(2014) Sodium and Cardiovas Risk

Lower Levels of Sodium Intake and Reduced Cardiovascular Risk
Nancy R. Cook, Lawrence J. Appel and Paul K. Whelton

Circulation. published online January 10, 2014;
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DOI: 10.1161/CIRCULATIONAHA.113.006032
Lower Levels of Sodium Intake and Reduced Cardiovascular Risk
Running title: Cook et al.; Lower Levels of Sodium and Reduced CVD Risk
Nancy R. Cook, ScD1; Lawrence J. Appel, MD, MPH2; Paul K. Whelton, MB, MD, MSc3
Division of Preventive Medicine, Brigham and Womens Hospital, Harvard Medical School,
Boston, MA; 2Welch Center for Prevention, Epidemiology, and Clinical Rese
Research,
earrch
ch,, Th
Thee Jo
John
Johns
hns
hn
Hopkins School of Medicine, Baltimore, MD; 3Dept of Epidemiology, Tulane University School
o Public Health and Tropical
of
Tropicaal Medicine,
Medicine, New Orleans,
Orlea
eaans
n , LA
Address
A
dd
dress forr Correspondence:
C rr
Co
rresp
ponden
en
ncee:
Nancy
Cook,
ScD
Nanc
Na
nccy R.
R C
ook,
oo
k S
k,
cD
Division of Pr
Preventive
rev
even
en
nti
tive
vee M
Medicine
edic
ed
iccin
ne
Brigham and Womens Hospital
Harvard Medical School
900 Commonwealth Ave East
Boston, MA 02215-1204
Tel: 617-278-0796
Fax: 617-264-9194
E-mail: ncook@rics.bwh.harvard.edu
Journal Subject Code: Etiology:[8] Epidemiology
1
Abstract
BackgroundRecent studies have raised the possibility of adverse effects of low sodium,
particularly less than 2300 mg/24hr, on cardiovascular disease (CVD). However, these
paradoxical findings might have resulted from suboptimal measurement of sodium and potential
biases related to indication or reverse causation.
Methods and ResultsPhases I and II of the Trials of Hypertension Prevention (TOHP)
collected multiple 24-hour urine specimens among pre-hypertensive individuals. During
extended post-trial surveillance, 193 cardiovascular events or CVD deaths occurred among 2275
participants not in a sodium reduction intervention with 10 (TOHP II) or 15 (TOHP
(TO
OHP I)
I) years
year
ye
arss of
ar
post-trial follow-up. Median sodium excretion was 3630 mg/24hr, with 1.4% of the participants
having
<1500
mg/24hr,
consistent
with
ha
avi
ving
ng iintake
ntak
nt
akee <1
ak
150
5000 mg/24hr and 10% <2300 mg
mg/2
24hr, consisten
nt wi
ith nnational
ational levels.
Compared
those
with
C
om
mpared to those
th
hosee with
with sodium
sod
odiu
ium
iu
m excretion
ex
xcre
cretio
on of
of 3600
36000 to
to <4800
<480
<4
8000 mg/24hr,
mg/24
mg/
/24hr,
4hr risk
rissk for
for th
thos
osee wi
os
ith
h ssodium
odd um
odiu
<2300
after
multivariable
adjustment
0.34-1.37,
<2
230
3000 mg/24hr
mg
g/2
/24h
4hrr wa
wass 332%
2% lo
llower
werr af
afte
terr mu
te
mult
ltiv
lt
ivarria
iv
iabl
blle ad
adj
just
just
stm
ment ((HR=0.68,
ment
HR=0
HR
= .688,
=0
8, 995%CI
5%CI
5%
CII = 0.3
.334-1.
1.337,, p
for trend = 0.13).
0.13
0.
13).
13
) There
).
The
h re was
as a linear
lin
inea
in
e r 17%
ea
17
7% increase
in
ncrrea
ease
s in
se
in risk
risk per
per 1000
100
000 mg/24hr
mg/2
mg
/24h
/2
4hrr (p=0.05).
4h
(p
p=00.0
.05)
5).. Spline
5)
curves supported a linear association of sodium with cardiovascular events, continuing to
descend from 3600 to 2300 and 1500 mg/24hr, although the data were sparse at the lowest levels.
Controlling for creatinine levels had little effect on these results.
ConclusionsResults from the TOHP studies, which overcome the major methodological
challenges of prior studies, are consistent with overall health benefits of reducing sodium intake
to the 1500 to 2300 mg/day range in the majority of the population, in agreement with current
dietary guidelines.
Key words: sodium, salt intake, cardiovascular disease prevention, nutrition, diet
2
The Institute of Medicine (IOM) recently convened a committee to review the effects of sodium
intake on health outcomes other than blood pressure, focusing on intake from 1500 to 2300
mg/24hr.1 While the final report supported population-wide efforts to lower sodium, it concluded
that there were insufficient data to support a lowering of sodium to <1500 mg/24hr, as
recommended by the American Heart Association,2,3 or to <2000 mg/24hr, as recommended by
the World Health Organization.4 The 2010 Dietary Guidelines for Americans5 recommend
lowering sodium to <1500 mg/24hr for a majority of adults and to <2300 mg/24hr for all others.
Several observational studies6 as well as randomized trials7,8 have examined the associations of
sodium and subsequent morbidity and mortality, and generally suggest a lowering of risk with
lower
ower sodium. However, few studies have examined
d absolute levels of sodium iintake
ntak
nt
ak
ke do
down
wn tto
o
those
hose considered in the IOM report.
Some
Som recent
reccen
entt studies have raised the possibility
posssib
ibillity of adversee effects
e feect
ef
ctss of
o very low sodium
intake
ntaake on card
cardiovascular
dio
iova
vasccul
va
u arr ddisease
isea
is
ease
ea
se ((CVD).
CVD
CV
D). Da
D).
Data
ataa fro
from
om thee FLEM
F
FLEMENGHO
LEM
EMEN
EN
NGHO
GHO and
and EP
EPOG
EPOGH
OG
GH cohorts
co
oho
hort
rtss
found
fo
oun
undd a higher
high
hi
gher
gh
er level
level
evel
e of
of CVD
CVD mortality
mo
ort
rtal
alit
al
ityy among
am
mon
ongg those
t osee inn the
th
the lowest
low
wesst tertile
tert
te
r ille of
rt
o ssodium.
odiu
od
ium.
m.9 Inn ad
addition,
ddi
dittioon,
data from patients
paatiien
ents
tss w
ithh CVD
it
CV
VD orr diabetes
dia
iabe
b tees suggested
be
sugg
su
gges
gg
este
es
teed a J-shaped
J-sh
Jshap
sh
aped
ap
ed curve,
cur
u ve
ve,, with
with an
a increase
inc
ncre
reas
re
asee in risk of
as
with
CVD and of mortality at both the upper and lower levels of sodium intake.10,11 The IOM
concluded, however, that these data were limited and their quality was insufficient to support the
assertion of an adverse effect on CVD at very low levels of sodium intake. All of the studies
reporting a paradoxical inverse or J-shaped association between sodium intake and CVD were
based on secondary analyses of studies that were not designed to assess this relationship. Major
concerns included suboptimal measurement of sodium and the potential for bias due to indication
or reverse causality. Most studies with urinary sodium excretion collected only a spot or single
24-hour urine specimen or included a high percent of participants with a pre-existing illness.
3
Phases I and II of the Trials of Hypertension Prevention (TOHP) collected multiple 24hour urine specimens over periods of either 18 months12 or 3-4 years.13 To represent long-term
usual intake of sodium, these measures were averaged among those not on an active sodium
intervention. In extended follow-up, a linear association of the sodium-potassium ratio with
CVD was identified.14 Sodium also showed a linear association, of borderline significance, with
CVD. The current report provides more detail on the relationship of sodium to CVD, particularly
at the low absolute sodium intake levels considered by the IOM. It also provides more detail
regarding the quality of the 24-hour urine collections, particularly the relationship of sodium and
creatinine, and the impact of the latter on the association of sodium with CVD.
Methods
TO
OHP T
ria
ri
als
als
TOHP
Trials
The
T
hee TOHP
T HP Follow-up
TO
Fol
ollo
low
lo
w-up
upp Study
Stu
tudy
dy was
was an
an observational
observaatiionaal ffollow-up
olllow
ow-u
-u
up of T
TOHP,
OH P, P
OHP
Phases
haase
sess I and
and II,
II and
and has
haas
be
een ddescribed
e cr
es
crib
ibed
ib
ed ppreviously.
reevi
viou
oussly.
sly.144 T
TOHP
OHP
OH
P I ttook
ook pplace
laace ffrom
ro
om Se
September
ept
ptem
embe
em
b r 19
be
1987
87 too Ja
January
anu
nuar
a y 11990,
ar
9990,, aand
nd
d
been
evaluated thee ef
effe
fect
ctss of
ct
o ffour
ouur ssupplement
upppl
plem
em
men
nt an
andd th
thre
reee li
re
ife
f sty
tyle
lee iinterventions,
nter
nt
erve
er
v nt
ntio
io
ons
ns,, in
incl
clud
udin
ud
ingg we
in
w
ight loss
effects
three
lifestyle
including
weight
and sodium reduction interventions, on blood pressure in 2,182 men and women aged 30-54
years with high normal blood pressure.12 Those in the active sodium reduction intervention were
excluded from the current analyses, leaving 1855 eligible TOHP I participants. In TOHP II,
which took place from December 1990 to March 1995, the effects of sodium reduction and
weight loss on blood pressure were tested over a longer 3-4 year follow-up period in a two-bytwo factorial design among 2,382 pre-hypertensive men and women age 30-54.13 Eligible
participants had a body mass index (BMI [calculated as weight in kilograms divided by height in
meters squared]) representing 110% to 165% of desirable body weight. Those in the active
4
sodium reduction group were excluded from the current analyses, leaving 1191 eligible TOHP II
participants.
During the trial periods, three to seven 24-hour urine collections were scheduled over 18
months in TOHP I and over three to four years in TOHP II. Usual intake of sodium or potassium
or their ratio was calculated as the mean of available urinary excretion measures at 5 (lifestyle
interventions) or 7 (nutritional supplement interventions) scheduled collections during 18 months
in TOHP I and at 3 or up to 5 scheduled collections during 3 years in TOHP II. Mean sodium
