as the threshold for significance. Within Stata 14.2
(Stata Statistical Software, Release 14 [2015]; StataCorp LP, College Station, TX, USA), the
main longitudinal analysis was performed with “mestreg”, a module that allows multilevel
modeling to be combined with a parametric analysis of survival-time outcomes. For the
M””13 an
estimation of DDI and the MSM longitudinal transitions analysis, we used the “JM” andd
“msm”14 R-packages, respectively

y [R Core Team (2017). R: A language and environment for
statistical
tatistical computing. R Foundation for Statistical Computing, Vienna, Austria. URL
http
https://www.R-project.org.
ps:
s://www.R
R-pprooje
j ctt.oorg
rg.
Results
The study sample included 2164 patients (50.4% males) with a total of 16,116 potassium
observations. The mean age was 73±11 years. Left ventricular systolic dysfunction (LVEF<40%)
was present in 31.2% of the patients, mid-range ejection fraction (LVEF 40-49%) in 15.6%, and
presHUYHGHMHFWLRQIUDFWLRQ/9()LQ.2%. The index admission was the first admission
ever for acutely decompensated HF in 38% of the patients. The mean discharge potassium level
was 4.3±0.48 mEq/L. At the index hospitalization, hypokalemia, normokalemia, and
hyperkalemia were observed in 77 (3.6%), 1965 (90.8%), and 122 (5.6%) patients, respectively.
Table 1 shows the baseline characteristics of the studied population relative to these three strata.
9
Overall, hyperkalemia at baseline was more frequent in association with older age, diabetes,
prior dyslipidemia, ischemic heart disease, worse NYHA class, greater comorbidity, lower
systolic blood pressure, higher heart rate, greater renal dysfunction, other electrolytic
disturbances, and less frequent treatment with ACEI/ARB and beta-blockers. On the other hand,
hypokalemia was more frequent in association with HF with preserved ejection fraction
(HFpEF), and in patients receiving more intensive depletive regimens.
During a median follow-up of 2.79 years (IQR 1.28, 4.91), 1090 patients died (50.4%),
which is a mortality rate incidence of 15% person-years and a median survival of 4.96 years. Of
these deaths, 781 (71.7%), 345 (31.7%), and 78 (7.2%) were cardiovascular in origin, HF-
elated, and sudden deaths, respectively.

related,
Observed K-3C transitions (no adjusted)
Of a total of 16,116 observations (P-Vs), 14,292 (88.7%) 1,260 (7.8%), and 564 (3.5%)
corrres
esponded tto
corresponded o no
orm
rmok
okal
ok alem
al em
mia
normokalemia, ia,, hyperkalemia,
hype
hyp rkkal
a emiaa, an
aandd hypokalemia,
hyypo
poka
kale
kalemi
lem a,, rrespectively.
mi espe
es pect
c ivel
ely.
el y. An obse
An s rv
se rvat
atio
at ionn of
io
observation
norm
rm
mokalemiaa w
normokalemia as fol
was llo
owedd by hypokalemia,
followed hyppokal
alemia, nnormokalemia,
orm
rmokkal
alem
e ia
em ia, andd hyperkalemia
hypeerkal
alemia onn 13
al 32 (0.92%
132 2%),
(0.92%),
(83.33%), andd 37
11,899 (83.3%), 372 (2.6%) occasions. An
A obs
b ervation of hy
observation hhypokalemia
pokalemia was followed by
hypokalemia (no change), normokalemia, and hyperkalemia on 352 (62.4%), 135 (23.9%), and 8
(1.4%) occasions. An observation of hyperkalemia was followed by hypokalemia,
normokalemia, and hyperkalemia (no change) on 3 (0.24%), 293 (23.3%), and 758 (60.2%)
occasions.
Long-term potassium monitoring (Kcumulative)
Risk-gradient trajectory was independently associated with mortality through a U-shaped
association (Figure 1). Values at both ends of Kcumulative were indicative of higher mortality risk
(overall p=0.001). Some snapshot comparisons at the lower side indicated that Kcumulative values
10
of 2.5, 3.0, and 3.5 mEq/L equated with HRs of 7.09 (95% CI:2.31-21.78), 1.86 (95% CI:1.18-
2.91), and 1.12 (95% CI:0.93-1.36), respectively. On the upper side, values of 5.0, 5.5, and 6.0
mEq/L were associated with HRs of 1.18 (95% CI:1.00-1.38), 1.39 (95% CI:1.05-1.84), and 1.67
(95% CI:1.12-2.496), respectively. Similarly, the adjusted-association between Kcumulative with
cardiovascular (Figure 2a) and HF-related mortality (Figure 2b) follows a similar non-linear
relationship. For sudden death, however, the association is best described as positive, with higher
risk along the continuum of Kcumulative (Figure 2c).
Long-term potassium dynamics (K-3C and K-3Cch)

Hypokalemia and hyperkalemia – with normokalemia as a reference – were independent
predictors of mortality (Omnibus p-value=0.0003) with HRs of 2.35 (95% CI:1.40-3.93,

