European Journal of Internal Medicine 24 (2013) 303–309

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European Journal of Internal Medicine

journal homepage: www.elsevier.com/locate/ejim

Review article

Evolving strategies for the use of spironolactone in

cardiovascular disease
Oscar M.P. Jolobe ⁎
Manchester Medical Society, Room 4.54 Simon Building, Brunswick Street, Manchester M13 9PL, United Kingdom

a r t i c l e i n f o a b s t r a c t

Article history: The evolution of strategies for the use of spironolactone and its analogue, eplerenone, has, over the years,
Received 13 June 2012 encompassed favourable modification of the natural history of symptomatic heart failure in subjects with
Received in revised form 11 November 2012 subnormal left ventricular ejection fraction (LVEF), and mitigation of the risk of new-onset atrial fibrillation
Accepted 12 November 2012
in mildly symptomatic systolic heart failure. Given the fact that these benefits might be attributable, at least
Available online 12 December 2012
in part, to mitigation of severity of diastolic dysfunction when the latter co-exists with subnormal LVEF,
Keywords:
what needs to be explored is the possibility of similar benefits from the use of these agents in patients
Spironolactone such as those with hypertension, and aortic valve stenosis, in whom left ventricular dysfunction is of the
Systolic predominantly diastolic subtype.
Diastolic © 2012 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
Dysfunction
Atrial
Fibrillation

1. Introduction 2. Evolving strategies for the use of spironolactone in

The rationale for the successful use of spironolactone and eplerenone,
respectively, for mitigating the risk of new-onset atrial fibrillation, clinical
deterioration, and death, in heart failure patients is to antagonise the
deleterious effects of activation of the renin–angiotensin–aldosterone sys-
tem (RAAS). Although these benefits have been shown only in heart fail-
ure patients with subnormal LVEF there is sufficient circumstantial
evidence to support the proposition that a similar benefit might be
generated by the use of these agents in patients with predominantly
diastolic left ventricular dysfunction. In addition to summarising
current indications for the use of these agents, the aim of this review
is to make a case for exploring the possibility that similar benefits
might be generated by the inclusion of these agents in the therapeu-
tic armamentarium for disorders such as hypertension, and aortic
valve stenosis, which are characterised by predominantly diastolic
left ventricular dysfunction.
Furthermore, given the almost universal use of loop diuretics in
symptomatic heart failure, regardless of left ventricular dysfunction
subtype, there is huge scope for coprescription of aldosterone antago-
nists to ameliorate the severity of diuretic-related neurohormonal acti-
vation in the hope that this might improve survival and mitigate the risk
of diuretic-related deterioration of renal function.
⁎ 1 Philip Godlee Lodge, 842 Wilmslow Road, Manchester M20 2DS, United Kingdom.
Tel.: +44 161 448 9034.
E-mail address: oscarjolobe@yahoo.co.uk.
cardiovascular disease
2.1. Milestones in the use of spironolactone and its analogue, eplerenone
The successful use of spironolactone for treatment of cardiovas-
cular disorders began with the documentation, in 1960, of its role
in the relief of “gross” oedema, when coprescribed with hydrochlo-
rothiazide, in a patient with heart failure who had responded only
minimally to the latter drug [1]. Severe heart failure remained the
main focus when this drug was used as “add-on” therapy, this time
in the RALES trial, where the participants were characterised by left
ventricular ejection fraction b 35%. Ninety nine per cent of those par-
ticipants belonged to New York Heart Association (NYHA) functional
Classes III and IV [2]. Background drug therapy consisted of angioten-
sin converting enzyme inhibitors (ACEI) in 100% of participants, and
94.5% were on loop diuretics. The important finding was that the addi-
tion of spironolactone to combined loop diuretic and ACEI treatment
resulted in a 30% reduction in the risk of death (relative risk of death,
0.70; 95% confidence interval, 0.60 to 0.82; pb 0.001). In order to achieve
this outcome within 12 months the number needed to treat (NNT)
would be 9. That study also documented a 35% reduction in frequency
of hospitalisation for worsening heart failure in patients randomised to
“add-on” spironolactone compared with participants randomised to
“add-on” placebo (relative risk of hospitalisation, 65; 95% confidence in-
terval, 0.54 to 0.77; pb 0.001) [2]. In a subsequent trial, entitled EPHESUS,
in which NYHA functional class was not specified, eplerenone was the
preparation utilised as “add-on” treatment, and this was in heart failure
patients who, in 86.5% of instances, were also either on ACE inhibitors

0953-6205/$ – see front matter © 2012 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.ejim.2012.11.007
304 O.M.P. Jolobe / European Journal of Internal Medicine 24 (2013) 303–309

or on angiotensin receptor blockers (ACEI/ARBs). Patients were Table 1b

randomised 30 days after an episode of myocardial infarction, and Numbers needed to treat in 3 major studies of aldosterone blockade.

