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RAAS Escape: A Real Clinical Entity that

May Be Important in the Progression of


Cardiovascular and Renal Disease
Jay Lakkis, MD, Wei X. Lu, MD, PhD, and Matthew R. Weir, MD*

Address electrolyte homeostasis, each local RAAS serves a function


*Division of Nephrology, Department of Medicine, University of that is specific to the tissue in which it is present. For exam-
Maryland School of Medicine, 22 South Greene Street, Suite N3W143, ple, one local RAAS is responsible for sodium reabsorption
Baltimore, MD 21201, USA.
E-mail: mweir@medicine.umaryland.edu
across the entire nephron and subsequent plasma volume
and circulatory homeostasis [2]. Excessive activation of a
Current Hypertension Reports 2003, 5:408–417
Current Science Inc. ISSN 1522-6417 second contributes to the development of cardiac hypertro-
Copyright © 2003 by Current Science Inc. phy and fibrosis in the heart [3], and a third influences the
central control of blood pressure in the brain where it is
thought to contribute to the hypertensive phenotype of
Interruption of the renin-angiotensin-aldosterone system
genetically hypertensive rat models [4–8]. Aberrations in
(RAAS) at different levels is target-organ protective in
this system have been implicated in various disease states
several disease states; however, complete blockade is unlikely
such as elevated arterial blood pressure, congestive heart
to be achieved due to escape mechanisms whenever blockade
failure (CHF), and kidney disease [9]. Interruption of this
is attempted, incomplete knowledge of the role of all
system by an angiotensin-converting enzyme inhibitor
elements of the RAAS, and lack of pharmacotherapy against
(ACE) or an angiotensin receptor antagonist (ARB) has
some elements that have been shown to contribute to
been shown to be protective in more than one way. How-
disease states. Aldosterone has been overlooked as a
ever, RAAS or aldosterone synthesis escape (as opposed to
mediator of RAAS escape and a key factor in target-organ
the term “ACE escape”) may be a more practical issue to
injury despite the use of available RAAS blockers. Aldoster-
evaluate as a risk for progression of cardiovascular and
one is thought to play a role in the development of hyperten-
renal disease in patients on ACE inhibitors or ARBs.
sion, alteration in vascular structure, vascular smooth muscle
hypertrophy, endothelial dysfunction, structural renal injury,
proteinuria, left ventricular remodeling, collagen synthesis,
and myocardial fibrosis. Aldosterone receptor antagonists
Aldosterone Synthesis and Receptors
Aldosterone, the principal physiologic mineralocorticoid, is a
have been shown to antagonize all these effects in experi-
steroid hormone formed as one of the end products of cho-
mental models. Clinical trials with aldosterone antagonists
lesterol metabolism. Its precursor, 18-hydroxycorticosterone,
showed an improvement in survival and left ventricular
is acted upon in a series of reactions by the enzyme aldoster-
mass index in patients with congestive heart failure, and a
one synthase (corticosterone methyloxidase). It is synthe-
reduction in urinary protein excretion and left ventricular
sized in the zona glomerulosa of the adrenal cortex, blood
mass index in patients with type 2 diabetes and early
vessels, myocardium, and brain. It exerts its effects through
nephropathy who developed aldosterone synthesis escape.
binding to the mineralocorticoid receptor, a ligand-depen-
Consequently, aldosterone receptor antagonists may have
dent transcription factor that has been localized to epithelial
specific benefits for reducing target-organ injury, particularly
tissues and nonepithelial tissues. Epithelial tissues include
if there is evidence of RAAS escape.
the distal nephron (mainly the renal collecting duct) [10–
12]; colon; salivary glands; sweat glands; retina and its
pigment epithelium [13]; and urinary bladder [14] and rectal
Introduction mucosa [15]; and nonepithelial sites include the heart (myo-
Elements of the renin-angiotensin-aldosterone system cardial cells); endothelial and smooth muscle cells of blood
(RAAS) contribute to different physiologic and disease vessels [16,17] and the brain (mostly neurons of the hippo-
states [1]. Two coordinated forms of this system exist: the campus, the dorsolateral septum, and brain stem motor
systemic RAAS and multiple local paracrine or autocrine nuclei) [18–24]; and the iris-ciliary body [25]. Aldosterone
tissue-specific RAASs. Whereas the systemic RAAS has the secretion is stimulated by angiotensin II, hyperkalemia, and
major role of regulating vascular tone and fluid and adrenocorticotropic hormone (ACTH).
RAAS Escape • Lakkis et al. 409