CI:1.440-
0-3.
3 93
3. 93,,
p=0.001) and 1.55 (95% CI:1.11-2.16, p=0.011), respectively. Figure 3 depicts the adjusted
survival
urvival probabilities
probabilities for each of these categories. We found no significant interactions between
hypo
pokkalemia an
po
hypokalemia and hy
hype
erkkal
alem
em
mia aamong
hyperkalemia mongg tthe
mo he mos
o t im
os
most mport
r an
rt antt clinical
important clin
cl i ic
icaal
al subgroups:
sub
ubgr
g oups
ps:: age,
ps age, gender,
gen
ende
ender,
de r
r,
diab
betes, ischem
diabetes, emicc eetiology,
em
ischemic tiol
ology,, rrenal
enal dys
y fuunctionn, aand
dysfunction, ndd LV
VEF ((Figure
LVEF F guree 44).
Fi ). S im
mil
ilar
a ly, noo ssignificant
Similarly, ig
gnificannt
nteractio
i ns were fo
interactions ffound
undd among baseline treatments (MRA and/or
and/o
/ r AC
A EI/A
/ RB
ACEI/ARBB use) or potassium
categories (hypokalemia and hyperkalemia, Figure 4).
The association of K-3C changes - from previous status – and mortality was determined
by estimating and plotting the adjusted survival probabilities of 4 groups of interest: Group 1:
persisting hypokalemic; Group 2: normalization from hypokalemia; Group 3: persisting
hyperkalemic; and Group 4: normalization from hyperkalemia. Patients at lower risk during
follow-up were those that remained within range of normokalemia (groups 2 and 4), whereas
patients with persisting hypokalemia (group 1) or persisting hyperkalemia (group 3) had the
worse prognosis (Figure 5).
11
Multistate analysis
The primary result from the multivariable-adjusted multistate analysis is presented in
Supplementary Figure 3. Indeed, the instantaneous transition rate from hypokalemia-to-
normokalemia is 38-fold the transition from normokalemia-to-hypokalemia; this means that it is
38-fold times more likely that a hypokalemic patient will become normokalemic than the
opposite. Similarly, it is 12-fold more likely that a hyperkalemic patient will become normal than
the opposite.
Discussion
To the best of our knowledge, this study is the first to evaluate the prognostic imp
pli
lica
cati
cat on
onss of the
implications the
ong-term longitudinal monitoring and dynamics of serum

long-term r potassium in HF. An important
finding was that the time-driven history of serum potassium exhibited adequate performance in
pred
dic
icting long-
predicting g-term
g- rm aall-cause
long-term l -ca
ll caus
causee mo
mort
rtal
rt a itty,
mortality,y either
eitheer modeled
mo
odeleed as a con
onntinu
tinu
n ouus variable
continuous vaari
riab
able
able or
or ca
ateego
gori
rize
ri
categorizedz d
ze
nto
o hypokalemia,
into hypokalem
mia
i , nnormokalemia,
orm
rmokaale
alemia, or hyp
yperkaleemia.
a. T
hyperkalemia. hiss ppredictive
hi
This red
ediictive
ve ability
abiiliity
y remained
remaineed after
aftter
af
adjusting for a comprehe

h nsive set of longitudinal
comprehensive longitudi
d nal and baseline prognosti
icators. Furthermore,
prognosticators.
when modeled as a continuous covariable, the prognostic relationship between serum potassium
and death exhibited a non-linear association, resembling a U-shaped curve with higher risk at
both ends of the distribution. Notably, the association between potassium levels and mortality
risk was confirmed for hypokalemia and hyperkalemia when potassium was categorized. When
analyzing the associations between potassium dynamics and death, patients who persisted with
hypokalemia or with hyperkalemia had significantly higher mortality risk, and the results were
similar for cardiovascular and HF-related deaths and consistent in the most representative
12
subgroups of the disease. In contrast, transitioning from hypokalemia or hyperkalemia to
normokalemia was associated with lower risk throughout the follow-up.
Several studies have evaluated the prognostic role of a single measurement of serum
potassium in different cardiovascular scenarios. Regarding chronic HF, several studies reported
that low serum potassium levels are associated with higher mortality.15-17 Regarding
hyperkalemia, in the Randomized Aldactone Evaluation Study (RALES) trial, the beneficial
effect of spironolactone was observed irrespective of potassium levels in the treatment arm
(4.54±0.49 mEq/L vs. 4.28±0.50 mEq/L, p<0.001), even though a U-shaped relationship
between potassium levels and mortality was reported in both the spironolactone and the placebo
group, with higher risk at potassium levels >5.5 mEq/L.18 In the Eplerenone in Mi
Mild
ld
dPPatients
atie
at ient
ientss
nt
Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF) trial, worsening renal
function and hyperkalemia (>5.5 mmol/L) were interrelated and

d associated with poor outcomes,
dw
and ere moree ffrequent
were req
equeent
eq n w h n ep
he
when eple
lere
lerenoone
re n (comp
eplerenone m arred too placebo)
mp
(compared p ac
pl aceb
e o) was aadded,
was d ed
dd d, al
aalthough
thou
tho gh
ou h th
hei
eirr
their
occurrence
occu
cu
urrence did
d nnot
ott eeliminate
limi
m natte the surviva
survival
val benefit
beneefi one.199 IInn contrast,
fit of eplerenone.
epl
pler
pl eren
er enon co
ontraast, otherr rrecent
ece
cent stu
studies
udies
failed to show an in
iindependent
dependent association between hyperkalemia and the
th
he riskk of mortal
mortality
lity in
HF.20 In the setting of acutely decompensated HF, evidence is even more scarce and conflicting.
By combining data from two large cohorts of patients with acute HF (Patients Hospitalized with
Acute Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal
Function [PROTECT] trial, and Coordinating Study Evaluating Outcomes of Advising and
Counseling Failure [COACH] trial), Tromp, et al. found that patients with higher serum
potassium levels had worse baseline risk profiles and outcomes. However, this association was
no longer significant after multivariable adjustment.21 Other authors also reported a neutral
prognostic association,22 and a recent study suggested better outcomes associated with serum
13
potassium during hospitalization.23 Most of these studies focused on the prognostic implication
of a single measurement or changes occurring during hospitalization, ignoring the potential
implications of long-term changes over time.
In the present study, hyperkalemia identified a subset of patients with worse baseline risk
profiles and less intense neurohormonal treatment at baseline, similar to the findings from prior
studies in acute HF.21 On the other hand, patients with hypokalemia had more intense diuretic
therapy, perhaps indicating greater fluid overload. Therefore, the question of causality arises as
to whether risk associated with low or high potassium levels is the result of harm related to
disruption of potassium homeostasis or rather the result of confounding factors associated with
or having led to serum potassium changes. Although residual confounders may ne