all were characterised by LVEF b 40%. In addition, 90% of participants Study Year of Primary outcome NNT to save one Ref
had clinical and/or radiographic signs of cardiac failure. Over a mean publication life in 1 year
follow-up period of 16 months, there were significantly (p = 0.005) RALES 1999 Death from all causes 9 [2]
fewer cardiovascular deaths in patients randomised to eplerenone EPHESUS 2003 Composite of death 50 [3]
as “add-on” treatment (relative risk, 0.83; 95% confidence interval, from any cause and
death from
0.79 to 0.95) [3]. In order to achieve this outcome within 12 months,
cardiovascular causes
NNT would be 50. The next focus was on patients with mild heart or hospitalisation for
failure symptoms (NYHA functional Class II) in the presence of heart failure, acute
LVEF 30% or less. In that trial, entitled EMPHASIS-HF, 93.5% of partic- myocardial infarction,
ipants were on ACEI/ARBs, 87% were on beta-adrenergic receptor stroke, or ventricular
arrhythmia
blockers, and 85% were on loop diuretics. Among patients randomised
EMPHASIS-HF 2011 Composite of death 51 [4]
to “add-on” therapy with eplerenone, as opposed to placebo, there from cardiovascular
was a reduction in the composite end point of death from cardiovascu- causes or
lar causes or hospitalisation for heart failure, when evaluated after a hospitalisation for
heart failure
median follow up of 21 months [4]. Hazard ratio for death as primary
New-onset atrial [5]
outcome 0.63 (95% CI 0.54 to 0.74). NNT computed for 12 months fibrillation or atrial flutter
follow-up amounted to 51. A secondary end point in that study was
the occurence of new-onset atrial fibrillation and/or atrial flutter, the
two arrhythmias together designated as “AFF”. The principal finding in
the study devoted to that secondary end point was that, at the end of
a 4 year follow up period eplerenone had generated a 1.8% absolute re- 2.2. Rationale for the use of aldosterone antagonists in cardiovascular
duction in the risk of AFF. Estimated hazard ratio for new onset AFF disease
amounted to 0.58 (95% CI 0.35 to 0.96; p = 0.034) [5]. Tables 1a and
1b document the data for NNT, as well as the inclusion and exclusion The beneficial effects of spironolactone and its analogue, eplerenone,
criteria for the four studies. are attributed to the fact that these agents are competitive antagonists
of aldosterone [6], the latter being the agent responsible for collagen de-
position in the myocardium [7]. With progressive accumulation of col-
lagen in the myocardium there is consequent evolution of a spectrum
of ventricular dysfunction that first appears during diastole and subse-
quently involves systole [7]. Primary aldosteronism is a prime example
of chronic exposure to aldosterone excess, and, in this disorder, plasma
Table 1a carboxy-terminal propeptide of procollagen type 1 (PICP) has been
Key inclusion and exclusion criteria in 4 major studies of aldosterone blockade. utilised as a measure of severity of myocardial fibrosis resulting from
this exposure. Even allowing for the fact that PICP blood levels increase
Study Inclusion criteria Exclusion criteria Ref
in proportion with myocardial collagen volume fraction when the latter
RALES NYHA Class III or IV Primary operable [2] is evaluated in essential hypertension [8], blood levels of this parameter
LVEF 35% or less Valvular disease
On ACE inhibitors Serum creatinine >221
are even higher in primary aldosteronism patients than in essential hy-
And loop diuretics mmol/l pertension patients matched by age, sex, and median blood pressure
Serum potassium > 5.0 [9].
mmol/l Furthermore, in a prospective study enrolling 20 subjects with
EPHESUS AMI 3–14 days previously Serum creatinine >220 [3]
aldosterone-producing adenoma, evaluation of this parameter, before
LVEF 40% or less mmol/l
Symptoms and signs of CHF Serum potassium > 5.0 and one year after excision of the tumour, revealed that the latter oper-
Or diagnosis of diabetes mmol/l ation significantly (p= 0.026) decreased PICP levels [10], most probably
Optimal medical therapy as a result of reversal of myocardial fibrosis. In the post-myocardial in-
EMPHASIS-HF Age 55 or more Acute myocardial [4] farction context [5], the beneficial effects of aldosterone blockade
2011 NYHA functional Class II infarction
LVEF 30% or less NYHA Class III or IV
might be attributable to the fact that, in the rat model of myocardial in-
Prior hospitalisation for a Estimated glomerular farction, deletion of the cardiomyocyte mineralocorticoid receptor pre-
cardiovascular reason filtration rate b 30 vents progressive adverse cardiac remodelling [11].
