Original

2012 Dustri-Verlag Dr. K. Feistle

ISSN 0946-1965
DOI 10.5414/CP201724
e-pub: April 27, 2012
Received
February 13, 2012;
accepted
March 13, 2012
Correspondence to
Prof. Ton Cleophas, MD,
PhD
Dept Medicine, Albert
Schweitzer Hospital, PO
Box 444, 3300 AK
Dordrecht, Netherlands
a.j.m.cleophas@asz.nl
Key words
meta-analysis salt
intake potassium
supplementation
hypertension
Potassium treatment for hypertension in
patients with high salt intake: A meta-analysis
Eric van Bommel
1
and Ton Cleophas
1,2
1
Department Medicine, Albert Schweitzer Hospital, Dordrecht, The Netherlands,
and
2
European College Pharmaceutical Medicine, Lyon, France
Abstract. Background: Previous meta-
analyses of potassium supplementation in pa-
tients with hypertension observed little or no
beneft, but failed to account the amount of salt
intake. Objective: To assess the effect on blood
pressure of potassium treatment in patients
with high salt intake. Methods: We meta-ana-
lyzed studies of patient populations with both
high salt and potassium intake. We searched
Medline, Google, major journals, Pubmed.
Publication bias, lack of heterogeneity, and
lack of robustness were assessed using stan-
dard procedures for such purposes. Results:
After the exclusion of 32 studies 10 studies
were left in the meta-analysis. A pooled reduc-
tion of systolic blood pressure of 9.5 mmHg
(95% confdence interval 10.8 to 8.1) and of
diastolic blood pressure 6.4 mmHg (7.3 to
5.6) was observed. These results were very
heterogeneous (I
2
-values of 94 and 95%). After
exclusion of single authored studies the results
fell but remained statistically signifcant, 7.1
mmHg (8.5 to 5.7), and 4.9 mmHg (5.8
to 4.0). Heterogeneity of systolic blood pres-
sure was no longer observed (I
2
-value 24.3%).
Some publication bias was observed. Conclu-
sions: 1. Potassium treatment reduces the blood
pressure substantially in hypertensive patients
with salt-rich diets. 2. The difference in magni-
tude of blood pressure reduction between dif-
ferent studies is probably related to the amount
of salt intake. 3. Patients with reduced salt in-
take beneft little from potassium treatment. 4.
Major meta-analyses published to date have
severely underestimated the potential beneft
of potassium treatment in patients with hyper-
tension.
Introduction
An early double-blind placebo controlled
trial found a mean decrease in systolic and
diastolic blood pressure of respectively 41
and 17 mmHg after 16-week treatment with
potassium supplementation [1]. Effects of
similar magnitude were not found by others,
but, nonetheless, a meta-analysis in JAMA
could conclude that potassium supplementa-
tion signifcantly reduced both systolic and
diastolic blood pressure with a pooled result
of 3 and 2 mmHg in 2,609 patients [2].
The authors also found that the higher the
sodium intake the greater the magnitude of
blood pressure reduction. These results were
challenged by a recent Cochrane meta-anal-
ysis that found no signifcant beneft from
potassium treatment, but salt intake was not
taken into account in this study [3].
Salt intake may, indeed, be a major co-
factor of the effects of potassium-intake as
suggested in several recent benchmark re-
views [4, 5]. Sodium-potassium pumps are
important for maintaining the water and elec-
trolyte homeostasis of the body. With much
sodium intake we may need much potassium
to get rid of the superfuous sodium, in order
to prevent water intoxication and volume-
related hypertension.
In this paper we took issue with these
assumptions, and tried to assess the hypoth-
esis that potassium supplementation would
be particularly effcacious for the treatment
of hypertension in patients with high salt-
intake. For that purpose we meta-analyzed
papers of patient populations with both high
salt and potassium intake.
Methods
We searched Medline, Google, ma-
jor journals, and Pubmed, as well as refer-
ence lists of selected articles on the subject.
Search terms were potassium supplementa-
tion, salt intake, hypertension. Studies were
included if they stated that patients were un-
treated, and had a salt intake of more than
International Journal of Clinical Pharmacology and Therapeutics, Vol. 50 No. 7/2012 (478-482)
Potassium treatment for hypertension in patients with high salt intake, a meta-analysis 479
170 mmol/24 h or, simply, stated high salt
intake. As black and Chinese populations
have a salt intake well over that amount [6,
7], studies largely consistent of such popu-
lations were included, even if they did not
measure the amount of salt-intake.
The endpoints of this analysis were the
impact of potassium supplementation on the
reduction of both systolic and diastolic blood
pressure.