eve
verr bee
never
completely controlled for in observational studies, one major feature of the present analyses is
he extensive state-of-the-art multivariable adjustment that has been performed, including

the
anal
a yses of trad
al
analyses adiitio
ad ona
n l ba
traditional ase
s line
ne aand
baseline nd ttime-updated
im
me-update
t d pr
te prog
gno
nost
stic
st icat
ic a or
orss. Ti
prognosticators. T me-v
me- arryi
ying
Time-varying ng ppotassium
o asssiium
ot
valu
ues were as
values sso
sociiated
associated d withh tthe
he risk off m ortaliity inn a U-shaped
mortality U-sha
-sshape
ped ma
manner
r. This
manner. Thi is consistent
cons
nsissteent with
ns witth
previous reports, although with less extensive adjustments, in patients with acute myocardial
infarction and hypertension.24,25 These findings suggest that both ends of the potassium
distribution may play a causative role in the development of clinical complications.15,16
Hypokalemia is well-known to lengthen the action potential, increase QT dispersion, and
favor a substrate of electrical inhomogeneity.15 However, we failed to find an association
between low potassium levels and the risk of sudden death. The most likely explanation is
insufficient statistical power due to the small number of events. Perhaps an alternative, or even
contributing factor, may be that half of the patients were categorized as HFpEF and better
adapted to chronic hypokalemia.26 Other evidence supports a causative role of hypokalemia in
14
processes linked to HF progression, such as peripheral muscle dysfunction, rhabdomyolysis,
impaired vasodilation, myocardial diastolic dysfunction, atherosclerosis, and diuretic
resistance.26,27
On the other side of the spectrum, hyperkalemia is a risk factor for asystole, ventricular
fibrillation, and/or cardiac arrest.24,28 However, we found that hyperkalemia characterizes a
subset of patients with more advanced disease and less intense treatment recommended by
guidelines.15,21 Therefore, excess risk is likely to be not only the result of the electrophysiological
effects of hyperkalemia per se, but also the result of comorbidities favoring the development of
hyperkalemia (such as poor renal function) as well as, possibly, a consequence of under-dosing
or discontinuation of RAAS inhibitor lifesaving therapy by physicians faced with

h the
the
development of hyperkalemia in their patients.
From the clinical perspective, and as suggested by current guidelines, the association
betw
ween serum
between m po
pota
taasssiu
potassiumium
m an
andd mo
mort
rtal
rt a itty foundd in
mortality i our
our study
stu
tudy
dy reinforces
rei
e nf
nfor
orce
or c s the
ce th need
neeed ffor
or its cclose
lose
los
se
moni
nito
ni t ring in patients
monitoring patiienntss with
with HF.
HF. Thus, it
it seemss advisable
advi
visaabl
blee to
to include
include
de thee m easuremeent off
ea
measurement
potassium in every labb assessment.
Based on our results, we encourage keeping serum potassium levels within normal range
as a critical therapeutic target. In patients with hyperkalemia, a complete withdrawal or down-
titration of RAAS inhibitor together with dietary potassium restriction should be the first-line
treatment choice in non-urgent situations.15 The use of potassium-binding resins may be
recommended, though they are not usually well tolerated.15 Recently, patiromer (a non-absorbed
potassium-binding polymer) and sodium zirconium cyclosilicate (an inorganic oral potassium-
binding polymer) have emerged as novel therapeutic agents with demonstrated efficacy and
acceptable safety and tolerability profiles with applicability to different cardiovascular
15
situations.15 What remains to be demonstrated is the efficacy and safety of these drugs in patients
with chronic HF, and whether their preventive use may mitigate the risk of hyperkalemia while
enabling RAAS inhibitor therapy optimization. In contrast, when mild hypokalemia is present,
up-titration of RAAS inhibitors, especially MRA therapy, and down-titration of loop diuretics
and thiazides is recommended in cases with euvolemia. In patients with persistent fluid overload
and in those with more severe hypokalemia, the use of potassium supplements may also be an
option.16 However, randomized studies evaluating the safety and efficacy of these different
strategies for the treatment of hypokalemia are lacking.

