AJH 2006; 19:750 –755
Efficacy of Add-On Aldosterone
Receptor Blocker in Uncontrolled Hypertension
Yehonatan Sharabi, Eldad Adler, Ari Shamis,
Naomi Nussinovitch, Avinoam Markovitz, and Ehud Grossman
Background: Uncontrolled hypertension (UH) may
be caused by hyperaldosteronism, and some experts rec-
ommend the routine use of aldosterone antagonists in this
condition. The purpose of this study was to evaluate the
efficacy of this approach and to characterize those who
respond effectively to an add-on aldosterone antagonist.
Methods: We retrospectively analyzed the effective-
ness of spironolactone, an aldosterone antagonist, used as
add-on therapy, compared with a standard add-on treat-
ment, in patients referred to a hypertension clinic with UH
despite the use of two or more antihypertensive drugs.
Results: A total of 340 patients (186 male) with an
average age of 63 ⫾ 14 years were followed for at least 3
months. Of the patients, 42 received add-on spironolac-
tone and 298 received an additional antihypertensive drug
other than spironolactone. Baseline characteristics were
similar in both groups. Blood pressure (BP) decreased
significantly in both groups. In patients who received
spironolactone, BP decreased by 23.2/12.5 mm Hg from
C
ontrolling hypertension is an important health con-
cern around the globe, as it is associated with a
significant reduction of cardiovascular morbidity and
mortality. Yet the rate of blood pressure (BP) control is low.
The prevalence of uncontrolled hypertension (UH) varies in
accordance with aspects of the clinical setting such as clinic
type and the medical history of the population studied.1
Several factors underlie the difficulty in controling BP, such
as inadequate combination of drugs, poor patient compliance,
and drug interactions. In many cases, UH results from sec-
ondary hypertension, of which the most common forms in-
volve sleep apnea, obesity, and hyperaldosteronism.2– 4
The prevalence of hyperaldosteronism has increased
dramatically over the last two decades. This increase may
be related to the availability of accurate assays for plasma
Received September 22, 2005. First decision November 15, 2005. Ac-
cepted November 16, 2005.
From the Hypertension Unit and Internal Medicine D, Chaim
Sheba Medical affiliated to the (YS, EA, AS, NN, AM, EG) Chaim
Sheba Medical Center, Tel Hashomer; Sackler Faculty of Medicine,
Tel Aviv University, Tel Aviv, Israel; and Clinical Neurocardiology
0895-7061/06/$32.00
doi:10.1016/j.amjhyper.2005.11.016
165 ⫾ 27/94 ⫾ 15 to 142 ⫾ 25/81 ⫾ 9 mm Hg, whereas
in patients who received other add-on therapy BP de-
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creased by 7.6/5.8 mm Hg from 160 ⫾ 24/91 ⫾ 12 to 152
⫾ 20/85 ⫾ 11 mm Hg (P ⬍ .05). Patients who received
spironolactone had lower serum potassium levels than
those who did not receive spironolactone 3.8 ⫾ 0.4 v
4.5 ⫾ 0.5 mmol/L respectively (P ⬍ .001). Potassium
levels ⬍4 mmol/L were associated with a greater re-
duction in BP.
Conclusions: Add-on spironolactone is a highly ef-
fective add-on treatment in UH, mainly in patients with
low serum potassium levels. Further studies assessing
serum potassium as a marker for treatment approach are
needed to establish the role of aldosterone antagonists in
the management of UH. Am J Hypertens 2006;19:
750 –755 © 2006 American Journal of Hypertension, Ltd.
Key Words: Spironolactone, uncontrolled hyperten-
sion, renin, aldosterone, potassium.
aldosterone and renin activity, the use of a liberal criterion
of aldosterone:renin ratio to diagnose hyperaldosteronism,
and the increased awareness of this condition.5 The prev-
alence of hyperaldosteronism ranges between 0.3% and
1% in general practice clinics and between 0.5% and 12%
in hypertension specialty settings.5–11 Recent data suggest
that the prevalence might be even higher. Fardella et al
found that 9.5% of 305 patients with essential hyperten-
sion were diagnosed with primary aldosteronism accord-
ing to rigorous biochemical criteria.6 Moreover, the
prevalence of hyperaldosteronism is particularly high in
cases of resistant hypertension (RH).12 Calhoun et al
found a prevalence of 20% in the setting of a referral
center,11 and Eide et al found a low-renin state in two
thirds of patients with resistant hypertension.13
(YS), National Institute for Neurological Disorder and Stroke, Na-
tional Institutes of Health, Bethesda, Maryland.
Address correspondence and reprint requests to Dr. Yehonatan
Sharabi, Clinical Neurocardiology Section, National Institute for Neuro-
logical Disorder and Stroke, National Institutes of Health, 10 Center
Drive, Bldg 10/6N252, Bethesda, MD 20892-1620.
© 2006 by the American Journal of Hypertension, Ltd.
Published by Elsevier Inc.
AJH–July 2006 –VOL. 19, NO. 7 ALDOSTERONE RECEPTOR BLOCKERS IN UNCONTROLLED HYPERTENSION 751