In mineralocorticoid-sensitive tissues, aldosterone mized spontaneously hypertensive rats [42], induces


diffuses across the basolateral plasma membrane into the lesions of malignant nephrosclerosis in the deoxycortico-
cytoplasm where it binds to and activates its receptor. sterone acetate-salt hypertensive rat model [43], and
When unbound, aldosterone receptors are in an inactive restores proteinuria and glomerulosclerosis in remnant
multiprotein complex of chaperones. Upon binding aldos- rats treated with losartan and enalapril to an extent similar
terone, the chaperones are released and the receptor to that seen in untreated remnant rats [44]. Rocha et al.
hormone complex is translocated into the nucleus where it [45•] concluded that spontaneously hypertensive stroke-
binds to hormone response elements on DNA, interacts prone rats (SHR-SPs) receiving the aldosterone antagonist,
with transcription initiation complexes, stimulates the spironolactone, for 3 to 4 weeks had similar blood pres-
synthesis of ribosomal and messenger RNA, modulates sure profiles but fewer nephrosclerotic histologic lesions
gene expression, and results in the production of aldoster- and less proteinuria than the placebo group. Furthermore,
one-induced proteins [26,27]. In epithelial tissue, its main control SHR-SPs and those who received an aldosterone
function is to maintain electrolyte homeostasis and intra- infusion over 2 weeks had significant proteinuria and renal
vascular volume. Aldosterone increases sodium reabsorp- injury. Captopril was protective against both proteinuria
tion in tight epithelia of the distal nephron, and the early and renal injury, and this protection was abolished by
phase of this stimulatory effect is thought to involve migra- reinfusion of aldosterone in a mechanism that was inde-
tion and activation of apical sodium channels (ENaC), pendent of blood pressure [46•]. In a third experiment,
resulting in an increase in sodium and water reabsorption male rats drinking 1% saline and receiving angiotensin II
and promoting tubular secretion of potassium [28,29]. In and a nitric oxide synthesis inhibitor developed hyperten-
nonepithelial tissue, recent data also suggest that aldoster- sion, severe proteinuria, and fibrinoid necrosis of renal
one has direct effects on the vasculature and has been asso- vessels. Adrenalectomy or administration of eplerenone to
ciated with vascular smooth muscle cell hypertrophy, these animals markedly reduced renal damage without
endothelial dysfunction, decrease in fibrinolysis, high significantly altering blood pressure, and restoration of
blood pressure, stroke, myocardial hypertrophy and aldosterone via an infusion restored damage [47•]. In a
cardiac fibrosis, autonomic dysfunction, proteinuria, and fourth experiment, control SHR-SPs and those receiving a
renal vascular injury. For example, in the blood vessels of 2-week course of captopril with aldosterone, or captopril
the heart and the brain, aldosterone receptors may be with angiotensin II, had a higher number of histologic
involved in vascular injury and repair responses [30–32]. renal lesions and more proteinuria than SHR-SPs receiving
Aldosterone increases sodium influx in vascular smooth captopril alone. When eplerenone was added to captopril
muscle cells and inhibits norepinephrine uptake in vascu- and angiotensin II, this group had statistically significantly
lar smooth muscle and myocardial cells [33,34]. It also less proteinuria and less histologic renal injury than the
directly participates in vascular smooth muscle cell hyper- captopril with angiotensin II group alone in a manner that
trophy. In short, a disturbance in its functions may result in was independent of blood pressure [46•].
hemodynamic instability, electrolyte disturbances, vascular In humans, several observational studies have linked
injury, myocardial dysfunction, arrhythmias, and sudden states of mineralocorticoid excess to cardiovascular and
cardiac death. Thus, it is thought that aldosterone receptor renal disease conditions. For example, hypertension is one
antagonism may protect against these disturbances, specifi- of the major clinical features of primary hyperaldoster-
cally vascular, myocardial, and renal injury. onism [48], congenital adrenal hyperplasia, and glucocor-
ticoid-remediable aldosteronism. In the latter condition, a
chimeric gene is formed from portions of the 11β-hydroxy-
Aldosterone and the Kidney lase gene and the aldosterone synthase gene resulting in
Sustained activation of aldosterone promotes progressive ACTH-stimulating aldosterone synthase, leading to persis-
renal injury. In the reduced renal mass model, animals tent hyperaldosteronism [49]. A possible role of aldoster-
develop remnant nephropathy characterized by aug- one synthase gene polymorphisms has been described;
mented citrate synthase activity, plasma aldosterone levels polymorphisms in or near the aldosterone synthase gene
and activity, and development of glomerular hypertrophy, (CYP11B2) are associated with variations in aldosterone
adrenal hypertrophy, arterial hypertension, proteinuria, production in males. This may modulate the activity of the
and structural renal injury in most animals. These effects, renin-angiotensin system and thereby contribute to blood
including plasma aldosterone levels, are decreased when pressure regulation [50]. However, different attempts
the animals undergo subtotal nephrectomy with adrena- involving different patient populations have failed to link
lectomy [35–39]. Similarly, animal models that either lack various polymorphisms of the CYP11B2 gene with salt
aldosterone (adrenalectomized Sprague-Dawley rats) or sensitivity, increased activity of the renin-angiotensin
are resistant to aldosterone actions (Wistar-Furth rats) are system [51], increased risk of myocardial infarction [52–
characterized by resistance to remnant nephropathy 54], level of 24-hour blood pressure [55,56], or essential
[36,38–41]. If aldosterone is reinstituted via an infusion, it hypertension [57]. On the other hand, some polymor-
markedly increases the blood pressure in adrenalecto- phisms in other patient populations were associated with
410 Antihypertensive Therapy: Renal Injury