Or plasma B-type natriuretic ml/min Although patients with left ventricular systolic dysfunction were the
peptide 250 pg/ml or more Serum potassium > 5.0
only ones enrolled in the trials which showed these beneficial effects of
On ACE inhibitors or ARBs mmol/l
On optimum dose aldosterone blockade [2–5], this does not necessarily discount a poten-
beta-blocker unless tial benefit in patients with predominantly diastolic heart failure, given
contraindicated the fact that many patients with subnormal LVEF have co-existing dia-
EMPHASIS-HF Age 55 or more Acute myocardial [5] stolic dysfunction [12,13]. For example, in a community study enrolling
2012 NYHA Class II infarction
LVEF 30% or less
1275 subjects aged 60–86, the observation was made that “rates of dia-
NYHA Class III or IV
Prior hospitalisation for a Estimated glomerular stolic dysfunction increased with decreasing EF (p= 0.0001)” to the ex-
cardiovascular reason filtration rate b 30 ml/min tent that “there were no subjects with EF (ejection fraction) equal to or
On plasma B-type natriuretic Serum less than 40% with normal diastolic function” [12]. In another study 82%
peptide 250 pg/ml or more potassium > 5.0 mmol/l
of subjects with LVEFb 40% had co-existing left ventricular diastolic dys-
On ACE inhibitors or ARBs
On optimum dose function, and left ventricular diastolic dysfunction was deemed to be
beta-blocker severe in 37% of those patients with LVEFb 40% [13]. Furthermore,
unless contraindicated in a study which enrolled 225 consecutive heart failure patients
Abbreviations: AMI, acute myocardial infarction; ACE inhibitor, angiotensin converting characterised by NYHA functional Classes II to IV in the presence
enzyme inhibitor; ARB, angiotensin receptor blocker; CHF, congestive heart failure. of LVEF b 35%, parameters of co-existing left ventricular diastolic
 O.M.P. Jolobe / European Journal of Internal Medicine 24 (2013) 303–309
dysfunction (comprising conventional indexes as well as tissue Doppler
and colour M-mode Doppler indexes) independently and significantly
(“p” values ranging from 0.026 to 0.001) predicted progression to
death/transplantation/heart failure hospitalisation [14]. The observa-
tion that co-existing diastolic dysfunction may be severe in approxi-
mately a third of patients with LVEF b 40% [13], and the observation
that coexisting diastolic dysfunction predicts subsequent clinical deteri-
oration in patients with subnormal LVEF [14] resonate with the obser-
vation that aldosterone receptor blockade favourably influences the
natural history of heart failure in approximately a third of patients
with LVEF b 40% [4], thereby implying that some of the benefits con-
ferred by spironolactone and its analogue [2–5] might be mediated, at
least in part, by mitigation of the severity of co-existing diastolic dys-
function. The possibility that patients with predominantly diastolic
left ventricular dysfunction might also benefit from aldosterone block-
ade is now being addressed by various studies. One of the earliest to re-
port its results is a study in which the secondary outcome appeared to
support the hypothesis that the antifibrotic action of aldosterone block-
ade could mitigate the severity of left ventricular diastolic dysfunction.
This was a study which enrolled symptomatic heart failure patients
(NYHA Class II or III) with left ventricular ejection fraction of 50% or
more, and B-type natriuretic peptide levels of 100 pg/ml or more. The
primary end point was a significant change in 6 minute walking dis-
tance. A secondary end point was a change in biomarkers of collagen
turnover. Among patients randomised to eplerenone, 95.2% were on
ACEI/ARBs vs 100% of counterparts randomised to placebo, and 95.2%
vs 100% were on diuretics. Although the primary outcome was not
achieved, what did emerge was that eplerenone generated a significant
reduction in serum markers of collagen turnover (procollagen type 1
aminoterminal peptide, p = 0.009, and carboxy-terminal telopeptide
of collagen type 1, p = 0.026), and this was associated with a significant
(p= 0.026) improvement in one of the parameters (E/E′ ratio) of left
ventricular diastolic function [15]. Two other trials, namely Aldo-HF
[16], and TOPCAT [17], are in progress, evaluating the effect of
spironolactone in symptomatic patients with heart failure associated
with left ventricular ejection fraction (LVEF) of 50% or more (Aldo-HF),
or LVEF 45% or more (TOPCAT). The two primary end points in Aldo-HF
will be a change in exercise capacity and in diastolic function after
12 months. In TOPCAT the primary end point will be a composite of car-
diovascular death, hospitalisation for heart failure, or aborted cardiac
arrest. New-onset atrial fibrillation will be a secondary end point.