These data suggest that overactivity of aldosterone may Data Analysis

contribute to the pathogenesis of UH, even when strict
The study population was divided into two groups accord-
criteria for the diagnosis of hyperaldosteronism do not
ing to the additional treatment: 1) those who had been
exist. Indeed it has been recently shown that aldosterone
given spironolactone (Spirono⫹) and 2) those who had
plays a role in the pathogenesis of essential hypertension.14
been given any other antihypertensive drug (Spirono⫺).
Moreover it has been shown that aldosterone antagonists
Results are presented as average ⫾ standard deviation. An
(AA) are very effective in UH patients, regardless of the
unpaired Student t test was used to compare continuous
presence of hyperaldosteronism, and that BP reduction with
variables, and a ␹2 test was used to compare parametric
spironolactone is similar among patients with and without
variables between the groups. A paired Student t test was
hyperaldosteronism.15 Some experts therefore recommend
used to assess BP response to treatment. To compare BP
adding spironolactone in cases of multidrug-resistant hy-
responses in patients who received spironolactone versus
pertenstion.16,17 Therefore the aim of this study was to
those who did not receive this agent, an unpaired Student
evaluate the efficacy of the aldosterone receptor blocker
t test for the differences was applied. A value of P ⬍ .05

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spironolactone, as the add-on drug, in patients who were
referred to our hypertension clinic with UH despite the use
of two or more antihypertensive medications. We also
aimed to characterize the factors that predict BP response
to AA.
Patients and Methods
A retrospective interventional study was conducted in the
hypertension clinic of the Chaim Sheba Medical Center,
Tel Hashomer, Israel. We analyzed the data of patients
who were referred to our hypertension clinic and were
seen by a hypertension specialist during the first quarter of
2003. Eligible patients for this study were those with
essential hypertension who were treated with two or more
antihypertensive medications and repeatedly had systolic
BP (SBP) ⬎140 mm Hg and diastolic BP (DBP) ⬎90 mm
Hg. Patients with confirmed hyperaldosteronism or clini-
cally suspected of having other causes of secondary hy-
pertension were not included in this analysis. After an
initial work-up, patients received additional antihyperten-
sive treatment at the discretion of the treating specialist
based on the patients’ clinical condition. Patients were
followed for at least 3 months.
was considered to be statistically significant.
Results
Patient Characteristics
The study population was comprised of 340 patients (186
men and 154 women) with UH, who were referred to the
hypertension clinic at the Chaim Sheba Medical Center,
Tel Hashomer Israel. The average age was 63 ⫾ 14 years,
and 80% were overweight. Among patients ⬍59 years of
age, men predominated. Most patients were initially taking
␤-blockers, angiotensin-converting enzyme inhibitors, cal-
cium channel blockers (CCB), or diuretics, or a combina-
tion of these (Fig. 1).
A total of 42 patients received spironolactone
(Spirono⫹ group) 12.5 to 25 mg as add-on therapy, and
298 patients (Spirono⫺ group) received additional one or
more drugs other than spironolactone. The drugs most
commonly were CCB (27%), ␣-blockers (23%), thiazide
diuretics (16%), blockers of the renin-angiotensin system
(ie, angiotensin-converting enzyme inhibitors or angioten-
sin-receptor blockers; 11%), and ␤-blockers (9%). Both
groups were similar in age, sex distribution, height, weight,

Data Collection
Antihypertensive treatemt at entry
Demographic and clinical characteristics of each subject
was recorded. Blood samples for laboratory work-up in- Spirono+ Spirono-
cluding lipid profile, renal function, and electrolytes were 70
* P < 0.05 vs. Spirono-
taken after overnight fasting. Diabetes mellitus was de- 60 *
% of patients