The current report has strengths and limitations that need to be addressed. In contrast to
most current evidence based on the assessment of a single potassium measuremen

measurement,
nt, tthis
h s st
hi stud
study
udyy is
ud
based on truly longitudinal data with repeated potassium measurements. The advantages of this
type
ype of design include increased statistical power and, most importantly, a more accurate and
eall-l
-liife approa
real-life ach tto
approach o th
he pr
the prog
oggno
nost
stic
st
prognostic ic iimpact
mp
pac
a t of ppotassium
o as
ot assium
um
m disturbances
dis
istu
turbban
tu nce
c s in HF.
F. By uusing
s ngg aall
si ll ddata
ataa
at
andd nnot
ot limiting
ng the
he analysis
ana
nalysiss to a single
singl
g e measurement,
measuurem
emeent,
t, we
we provide
prov
ovidee a more
mo
ore comprehensive
coompreh
hen
enssivve
dynamic assessment off the association between serum potassium and mortali
mortality.
ity.
A number of limitations need to be pointed out. First, an important limitation of this
study is that it is observational and, as such, prone to bias due to unmeasured confounding.
Second, the potential for ascertainment bias induced by informative drop-out was minimized by
using a joint modeling regression approach of the longitudinal and survival portion of the data,
but cannot be completely accounted for. Third, as a single center study, the generalizability of
these results to other populations needs to be evaluated. This is especially true, given the high
baseline risk and mortality found in this registry. Fourth, the lack of follow-up information on
several clinical variables, including treatments, precludes their use as covariables in a time-
16
varying manner; not having all therapeutic changes along the follow-up precludes an accurate
evaluation of the interaction between RAAS inhibition/potassium supplements and the exposure.
Finally, some performance metrics (reclassification) are lacking because methodology does not
yet exist for repeated-measure/survival data.
Conclusions
In a large non-selected cohort of patients discharged from an episode of acutely decompensated
HF, low as well as high serum potassium levels – measured in a time-varying setting - were
associated with higher risk of mortality through a U-shaped trajectory. Likewise, when modeling
potassium as clinical categories, we found that patients with hypokalemia or hyperkalemia also
had
d a higher risk of mortality. Analysis of potassium dynamics revealed that the persistence
perrsi
s st
sten
e ce
enc ooff
hypokalemia or hyperkalemia at follow-up identified a subset of patients with high mortality risk
compared with those who persisted or became normokalemic. Appropriately designed trials of
traateegies aimed
strategies aimeed att maintaining
mai
a nt
ntai
a ni
ai n ng normokalemia
nor
ormo
m ka
kalemiaa and
a d nott compromising
an comp
compro
mpr miisiing the
the
h use
se of
of guideline-
guidel
gu e in
el ne-
eco
ommended lifesaving
recommended liife
fesaaviing therapy
theerapy are w arranted
d.
warranted.
Disclosures
J.N. received board membership fees and travel expenses from Novartis, Roche Diagnostics,
Abbott, Rovi, and Vifor. A.B.-G. received board membership fees and travel expenses from
Novartis, Roche Diagnostics, and Critical Diagnostics. F.Z. received personal fees (Consultancy;
DSMB; Steering Committees; Speaker fees) from: Actelion, Amgen, AstraZeneca, Bayer,
Boehringer, Boston Scientific, CEVA, CVRx, Vifor-Fresenius, GE Healthcare, J&J, KBP
BioSciences, Livanova, Mitsubishi, Novartis, NovoNordisk, Pfizer, Quantum Genomics,
Relypsa, Resmed, Roche, Takeda, ZS Pharma, Founder: CardioRenal, CVCT. PR received
17
Personal fees (consulting) from Bayer, Grünenthal, Novartis, Relypsa, AstraZeneca, Stealth
Peptides, Fresenius, Vifor Fresenius Medical Care Renal Pharma, and CTMA; lecture fees from
CVRx; cofounder CardioRenal. G.M. received speaker fees from Abbott. J.L.G. received board
membership, speaker and consulting fees from Astrazeneca, Vifor Fresenius medical Care Renal
Pharma. OH received speaker fees from Roche. M.M. received consulting honoraria from
Amgen, Bayer, Novartis, and Servier, and speaker’s fees from Abbott Vascular, Bayer, and
ResMed. J.S. has received speaker fees from Astra-Zeneca, Abbott, and Edwards Lifesciences.
All other authors declare no conflict of interest.

Sources of Funding
This work was supported by grants from Centro de Investigación Biomédica en Red de
Enfermedades Cardiovasculares (16/11/00420, 16/11/00403), Fondo Europeo de Desarrollo
Regi
gioonal and Proyecto
gi
Regional Proyyec
Pr e to
o Integrado
Int
nteg
e ra
rado
do de
de Excelencia
Ex
xce
c lencia
i (PI
ia PIE155/0
/000
0013
00 1 )..
13
(PIE15/00013).
Re
R f rences
fe
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Circulation. 1992;85:I70–I76. PMID: 1728508.
21
Table 1. Baseline characteristics
K <3.5 mEq/L K 3.5 – 5.0 K >5.0 mEq/L All sample p-