and potassium excretions, representing usual intake, were computed over all collections among
pre-hypertensive individuals not in the sodium reduction intervention. All of the urinary sodium
relationships
could
and potassium measures were expressed as mg/24hr. To explore whether the rela
laation
o sh
on
ship
ipss co
ip
cou
uld
collections,
be affected by under-collection, measures of creatinine were computed over the same collections
along
(Cr/Wt),
the
sodium-to-creatinine
allonng wi
with
th tthe
h ccreatinine-to-weight
he
reaatinine-to-weight
re
at
ratio (Cr/Wt
t),
), th
he sodium-to-cr
c eati
tiini
ninne ratio (Na/Cr), the
potassium/creatinine
the
sodium/potassium
potaass
s ium/crea
eati
tini
ti
nine
ne rratio
atio
at
io ((K/Cr),
K/C
K/
Cr) aand
Cr),
n th
nd
he so
odium
m/p
potaass
assium
sium
m rratio
atiio
at
io ((Na/K).
Na/K
Na
/K).
/K
).
TOHP
Follow-up
TO
OHP F
ollo
ol
lowlo
w-up
up
The observat
observational
follow-up
approximately
tio
ona
n l fo
foll
lllow
ow-u
up fo
fforr CV
CVD
D be
bbegan
gann in 20
ga
22000,
00,, ap
00
ppr
prox
oxim
ox
im
mat
a elly 10 yyears
ears
ea
rs aafter
fter
ft
er tthe
h end of
he
TOHP I and 5 years after the end of TOHP II, and included a total of 4,526 TOHP I and II
participants (with 38 participating in both TOHP I and TOHP II) (Figure 1). Of these, 2,974
were not in a sodium reduction intervention, had available sodium excretions, and remained alive
and CVD-free at the end of the trial periods. The follow-up was conducted centrally by mail and
phone from the TOHP coordinating center at the Brigham and Womens Hospital, Boston,
Massachusetts, and was approved by institutional review boards there and at the participating
clinic centers. Follow-up questionnaires focused on collection of CVD endpoints that had
occurred following the conclusion of the trials. Additional questionnaires were sent at two-year
5
intervals, up through early 2005, with interim annual postcards to collect information on address
changes and new study endpoints.
The primary endpoint for the follow-up study was CVD or CVD death, including
myocardial infarction (MI), stroke, coronary artery bypass graft (CABG), percutaneous
transluminal coronary angioplasty (PTCA), or death from cardiovascular disease. Upon
notification of occurrence of a primary nonfatal endpoint, consent was sought to obtain medical
records. These were reviewed by a study physician, blinded to the participants intervention
assignment, to confirm the reported events. Disconfirmed endpoints were excluded from the
subsequent analyses. An NDI search was performed in the fall of 2001 and summer of 2005 to
non-respondents
ascertain deaths from trial termination through December 2003 among non-resp
ponde
d nts
de
nts to tthe
he
he
questionnaires. End point information was obtained for 2275 participants (2312 including
duplicates
Response
du
upl
plic
icat
ic
ates
at
ess iin
n bboth
oth
th
h ttrial
r al phases), for an overall response
ri
res
esspo
p nse rate of 76.5%.
766.55%.. R
es
esponse
was slightly
higher
hi her
high
e amongg TOHP
TOH
OHP
P II
I participants
par
arti
tici
ti
cipa
ci
pant
ntss (78.4%)
nt
(78.
(7
8.4%
4%)) compared
comp
pared
d to
to their
th
heir
eir counterparts
couunte
unterrpaarts
artss in
in TOHP
TO
OHP I ((75.8%),
75.8
75
.8%
8%),
but
bu
ut did
did not
not differ
diff
di
ffer
err by
by sodium
sodium
dium quartile
quaart
rtil
ilee either
il
eiith
her crudely
cru
udelly (p=0.39),
( =0.3
(p
.39
39), or
o in
in fully
full
fu
llyy adjusted
adju
adju
ustted
e logistic
log
ogissticc
regression
analyses
(p=0.96)
egression ana
naaly
lyse
sees (p
(p=0
=0
0.9
96) ((Supplemental
Su
upp
pple
l me
le
m nt
n al
a Table
Tab
able
l 1).
le
1).
Statistical analysis
As described above, sodium levels were averaged across all collections during the course of the
trial periods in those not in an active sodium intervention who remained alive and CVD-free at
the end of the trial periods. Absolute levels were grouped into categories defined as <2300, 2300
to <3600, 3600 to <4800, and 4800 mg/24hr or higher, where 2300 represents current guideline
recommendations for adults,5 and 3600 represents the median sodium intake in the US
population aged 31-50.15 Baseline characteristics were expressed as percents or means, and were
tested for trend over sodium categories using chi-square statistics or regression analysis.
6
Cox regression models estimated the hazard ratio (HR) for the linear effect of sodium and
for the defined above. The baseline hazard was stratified by trial and those who were in both
phases contributed time to the end of TOHP I until entry into TOHP II as well as any follow-up
from the end of TOHP II. Models were adjusted for clinic, age, sex, race/ethnicity, and other
treatment assignments (model 1), additionally for education, baseline weight, alcohol use,
smoking, exercise, potassium excretion, and family history of cardiovascular disease (model 2),
and also for changes in weight, smoking, and exercise during the trial periods (model 3), as prespecified.14 Penalized splines with four degrees of freedom were fit using SPlus to examine
linearity of effect;16 introducing more flexibility did not alter the relation in the lower range of
sodium.
odium.
We also conducted several sensitivity analyses controlling for Cr/Wt in the multivariable
mode
mo
models
dels
de
ls to
to adjust
adjjustt for
ad
for
or potential inadequacy of the ur
uurine
ine collections.
s. F
First,
irst
stt, w
wee estimated the withinperson
variability
measures
creatinine
(mg/24hr)
weight
(Cr/Wt)
pers
son
o variabi
iliity
y ooff meas
m
eas
asur
ures
es ooff cr
cre
eatinnine (m
eat
mg/224h
24hr) divi
ddivided
ivide
dedd bby
de
yw
eiigh
g t in
n kkilograms
ilog
ilog
gra
r ms
m (Cr
Cr/W
Cr
/Wt
Wt)
t)
using
us
usin
ingg mixed
in
m xeed effects
mi
effe
ef
feectts models.
moddels
del . The
The coefficient
coef
co
efffici
ficiien
entt off variation
var
ariiatiion (CV)
(CV
CV)) was
wass co
wa
ccomputed
mputed
mput
ed ffor
o eeach
or
ac
ach
Wee th
then
with
participant. W
hen cconducted
onduuct
on
cted
e aanalyses
ed
n ly
na
lysees th
that
a eexcluded
at
x lud
xc
uded
e tthose
ed
hose
ho
se w
ithh CV
it
CVss ooff 20
220%
% or hhigher
igher and off
ig
30% or higher. In addition, we ran models controlling for Cr/Wt or the CV of Cr/Wt in the
model.17,18 Finally, we ran models including sodium, potassium, and Cr/Wt in the same models,
as well as Na/Cr, K/Cr, and Cr/Wt. These were expressed per standard deviation (SD) for easier
comparison of effect sizes. All analyses were conducted in SAS version 9.2, except as noted.
Results
Baseline levels
Sodium and other excretion data were averaged across all measures during the trial periods, with
7
a median of 5 measures (range, 1-7). Median sodium excretion among the participants with
follow-up data was 3630 mg/24hr, with 1.4% of the participants <1500 and 10% <2300 mg/24hr,
consistent with national levels.15 Levels were higher in men, with medians of 3934 mg/24hr in
men and of 3078 mg/24hr in women. Those in TOHP II, all with a BMI exceeding ideal body
weight, had higher levels than participants in TOHP I, with medians of 3666 and 4292 mg/24hr
in TOHP I and II, respectively, in men and of 2869 and 3340 mg/24hr, respectively, in women.
Characteristics of participants by absolute level of sodium excretion are provided in
Table 1. Those with the lowest sodium levels were more likely to be college educated, more
likely to drink alcohol and to exercise at least once/week, although these relationships were less
consistent in women. Weight was directly correlated with sodium intake, thoughh cha
h ng
ha
ngee in
change
weight during the trial periods was not. Blood pressure levels, which were restricted during
en
nro
oll
llm
ment due
ment
due to
to eligibility
e igibility criteria, were not cor
el
orre
or
related with sodium
soddiu
i m levels.
levvels.
le
ve
enrollment
correlated
Baseli
ine ur
rina
nary
ry eexcretion
xcre
xc
rettion
re
tionn llevels
evelss aree sh
eve
how
wn in Table
Tabl
Ta
blle 2 bby
y phase
phas
ph
asse and
and gend
ggender.
end
der
e . Median
M di
Me
dian
an
n
Baseline
urinary
shown
potassium
pota
po
tass
ta
sssiu
i m ex
excr
excretion
cret
ettio
on wa
w
was
ass 23
22327
27 m
mg/24hr,
g/24
g/
2 hr,
24
hr an
andd wa
wass hi
high
higher
g er iin
gh
n me
men
en (250
((2502
250
5022 mg
mg/2
mg/24hr)
/2
24h
4hr)
r) tthan
hann wome
ha
w
women
ome
m n
1952 mg/24h
4h
hr)
r),, bu
butt si
imi
m laar by
b pphase.
h se
ha
se. Me
Medi
dian
di
an ccreatinine
rea
eati
tiini
n ne w
as 11569
5699 mg
56
mg/2
/24h
/2
4hr,
4h
r aagain
r,
gain
ga
in hhigher
i her in men
ig
n
(1952
mg/24hr),
similar
Median
was
mg/24hr,
(1726 mg/24hr) than women (1155 mg/24hr). The median creatinine/weight ratio was 19.3 in
men and 15.0 in women. Both potassium and creatinine, as well as Cr/Wt, Na/K, and Na/Cr,
were positively associated with average sodium excretion.
We computed the coefficients of variation for the Cr/Wt data, using the within-person
standard deviation. These were slightly higher in women and in TOHP II, with medians of 18%
and 20% for men and women, resp., in TOHP I, and of 15% and 18% for men and women, resp.,
in TOHP II. The CVs declined across absolute levels of sodium in men, but were more stable in
women, as were the percents with CVs above 20% or 30%.
8
Association with CVD