50 *
fined as being present if patients used hypoglycemic *
40
agents or if fasting blood glucose levels were repeatedly
30
ⱖ126 mg/dL. Chronic renal failure was defined as plasma 20
creatinine ⬎1.4 mg/dL for men and ⬎1.2 mg/dL for 10
women. 0
The BP was recorded at least on two occasions before cs er
s EI
s
HP P Bs ers
eti ck AC BD DH AR ck
ur BN
intervention and at the end of the follow-up period, and the Di a blo CC CC a blo
t ph
Be Al
levels were averaged. Both SBP and DBP were measured Drug class
according to American Heart Association guidelines, us- FIG. 1. Antihypertensive therapy at entry according to the study
ing a mercury column sphygmomanometer. The BP was group: add-on spironolactone (Spirono⫹) and control (Spi-
measured twice each time by skilled, trained physicians rono⫺). ACEI ⫽ angiotensin-converting enzyme inhibitors; ARB ⫽
angiotensin 2 receptor blockers; CCB/DHP ⫽ calcium channel
after the patient has rested 5 min in the sitting position, and blockers/dihidropiridines; CCB/NDHP ⫽ calcium channel block-
the average of the measurements was recorded. ers/nondihydropyridines.
752 ALDOSTERONE RECEPTOR BLOCKERS IN UNCONTROLLED HYPERTENSION AJH–July 2006 –VOL. 19, NO. 7

Table 1. Baseline characteristics of the group re- 68%, and 24% for SBP, DBP, and both, respectively (P ⬍
ceiving add-on spironolactone (Spirono⫹) and the .05 between groups).
control group (Spirono⫺)
Serum Potassium and
Spiroⴙ Spiroⴚ P Responsiveness to Spironolactone
Characteristic (n ⴝ 42) (n ⴝ 298) value
Age (y) 62 ⫾ 12 63 ⫾ 14 NS At the end of the follow-up, the average potassium levels
Male (%) 64% 54% NS increased significantly from 3.8 ⫾ 0.4 to 4.3 ⫾ 0.4
Diabetes mellitus 38% 24% ⬍.05 mmol/L (P ⬍ .05) among the Spirono⫹ group and re-
CRF 21% 9% ⬍.05 mained the same (4.5 ⫾ 0.5 mmol/L) in the Spirono⫺
Dyslipidemia 90% 72% NS
group. The BP reduction after the addition of spironolac-
IHD 17% 16% NS
History of stroke 10% 11% NS tone was significantly greater among 21 patients with
PVD 19% 19% NS initial serum potassium levels ⬍4 mmol/L than among
those with initial potassium levels ⱖ4 mmol/L (28 ⫾

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CRF ⫽ chronic renal failure; IHD ⫽ ischemic heart disease; PVD ⫽
peripheral vascular disease.
heart rate, and BP at the beginning of the follow-up period
(Tables 1 and 2). Patients who received spironolactone had
a greater prevalence of diabetes mellitus and on average a
greater left ventricular mass (Tables 1 and 2). These pa-
tients were also more likely to be treated with CCB and
diuretics at entry than were the control subjects (Fig. 1).
The Spirono⫹ group had, on average, slightly higher
plasma creatinine levels as well as lower potassium levels
than the Spirono⫺ group (Table 3). In addition, 50% of
the Spirono⫹ group had serum potassium levels ⬍4
mmol/L compared with 12.4% in the Spirono⫺ group.
Efficacy of Add-On Spironolactone
All patients tolerated spironolactone well, and only one pa-
tient developed transient hyperkalemia. During follow-up,
both SBP and DBP decreased significantly (P ⬍ .05 v
baseline) (Fig. 2). The BP decreased by 23.2/12.5 mm Hg
from 165 ⫾ 27/94 ⫾ 15 to 142 ⫾ 25/81 ⫾ 9 mm Hg in
patients who received spironolactone, whereas it decreased
by 7.6/5.8 mm Hg from 160 ⫾ 24/91 ⫾ 12 to 152 ⫾ 20/85
⫾ 11 mm Hg in those who received other add-on therapy
(P ⬍ .05 between the group). At the end of the follow-up,
54.7% of the Spirono⫹ group achieved the SBP goal of
⬍140 mm Hg, 78.6% achieved the DBP goal of ⬍90, and
50% achieved both SBP and DBP control. For the Spi-
rono⫺ group the corresponding control rate was 26%,
17/13 ⫾ 25 mm Hg in patients with low potassium levels
compared with 14 ⫾ 13/ 4 ⫾ 11 in those with normal
potassium levels; P ⫽ .04 for SBP and P ⫽ 0.01 for DBP).
Discussion
Treating UH is a challenge for both physicians and pa-
tients. The high prevalence of hyperaldosteronism has led
some clinicians to suggest treating these patients with
add-on aldosterone-receptor antagonist, even without evi-
dence of hyperaldosteronism. In this study we have retro-
spectively evaluated such an approach and characterized
the patients who received spironolactone compared with
those who received other types of drugs. Our findings
clearly demonstrated high efficacy of add-on spironolac-
tone. The patients had some suggestion of subclinical
hyperaldosteronism (such as low-normal serum potassium
levels, slightly more severe hypertension, and greater left
ventricular mass) than those who did not receive spirono-
lactone. This may explain why hypertension specialists
choose to add spironolactone.
The suggestion to use add-on spironolactone in UH
even without evidence of hyperaldosteronism derived
from a study in which spironolactone was added to the
drug regimen of patients with UH. The SBP and DBP
decreased by 25 mm Hg and 15 mm Hg respectively in
subjects with hyperaldosteronism and by 26 mm Hg and
11 mm Hg in subjects without hyperaldosteronism.15 In
fact the British Hypertension Society guidelines included
in their algorithm aldosterone antagonist as a step 4 drug