Variables (n=77) mEq/L (n=122) (n=2164) value
(n=1965)
Demographics and medical history
Age, years 72 ±12 73±11 76±9 73±11 0.003
Male, n (%) 34 (44.2) 979 (49.8) 77 (63.1) 1090 (50.4) 0.009
Hypertension, n (%) 66 (85.7) 1557 (79.2) 99 (81.1) 1722 (79.6) 0.348
Diabetes, n (%) 37 (48.1) 871 (44.3) 87 (71.3) 995 (46.0) <0.001
Dyslipidemia, n (%) 46 (59.7) 1007 (51.2) 77 (63.1) 1130 (52.2) 0.016
Smoker, n (%) 9 (11.7) 231 (11.8) 9 (7.4) 249 (11.5) 0.339
Former smoker, n (%) 19 (24.7) 458 (23.3) 43 (35.2) 520 (24.0) 0.011
Ischemic heart disease, n (%) 25 (32.5) 721 (36.7) 72 (59.0) 818 (37.8) <0.001
Valvular heart disease, n (%) 23 (29.9) 582 (29.6) 34 (27.9) 639 (29.5) 0.917
NYHA class III/IV†, n (%) 6 (7.8) 320 (16.3) 37 (30.3) 363 (16.8) <0.001
Charlson comorbidity index, n <0.001
(%)
0 20 (26.0) 421 (21.4) 10 (8.2) 451 (20.8)
1-2 29 (37.7) 975 (49.6) 28 (23.0) 1032 (47.7)
3-4 22 (28.6) 409 (20.8) 47 (38.5) 478 (2
(22.1))
>4 6 (7.8) 160 (8.1) 37 (30.3) 203
20
03 (9.4)
(9.4
(9 .4
4)
Vital signs on admission
Heart rate, bpm 99±25 99±28 93±27 99±28 0.064
SBP, mmHg 154±38 149±33 136±30 149±33 <0.001
DBP, mmHg 87±21 82±19 74±18 82±19 <0.001
Electrocardiogram
ocardiiog ogrramm
Atrial fibrillation,
fibriill
llat
ation, n ((%)
at %) 40 (51.9) 852 (43.
(43.4)
3.4) 52 (42.6)
(42.6) 944 (43.6) 0.321
LBBB,, n (%) (%%) 26
6 (33.8)
(33.8)
8) 607
60
07 (30.
(30.9)
0.9) 45
5 (36.9)
(36
36.9)
9 678
67 8 (31.
(31.3)
1.3)
3) 0.343
Laboratory
atooryy data
Hemoglobin,
globbinin, g/dL 12
12.3±1.8
2.3±1.8 12
12.6±1.9
2.6
6±11.9
9 11.6
11.6±2.1
6±2.1 12.5
12.5±1.9
.5±1
±1.9
9 <0.001
Anemia ia (CD
(CDC
CDC
CD C criter
criteria),
ria
ia),
), n (%)% 40
0 (51.9)
(51
5 .9)) 994
99 4 (50.
(50.6)
0.6) 85 (69.7)
(69.7) 1119
11
119
1 (51.7)
(51
51.7) <0.001
Lymphocyte
hocytte cou unt, x1003 cell
count, cells/mL
lls//mL 1517±954
1517
15 177±954 4 1764±1355
1
17764
6 ±135
64 3 5
35 1388±810
1
13 888±810
10 1734±1321
1734
17 34±1
±1132
3 1 0.003
hocyte count <1500 x103
Lymphocyte 52 (67.5)
(67 5) 1079 (54
(54.9)
9) 83 (68.0)
(68 0) 1214 (56
(56.1)
1) 0.002
cells/mL, n (%)
Creatinine*, mg/dL 0.91 (0.78-1.17) 1.10 (0.90-1.40) 1.50 (1.18-2.08) 1.10 (0.90-1.46) <0.001
eGFR, mL/min/1.73 m2 71±25 62±25 48±23 62±25 <0.001
eGFR <60 mL/min/1.73 m2, n (%) 22 (28.6) 963 (49.0) 93 (76.2) 1078 (49.8) <0.001
Serum sodium*, mEq/L 139 (136-141) 139 (137- 142) 137 (135- 139) 139 (136-142) <0.001
Serum sodium <135 mEq/L, n (%) 15 (19.5) 356 (18.1) 44 (36.1) 415 (19.2) <0.001
NT-proBNP*, pg/mL 3149 (1458-6827) 4316 (2318-7735) 6398 (2922-11918) 4342 (2321- 7980) <0.001
CA125*, U/mL 75 (27-149) 53 (24-124) 59 (28-142) 54 (24-125) 0.115
Echocardiography
LVEF, % 52±15 50±15 47±15 50±15 0.053
LVEF categories 0.221
<40%, n (%) 17 (22.1) 612 (31.1) 45 (36.9) 674 (31.2)
40-49%, n (%) 11 (14.3) 308 (15.7) 19 (15.6) 338 (15.6)
Q 49 (63.6) 1045 (53.2) 58 (47.5) 1152 (53.2)
Treatment at admission
Intravenous furosemide dose at 62.9±34.3 27.6±45.0 58.2±55.0 30.6±46.2 <0.001
admission, mg/day
Treatment at discharge‡
Furosemide, n (%) 65 (84.4) 1497 (76.2) 100 (82.0) 1662 (76.8) 0.093
22
Torsemide, n (%) 12 (15.6) 445 (22.6) 22 (18.0) 479 (22.1) 0.182