decreased nocturnal blood pressure and possibly a lower at physiologic concentrations had a direct nongenomic
prevalence of previous cardiovascular disease [55,56], left rapid vasoconstrictive effect on the resistance arteries in
ventricular hypertrophy in patients with essential hyper- vivo, suggesting a possible vascular role of this steroid in
tension [57], and pathogenesis of hypertrophic cardio- hypertension and diseases of elevated peripheral vascular
myopathy [58]. resistance [64].
In humans with CHF, plasma aldosterone concentra-
tions may reach 20 times the normal level. Human subjects
Aldosterone and the Cardiovascular System suffering from primary hyperaldosteronism show more
In uninephrectomized Sprague-Dawley rats, aldosterone myocardial fibrosis, as assessed by echocardiography, than
increased arterial stiffness associated with fibronectin accu- essential hypertensive patients. Furthermore, aldosterone
mulation without any reduction in wall stress. Eplerenone increases endothelin receptor expression, which also might
prevented such stiffness and blunted the increase in pulse cause myocardial fibrosis. Blockade of aldosterone recep-
pressure, suggesting a direct role for mineralocorticoid tors, in addition to standard therapy including ACE inhibi-
receptors in mechanical and structural alterations of large tors, reduced mortality among patients with severe heart
vessels in rat hyperaldosteronism [59]. On the other hand, failure [65••,66••]. Thus, it is thought that aldosterone
alterations in vascular structure, mechanics, and composi- promotes collagen synthesis and structural remodeling of
tion induced by angiotensin II were partially prevented by the heart.
spironolactone, independently of blood pressure reduc-
tion, providing further evidence that some actions of
angiotensin II on resistance arteries are mediated by aldos- Aldosterone and the Brain
terone [60]. It is also thought that aldosterone upregulates The brain RAAS has been implicated in the central regula-
angiotensin II receptors in vascular smooth muscle cells, tion of the cardiovascular system, body water balance,
enhancing its vasopressor effects and promoting smooth cyclic regulation of reproductive hormones, and behaviors.
muscle cell hypertrophy [61]. It also exerts some influence over the secretion of pituitary
Several experiments have nicely illustrated that a high hormones. Most of these effects are mediated by the bind-
aldosterone state promotes stroke and cerebrovascular ing of the angiotensin receptor type 1 to angiotensin II and
histologic lesions in animal models. These effects were angiotensin III. Less is known about the functional impor-
antagonized by classical RAAS blockers, but an aldosterone tance of the angiotensin receptor type 2 site, which also
infusion restored damage despite this blockade, and add- binds angiotensin II and angiotensin III, but it has been
ing eplerenone reduced the injury despite the ongoing implicated in vascular growth and cerebral blood flow.
aldosterone infusion [43,45•–47•]. In a model of angio- Recently, an angiotensin receptor type 4 site has been dis-
tensin II hypertension, Wistar rats were given 1% NaCl to covered that binds angiotensin IV and is prominent in
drink and infused with angiotensin II. Eplerenone and cerebral cortex, hippocampus, basal ganglia, cerebellum,
adrenalectomy attenuated the increase in heart weight to and spinal cord, as well as several peripheral tissues includ-
body weight ratio induced by angiotensin II infusion ing kidney, bladder, heart, spleen, prostate, adrenals, and
despite similar levels of hypertension in all groups. Histo- colon. The angiotensin receptor type 4 site may mediate
logic examination of the hearts in the angiotensin II/salt memory acquisition and recall and the regulation of blood
and the angiotensin II/salt/adrenalectomy/aldosterone flow. However, the function of the angiotensin receptor
groups showed myocardial and vascular injury in the form type 4 receptor subtype in peripheral tissues remains
of arterial fibrinoid necrosis, perivascular inflammation unknown, although it appears to be involved in kidney
(primarily macrophages), and focal infarctions. Myo- blood flow [67].
cardial injury and expression of inflammatory mediators
were markedly attenuated by eplerenone treatment and
adrenalectomy. The authors concluded that aldosterone Aldosterone Synthesis Escape
plays a major role in angiotensin II-induced vascular As a Means of RAAS Escape
inflammation in the heart [62]. Aldosterone has also been Based on the above data, it becomes imperative that blockade
shown to cause interstitial fibrosis, thus contributing to left of the RAAS does not spare aldosterone. In fact, ample clinical
ventricular remodeling in CHF. In dogs with induced heart data indicate that in a considerable proportion of patients
failure, long-term therapy with eplerenone prevented pro- treated with long-term ACE inhibitors, aldosterone secretion
gressive left ventricular dysfunction and attenuated left and/or angiotensin II can escape ACE-1 inhibition, thus sug-
ventricular remodeling through reduction in cardiomyo- gesting that aldosterone, or another unknown mediator, plays
cyte cross-sectional area, reduction of volume fraction of an important role in the various disease states.
reactive interstitial fibrosis, and reduction of volume Some patients on long-term ACE inhibitor or ARB ther-
fraction of replacement fibrosis [63]. apy fail to show any suppression in serum aldosterone levels
In a randomized, placebo-controlled, double-blinded [68•,69••], while others have an initial phase of suppression
crossover study on 10 healthy male volunteers, aldosterone but later develop “escape” from ACE inhibition and manifest
RAAS Escape • Lakkis et al. 411