Publication bias was assessed by Christ-
mas tree plots [8], heterogeneity was assessed
by fxed effects tests for heterogeneity and I
2
-
values [9], robustness was assessed by meta-
analyzing higher and lower quality studies
separately with the presence of multiple au-
thors as criterion of high quality [19]. For the
purpose single and multiple authored papers
were analyzed separately.
Statistical analysis
Let x
1
, x
2
, ..., x
k
be the mean reductions
in systolic and diastolic blood pressures of
the separate studies. The weighted average
reductions were calculated as
X
w
w x
w
i
i
k
i i
i
k
1
1
=
=
=
/
/
and their standard errors are
( )
( ) ( )
se X
w
w Var x
/
w
i
i
k
i
k
1
2
2
1
1
1 2
=
=
=
R
T
S
S
S
SS
;
V
X
W
W
W
WW
E /
/
The weight w
i
is a function of the stan-
dard error of x
i
, denoted as se(x
i
):
( ( ) )
w
se x
1
i
1
2
=
Heterogeneity was assessed with Co-
chrans Q-test where the test statistic Q fol-
lows a c
2
-distribution and is given by the
equation:
( ) w x X i
i
k
w
1
1
2
-
=
/
I
2
-statistic was calculated by the equa-
tion:
% ( ) / I Q k Q 100 1
2
= - - 6 @
50% was used as a cut-off for heteroge-
neity.
Results
Table 1 shows the characteristics of the
10 studies [1, 10, 11, 12, 13, 14, 15, 16, 17,
18] after the exclusion of 32 studies that did
not meet the above criteria for inclusion. In
all of the studies patients on antihypertensive
drugs were excluded. Column 7 shows salt
intake as estimated by the authors. Some of
the estimates were based on sampling, but
most were based on the judged salt intake
levels based on ethnicity.
The Tables 2 and 3 show a pooled reduc-
tion of systolic blood pressure of 9.5 mmHg
(95% confdence interval (CI) 10.8 to 8.1)
and of diastolic blood pressure 6.4 mmHg
(95% CI 7.3 to 5.6). These results were very
heterogeneous with I
2
-values of 94 and 95%.
After exclusion of single-authored stud-
ies (Tables 4, 5) the pooled results were
somewhat less impressive but remained sta-
tistically very signifcant, 7.1 mmHg (8.5
to 5.7), and 4.9 mmHg (5.8 to 4.0). In
the pooled systolic blood pressure data the
presence of heterogeneity could now be re-
jected with an I
2
-value of 24.3%.
Figure 1 shows a Christmas tree plot of
the systolic blood pressure reductions of the
separate studies. Small studies with small
results are obviously missing. This is com-
patible with the presence of some publica-
tion bias. No quantitative analyses were per-
formed here, because of the small number of
studies.
Discussion
In this meta-analysis, a pooled reduction
of both systolic and reduction of 9.5 and 6.4
mmHg, respectively, was observed. This is
much more than the pooled results of pre-
vious meta-analyses [2, 3]. However, these
meta-analyses failed to take salt intake into
van Bommel and Cleophas 480
account, and many hypertensive patients are
currently sodium depleted as a consequence
of previous treatment with thiazides either
separately or included in composite formula-
tion drugs, and such patients may less beneft
from potassium treatment.
The magnitude of the blood pressure re-
duction, as observed in our study, is largely
similar to that of most modern antihyperten-
sive treatments, and potassium supplementa-
tion seems, therefore, to serve as an adequate
therapeutic alternative for these patients.
The heterogeneity between the studies may
be due to their different levels of salt intake.
This is supported by the observed lack of
heterogeneity of systolic blood pressures af-
ter removing the study with the largest an-
tihypertensive effect and, probably, also the
largest salt intake.
Hypertension is the frst killer worldwide
[4], and under-treatment is common [4, 20].
Particularly, hypertensive patients lack, no-
toriously, compliance with non-drug treat-
ments including salt intake reduction [21].
According to the current study an alternative
and, maybe, better solution might be to pre-
scribe potassium supplementation, especially
to patients with high salt intake. Potassium,
obviously, exerted a benefcial effect in these
patients. The benefcial effects of potassium
increasing drugs like potassium increasing
diuretics, renin angiotensin blockers, and
aldosterone inhibitors may at least be partly
due to the same mechanism. Additional ad-
vantages of potassium supplementation is
that it seems to have added cardiovascular
Table 1. Studies included in the meta-analysis, study characteristics.