Hydrochlorothiazide, n (%) 10 (13.0) 124 (6.3) 6 (4.9) 140 (6.5) 0.050
Furosemide equivalent dose, mg/day 86±46 74±39 80±36 75±39 0.015
Spironolactone, n (%) 11 (14.3) 395 (20.1) 22 (18.0) 428 (19.8) 0.401
Eplerenone, n (%) 13 (16.9) 263 (13.4) 21 (17.2) 297 (13.7) 0.351
Aldosterone receptor blockers, n (%) 24 (31.2) 658 (33.5) 43 (35.2) 725 (33.5) 0.837
Oral potassium supplements, n (%) 32 (41.6) 131 (6.7) 2 (1.6) 165 (7.6) <0.001
Beta-blockers, n (%) 63 (81.8) 1275 (64.9) 86 (70.5) 1424 (65.8) 0.005
ACEI, n (%) 28 (36.4) 772 (39.3) 42 (34.4) 842 (38.9) 0.507
ARB, n (%) 29 (37.7) 572 (29.1) 25 (20.5) 626 (28.9) 0.029
ACEI or ARB, n (%) 57 (74.0) 1344 (68.4) 67 (54.9) 1468 (67.8) 0.004
NYHA: New York Heart Association; SBP: systolic blood pressure; DBP: diastolic blood pressure; LBBB: left bundle
branch block; eGFR: estimated glomerular filtration rate; NT-proBNP: amino-terminal pro-brain natriuretic peptide;
CA125: carbohydrate antigen 125; LVEF: left ventricle ejection fraction; ACEI: angiotensin-converting enzyme
inhibitor; ARB: angiotensin receptor blocker.
Values for continuous variables are expressed as mean ± standard deviation unless otherwise specified.
* Values expressed as median (interquartile range).
† Last NYHA under stable conditions, prior to admission.

‡Administered at discharge or during hospitalization in case of in-hospital deaths.
23
Figure Legends
Figure 1. A multivariable-adjusted analysis depicting the non-linear association between the
continuum of time-updated serum potassium values and the hazard ratios for all-cause mortality.
The shape of the curve was determined by modeling serum potassium with a fractional
polynomial with 4 degrees of freedom [-2 -1]. Shaded area represents the 95% CI, and were
centered at the median of potassium in the sample (4.3 mEq/l). Thus, any portion of the curve
above the y-scale reference line of 1 is statistically significant. The omnibus p-value for the
entire trajectory was p=0.0012.
Figure 2. A multivariable-adjusted analysis depicting the non-linear association between the
continuum of time-updated serum potassium values and the hazard ratios for specific causes of
deat
a h as outcom
at
death me. Shaded
outcome. S ad
Sh a ed area
areea re
repr
pres
pr e en
nts
t the 995%
represents 5% CI,, aand
nd we e ce
er
were cent
nterred
e att th
centered thee me
m dian
a ooff
an
median
pota
taassium in the
potassium he sample
sam
ampplee (4.33 mEq/l).
) Thus,
Thus, any
n portion
ny por
ortion
on of
of the
th curve
curv
rve above
ab
bovee the
the y-scale
y-sccalee reference
referenc
nce
ine of 1 is statistically significant. The omni

line ibus p-value associated
omnibus associiated
d to each trajectory was
included in the figure.
2a. Cardiovascular mortality: fractional polynomial with 4 degrees of freedom [-2 -2]
2b. Heart failure-related mortality: fractional polynomial with 4 degrees of freedom [-2 2]
2c. Sudden death: fractional polynomial with 2 degrees of freedom [-2]
CV: cardiovascular; HF: heart failure.
Figure 3. Adjusted survival probabilities associated with potassium categories. Omnibus p-
value=0.0003.
24
Figure 4. Subgroup analysis of serum potassium and all-cause mortality.
eGFR: estimated glomerular filtration rate; LVEF: left ventricular ejection fraction; MRA:
mineralocorticoid receptor antagonists; ACEI: angiotensin converting enzyme inhibitors; ARB:
angiotensin receptor blockers.
Figure 5. Adjusted survival probabilities associated with changes in potassium category.
Omnibus p-value<0.0001.
25
1
All-cause mortality
20.0
p=0.0012
djusted Hazard Ratios
10.0
0
5.0
Adjusted
2.0
A
1.0
2.5 3.5 4.5 5.5 6.5 7.5

Serum potassium, mEq/L
Risk-gradient trajectory centered at median potassium value of 4.3 mEq/L
2
2a CV death 2b HF death 2c Sudden death

10.00
p=0.0015 p=0.0038 5.00
10.0 20.0
2.00
Hazard Ratios
1.00
Adjusted Hazard Ratios
Hazarrd Ratios
10.0 0.50
5.0
d Hazard
Adjusted Hazard
0.10
5
5.
5.0
.0
djusted
Adjusted
Adjusted
2.0
0.0
0.01
2.0
0
A
1.0
1.0 p=0.0293
0.6 0.8
2.5 3.5 4.5 5.5 6.5 7.5 2.5 3.5 4.5 5.5 6.5 7.5 2.5 3.5 4.5 5.5 6.5 7.5
Serum potassium, mEq/L Serum potassium, mEq/L Serum potassium, mEq/L
Risk-gradient trajectory centered at median potassium value of 4.3 mEq/L
3
All-cause mortality
1.0
Potassium <3.5 mEq/L
Potassium 3.5 to 5.0 mEq/L
lative probability 0.9 Potassium >5 mEq/L
0.8
Cumulative
Cumul
0.7
p=0.0003
p=0.0003
0.6
06
0 1 2 3 4 5
Follow-up time, years
Subgroup analysis p-value for
Interaction
Hypokalemia vs. normokalemia
4 Age ≤ 75, years
Age > 75, years
Hyperkalemia vs. normokalemia p=0.730
Age ≤ 75, years
Age > 75, years
Female
Male
Female
Male
No Diabetes Mellitus
Diabetes Mellitus
No Diabetes Mellitus
Diabetes Mellitus
No ischemic etiology
Ischemic etiology
rkalemia vs. normokalemia
Hyperkalemia p=0.173
No ischemic etiology
Ischemic etiology
Hypokalemia
okalemia vvs. normokalemia
s. no
ormokalemia
eGFRR≥6 0 mL/
60 /min/1.73
mL/min/1.73 3 m2
m2
eGFR
eGFFR < 60 mL/min/1.73
mL/min 3 m2
n/1.73 m2
p=0.151
Hyperkalemia
rkallem normokalemia
mia vs. normokale emia
eGFR
eGFFR ≥ 60 mL/min/1.73
mL/min 3 m2
n/1.73 m2
eGFRR < 60
60 mL/min/1.73
mL/m min/1.73
3 m2
m2
okalemia vvs.
Hypokalemia s. no
ormokalemia
normokalemia
LVEF < 40%
LVEF 40-49%
LVEF ≥ 50%
p=0.895
Hyperkalemia vs. normokalemia
LVEF < 40%
LVEF 40-49%
LVEF ≥ 50%
No use of MRA
Use of MRA
No use of MRA
Use of MRA
No use of ACEI/ARB
Use of ACEI/ARB
p=0.500
Hyperkalemia vs. normokalemia
No use of ACEI/ARB
Use of ACEI/ARB
0.6 0.8 1.0 2.0 4.0 6.0 8.0 10.0
Hazard Ratios (95% CIs)