What also needs to be addressed by future trials is the therapeutic po-
tential of aldosterone blockade in pulmonary hypertension secondary
to left ventricular failure, so-called type 2 pulmonary hypertension, an
entity more prevalent in diastolic than in systolic heart failure [18]. In
the former context, type 2 pulmonary hypertension may be a feature
in as many as 83% of cases [19], where it may be a significant (p=
0.02) predictor of mortality risk [19]. According to the animal model
of type 2 pulmonary hypertension, its manifestations include, not only
an increase in the percentage of fully muscularised lung vessels (as a re-
sult of the activity of endothelin-1) [20], but also marked vascular and
lung fibrosis [18]. Also in the animal model, spironolactone appears to
be capable of attenuating the severity of pulmonary hypertension, albeit
when the latter is artificially induced by monocrotaline [21]. The latter
agent induces primary pulmonary hypertension through a mechanism
that involves elevated levels of endothelin-1 (ET-1). The later, in turn,
activates synthesis of aldosterone in pulmonary artery endothelial
cells, an associated outcome being an increase in pulmonary artery
pressure and pulmonary vascular remodelling. These vascular out-
comes were prevented when the experimental animals were treated
with spironolactone starting at the time of monocrotaline injection. In
untreated animals where some of the stigmata of pulmonary hyperten-
sion were already established, spironolactone was shown to be capable
of reversing changes such as pulmonary hypertension and perivascular
fibrosis [21]. The animal model of ET-1 mediated pulmonary hyperten-
sion has, as its counterpart, the vasoconstrictor response to ET-1
305
documented in strips of isolated human pulmonary resistance arteries
[22]. In vivo, when pulmonary hypertension is secondary to mitral ste-
nosis, elevated levels of ET-1 are found in venous blood, and ET-1 levels
in the pulmonary capillaries correlate significantly (r= 0.33; p = 0.04)
with mean pulmonary artery pressure [23]. The prevalence of second-
ary pulmonary hypertension is also high in aortic stenosis, where, as
many as 50% of a cohort of 388 patients with symptomatic severe aortic
stenosis were documented as having mild to moderate pulmonary hy-
pertension, and 15% had severe pulmonary hypertension [24]. Further-
more, when plasma ET-1 levels were evaluated in the absence of heart
failure in 54 consecutive patients with symptomatic aortic stenosis
blood levels of this parameter were significantly (p= 0.019) higher
than in healthy controls. Among these 54 patients with aortic stenosis,
mean pulmonary artery pressure amounted to 24.1 mm Hg (range
8–75 mm Hg), and blood levels of ET-1 were significantly (r= 0.631;
p b 0.001) correlated with mean pulmonary artery pressure [25]. The
hope that spironolactone might reverse secondary pulmonary hyper-
tension in disorders such as mitral stenosis and aortic stenosis has, how-
ever, to be tempered by the observation that the animal model of
secondary pulmonary hypertension shows that pulmonary fibrosis is
still an eventual outcome in spite of pretreatment with spironolactone
[26]. This anomaly may be attributable to the fact that the profibrotic ac-
tion of ET-1 on lung parenchyma may be quite independent of the ef-
fects (potentially reversible by spironolactone) [21] exerted by this
agent on pulmonary vasculature.
Both in studies which enrol patients with predominantly diastolic
heart failure and in studies which enrol patients with predominantly
systolic heart failure, there may be an additional but poorly quanti-
fied potential benefit from coprescription of aldosterone antagonists,
and this might be mitigation of the severity of loop diuretic-related
RAAS activation, given the fact that even frusemide doses as low as
40 mg/day trigger activation of the RAAS cascade [27]. The adminis-
tration of loop diuretics also increases sympathetic drive [28], sym-
pathetic overactivity being, in turn, a risk factor for progressive
heart failure and sudden death [29]. Angiotensin II is the link be-
tween the RAAS and sympathetic drive in that angiotensin II is the
trigger for centrally mediated activation of sympathetic drive [30].