During the post-trial follow-up, 193 cardiovascular events or CVD deaths occurred. First events
included 68 MIs, 77 coronary revascularizations, 22 strokes (1 participant reported both MI and
stroke), and 27 CVD deaths. Crude proportions developing CVD were lowest in the two lower
sodium excretion groups in each phase (Table 3). In models adjusted for clinic, treatment
assignment and demographic variables (model 1), for these plus baseline covariables (model 2),
and additionally for changes in weight, smoking and exercise over the trial periods (model 3),
there was a non-significant trend of increasing risk with increasing sodium level. In the fully
adjusted model, compared to those with sodium 3600 to <4800 mg/24hr, risk for those with
sodium
odium <2300 mg/24hr was 32% lower after multivariable adjustment (p for trend
tren
nd = 0.13).
0.13
0.13
13).
). When
When
sodium
odium was considered as a continuous term, riskk increased linearly, with a 17% increase in risk
per
model.
pe
er 1000
1000 mg/24hr
mg/
g/24
2 hr (p=0.054)
(p=0.054) in the fully adjusted
ed
dm
odel.
supports
association
CVD
The spline
sppliine plot
plo
lott ((Figure
Figu
Fi
gure
gu
re 22)) su
upp
ports a llinear
ineaar ass
sociat
soci
attio
on ooff ssodium
od
diu
ium
m wi
with
th
hC
VD ((P=0.044),
P=0.
P=
0.04
0444),
04
with
the
curve
continues
wi
ith a p vvalue
alue
al
ue ffor
or nnonlinearity
onnlinnea
nearit
itty = 0.76
00.76.
.76
7 . In
n pparticular,
ar icu
arti
cullar,
ar, th
he cu
cur
rve co
rve
cont
nttin
inue
uees to
to ddescend
esce
es
c nd ffrom
ce
ro
om 36
3600
00 tto
o
this
nonlinear
curve,
2300 and 1500
150
00 mg/24hr,
mg/2
mg
/24h
/2
4h
hr,
r although
alt
ltho
houg
ho
ug
gh the
th
he data
data are
are sparse
spar
sp
arse
ar
see att the
the lowest
l we
lo
west
s llevels.
eveels
ev
ls.. In thi
hiss no
hi
nonl
n in
nl
i ear curve
e
compared to those consuming 3600 mg/24hr, the estimated HRs for those consuming 2300 and
1500 mg/24hr were 0.78 and 0.69, respectively.
To determine the impact of differences in creatinine levels on the association of sodium
and CVD, we conducted several sensitivity analyses (Table 4). We first excluded all those with a
CV for Cr/Wt of 20% or greater, leaving a sample size of 1298 participants. The association of
sodium with CVD was slightly stronger, with hazard ratios that were 33% lower in those <2300
mg/24hr and 35% higher in those 4800 mg/24hr, but the trend was not statistically significant.
The linear trend also increased to a 20% increase in risk per 1000 mg/24hr (p=0.09). When
9
excluding those with a CV for Cr/Wt of 30% or greater, or when controlling for Cr/Wt or the CV
of Cr/Wt in the model, there was little change in the estimated coefficients, though the effect of
sodium became stronger with control for the CV of Cr/Wt.
For easier comparison, we further considered the excretion variables expressed per
standard deviation (Supplemental Table 2). The average creatinine/weight ratio was not a
predictor of CVD by itself, with a small 4% increase in risk per SD (p=0.72). When the first
baseline measure of Cr/Wt was used, rather than the average over the trial period, however, the
risk increased by 20% per SD (p=0.0087) (data not shown). The risk of CVD increased by 21%
per SD of average sodium excretion (p=0.05) and decreased by 15% per SD of average
Similar
results
were
potassium excretion (p=0.12), with little change after adjustment for Cr/Wt. Sim
milar
il r res
esul
es
ults
ul
ts w
ee
er
seen
een using the sodium/ creatinine and potassium/creatinine ratios.
Discussion
D
isc
scussion
c
presence
Ann extensive
ext
xten
ensi
sive
ve body
bod
dy of information
infor
orma
mati
ma
tiion documents
doc
ocum
umen
um
entts the
en
the pr
res
esen
ence
en
ce ooff a ddirect
ire
rect
re
c rrelationship
ct
ellat
atio
io
ons
nshi
h p betw
hi
bbetween
e weeen
sodium
intake
pressure.
During
meta-analyses
odium intak
ke an
aand
d bl
bblood
o d pr
oo
res
essu
suure
re.. Du
D
ring
ri
ng tthe
he ppast
ast yyear,
e r,, tthree
ea
hree
hr
e nnew
ee
e m
ew
etaet
a an
aanal
a ys
al
yses
es ooff ra
rrandomized,
ndomized
d,
controlled clinical trials were published.19-21 Although they differed in their trial inclusion and
exclusion criteria, each of the meta-analyses reported a significant and clinically important
decrement in blood pressure following a reduction in sodium intake. Consistent with prior
knowledge, the reduction in blood pressure was greater in those with a higher starting level of
blood pressure, older persons, African-Americans, and those with a more successful intervention.
In the meta-analyses that are most generalizeable to clinical practice and public health,17,19 total
cholesterol and catecholamine levels were essentially unchanged and changes in urinary protein
excretion were consistent with a beneficial effect of sodium reduction. Blood pressure is one of
10
the best validated surrogate markers for CVD,22-24 and has been identified as one of the leading
preventable causes of death in the U.S.25
Direct observations of the relationship between sodium reduction and CVD are more
limited, especially at lower absolute levels of sodium intake. A preponderance of reports based
on observational epidemiology support the presence of a direct relationship between sodium
intake and CVD, especially for stroke.26 While the DASH-Sodium clinical trial demonstrated an
increasingly beneficial effect of reduced sodium intake on blood pressure at progressively lower
levels of dietary sodium down to 1500 mg/day,27 some reports have identified null, inverse or Jshaped relationships with CVD.26
In its most recent review of dietary sodium,1 the IOM committee was cha
charged
haarg
rged
e w
ed
with
ithh
it
examining the effects of very low levels of sodium intake in the range of 1500-2300 mg/day on
health
he
eal
alth
th ooutcomes,
utco
ut
com
co
mes,
s, ddefined
e ined as clinical CVD events
ef
events.
tss. T
This
his and other rreviews
e ieews have uniformly
ev
concluded
co
oncluded
nc
that
at tthe
h uunderlying
he
nder
nd
errlyin
lyin
ingg da
data
taa sshowing
hoowing ad
adverse
dverrsee ef
effects
ffects
ffe
ectss ooff so
sodium
odium inn th
this
is rrange
ange
an
ge aare
ree ooff
,19
9,26
,2
insufficient
support
nsu
suff
ffic
ff
icie
ic
ient
ntt qquality
uallity
ua
y tto
o su
upp
p orrt a fi
firm
rm cconclusion.
oncl
on
cluusio
cl
us on.
n 11,19,26
Many
M
anyy su
an
suff
suffer
ffferr ffrom
r m so
ro
som
some
me combination
me
com
mbina
naatiion of
of
potential for bi
bias
a iin
as
n th
thee as
aassessment
sess
se
ssme
ss