All-cause mortality
5 1.0
0.9
mulative probability 0.8
0.7
Cumulative
0.6
0 .6
6
um
0.5 Hypokalemia
Hy
ypokale
le
emi
mia to hypokalemia
hyp
yp
pokalem
mia
C
Hypokalemia
Hy
ypokalle
lemia to normokalemia
normoka
ale
emia
0.4
0.
.4 Hy
Hyperkalemia
yperkallem
emia
ia to hyperkalemia
hype
hy
ype
p rka
alem
emia
Hype
Hyperk
pe rkal
rk alem
al emia
em
Hyperkalemia ia to
to normokalemia
norm
no rmok
rm okal
ok alem
al emia
em ia
p<0.0001
p<0 0001
0.3
0 1 2 3 4 5
Follow-up time, years
Long-Term Potassium Monitoring and Dynamics in Heart Failure and Risk of Mortality
Julio Núñez, Antoni Bayés-Genís, Faiez Zannad, Patrick Rossignol, Eduardo Núñez, Vicent Bodí,
Gema Miñana, Enrique Santas, Francisco J. Chorro, Anna Mollar, Arturo Carratalá, Jorge Navarro,
Jose Luis Gorriz, Josep Lupón, Oliver Husser, Marco Metra and Juan Sanchis
Circulation. published online October 12, 2017;

Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 2017 American Heart Association, Inc. All rights reserved.
Print ISSN: 0009-7322. Online ISSN: 1524-4539
The online version of this article, along with updated information and services, is located on the
World Wide Web at:
http://circ.ahajournals.org/content/early/2017/10/11/CIRCULATIONAHA.117.030576
Data Supplement (unedited) at:

http://circ.ahajournals.org/content/suppl/2017/10/11/CIRCULATIONAHA.117.030576.DC1
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in
Circulation can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office.
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SUPPLEMENTAL MATERIAL
Supplemental figure 1 Flowchart for patient inclusion
and follow-up
AHF registry
N = 2642
N = 234 Death at the index

N = 2408
hospitalization
Discharged alive with no

Included in the study N = 244
further follow-up
N = 2164
or follow-up in other centers
Total person-visits = 16116 Death at follow-up = 1090

Visits per patient: median = 5, IQR (3 - 9) Median follow-up = 2.79 years; range (0.03 – 12.8)
Total person-years = 7344
2 visits = 296 patients (13.7%) Incidence rate = 0.148
3 visits or less = 583 patients (26.9%)
4 visits or less = 824 patients (38.1%) 25 percentile survival time = 1.74 years
5 visits or less = 1083 patients (50.0%) Median survival time = 4.96 years
75 percentile survival time = 9.76 years
Supplemental figure 2 Predictors of all-cause mortality
Age, per 5 years
SBP, per 20 mmHg
Heart rate, per 20 mmHg
Anemia
eGFR (MDRD) < 60 mL/min/1.73 m2
Lymphocyte count < 1500 x 103 cells/mL
Serum sodium ≤135 mEq/L
Beta-blockers
Log NT-proBNP pg/mL
CA125 > 35 U/mL
Potassium categories
<3.5 mEq/L
3.5 to 5.0 mEq/L
> 5 mEq/L
Potassium-modifiers
None
MRA
ACEI/ARB
Both
LVEF categories
< 40%
40-49%
≥ 50%
NYHA class
Class I
Class II
Class III or IV
Charlson’s index categories
n= 0
n=1 - 2
n=3 - 4
n≥ 5
Time variable (log-transformed)
log follow-up time (years)
0 1.0 2.0 4.0 6.0
Hazard Ratios (95% CIs)
Supplemental figure 3 Instantaneous transitions hazard rates and their respective ratios
Hypokalemia (prev) to Normokalemia (prev) to

RATIO 1 Normokalemia (after) Hypokalemia (after)
N=135 P-Visits N=135 P-Visits
iTH = 2.16; 95% CI (1.81-2.57) iTH = 0.06; 95% CI (0.05-0.07)
iTHr = 38.07; 95% CI (31.8-45.6)

P < 0.0001
Hyperkalemia (prev) to Normokalemia (prev) to

RATIO 2 Normokalemia (after) Hyperkalemia (after)
N=293 P-Visits N=372 P-Visits
iTH = 1.64; 95% CI (1.45-1.84) iTH = 0.14; 95% CI (0.12-0.15)
iTHr = 12.0; 95% CI (10.7-13.5)