The central activity of angiotensin II is mimicked by aldosterone
[31], which crosses the blood–brain barrier from the circulation,
and is also synthesised in brain tissue [31]. This central pool of aldo-
sterone has been shown to be capable of generating an output of
sympathetic activity in its own right, and when this output is exces-
sive, it can be significantly attenuated by aldosterone blockade spe-
cifically targeted at central nervous system areas known to be
associated with “prominent aldosterone binding” [32]. This was the
case in the rat model of myocardial infarction where progression to
heart failure was mitigated by aldosterone antagonists targeted at
the area anteroventral to the third ventricle and also targeted at
the paraventricular nucleus [32]. Diuretic-related activation of the
neurohormonal cascade appears to be indicative of the potential for
diuretics to have a detrimental effect on the natural history of con-
gestive heart failure. On the one hand, as in one study, the more se-
vere the degree of cardiac decompensation the greater the need for
higher doses of frusemide (normalised to body surface area) for
symptom control. Mortality in such patients is determined by the se-
verity of cardiac failure irrespective of the requirement for higher
doses of frusemide [33]. In clinically stable patients, however, “di-
uretics have an even greater association with increased mortality”
[33], and this appears to be attributable to the fact that, in these pa-
tients, even on multivariate analysis, normalised frusemide dose is
an independent (p = 0.01) marker of worse prognosis [33]. One in-
terpretation of these findings is that, during the compensated
phase of heart failure, an inappropriately high maintenance dose of
diuretics may have stabilised symptoms at the cost of excessive acti-
vation of the neurohormonal cascade. The latter complication, in
turn, might have had a detrimental effect on the natural history of
306 O.M.P. Jolobe / European Journal of Internal Medicine 24 (2013) 303–309
CHF in those subjects. Over and above its potential impact on surviv-
al [33], diuretic-related activation of the neurohormonal cascade is
now believed to have adverse effects on renal function [34]. These
deleterious effects are mediated principally by angiotensin II,
which is not only a potent stimulator of the sympathetic nervous sys-
tem [34], but, also, a mediator of renal fibrogenesis [35]. Sympathetic
overactivity compounds the deleterious effects of angiotensin II by
activating the RAAS via adrenergic receptors located in the
juxtaglomerular apparatus [36]. This secondary activation of the
RAAS cascade might, if anything, aggravate renal damage, given the
profibrotic effect on renal tissue which aldosterone possesses in its
own right [37]. In laboratory animals the renal profibrotic effect is
evident even when hyperaldosteronism is secondary to activation
of the RAAS by hydrochlorothiazide [38]. Accordingly, the observa-
tion has been made that “there is a growing body of laboratory and
clinical evidence supporting the use of inhibitors of aldosterone ac-
tion in patients with both glomerular and tubular diseases” [39]. Fur-
thermore, given the fact that diuretics, are, presently an inescapable
adjunct to the management of symptomatic congestive heart failure
[40], coprescription of aldosterone antagonists might well be the op-
timum strategy for mitigating their harmful effects on the kidney.
2.3. Aldosterone antagonists and hyperkalaemia
However, notwithstanding its potential benefits, it also has to be
recognised that aldosterone blockade is a major risk factor for
hyperkalaemia, especially in the elderly [41]. In one study, among 566
heart failure patients aged 60 or more, including 93% on ACEI/ARBs,
92% on loop diuretics, 38% on spironolactone, hyperkalaemia (serum
potassium 5.5 mmol/l or more) was significantly (p= 0.04) more prev-
alent in the subgroup coprescribed spironolactone. Baseline dosages of
spironolactone and loop diuretics, respectively, were also higher in pa-
tients who subsequently developed hyperkalaemia. Furthermore,
among the 76 patients who developed hyperkalaemia, the average esti-
mated glomerular filtration rate at the time of hyperkalaemia was sig-
nificantly lower (pb 0.01) than it had been during normokalaemia
[41]. Accordingly, by multivariate analysis, baseline serum potassium,
serum creatinine, dose of spironolactone, and NYHA class, were four
of the five independent predictors of hyperkalaemia [41]. In a reanalysis
of data from the same study it also emerged that intensification of loop
diuretic treatment was significantly associated (pb 0.001) with worsen-
ing of renal function [42]. Accordingly, in those instances where
prerenal uraemia is attributable to the intensity of loop diuretic treat-
ment it is conceivable that timely downward titration of loop diuretic
dose might avert hyperkalaemia attributable to worsening renal func-
tion. This hypothesis is supported by the observation that addition of
spironolactone to combined loop diuretic and ACE-inhibitor therapy
can have a profound diuretic-sparing effect, resulting in pre-renal
uraemia, if the precaution is not taken to “scale down” the dose of
loop diuretics during the course of treatment [43]. Over and above the
fact that spironolactone-related augmentation of diuresis might gener-
ate prerenal uraemia [43], aldosterone antagonists such as eplerenone
can cause renal dysfunction in their own right, as shown by a study
which enrolled patients who had deteriorated into heart failure follow-
ing an episode of myocardial infarction [44]. In that study 2918 patients
were randomised to eplerenone and 2874 to placebo. Background ther-
apy consisted of ACEIs/ARBs in 87%, and diuretics in 59%. Over a period
of 24 months, a significantly (pb 0.0001) greater decline in eGFR was
documented in the eplerenone group than in the placebo group [44].