ment
me
n ooff so
nt
sodi
dium
di
um iintake,
ntak
nt
ake,
ak
e, rev
ever
ev
erse
er
se ccausality,
ausaali
au
lity
ty,, re
ty
resi
sidu
si
d al cconfounding
du
onfo
on
f unding and
fo
d
sodium
reverse
residual
random error. Despite this, the reports of a paradoxical inverse or J-shaped association between
sodium intake and CVD have received considerable media28,29 as well as scientific community
attention30-32 and have been the basis for addition of sodium to food products.33
Several analyses of CVD or total mortality were based on NHANES data, which
employed a single 24-hour diet recall to estimate sodium intake. This approach underestimates
sodium intake by failing to measure sodium added at the table, in the kitchen, in supplements, or
in drinking water. Falsely low estimation due to underreporting of food and beverage intake and
portion sizes is also a concern. Finally, inaccuracies can result from changes in commercial food
11
composition that are not reflected in the nutrient databases used to estimate sodium content. Use
of food frequency questionnaires to estimate sodium intake is prone to many of the same
challenges encountered with use of dietary recalls. In addition, sodium content can vary
considerably across brands of processed foods, which are typically incompletely assessed in
these questionnaires.
The gold standard for sodium assessment in healthy persons is 24-hour urine collection.
Overnight and spot urine samples are less burdensome for study participants and research staff.
However, they are affected by diurnal variation, and the methods supporting the validity of their
use are inadequate. They represent a weak substitute for 24-hour urine collections, especially
when they are used to estimate sodium intake and relationships in an individual..266 D
Despite
esspi
pite
te bbeing
eing
eing
considered the gold standard, even 24-hour collections are subject to quality control concerns,
particularly
paarttic
icul
ular
ul
arly
ly uunder-collection
nder
nd
er--collection
er
-c
of urine specimens.
s. M
Measurements
easurements ba
bbased
sedd on a single 24-hour urine
fail
fail to
to capturee day-to-day
day--to
da
o-d
- ay variability,
var
ariiabil
abilit
i y,
it
y, m
making
akin
ng tthem
hem
m lless
esss than
than
n ooptimal
ptiimall fo
for st
stud
study
uddy of tthe
he w
withinithi
hinhi
nperson
between
pers
pe
rson
rs
on rrelationship
elat
el
atio
at
ions
io
nshhipp be
etw
wee
een sodium
sodi
dium
um aand
nd CVD.
CVD
VD..
The TOHP
TO
OHP Follow-up
Folllo
oww-up
up Study
Stu
tudy
dy used
use
sedd an average
ave
v ra
rage
ge of
of 3-7
3-7
7 carefully
car
aref
eful
ef
ullly collected
col
olle
lect
le
c ed
ct
d 24-hour
244 ho
hour
u urine
collections as a measure of sodium exposure, greatly reducing bias due to measurement error and
random error due to within-person variability over time. We found a continued decrease in CVD
events among those with sodium levels as low as 1500 mg/day, with no evidence of a J-shape
when examining spline curves. Risk reductions among those at the lowest levels of sodium
excretion were substantial, with a 32% reduction among those excreting less than 2300 mg/day,
although this was not statistically significant due to small numbers in this subgroup and limited
power.
To further consider the quality of urine specimens, we also adjusted for creatinine using
12
various approaches. Since the rate of creatinine formation is fairly constant in healthy
individuals, urinary creatinine serves as a measure of completeness of urine collection.17 Those
with the lowest levels of urinary creatinine excretion are likely to include individuals who have
collected an incomplete 24-hour specimen. They may be less likely to exhibit healthy behaviors
and more likely to have poorer health outcomes. Creatinine level, however, is also related to
other factors, such as age, race, and BMI.17 While average sodium levels in TOHP were
positively associated with creatinine levels and the Cr/Wt ratio, these had little impact on the
relationship between sodium and CVD in these analyses.
In our study, the average Cr/Wt was not a predictor of CVD. However, when using only
he first baseline urinary excretion, it was a strong predictor. This suggests that uusing
sing
si
n tthe
ng
he aaverage
vera
ve
rage
g
the
for many measurements over several years, as in these TOHP analyses, adjusts for variations in
di
ilu
uti
tion
on aand
nd rremoves
em
mov
oves
e any effect of under-collecti
tion
ti
on, as well as red
on
ed
duc
u in
ng w
ithin-person
dilution
under-collection,
reducing
within-person
vvariability.
ariiab
a ility. Estimates
Est
stim
imaates bbased
im
ased oon
ased
n a si
sin
ngle uurine
ngl
rinee ccollection,
olleection,
n, hhowever,
owev
eveer, ma
mayy bbee ddistorted
isttort
is
torted
ed bby
y un
nder
dersingle
under9,34
,334
co
oll
llec
eccti
tion
on ooff th
thee sp
pec
eciimen
imen,9,3
aand
nd iinn such
suuch a cir
circumstance
ircu
ir
cums
cu
m taanc
ms
ncee creatinine
crea
crea
eati
t nine
ti
ne adjustment
adjuustm
ustm
men
nt sh
should
hould
d bbee
collection
specimen,
considered.
Reverse causation is another important source of error in observational studies of the
relationship between dietary sodium and CVD. This is most likely an issue in studies that include
patients with heart failure, coronary heart disease, chronic kidney disease, diabetes mellitus, or
even hypertension. Such patients are likely to reduce their sodium intake either because of a poor
diet or health advice. This can result in an inverse relationship between sodium intake and CVD
that is a consequence of their underlying disease rather than the lower intake of dietary sodium
(reverse causation). In many of these studies the situation is further compounded by the use of
potent diuretics and other medications that can distort estimates of sodium intake. Often, the
13
number of CVD events in these studies is small so that even a trivial number of events resulting
from reverse causation can distort the results. Eliminating early periods of follow-up and
controlling for illness in the analysis may not be a sufficient remedy. Indeed, controlling for
blood pressure, hypertension, or hypertension medication in the analysis may eliminate the
indirect effect of sodium through blood pressure, which may be the main biologic mechanism.35
A major strength of the TOHP follow-up analyses is that the cohorts were restricted to healthy,
free living prehypertensive individuals who were not taking blood pressure medications. Thus