Table 2. Baseline hemodynamic characteristics of the group receiving add-on spironolactone (Spirono⫹)
and the control group (Spirono⫺)

Characteristic Spiroⴙ (n ⴝ 42) Spiroⴚ (n ⴝ 298) P value

BMI (kg/m ) 2
30.6 ⫾ 7 28.8 ⫾ 5.4 NS
Baseline SBP (mm Hg) 166 ⫾ 27 160 ⫾ 24 NS
Baseline DBP (mm Hg) 94 ⫾ 15 91 ⫾ 12 NS
Baseline HR (beats/min) 70 ⫾ 9 68 ⫾ 11 NS
IVS per echo (mm) 1.18 ⫾ 0.16 1.09 ⫾ 0.19 ⬍.05
LV mass per echo (g/m2) 136 ⫾ 43 117 ⫾ 30 ⬍.05
BMI ⫽ body mass index; DBP ⫽ diastolic blood pressure; HR ⫽ heart rate; IVS ⫽ interventricular septum; LV ⫽ left ventricular; SBP ⫽ systolic
blood pressure.
AJH–July 2006 –VOL. 19, NO. 7 ALDOSTERONE RECEPTOR BLOCKERS IN UNCONTROLLED HYPERTENSION 753

Table 3. Baseline biochemical characteristics of the group receiving add-on spironolactone (Spirono⫹) and
the control group (Spirono⫺)

Characteristic Spiroⴙ (n ⴝ 42) Spiroⴚ (n ⴝ 298) P value

Fasting glucose (mg/dL) 112 ⫾ 27 111 ⫾ 47 NS
HbAlc (%) 6.1 ⫾ 0.4 7.4 ⫾ 1.9 NS
Creatinine (mg/dL) 1.14 ⫾ 0.3 1.04 ⫾ 0.3 .04
Sodium (mEq/L) 142 ⫾ 3 141 ⫾ 4 NS
Potassium (mEq/L) 3.8 ⫾ 0.4 4.5 ⫾ 0.5 ⬍.0001
Total cholesterol (mg/dL) 208 ⫾ 37 210 ⫾ 37 NS
Triglycerides (mg/dL) 156 ⫾ 68 159 ⫾ 74 NS
HDL cholesterol (mg/dL) 45 ⫾ 12 48 ⫾ 14 NS
LDL cholesterol (mg/dL) 133 ⫾ 37 128 ⫾ 31 NS

HbAlc ⫽ hemoglobin A1C; HDL ⫽ high-density lipoprotein; LDL ⫽ low-density lipoprotein.