Given the fact that the risk of hyperkalaemia is inherent in the use of al-
dosterone antagonists, and that this risk may be compounded by wors-
ening renal function attributable to this treatment modality [43,44],
both risks can, to a certain extent, be mitigated by strict pretreatment
evaluation of patients, and by strict monitoring during the course of
treatment. Accordingly, during pre-treatment evaluation, clinicians
should be aware not only of unmodifiable baseline risk factors such as
decompensated heart failure, chronic kidney disease, diabetes mellitus,
and advanced age, but also of modifiable risk factors which might
emerge during the course of treatment, and these include volume
depletion, coprescription of other drugs which concomitantly inter-
fere with renal potassium excretion, and coadministration of hidden
sources of potassium [45]. What might escape recognition is the in-
take of over the counter nonsteroidal anti-inflammatory drugs,
which then interfere with renal potassium excretion, and intake of
excessive amounts of potassium via dietary sources (such as salt sub-
stitutes), and via herbal remedies. The risk of hyperkalaemia can also
be mitigated by avoidance of spironolactone and eplerenone in pa-
tients with eGFR below 30 ml/min [45], and by administration on al-
ternate days in patients with eGFR between 30 and 50 ml/min.
Above all, the dose of spironolactone should not exceed 25 mg/day
when used with ACEI/ARBs [45], especially in view of the study
documenting severe hyperkalaemia (serum potassium 6 mmol/l or
more) among 44 heart failure patients on spironolactone as add-on
therapy to ACEI/ARB medication. These patients had been admitted
to a hospital serving a population of about 250,000 during the period
January 1999 to December 2003. In 43 out of the 44 patients the dose
of spironolactone had been as high as 50–200 mg/day [46]. In com-
parison with eplerenone, however, spironolactone might, itself, be
a safer option, judging by a meta-analysis which indicated that the
risk of hyperkalaemia might be lower with spironolactone than with
eplerenone [47]. According to that meta analysis, which included 3
studies using eplerenone, 3 studies using canreonate (also an aldoste-
rone antagonist), and 10 studies using spironolactone, risk ratio (RR)
for serious hyperkalaemia (6.0 mmol/l or more) amounted to 1.72
(95% Confidence Interval, 1.19–2.47; p = 0.004) for eplerenone, and
1.80 (95% CI, 0.83–3.91; p = 0.14) for other aldosterone antagonists
[47]. Accordingly, eplerenone should, arguably, be used only in the
event of the development of spironolactone-related gynaecomastia.
Other strategies for “on treatment” monitoring of serum potassium
should include, at the very least, evaluation of this parameter seven
days after initiation of the aldosterone antagonist, and also seven days
after any increment in the dose [45]. Additional evaluations of this pa-
rameter should be tailored to the individual circumstances of the case.
2.4. The antiarrhythmic potential of aldosterone antagonists
The successful use of eplerenone in primary prevention of atrial
fibrillation (albeit in patients with subnormal LVEF) [5] was an impor-
tant development, with major implications for management of other
risk factors for this arrhythmia. The rationale for the use of aldosterone
antagonists in primary prevention of AF is that direct proarrhythmic ef-
fects of angiotensin II can be suppressed by angiotensin I blockade in the
human atrial myocardium [48]. Accordingly, chronic inhibition of the
renin angiotensin aldosterone system (RAAS) would be expected to re-
duce the incidence of AF, especially in view of the fact that patients with
AF have significantly (p b 0.001) higher atrial mineralocorticoid ex-
pression than subjects with normal sinus rhythm [49], and this
degree of expression appears to augment the genomic effects of
aldosterone. One interpretation of these observations is that AF
“begets” AF by augmenting genomic effects of aldosterone. The
corollary is that paroxysmal AF (PAF) might also “beget” persistent
AF by the same mechanism, and that chronic aldosterone blockade
might delay the transition from PAF to permanent AF. Atrial fibrilla-
tion is also characterised by atrial fibrosis [50], the latter arguably the
end result of chronic activation of the RAAS. Furthermore, in compar-
ison with patients with paroxysmal AF, patients with persistent AF
have significantly (p b 0.001) higher levels of tissue inhibitor of ma-
trix metalloproteinases-1. Levels of this parameter were also signifi-
cantly (p b 0.001) lower in control subjects with sinus rhythm than in
either paroxysmal AF or persistent AF subjects [51]. These observa-
tions, which imply a link between collagen turnover and burden of
 O.M.P. Jolobe / European Journal of Internal Medicine 24 (2013) 303–309
AF, lend weight to the argument that aldosterone blockade might
delay the transition from paroxysmal AF to persistent AF.