reverse causation is very unlikely to have been an issue in the TOHP follow-up study. However,
since it did not include those with high blood pressure, it could also have eliminated those who
were most sensitive to the effects of sodium on blood pressure, and in whom thee impact
imp
m acct on CVD
C VD
could be even stronger.
Limi
Li
mita
mi
t tion
ta
onss of
on
o the current analyses should
ld also
also be considered.
consider
erred. First,
Firrst,
Fi
rs the response rate to
Limitations
he TOHP
TOHP follo
low
w-up
up questionnaires
queest
stio
ionn
io
nnai
nn
aire
ress was
re
was lesss than
thann 880%.
0%
%. Ho
owe
weve
veer, m
ucch of tthis
hiss wa
hi
wass du
due to
the
follow-up
However,
much
ch
han
ange
gess in aaddress
ge
ddre
dd
reesss aafter
ftter 55-10
- 0 yyears
-1
ears
ea
rs ooff no ccontact;
onta
on
taact
c ; th
he rresponse
esp
spoonse
onse rrate
a e wa
at
was 85%
85% am
amon
ongg th
on
hosse w
ith
th
ha
changes
the
among
those
with
valid address.
s. We
We also
alsoo collected
collle
lect
cted
ct
d information
inf
nfor
o ma
mati
tion
ti
on on
on cardiovascular
card
ca
rdio
rd
iova
vasc
va
scul
sc
ular
ul
ar ddeaths
eaath
thss fo
forr al
alll pa
part
rtic
rt
icip
ic
ipan
ip
a ts through
h
participants
the NDI. In addition, there was no difference in response by sodium level, reducing the
likelihood of bias. Second, it is unclear if sodium levels were maintained throughout follow-up.
However, this concern is shared by most observational studies, and our repeat 24-hour urine
collections over 1-4 years represent very accurate assessments of usual sodium intake. Third, we
cannot rule out residual confounding. Those on a low sodium diet may exhibit other healthy
lifestyle behaviors, including better diet quality and increased exercise. We adjusted for weight,
exercise and smoking in our models, as well as changes in these during the intervention periods,
but uncontrolled confounding remains a possibility.
14
Approximately 37% of US adults have prehypertension,36 and these data show that they
would benefit from sodium reduction. Given the strong impact of sodium on blood pressure
among hypertensives, the 16% of US adults with hypertension36 would also be expected to
benefit. Thus, these results are consistent with overall health benefits of reducing sodium intake
to the 1500 to 2300 mg/day range in the majority of the population, in agreement with current
dietary guidelines.5 While there is likely a biologic benefit to lowering sodium to these levels,
however, only 1% of US adults have a sodium intake as low as 1500 mg/24hr currently,15 and
fewer than 10% have intakes less than 2300 mg/24hr. Reasonable questions remain about the
practical implementation37 of such low sodium targets, but even a small reduction in the
populations average intake of dietary sodium could result in a major improveme
improvement
meent iin
n CV
CVD
D
health.38,39
Funding
F
un
nd
nding
Sour
Sources:
rcees:: T
TOHP
OHP
OH
P I an
andd III w
were
ere ssupported
er
uppportedd bby
y ccooperative
oopeeraati
oope
tivve aagreements
greeement
gr
ment
ntss HL
HL37849,
L37
3784
849,
84
9,
HL37852,
HL37
HL
3785
37
852,, H
HL37853,
L 7853,
L3
53, HL
HL37854,
L37
378854,
854,
4 H
HL37872,
L3778772,
L3
72, HL
HL37
HL37884,
3788
884,
88
4, H
HL37899,
L378
L3
7899
78
99,, H
HL37904,
L37
37
79004, H
HL37906,
L379
L3
79
906,, HL37
H
HL37907,
L37
7907,
andd HL
HL37
HL37924,
3792
924,, aand
nd
d tthe
he TOH
TOHP
OHP
P Fo
Foll
Followllow- up
pS
Study
tudy
tu
dy w
was
as su
supp
supported
ppor
orte
tedd byy ggrant
rant
ra
n HL57915,
HL5
L579
7915
15, all
all from
om the
the
National Heart,
Hea
eaart
rt, Lung,
Lung
Lu
ng, and
ng
and Blood
Blooodd Institute
Bl
Inst
In
stittut
utee (NHLBI),
(N
NHL
HLBI
BI),
BI
) National
),
Nat
atio
iona
io
nall Institutes
na
Instit
In
ittut
utes
es of
of Heal
H
Health.
eal
alth
th. Th
th
The NHLBI
had no role in the design and conduct of the study; collection, management, analysis, and
interpretation of the data; and preparation, review, or approval of the manuscript; and decision to
submit the manuscript for publication. Dr. Cook had full access to all of the data in the study and
takes responsibility for the integrity of the data and the accuracy of the data analysis.
Conflict of Interest Disclosures: Dr. Appel is an investigator on a grant from the McCormick
Foundation.
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15
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19
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Ab
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to N,
N Ziolkovska
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N Hooper
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Ho
oper
er L,
L Elliott
Elli
El
liot
ottt P,
P Cappuccio
Cap
appu
pucc
ccio
io FP,
FP Meerpohl
Mee
eerp
rpoh
ohll JJ.
JJ Effect
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Ef
fect
ct of
of lower
lowe
lo
werr
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24. IOM (Institute of Medicine). Evaluation of biomarkers and surrogate endpoints in chronic
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25. Danaei G, Ding EL, Mozaffarian D, Taylor B, Rehm J, Murray CJL, Ezzati M. The
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28. Kelland K. Special report: a pinch of doubt over salt. Reuters. September 1, 20
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CD.
Public
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surrogates.
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31
1. Furberg
Fu
g CD
C
D. Pu
P
blic
bl
icc hhealth
ealt
ea
lthh po
poli
lici
li
cies
es:: no pplace
lace
la
ce ffor
or sur
urro
roga
ro
gate
ga
t s. Am J H
y errte
yp
tens
ns.. 2012;25:21.
ns
2012
20
12;2
;25:
;2
5:21
21..
21
32.
McCarron
DA.
Data
rather
than
opinion
that
clinical
must
32
2. M
cCarron
on D
A. Da
ataa ra
ath
herr tha
h n op
pin
nionn ddictates
ictaates th
hat a ddefinitive
efin
nitiive cl
lin
nic
icaal ttrial
rial m
ri
ust ddetermine
ust
eterm
rmine
rm
iff the
Hypertens.
the US
US governments
govvern
go
vernme
ment
nts sodium
sod
odiu
iu
um guideline
guiideli
gu
deliinee Is
Is safe
saafe
f and
and effective.
efffec
ecttive
tivee. Am J H
yp
per
erte
tens
te
ns.. 2011;24:859ns
20111;;24
20
;24:85
4:8599860.
0.
33.
salt.
33 Arumugam
Arum
Ar
umug
ugam
am N.
N Campbell
Camp
Ca
mpbe
bell
ll Soup
Sou
oupp increases
incr
in
crea
ease
sess sodium
sodi
so
dium
um as
as new
new studies
stud
st
udie
iess vindicate
vind
vi
ndic
icat
atee sa
salt
lt Forbes.
Forb
Fo
rbes
es July
Jul
ulyy
18, 2011.