elevations in plasma levels of either angiotensin II, aldoster- [75,76] but does not explain all the effects observed in the
one, or both [68•,69••,70•,71]. For example, in a study that escape groups in human trials [77–79].
followed 25 hypertensive patients treated with ACE inhibi- Thus, aldosterone synthesis escape may be partially
tors, there was no relationship between the level of ACE inhi- responsible for the incompleteness of the RAAS blockade
bition and plasma aldosterone concentrations, which rose in and may explain some of the undesirable outcomes observed
parallel with the duration of ACE inhibitor treatment [68•]. in many cardiac, hypertensive, and diabetic patients despite
Similarly, when aldosterone synthesis escape was defined as ongoing treatment with ACE inhibitors or ARBs.
an increased plasma aldosterone concentration compared
with the value pretreatment after 40 weeks of therapy with an
ACE inhibitor, escape was observed in 38 of the 75 patients Aldosterone Receptor Antagonist Therapy in
(50.7%) with essential hypertension and in 17 of 37 patients Addition to RAAS Blockade in Patients with
in the subgroup with left ventricular hypertrophy. Left Cardiovascular or Renal Disease
ventricular mass index did not change in patients with aldos- The major clinical evidence for the use of aldosterone
terone synthesis escape but decreased significantly in patients receptor antagonists in humans comes from two large
without escape, with the authors concluding that aldoster- clinical trials in patients with systolic CHF.
one synthesis escape may abate the beneficial effects of an In the Randomized Aldactone Evaluation Study (RALES),
ACE inhibitor on left ventricular hypertrophy [70•]. In 45 spironolactone was added to standard pharmacotherapy of
patients with type 2 diabetes mellitus with the same previous severe CHF (ACE inhibitor if tolerated, loop diuretic, digitalis,
definition of aldosterone synthesis escape after 40 weeks of vasodilators) and conferred a 30% survival benefit to patients
therapy with an ACE inhibitor on a standard dietary sodium in the spironolactone group [65••] (Fig. 1). The mechanism
and potassium intake, 18 patients (40%) developed escape, of action of spironolactone is still debated, but the authors
and when 13 of the 18 were treated with spironolactone for report that in patients with CHF, high baseline serum levels of
the 24-week study period, urinary albumin excretion and left markers of cardiac fibrosis synthesis are significantly associ-
ventricular mass index were significantly reduced without ated with poor outcome and decreased during spironolactone
blood pressure change [69••]. However, the prevalence of therapy [65••]. The benefit from spironolactone was associ-
aldosterone synthesis escape may change with the definition ated with higher levels of collagen synthesis markers, suggest-
uses; for example, when aldosterone synthesis escape was ing that limitation of the excessive extracellular matrix
defined as plasma aldosterone levels above the normal range turnover may be one of the various extrarenal mechanisms
(> 42 nmol/L) in 132 patients with CHF (ejection fraction contributing to the beneficial effect of spironolactone in