The most recent support for the role of aldosterone in the
aetiopathogenesis of atrial fibrillation comes from the rat model of
aldosterone-induced atrial fibrillation [52]. In that study a comparison
was made between rats which had received a continuous subcutaneous
infusion of aldosterone (Aldo subgroup group) vs controls without al-
dosterone treatment. Subsequent evaluations showed that there was
no difference between the two groups with respect to parameters of
systolic or diastolic function, and also no difference in terms of left atrial
or right atrial load. Nevertheless, there was a significant (pb 0.001) pro-
longation of P-wave duration in the Aldo vs control subgroup. To test
whether aldosterone pretreatment predisposed to atrial arrhythmias,
oesophageal burst pacing was then performed, with the result that
sustained atrial arrhythmias were induced in all eleven members of
the Aldo subgroup. A similar result was obtained in only two of the
nine members of the control subgroup. This difference was significant
(p= 0.03). Over and above these electrophysiological differences, inter-
stitial fibrosis was significantly increased, both in the left atrium (p=
0.01), and in the right atrium (p= 0.04), in the Aldo subgroup vs the
control subgroup [52]. Primary aldosteronism is the human counterpart
of the rat model of aldosterone-induced atrial fibrillation. In that disor-
der there is a 12-fold higher prevalence of AF (95% Confidence Interval
3.2 to 45.2) compared with essential hypertension [53]. Accordingly,
the mechanism for the potential benefit of spironolactone and its ana-
logues might well be blockade of the neurohormonal cascade which
generates the electrical and structural substrate necessary for initiation
and perpetuation of atrial fibrillation [54].
2.5. A potential to mitigate risk of hypertension-related atrial fibrillation
In the context of hypertension, what has been documented is that
increasing severity of this disorder is accompanied by progressive dete-
rioration in left ventricular diastolic function and deterioration in left
atrial expansion [55]. This might explain why severity of diastolic dys-
function is significantly (p= 0.001) associated with increased risk of
non-valvular AF [56]. Accordingly, thanks to its efficacy as “add-on”
treatment in resistant hypertension [57,58], spironolactone may well
be the agent of choice, not only for reversing the deleterious effects of
poorly controlled hypertension [55], but also for delaying the onset of
hypertension-related AF. As add-on therapy, to combined ARB, calcium
channel blocker, and hydrochlorothiazide therapy, spironolactone ap-
pears to be superior even to add-on ramipril [58]. In a trial which en-
rolled patients with eGFR 40 ml/min or more, and in which the end
point was control of resistant hypertension so as to achieve a daytime
ambulatory blood pressure b 135/85 mm Hg, that goal blood pressure
was obtained in significantly (pb 0.0001) more spironolactone treated
patients than in ramipril-treated patients. Hyperkalaemia (serum po-
tassium 5.5 mmol/l or more) occurred in 3 spironolactone-treated pa-
tients, and in none of the ramipril treated patients. Creatinine increase
of >35% occurred in 2 patients in the former category, and in none of
the patients in the latter category [58].
Notwithstanding the efficacy of aldosterone antagonists in resis-
tant hypertension [57,58], they are not regarded as first line agents
[59], even though they are free of some of the side effects of thia-
zides, which have been recommended, as recently as 2009, for inclu-
sion in the first-line drug “package” [59]. These side effects include
activation of the RAAS [60], which has the potential to blunt the an-
tihypertensive efficacy of these agents [61], and activation of the
sympathetic nervous system [62], which can be attenuated by
coprescription of spironolactone [63]. Proof of the latter concept was
obtained in a study involving 17 subjects with untreated stage 1 hyper-
tension. In that study chlorthalidone-related decrease in ambulatory
blood pressure (from a mean baseline value of 135/84 mm Hg to a
mean value of 124/78 mm Hg) was accompanied by a significant
(pb 0.01) increase in sympathetic nervous system activity. The addition
307
of spironolactone to chlorthalidone returned sympathetic nervous sys-
tem activity to baseline levels [63]. As is the case with loop diuretic ac-
tivation of the sympathetic drive in heart failure patients [28] the effect
of thiazide-related augmentation of sympathetic nerve activity [62,63]
on long-term prognosis in hypertension remains to be fully quantified,
and might yet prove to be relevant to the eventual emergence of
hypertension-related atrial fibrillation. What is already known, howev-
er, is that, in hypertension, there is a powerful and positive correlation
(r= 0.76; p b 0.0001) between central sympathetic drive and left ven-
tricular mass index [64]. At least in the context of aortic stenosis, an in-
crease in left ventricular mass index, is, in turn, significantly (p= 0.03)
associated with new-onset AF [65]. Outside the context of its association
with left ventricular hypertrophy [64], sympathetic overactivity has
also been shown to be an associated feature of primary aldosteronism
(PA) [66], the latter being a disorder characterised by a 12-fold higher
prevalence of AF compared with essential hypertension [53]. An addi-
tional feature of PA-related sympathetic overactivity is that it is signifi-
cantly (p= 0.01) ameliorated by resection of the adrenal adenoma [66].