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increase cardiovascular mortality? Kidney Int. 2011;80:696-698.
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Epidemiol. 1992;3:143-155.
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Galea G, Gaziano T, Geneau R, Haines A, Hospedales J, Jha P, Keeling A, Leeder S, Lincoln P,
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Goldman L. Projected effect of dietary salt reductions on future cardiovascular disease. N Engl J
Med. 2010;362:590-599.
19
Table 1. Baseline characteristics among participants with follow-up information in the Trials of Hypertension Prevention by
categories of urinary sodium excretion (mg/24hr).
TOHP I (N=1397)
Sodium Excretion (mg/24hr)
<2300 2300-<3600 3600-<4800 4800
MEN
N
Age (yrs)
Black (%)
College
ge degree (%)
Current
nt smoker (%)
Past smoker
moker (%)
Alcohol
ol (% 1 drink/wk)
Exercise
ise (% once/wk)
Weight
ht (lbs))
Change
gee inn wt (lbs)*
(lb
lbs)
s)*
s)
*
SBP
Change
SBP*
gee in
n SB
S
P*
DBP
ge inn DBP*
ge
Change
MEN
ME
E
WOMEN
N
yrs))
Age (yrs)
(%)
Black (%)
ge degree (%)
College
nt smoker
smok
sm
oker
er (%)
(%)
Current
Past smoker (%)
Alcohol (% 1 drink/wk)
Exercise (% once/wk)
Weight (lbs)
Change in wt (lbs)*
SBP
Change in SBP*
DBP
Change in DBP*
88
42.1
14.8
84.1
10.2
34.1
63.6
82.6
175.8
175
75.8
-1.6
1.6
124.3
124.
12
43
-3.7
-3.
37
3.
84.0
84
4.00
-4.
43
-4.3
382
42.8
6.5
71.2
10.7
30.9
55.2
73.3
185.4
-1.4
124.2
-4.3
-4
4.3
.
883.7
37
3.
-4.33
-4.3
354
43.3
8.8
68.8
10.5
37.4
52.5
70.4
198.1
-2.2
125.2
--4.5
4.5
4.
5
84.0
84.0
-4.
45
-4.5
168
42.7
7.7
66.7
10.1
40.5
42.9
65.9
211.4
4
-3.3
125.33
-4.7
-4
.77
83.7
83.
37
4
-4.8
01
101
44.6
44.6
19
.8
8
19.8
446.5
65
6.
114.8
48
27.7
41.6
62.6
151.3
0.06
125.2
-3.7
83.7
-4.7
2 8
20
208
44.
47
44.7
222.6
2.6
6
46
6.2
46.2
10
6
10.6
25.5
28.8
60.8
162.4
0.12
125.7
-3.5
83.7
-4.4
73
43.0
28
.8
8
28.8
442.5
25
2.
111.0
10
21.9
23.3
60.3
174.1
-0.8
125.3
-2.7
84.5
-4.7
223
3
42.
27
42.7
330.4
0.4
4
39.1
39
.1
21
7
21.7
13.0
39.1
56.5
183.7
0.6
123.9
-6.4
83.6
-5.9
P for
Trend
TOHP II (N=915)
<2300 2300-<3600 3600-<4800 4800
P for
Trend
0.42
0.44
0.010
0.90
0.039
0.001
0.005
<0.0001
0.083
0.080
0.31
0.31
31
0.94
94
0.335
0.35
18
42.7
11.1
100.0
22.2
16.7
55.6
88.9
202.4
-6.1
127.7
-4.22
85.8
85.
5.8
8
-7.2
-7.2
142
43.6
10.6
72.5
7.0
42.2
42.2
77.5
207.5
207
0 .5
11.9
.
.9
127.5
127.
12
7.5
5
-0.4
-0.
0.4
0.
4
86.1
86
6
-2.
29
-2.9
252
43.6
9.5
5
67.1
67.1
1
88.3
.3
3
41.7
411.77
44.0
71.4
213.8
1.3
126.7
-0.9
-0
0.99
885.9
5.9
5.
9
-3.33
-3.3
202
42.5
7.9
7.
9
62.9
62.
29
88.9
.9
9
39.1
39.1
1
40.1
68.3
229.2
1.8
127.6
--1.1
1.1
1.
1
86.2
86
.2
-2.9
-2.9
0.17
00.38
0.003
0.
00.72
0.74
0
00.36
0.019
0.
<0.0001
<0.
0.35
0
00.88
00.99
00.52
0
0.26
0.03
0.
036
6
0.036
00.12
.12
12
00.45
.45
5
00.88
88
0.14
0.094
0.60
<0.0001
0.86
0.70
0.73
0.26
0.54
229
9
44.
44.4
334.5
4.5
5
62.1
62
.1
10
3
10.3
34.5
13.8
58.6
172.7
3.0
128.2
0.9
85.7
-2.4
161
16
6
443.8
3.8
3.
8
30
.44
30.4
550.3
0.3
0.
3
88.7
7
28.6
19.9
59.6
181.4
1.9
128.4
0.5
85.7
-2.4
89
9
43.11
43
228.1
8.1
1
44.9
44
.
.9
113.5
35
25.8
14.6
53.9
192.0
4.3
128.2
2.6
85.8
-2.0
222
2
444.0
4.0
4.
0
18
.2
2
18.2
45.4
99.1
1
36.4
27.3
63.6
203.1
3.9
130.0
0.2
86.2
-3.2
00.45
00.21
00.15
00.56
0.86
0.69
0.82
<0.0001
0.32
0.48
0.47
0.44
0.97
Data represent means or percentages. SBP indicates systolic blood pressure; DBP, diastolic blood pressure. * Change during the trial periods.
20
Table 2. Baseline urinary excretion variables among participants with follow-up information in the Trials of Hypertension Prevention
by categories of urinary sodium excretion (mg/24hr).
TOHP I
<2300 2300-<3600 3600-<4800 4800
MEN
N
Sodium
m (mg/24hr)
Potassium
sium (mg/24hr)
Sodium/Potassium
m/Potassium
Creatinine
nine (mg/24hr)
Cr/weight
ight (mg/kg)
Sodium/Cr
m/Cr
CV Cr/wt
r//wt (%)(median)*
(%)
%)(m
(med
(m
edia
ed
ian)
ia
n*
n)
% CV
Cr/wt
20%*
VC
r/wt
w >=
wt
> 20%
0%*
*
% CV
Cr/wt
30%*
VC
r/wt
/w >= 30%
%*
WOMEN
M N
ME
N
Sodium
m (mg/24hr)
(mg
mg/2
/24h
/2
4hr)
r)
Potassium
(mg/24hr)
sium
m (m
g/24
g/
/24
24hr
hr))
Sodium/Potassium
m//P
/Potas
t sium
i
Creatinine
nine (mg/24hr)
Cr/weight (mg/kg)
Sodium/Cr
CV Cr/wt (%)(median)*
% CV Cr/wt >= 20%*
% CV Cr/wt >= 30%*
88
1928.2
1986.1
1.13
1270.2
16.2
1.66
223.6
23
3.6
.
61.2
61
.2
330.6
30
0.6
6
382
3054.5
2357.8
1.47
1508.6
18.2
2.12
19.7
448.8
8.8
225.7
57
5.
354
4145.8
2665.2
1.71
1705.8
19.3
2.50
16.4
34.0
.
16
16.3
6.3
168
5923.0
3058.0
2.11
1993.2
21.1
3.04
17.7
7
441.6
1.6
1.
6
18.6
18.
86
1101
01
1847.6
184
847.
47.6
6
1653.2
1653
16
53.2
.2
11.27
.27
27
8894.3
94.33
94
13.3
2.21
21.0
52.0
31.6
200
208
2908.1
2908.1
8.
11920.0
9 0.
92
0.0
0
11.67
.6
67
67
1097.6
109
097.
09
76
15.1
2.74
19.8
47.6
22.1
73
44088.6
088.
08
86
2243.3
2243
.33
11.96
.96
96
1277.2
1 77.2
12
72
16.4
3.26
20.7
52.9
25.7
2233
5941.2
5941
59
41.2
41
.2
22622.4
622.
62
24
22.38
.38
38
1546.4
154
546
6.4
18.9
3.95
21.9
60.0
25.0
P for
Trend
TOHP II
<2300 2300-<3600 3600-<4800 4800
P for
Trend
<0.0001
<0.0001
<0.0001
<0.0001
<0.0001
0.0007
<0.0001
<
<0
.000
001
1
0.0013
0.00
013
18
1995.2
2176.8
1.08
1483.3
16.5
1.42
17.6
43.8
225.0
5.0
5.
0
142
3119.5
2341.4
1.48
1703.6
18.3
1.91
19.4
19
9.4
447.0
7.0
7.
0
18.2
18
8.2
252
4200.5
5
2694.4
269
94..4
11.72
.72
72
1936.0
20.1
2.24
14.6
34.4
34 4
15.1
15.1
5.1
202
55728.8
728.
72
8.8
8
2919.9
2919
29
19.9
19
.99
2.14
2.
1
14
2175.4
21.1
2.70
13.1
22.8
22.
2.8
9.8
9.8
<0.0001
<0.
<0.0001
<
0
0.
<0.0001
<0.
<0.0001
<0.
<0.0001
<0.
<0.0001
<0.
<0.0001
<0.
0.013
0.
<0.0001
<0.
0.00
0001
01
<0.0001
<
0.00
0001
00
01
<0.0001
<0.000
<0
0001
<0.0001
<0.0001
0.92
0.61
0.38
29
29
1965.0
1965
965.00
11522.6
522.
52
26
11.51
.51
51
1017.4
10177.44
13.1
2.11
22.1
65.4
26.9
161
6
33032.8
032.
03
28
1962.2
1962
19
62.22
11.76
.766
11239.2
239
23
9.2
2
15.1
2.54
17.5
38.2
16.4
89
8
4034.6
4 34
40
34.6
.66
22168.4
168.
16
84
8.
22.06
.06
06
1417.2
1417
14
17.22
16.4
3.00
17.4
32.5
13.8
22
22
55596.7
596.
96.7
7
2637.4
2637
26
37.4
.4
22.34
.34
34
1522.1
16.6
3.99
16.1
31.8
18.2
<0.0001
<
0
0.
<0.0001
<
0
0.
<0.0001
<0.
0.
<0.0001
<0.0001
0.39
0.016
0.35
Data represent means unless otherwise indicated. Cr indicates creatinine; Cr/wt, creatinine/weight ratio; CV, coefficient of variation.
* In those with at least 2 urine excretions.
21
Table 3. Cardiovascular events after the Trials of Hypertension Prevention by categories of urinary sodium excretion (mg/24hr).
<2300
TOHP I
CVD events/ Total (%)
TOHP II
CVD events/ Total (%)
Model
el 1
HR
R
95%CI
%CI
Model
el 2
HR
R
95%CI
%C
CI
Model
ell 3
HR
R
95%CI
% I
%C