< 45%) receiving long-term therapy with ACE inhibitors for patients with CHF [80]. A 6-month course of spironolactone,
over 6 months, the prevalence of aldosterone synthesis at a dose of 12.5 to 50 mg daily added to standard therapy
escape was only 10% (13 of 132) [71]. improves cardiac sympathetic nerve activity and symptoms
With the use of ACE inhibitors, occurrence of cardiovas- (New York Heart Association [NYHA] class) in patients with
cular events has been reduced, but not entirely prevented in CHF when compared with placebo, but has no effect on left
patients with severe CHF [72]. In this subset of patients with ventricular ejection fraction [81]. Spironolactone, at a daily
CHF, the phenomenon of “aldosterone synthesis escape” has dose of 12.5 to 50 mg for 12 months, improves left ventricu-
been linked to the DD genotype of the ACE gene polymor- lar end-systolic volumes and left ventricular systolic and dias-
phism, which has been shown to contribute to the modula- tolic function (ejection fraction and filling pattern);
tion and adequacy of the neurohormonal response to long- furthermore, it improves exercise tolerance at the highest
term ACE inhibitor administration [71]. Some studies involv- administered dose [82]. Similarly, 4 months of treatment
ing surrogate measures of outcome such as cardiopulmonary with spironolactone improved the left ventricular volume and
exercise testing in patients with CHF showed that mean peak mass, as well as decreased plasma level of brain-natriuretic
oxygen consumption and the slope of the relation between peptide, a biochemical marker of prognosis and/or ventricu-
ventilation and carbon dioxide production is significantly lar hypertrophy in nonischemic patients with CHF [83]. Simi-
worse in patients with aldosterone synthesis escape lar findings were also reported by other investigators [70•].
compared with those without it [73]. Major clinical trials In a recent randomized double-blinded trial, the
have shown that this escape has contributed to all-cause Eplerenone Post–Acute Myocardial Infarction Heart Failure
morbidity and mortality in patients with CHF [65••,66••]. Efficacy and Survival Study (EPHESUS) [66••,84,85], 6632
However, the escape effects do not seem to be limited to patients with heart failure as a complication of acute myo-
patients with CHF or left ventricular hypertrophy, because cardial infarction on standard therapy, including ACE inhib-
despite the fact that ACE inhibitors reduce the severity of pro- itors or ARBS, and a serum creatinine less than 2.5 mg/dL
teinuria in patients with nondiabetic renal disease, a propor- were randomized within 3 to 14 days to receive either
tion of these patients escape the antiproteinuric effect and eplerenone 25 mg daily titrated after 4 weeks to 50 mg daily
subsequently develop an exacerbation of renal dysfunction (3313) or placebo (3319). The study continued until 1012
[74]. Adding an ARB to an ACE inhibitor decreases the mag- deaths occurred, and during a mean follow-up of 16
nitude of “aldosterone synthesis escape” in animal models months, there were additional reductions in overall mortal-
412 Antihypertensive Therapy: Renal Injury