N Design Age Gender Co-med Salt intake Race
1. McGregor 1982 [10] 23 crossover adult m/f no high salt intake 20% Blacks, 30% Asia (Charing
Cross Hospital London)
2. Siani 1987 [11] 37 parallel 21 61 m/f no > 170 mmol Caucasians
3. Svetkey 1987 [12] 101 parallel 51 12 m/f no high salt intake Blacks twice as many as the US
average (Durham, NC)
4. Krishna 1989 [13] 10 crossover adult m no 200 mmol Caucasians
5. Obel 1989 [1] 48 parallel 20 60 m/f no > 170 mmol Blacks
6. Patki 1990 [14] 37 crossover 49 8 m/f no 192 mmol Asians
7. Fotherby 1992 [15] 18 crossover 66 79 m/f no high salt intake Caucasians with low renin hyperten-
sion consistent with high salt intake
8. Brancati 1996 [16] 87 parallel 37 65 m/f no high salt intake African Americans
9. Gu 2001 [17] 150 parallel 35 64 m/f no high salt intake Chinese
10. Sarkkinen 2011 [18] 45 parallel 25 75 m/f no high salt intake Caucasians
Co-med = concomitant medication; m/f = male/female.
Table 2. Meta-analysis of the difference in systolic blood pressures (mmHg)
in patients treated with potassium vs. those with placebo, in 556 patients, fol-
low-up 8 16 weeks.
N Difference systolic Standard error
1. McGregor 1982 [10] 23 7.0 3.1
2. Siani 1987 [11] 37 14.0 4.0
3. Svetkey 1987 [12] 101 6.4 1.9
4. Krishna 1989 [13] 10 5.5 3.8
5. Obel 1989 [1] 48 41.0 2.6
6. Patki 1990 [14] 37 12.1 2.6
7. Fotherby 1992 [15] 18 10.0 3.8
8. Brancati 1996 [16] 87 6.9 1.2
9. Gu 2001 [17] 150 5.0 1.4
10. Sarkkinen 2011 [18] 45 11.3 4.8
Pooled difference = 9.48 (95% CI 10.82 to 8.13); c
2
-value = 206.9; p-value
= < 0.0001. Heterogeneity c
2
-value = 152.6, 9 degrees of freedom, p < 0.0001.
I
2
-value = 94.1% (< 50% cut-off for no heterogeneity).
Table 3. Meta-analysis of the difference in diastolic blood pressures (mmHg)
in patients treated with potassium vs. those with placebo, in 556 patients, fol-
low-up 8 16 weeks.
N Difference diastolic Standard error
1. McGregor 1982 [10] 23 4.0 2.5
2. Siani 1987 [11] 37 10.5 3.0
3. Svetkey 1987 [12] 101 4.1 1.1
4. Krishna 1989 [13] 10 7.4 3.0
5. Obel 1989 [1] 48 17.0 1.2
6. Patki 1990 [14] 37 13.1 1.0
7. Fotherby 1992 [15] 18 6.0 3.0
8. Brancati 1996 [16] 87 2.5 0.9
9. Gu 2001 [17] 150 0.6 0.9
10. Sarkkinen 2011 [18] 45 4.5 3.2
Pooled difference = 6.42 (95% CI 7.25 to 5.59); c
2
-value = 230.4; p-value
= < 0.0001. Heterogeneity c
2
-value = 190.7, 9 degrees of freedom, p < 0.0001.
I
2
-value = 95.3% (< 50% cut-off for no heterogeneity).
Potassium treatment for hypertension in patients with high salt intake, a meta-analysis 481
benefts including the prevention of stroke,
renal failure, and cardiac arrhythmias [22].
In contrast, potassium treatment is, of
course, deleterious in patients with substan-
tial renal failure as commonly observed in el-
derly. Some physicians may fnd it hazardous
to prescribe potassium supplements without
accurate monitoring, and might prefer po-
tassium-enriched diets as a safe alternative.
The DASH (Dietary Approaches to Stop Hy-
pertension) trial [23] prospectively tested in
hypertensive patients a potassium-enriched
diet against control, and found systolic and
diastolic blood pressure reduction of 11.4
and 5.5 mmHg, respectively. This effect
seems even larger than the one observed in
our study. However, the potassium-enriched
diet in DASH also contained more constitu-
ents like fber, protein, caretenoid and folate,
and less total fat, saturated fat, and choles-
terol. This may have contributed to an addi-
tional antihypertensive effect. Nonetheless, a
potassium-enriched diet seems a good alter-
native to potassium tablets, and in addition,
it is simple. It just requires some fruit and
vegetables.
Conclusions
1. Potassium reduces the blood pressure
substantially in hypertensive patients with
salt-rich diets.
2. The difference in magnitude of blood
pressure reduction between different studies
is related to the amount of salt intake.
3. Patients with reduced salt intake ben-
eft little from potassium.
4. Major meta-analyses published to date
have severely underestimated the potential
beneft of potassium treatment in patients
with hypertension.
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Table 4. Meta-analysis of the difference in systolic blood pressures (mmHg)
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they are at risk of not being published, and, thus,
suggests the presence of some publication bias.
van Bommel and Cleophas 482
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