Renal artery denervation is the alternative interventional strategy for
reducing sympathetic overactivity, over and above its effect in improv-
ing the control of resistant hypertension. In order to test the hypothesis
that this strategy would also reduce the recurrence rate of AF following
catheter ablation therapy a randomised trial was undertaken where a
comparison was made of pulmonary vein isolation with concomitant
renal artery denervation (13 patients) vs pulmonary vein isolation
without concomitant renal artery denervation (14 patients). In that
study adjunctive renal artery denervation significantly ameliorated
the severity of hypertension (pb 0.001), and also significantly (p=
0.033) reduced the risk of recurrence of AF one year or more after AF ab-
lation therapy [67]. Given the documentation that sympathetic overac-
tivity is, at least in part, aldosterone dependent [66], and the
documentation that the risk of AF recurrence can be mitigated by sym-
pathetic denervation [67], aldosterone blockade may, therefore, be a
treatment option, not only for management of resistant hypertension,
but also for delaying the onset of hypertension-related atrial fibrillation.
In the specific instance of aortic stenosis, by delaying the onset of
hypertension-related atrial fibrillation, that strategy might also delay
the onset of heart failure [68] and non haemorrhagic stroke [68].
3. Conclusions
Given the ubiquitous nature of the mineralocorticoid receptor, in-
cluding its presence in the paraventricular nucleus of the hypothalamus
where it modulates blood pressure and renal function by increasing
sympathetic output to blood vessels, heart and kidney [69] there are
huge opportunities to alter the natural history of cardiovascular disease
by adding aldosterone antagonists to standard treatment for a variety of
cardiovascular disorders. The hope that we share with one commenta-
tor is that the outcome of ongoing trials of third generation and fourth
generation aldosterone antagonists will be an improved benefit vs risk
profile of these agents, in association with more balanced tissue distri-
bution, and significant concentration in the cardiovascular system
[70]. The increasing awareness of the renal profibrotic potential of an-
giotensin II [35] and aldosterone [39] also increases the scope of the
beneficial effect that might accrue from the use of aldosterone antago-
nists. Of special relevance is the potential for coprescription of these
agents to mitigate the risk of renal side effects attributable to the use
of some diuretic subclasses.
Learning points
• Aldosterone antagonists such as spironolactone and eplerenone
have conclusively been shown to have a favourable effect on the
natural history of systolic heart failure.
• In addition, a recent study suggests that these agents may have a
role in the primary prevention of AF.
308 O.M.P. Jolobe / European Journal of Internal Medicine 24 (2013) 303–309
• Arguably, these favourable effects might, at least in part, be attribut-
able to amelioration of the severity of diastolic dysfunction when it
coexists (as it does in most cases) with subnormal LVEF.
• Accordingly future research should address the use of these agents
where left ventricular dysfunction is of the predominantly diastolic
subtype, especially in the context of hypertension and aortic valve
stenosis.
• Irrespective of subtype of ventricular dysfunction, aldosterone
blockade might also have a role in mitigating the severity of adverse
outcomes attributable to RAAS activation (and associated activation
of the sympathetic nervous system) by loop diuretics, and by
chlorthalidone.
• A potential additional benefit might be amelioration of severity of
type 2 pulmonary hypertension, and the potential to mitigate the
risk of renal damage attributable to the use of some diuretic sub-
classes.
• In order to optimise the benefit/risk profile of these drugs, clinicians
should exercise vigilance in evaluating prospective candidates for
treatment by these agents, and equal vigilance in monitoring those
already on treatment.
Conflict of interests
I have no conflict of interest.
Acknowledgement
For the NNT data I am grateful to the recent publication by Zannad
et al. [71].
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