Figure 1. Kaplan-Meier analysis of the


probability of survival among patients in
the placebo group and patients in the
spironolactone group. The risk of death
was 30% lower among patients in the
spironolactone group than among patients
in the placebo group (P < 0.001).
(Adapted from Pitt et al. [65••].)

ity (relative risk, 0.85; P = 0.008) and the rate of death from Spironolactone is a potent competitive mineralocorti-
cardiovascular causes (relative risk, 0.83; P = 0.005). The rate coid receptor antagonist with agonist activity for estrogen
of death from cardiovascular causes or hospitalization for and progesterone receptors [87–89]. Therefore, it is associ-
cardiovascular events was reduced by eplerenone (relative ated with gynecomastia, breast pain, and impotence in
risk, 0.87; P = 0.002), as was death from any cause or any men and diminished libido and menstrual irregularities in
hospitalization (relative risk, 0.92; P = 0.02). There was also women. Time to peak concentration is 1 to 3 hours. No sig-
a reduction in the rate of sudden death from cardiac causes nificant accumulation occurs with multiple dose adminis-
(relative risk, 0.79; P = 0.03) (Fig. 2). tration. The oral form appears to be well absorbed (73%),
In a recent clinical trial, 45 patients with type 2 diabe- but the venous form is not available. It is highly protein
tes and early nephropathy, defined by the presence of bound (90%) and metabolized in the liver to active metab-
micro- or macroalbuminuria with a 24-hour creatinine olites. Its elimination half-life is 1.3 to 1.4 hours. It is
clearance more than 60 mL/min, were treated with tran- excreted in the urine (53%) and in the feces (20%).
dolapril, an ACE inhibitor. After 40 weeks of therapy, 18 Eplerenone is also a competitive mineralocorticoid recep-
patients developed aldosterone synthesis escape with a tor antagonist; it is a 9-alpha, 11-alpha epoxy derivative of
significantly lower reduction in protein excretion than the spironolactone. In vitro, it is approximately 24 times less
nonescape group. In 13 out of 18 patients who developed potent in blocking mineralocorticoid receptors compared
aldosterone synthesis escape, spironolactone (25 mg daily) with spironolactone; however, it is more selective and has
was added to trandolapril, and after a 24-week follow-up, little agonist activity for estrogen and progesterone receptors
urinary albumin excretion and left ventricular mass index [87–89]. Therefore, it is associated with a lower incidence of
were significantly reduced without blood pressure change gynecomastia, breast pain, and impotence in men and dimin-
[69••] (Fig. 3). Another recent clinical trial demonstrated ished libido and menstrual irregularities in women. However,
that in diabetic hypertensives with microalbuminuria, add- this difference in potency is diminished in vivo. Time to peak
ing eplerenone to ACE inhibitor therapy was capable of concentration is 1 to 2 hours. No significant accumulation
reducing proteinuria more than the ACE inhibitor alone occurs with multiple dose administration. Its oral form
independent of blood pressure reduction [86]. appears to be well absorbed but the absolute venous form is
not available. Protein binding is low (49%) and metabolism
is thought to occur in the liver to inactive metabolites. Its
Clinical Pharmacology of Aldosterone elimination half-life is 3.5 to 5.0 hours. It is excreted in the
Receptor Antagonists urine (66%) and in bile (32%).
Two aldosterone receptor antagonists have been described Eplerenone lowers blood pressure when dosed at 25,
to date: spironolactone and eplerenone. 50, or 200 mg twice daily in a dose-dependent fashion
RAAS Escape • Lakkis et al. 413