2300-<3600
3600-<4800
4800
P Value
HR per
for Trend 1000 mg/d P Value
15/189 (7.9)
48/590 (8.1)
40/427 (9.4)
23/191 (12.0)
2/47 (4.3)
13/303 (4.3)
34/341 (10.0)
18/224 (8.0)
0.92
0.53-1.60
0.80
0.56-1.13
1.00
(Reference)
1.11
0.75-1.64
0.18
0.118
1.13
1 13
1.
11.00-1.27
.000-1
.00
0-1.27
1.27
0.044
0.
0.87
0.48-1.58
0.78
0.54-1.13
1.00
(Reference)
(R
1.12
0.74-1.67
0.74-1.6
.677
0.19
1.18
1.02-1.36
0.025
0.
0.68
0.6
.688
00.34-1.37
0.
344-1
1.3
.37
37
0.75
0 75
0.
0.50
0.
0.50-1.11
5 -1
50
-1.11
1.00
1.000
(Ref
(Reference)
R erren
ence
nce))
1.05
1 055
1.
00.68-1.62
0.
6 -1
68
-1.6
.62
.6
0.13
0.13
13
1.17
1.17
11.00-1.36
. 0-1
.0
-1.36
1.36
0.054
0.
From C
Cox
ox pproportional
roportional hazardss regres
regression
e
sionn models
si
model
els
l stratified
stratified
ed by
by trial
triall phasee and
tr
n adjusted
ad
dju
usted
te as follows:
foll
fo
llow
ll
ows:
ow
s Model
Model 1 (age, ssex,
e , ra
ex
race/ethnicity,
ce/e
e th
thnicity, cclinic,
lini
in c,, aand
nd tre
nd
treatment
atment
at
e
assignment),
m nt),
me
) Model 2 (Model
),
(Mo
Moodel 1 variab
variables
a
les pl
le
pplus
us education
edu
d cati
ation
o status,
staatu
tus,
s, bbaseline
ase
seline
e
w
weight,
eigh
ig t, aalcohol
l oh
lc
ohol use,
use
se, sm
smok
smoking,
o ing,
n exercise,
exe
x rc
rcise, pot
potassium
o assi
ssium
m exc
excretion,
x re
retion,
n an
and
nd fa
ffamily
ami
m ly
l hhistory
istory
s ry
r of
cardiovascular
weight,
cardiovascular
vaasc
scular
lar disease),
dis
isease
se)),
), and
and Model
Mod
o el
e 3 (Model
(Mo
M de
d l 2 variables
vari
ar ab
able
ble
l s pl
plus
u cchanges
us
hanges
ges iin
n we
weig
ig
ght
ht,, sm
ssmoking,
o ing,
ok
ng and
and eexercise
x rc
xe
rcisse du
dduring
ring
ri
ing tthe
he trial
al pperiods).
erio
ri ds
ds)). CV
CVD
VD in
iindicates
diica
c tes
es ca
rd
diova
ovasc
disease;
HR,
ratio;
CI,
e H
e;
R, hhazard
azar
az
ardd ra
rati
tio;
o C
I, cconfidence
onfi
on
fide
fi
denc
de
ncee interval.
nc
inte
in
terv
te
r al.
22
Table 4. Cardiovascular events after the Trials of Hypertension Prevention by categories of urinary sodium excretion (mg/24hr)
Sensitivity analyses adjusting for creatinine.
<2300
2300-<3600
3600-<4800
Excluding those with CV Cr/Wt >= 20%* (CVD events/ Total = 104/1298)
HR
0.67
0.83
1.00
95%CI
0.23-1.91
0.48-1.44
(Reference)
Excluding
luding those with CV Cr/Wt >= 30%* (CVD events/ Total = 141/1780)
R
0.79
HR
0.71
1.00
95%CI
0.30-1.68
0.50-1.24
5%CI
(Reference)
Controlling
trolling for Cr/Wt in Model (CVD events/ Total = 193/2312)
HR
R
0.70
0.76
1.00
95%CI
5%CI
0.34-1.45
0.51-1.13
(Ref
(R
(Reference)
e erence)
Controlling
tro
roll
llin
ll
ingg ffor
in
orr CV Cr/
Cr/Wt
r/Wt
W iin
Wt
n Model * (CVD events/ Total = 18
180/
180/2218)
0 22
2 18)
HR
R
0.61
0.61
0.72
0.772
1.000
95%CI
5%C
%CI
CI
0.29-1.28
0.29
0.
29-1
29
-1.2
-1
.28
28
00.48-1.09
0.
488-1.09
1
(R
(Reference)
Referen
e ce
en
ce)
4800
P Value HR per 1000