P < 0.0001
SUPPLEMENTAL FIGURE LEGENDS
Supplemental figure 1. Flowchart for patient inclusion and follow-up.
AHF: acute heat failure
Supplemental figure 2. Model estimates for of all-cause mortality
SBP: systolic blood pressure; eGFR: estimated glomerular filtration rate; NT-proBNP: amino-
terminal pro-brain natriuretic peptide; CA125: antigen carbohydrate 125; MRA:
mineralocorticoid receptor antagonists; ACEI: angiotensin converting enzyme inhibitors; ARB:
angiotensin receptor blockers; LVEF: left ventricular ejection fraction; NYHA: New York Heart
Association
Supplemental figure 3. Instantaneous transitions hazard rates and their respective ratios.
iTH: instantaneous transitions hazard rates; CI: confidence interval; P-Visits: patient-visits.

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10.1161/CIRCULATIONAHA.117.

Long-Term Potassium Monitoring and Dynamics in Heart Failure

Julio Núñez, PhD1,2*; Antoni Bayés-Genís, PhD2,3*; Faiez Zannad, PhD4;

Address for Correspondence:

Background—The prognostic value of long-term potassium monitoring and dynamics in heart

Key Words: potassium; mortality; heart fail

accordingly, transitioning from hypo/hyperkalemia to normokalemia was independently

common after an episode of acutely decompensated HF.1-6

potassium supplements, and renin-angiotensin-aldosterone system (RAAS) blockers, including

prognostic implications of a single measurement of serum potassium in patients with

cohort of patients discharged

Study group and protocol

for purposes of reproducing the results or replicating the procedure.

We analyzed 2642 patients consecutively discharged after admission for acutely

presentation and discharge, medical history, laboratory tests, 12-lead electrocardiogram,

ubsequent hospitalizations for HF decompensation.

Left ventricular ejection fraction (LVEF) was assessed by echocardiography (Agilent

the previous observation as reference): 1) normokalemia-to-normokalemia, 2) normokalemia-to-

hypokalemia, 3) normokalemia-to-hyperkalemia, 4) hypokalemia-to-hypokalemia, 5)

hypokalemia-to-normokalemia/hyperkalemia, 6) hyperkalemia-to-hyperkalemia, and 7)

2 to 78, with a median of 5. The chronological distribution of the number of measu

classification used by the American Heart Association. Deaths of cardiovascular etiology

HF death when it occurred in the setting of progressive clinical deterioration of HF symptoms

Investigators in charge of endpoint adjudication were blinded to medical information, including

Helsinki and was approved by an institutional review committee.

hypokalemia, normokalemia, and hyperkalemia were compared by ANOVA, Kruskall–Wallis, or

chi-squared tests as appropriate.

Multilevel survival analysis.

urvival (time-to-event endpoint) aspects of the data. We fit a two-level model wi

with 95% confidence intervals (CIs).

patient-visits (P-Vs). These transitions were adjusted by gender, eGFR-time-varying <60

transitions, we focused on the ratio of the following two: iTHr1 = [hypokalemia-to-

normokalemia] / [normokalemia-to-hypokalemia] as surrogate of the relative frequency of

becoming normokalemic (from a previous hypokalemic state) vs becoming hypokalemic from

previous normokalemia; and iTHr2 = [hyperkalemia-to-normokalemia] / [normokalemia-to-

hyperkalemia] as surrogate of the relative frequency of normalization from a previous

hyperkalemic state vs becoming hyperkalemic from previous normokalemia.

modeling to be combined with a parametric analysis of survival-time outcomes. For the

“msm”14 R-packages, respectively

was 4.3±0.48 mEq/L. At the index hospitalization, hypokalemia, normokalemia, and

(HFpEF), and in patients receiving more intensive depletive regimens.

elated, and sudden deaths, respectively.

Observed K-3C transitions (no adjusted)

(1.4%) occasions. An observation of hyperkalemia was followed by hypokalemia,

Long-term potassium monitoring (Kcumulative)

Risk-gradient trajectory was independently associated with mortality through a U-shaped

(95% CI:1.12-2.496), respectively. Similarly, the adjusted-association between Kcumulative with

risk along the continuum of Kcumulative (Figure 2c).

Long-term potassium dynamics (K-3C and K-3Cch)

Hypokalemia and hyperkalemia – with normokalemia as a reference – were independent

predictors of mortality (Omnibus p-value=0.0003) with HRs of 2.35 (95% CI:1.40-3.93,

categories (hypokalemia and hyperkalemia, Figure 4).

persisting hypokalemic; Group 2: normalization from hypokalemia; Group 3: persisting

worse prognosis (Figure 5).

The primary result from the multivariable-adjusted multistate analysis is presented in

Supplementary Figure 3. Indeed, the instantaneous transition rate from hypokalemia-to-

normokalemia is 38-fold the transition from normokalemia-to-hypokalemia; this means that it is

ong-term longitudinal monitoring and dynamics of serum

adjusting for a comprehe

subgroups of the disease. In contrast, transitioning from hypokalemia or hyperkalemia to

normokalemia was associated with lower risk throughout the follow-up.

function and hyperkalemia (>5.5 mmol/L) were interrelated and

of a single measurement or changes occurring during hospitalization, ignoring the potential

Julio Núñez, PhD1,2; Antoni Bayés-Genís, PhD2,3; Faiez Zannad, PhD4;