Figure 2. Kaplan-Meier estimates of the rate of death from any cause (A), the rate of death from cardiovascular causes or hospitalization
from cardiovascular events (B), and the rate of sudden death from cardiac causes (C). CI—confidence interval; RR—relative risk.
(Adapted from Pitt et al. [66••].)
414 Antihypertensive Therapy: Renal Injury

Figure 3. Changes in systolic blood pressure


(lightly shaded bars), diastolic blood pressure
(darkly shaded bars) (A), and left ventricular
mass index (LVMI) (B) before and after treat-
ment with spironolactone and an angiotensin-
converting enzyme (ACE) inhibitor for 24
weeks. Data represent mean ± standard
deviation (SD). Changes in average (C)
and each patient’s data (D) of urinary
albumin excretion (UAE) before and after
treatment with spironolactone and an ACE
inhibitor for 24 weeks. Data represent
mean ± SD. *P < 0.05 vs baseline value.
(Adapted from Sato et al. [69••].)

[90]. Changes in blood pressure were greater with twice seen in the placebo group, making the difference between
daily dosing (50 mg twice a day = -11.7 mm Hg systolic the two groups statistically significant. Serious hyperkale-
reduction) as opposed to single daily dosing (100 mg every mia occurred in 1% of patients in the placebo group and
day = -7.9 mm Hg systolic reduction) using 24-hour ambu- 2% of patients in the spironolactone group (P = 0.42).
latory measurements [90]. When added to existing antihy- Gynecomastia or breast pain was reported by 10% of the
pertensive therapy with an ACE inhibitor or an angiotensin men in the spironolactone group and 1% of the men in the
II receptor blocker, 50 to 100 mg of eplerenone for 8 weeks placebo group (P < 0.001), causing more patients in the
resulted in a statistically significant reduction in systolic spironolactone group than in the placebo group to discon-
blood pressure when compared with placebo in a cohort of tinue treatment (P = 0.006) [65••].
341 patients [91•,92]. Additional reductions in blood pres- In the EPHESUS trial, serious hyperkalemia occurred in
sure were 6.0 mm Hg systolic with the ACE inhibitor and 5.5% of patients in the eplerenone group, as compared
6.6 mm Hg with the angiotensin II receptor blocker. with 3.9% of those in the placebo group (P = 0.002). More
patients with serious hyperkalemia were hospitalized in
the eplerenone group than in the placebo group. In each
Safety, Tolerability, and Adverse Reactions treatment group, the incidence of hyperkalemia was higher
Eplerenone, unlike spironolactone, has fewer endocrine among patients with a lower baseline creatinine clearance
side effects due to a more selective aldosterone receptor; (P < 0.001). Patients who had serious hyperkalemia were
however, like spironolactone, it can be associated with the also more likely than those who did not have serious
development of hyperkalemia in the patients that benefit hyperkalemia to have a serum potassium concentration of
from it most, namely diabetics with microalbuminuria and more than 5.5 mmol/L or a calculated creatinine clearance
patients with mild renal failure. More clinical trials with of less than 70 mL per minute at the week one visit [66••].
eplerenone are needed to establish its safety profile in In the trial that included 45 patients with diabetes
these patient populations. mellitus type 2 and early nephropathy by Sato et al. [69••],
In both the RALES and EPHESUS trials, patients with a there was no change in serum potassium concentration
serum creatinine concentration of more than 2.5 mg/dL or between the group of 27 patients that did not develop
a serum potassium concentration of more than 5.0 mmol/L aldosterone synthesis escape (and thus did not receive
were excluded, and serious hyperkalemia was defined by a spironolactone) and the group of 18 patients that devel-
serum potassium concentration of at least 6.0 mmol/L. oped aldosterone synthesis escape (and thus received
In the RALES trial, the median potassium concentra- spironolactone). Furthermore, within the same group of
tion in the spironolactone group increased by 0.30 mmol patients who developed aldosterone synthesis escape, there
per liter during the first year of follow-up, with no change was no change in serum potassium concentration when
RAAS Escape • Lakkis et al. 415

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