for Trend
mg/d
P Value
1.35
0.76-2.42
0.14
1.20
0.97-1.50
0.094
1.00
0.61-1.65
0.31
1.1
.188
1.18
00.98-1.42
.98.9
8-1.
1.42
42
0.
0.078
1.03
0.66-1.600
0.19
1.16
0.98-1.37
0.
0.085
1.10
1.1
.10
00.71-1.71
0.
71-1
71
-1.7
.711
0.066
0.06
0.
0666
1.18
1.18
11.01-1.39
.01-1.
-1.
1.39
39
0.040
0.
From Cox
Cox proportional
proportional hazardss regres
regression
e
sionn models
si
model
els stratified
stra
r tified
ed by
by trial
triall phasee and
tr
n adjusted
adju
usted
te for
or aage,
ge,, se
ge
ssex,
x,, rac
race/ethnicity,
e/ethn
e/
h icity,, cclinic,
lini
in c, an
and
nd treatment
treatment
m t as
aassignment,
signme
si
nm nt,, educ
education
du at
status, ba
smoking,
history
and
weight,
bbaseline
seli
eli
l ne weight, aalcohol
lcoholl uuse,
lc
se, smok
mo in
ing, eexercise,
xercis
xe
i e, potassium
is
potaass
s ium
um ex
eexcretion,
cretio
ti n,
n, and ffamily
amil
mi y hi
hist
sttor
oryy of
o ccardiovascular
ardiov
o as
ascular di
ddisease,
sease,
e, an
nd changes
c ange
ch
g s in w
eigh
g t, smoking,
smo
m ki
mo
k ng, and
exercise
ratio;
CV,
hazard
see during
dur
u in
ingg the
th trial
trria
iall periods.
peri
pe
riod
ods.
s Cr/wt
Cr/
r/wt
wt indicates
i di
in
dica
cate
t s creatinine/weight
c eati
cr
ati
tini
nine
nee/w
/wei
eigh
ght
h rati
ra
atio;
o;; C
V,, ccoefficient
oeff
ffi
f cien
ie t of
o vvariation;
a iaati
ar
t on;
n; HR
HR,, ha
haza
azaard
r rratio;
a io;
at
o; CI
CI,, confidence
con
onfi
nfide
denc
nce
ce interval.
i terv
in
rval.
l.
* In those
with
ose
s w
ithh att lleast
it
east
ea
st 2 uurine
rine
ri
ne eexcretions.
xccre
reti
tiion
o s.
s.
23
Figure Legends:
Figure 1. Flow diagram for TOHP follow-up.
Figure 2. Spline plot of the hazard ratio for cardiovascular disease by mean sodium excretion
expressed as mg/24hr, adjusted for covariables. P value for linearity = 0.044; p value for
nonlinearity = 0.76. Rug plot indicates distribution of sodium excretion.
24
Figure 1
20
10
Hazard Ratio
0.5
0.2
1000
Figure 2
2000
3000
4000
5000
6000
Excretion
(mg/day)
Downloaded from http://circ.ahajournals.org/Na
at BIREME
/ UNIFESP
on February 21, 2014
7000
8000
9000
Supplemental Material
2
Supplemental Table 1. Follow-up response after the Trials of Hypertension Prevention by categories of
urinary sodium excretion (mg/24hr).
<2300
2300-<3600 3600-<4800
4800
P Value
for Trend
OR per
1000
mg/d
P
Value
TOHP I
Responded/ Total (%)
189/246
(76.8)
590/775
(76.1)
427/566
(75.4)
191/257
(74.3)
47/66
(71.2)
303/407
(74.4)
341/413
(82.6)
224/281
(79.7)
0.88
0.64-1.22
0.86
0.70-1.07
1.00
(Reference)
0.82
0.63-1.07
0.95
1.01
0.84
0.93-1.09
0.88
0.62-1.26
0.85
0.68-1.06
1.00
(Reference)
0.82
0.62-1.09
0.85
1.02
0.73
0.93-1.11
1.05
0.69-1.58
0.82
0.64-1.06
1.00
(Reference)
0.84
0.62-1.15
0.96
1.01
0.85
0.91-1.12
0.39*
TOHP II
Responded/ Total (%)
Model 1
OR
95%CI
Model 2
OR
95%CI
Model 3
OR
95%CI
* From Cochran-Mantel-Haenszel analysis of trend.
From logistic regression models stratified adjusted as follows: Model 1 (phase, age, sex, race/ethnicity,
clinic, and treatment assignment), Model 2 (Model 1 variables plus education status, baseline weight,
alcohol use, smoking, exercise, potassium excretion, and family history of cardiovascular disease), and
Model 3 (Model 2 variables plus changes in weight, smoking, and exercise during the trial periods). CVD
indicates cardiovascular disease; OR, odds ratio; CI, confidence interval.
Supplemental Table 2. Cardiovascular events after the Trials of Hypertension Prevention Sensitivity
analyses of linear effects of average urinary excretions expressed in standard deviation units.
Model A
Cr/Wt (per SD)
Model B
Na (per SD)
Model C
K (per SD)
Na (per SD)
Model D
Cr/Wt (per SD)
K (per SD)
Na (per SD)
Model E
Na/Cr (per SD)
Model F
K/Cr (per SD)
Na/Cr (per SD)
Model G
Cr/Wt (per SD)
K/Cr (per SD)
Na/Cr (per SD)
HR
95% CI
1.04
0.86-1.25
0.72
1.13
0.95-1.35
0.18
0.85
1.21
0.70-1.04
1.00-1.48
0.12
0.054
1.03
0.84
1.20
0.82-1.30
0.68-1.04
0.98-1.48
0.80
0.12
0.085
1.12
0.94-1.32
0.20
0.83
1.16
0.67-1.02
0.98-1.39
0.078
0.088
1.04
0.83
1.17
0.86-1.26
0.67-1.03
0.98-1.40
0.67
0.087
0.079
From Cox proportional hazards regression models stratified by trial phase and adjusted for age, sex,
race/ethnicity, clinic, and treatment assignment, education status, baseline weight, alcohol use,
smoking, exercise, potassium excretion, and family history of cardiovascular disease, and changes in
weight, smoking, and exercise during the trial periods. Na indicates sodium; K, potassium; Cr, creatinine;
Wt, weight; HR, hazard ratio; CI, confidence interval.

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Lower Levels of Sodium Intake and Reduced Cardiovascular Risk

Nancy R. Cook, Lawrence J. Appel and Paul K. Whelton

Data Supplement (unedited) at:

Downloaded from http://circ.ahajournals.org/ at BIREME / UNIFESP on February 21, 2014

Lower Levels of Sodium Intake and Reduced Cardiovascular Risk

Journal Subject Code: Etiology:[8] Epidemiology

Association with CVD

disease. Washington, DC: The National Academies Press; 2010.

Billo N, Casswell S, Cecchini M, Colagiuri R, Colagiuri S, Collins T, Ebrahim S, Engelgau M,

Sodium Excretion (mg/24hr)

P Value HR per 1000

Figure 1. Flow diagram for TOHP follow-up.

Downloaded from http://circ.ahajournals.org/ at BIREME / UNIFESP on February 21, 2014

* From Cochran-Mantel-Haenszel analysis of trend.

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