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for UH regardless of the presence of hyperaldosteron-
ism.17 Our study reinforces this recommendation, partic-
ularly in patients who have low-normal potassium levels
or who show echocardiographic or electrocardiographic
signs of left ventricular hypertrophy. It is noteworthy that
some of the patients with UH who received add-on spi-
ronolactone were already taking a thiazide diuretic, and
the relatively low-potassium levels could be attributed to
the diuretic use. We did not discontinue the thiazide while
adding spironolactone.
One unresolved question is whether every patient with
UH should have a plasma renin:aldosterone ratio deter-
mined to diagnose hyperaldosteronism before an aldoste-
rone receptor antagonist can be offered. Although the
plasma renin:aldosterone ratio is becoming the standard
screening test to identify hyperaldosteronism, some re-
ports suggest that it still has limited accuracy along with
suboptimal sensitivity and specificity.18,19 In a recent
FIG. 2. Systolic blood pressure (SBP) and diastolic blood pressure
(DBP) levels at baseline and at the end of follow-up according to the
study group: add-on spironolactone (Spirono⫹) and control (Spi-
rono⫺). *P ⬍ .05 v baseline.
study, the efficacy of aldosterone given to uncontrolled
hypertensive patients with renin:aldosterone ratio of 400
was evaluated.20 It was found that 14% of the subjects had
normal aldosterone levels, yet the BP still fell by 26/11
mm Hg. Therefore the need to determine the renin:aldo-
sterone ratio before treatment with AA is questionable. On
the other hand, Nishizaka et al21 suggested that despite its
high false-positive rate, the renin:aldosterone ratio still has
clinical value in the diagnosis of hyperaldosteronism. In
most of our patients, we added spironolactone without
measuring the renin:aldosterone ratio, because the patients
had severe hypertension despite treatment with two or
more drugs, and at that time we considered it unsafe to
withdraw treatment simply to measure renin and aldoste-
rone. It is important to note that Nishizaka et al21 recently
reported that the renin:aldosterone ratio is valid as a
screening test for hyperaldosteronism even in patients
whose BP values are stable with antihypertensive treat-
ment. Clinical judgment, mostly driven by the potassium
levels, was sufficient evidence to offer spironolactone,
which eventually proved to be highly effective in control-
ling BP. The concern raised regarding the usefulness (or
lack thereof) of screening for primary aldosteronism22 and
its clinical implications,19 and the overall efficacy of spi-
ronolactone even in patients without hyperaldosteronism,
may lead to routine use of the criterion of low or low-
normal potassium levels as an indication for spironolac-
tone therapy in multidrug-resistant hypertension.
In our study population, definitive hypokalemia (potas-
sium level ⬍3.5 mmol/L) was relatively rare, but 50% of
patients who received spironolactone had serum potassium
levels ⬍4 mmol/L. Recently it has been shown that hy-
pokalemia is not as common as previously thought in
hyperaldosteronism, and many patients with hyperaldoste-
ronism have normal potassium levels.6,10,12,20 In our study
population, the response to spironolactone was signifi-
cantly better in patients with potassium levels ⬍4 mmol/L
than in those with potassium levels ⱖ4 mmol/L. Whether
this reflects a higher prevalence of subtle hyperaldosteron-
ism or a higher renin:aldosterone ratio is not known.
Regardless of the reason, it seems that serum potassium
754 ALDOSTERONE RECEPTOR BLOCKERS IN UNCONTROLLED HYPERTENSION
may predict an improved response to spironolactone.
Moreover the selection of patients on the basis of low-
normal potassium levels may lower the risk of developing
hyperkalemia. In our cohort, patients who were already
taking a thiazide remained on this regimen while adding
AA. This cautious approach may explain the low rate of
clinically hazardous hyperkalemia23 and why only one
patient in our cohort developed hyperkalemia. It seems
that when the decision to add AA is based on baseline
serum potassium, renal function and concomitant medica-
tions, the risk of developing hyperkalemia is relatively
low. This is a practical lesson that one may take from our
report.
The importance of the aldosterone antagonist surpasses
its ability to control BP. Aldosterone promotes renal so-
dium retention,24 potentiates the actions of angiotensin II,25
impairs endothelial function,26 and reduces vascular compli-
ance.27 In addition, aldosterone may promote hypertension
through central nervous system mechanisms.28 As a con-
sequence, at least in selected patients with hyperaldoste-
ronism, spironolactone is shown to have antihypertrophic,
anti– cardiac fibrosis properties as well as potentially to
improve endothelial function; these pathologic conditions,
if untreated, collectively and individually link hyperten-
sion to its deleterious cardiovascular consequences.29
The use of spironolactone is limited by its side effects,
mainly gynecomastia. This usually occurs after long-term
therapy and is dose-dependent, with a high prevalence if
ⱖ50 mg of spironolactone is used. In our study, no patient
complained of gynecomastia. It is possible that it is be-
cause of the short duration of follow-up and the relatively
low doses that were used. The introduction of the new
selective aldosterone antagonist eplerenone may reduce
the clinical side effects in men.30,31 Thus wide use of
aldosterone antagonists in selected patients, guided by po-
tassium levels, may improve BP control in patients with UH.
Study Limitations
It is noteworthy that there was a small but statistically
significant difference in baseline creatinine levels between
the two groups and that this may be a confounding factor.
In addition this was a retrospective study, and therapy was
based solely on the clinical judgment of the hypertension
specialist in a referral center. Therefore the applicability of
our experience to the primary care setting might be lim-
ited. Also the recommendations should be taken with
caution, as the population sample is too small to draw
clinically significant conclusions. A prospective study is
required to confirm the approach of adding aldosterone
antagonists to patients with UH who have low-normal
serum potassium levels and whose measured renin: aldo-
sterone ratios have not been measured.
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