Terapia en Hipertension Aparentemente Resistente 2015
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Transcript of Terapia en Hipertension Aparentemente Resistente 2015
REVIEW ARTICLE
Drug Therapy of Apparent Treatment-Resistant Hypertension:Focus on Mineralocorticoid Receptor Antagonists
Daniel Glicklich1,2,3• William H. Frishman3
Published online: 19 March 2015
� Springer International Publishing Switzerland 2015
Abstract Apparent treatment-resistant hypertension
(aTRH) is defined as blood pressure (BP) [140/90 mmHg
despite three different antihypertensive drugs including a
diuretic. aTRH is associated with an increased risk of
cardiovascular events, including stroke, chronic renal fail-
ure, myocardial infarction, congestive heart failure, aortic
aneurysm, atrial fibrillation, and sudden death. Preliminary
studies of renal nerve ablation as a therapy to control aTRH
were encouraging. However, these results were not con-
firmed by the Symplicity 3 trial. Therefore, attention has
refocused on drug therapy. Secondary forms of hyperten-
sion and associated conditions such as obesity, sleep apnea,
and primary aldosteronism are common in patients with
aTRH. The pivotal role of aldosterone in the pathogenesis
of aTRH in many cases is well recognized. For patients
with aTRH, the Joint National Committee-8, the European
Society of Hypertension, and a recent consensus confer-
ence recommend that a diuretic, ACE inhibitor, or an-
giotensin receptor blocker and calcium channel blocker
combination be used to maximally tolerated doses before
starting a ‘fourth-line’ drug such as a mineralocorticoid
receptor (MR) antagonist. Although the best fourth-line
drug for aTRH has not been extensively investigated, a
number of studies summarized here show that an MR an-
tagonist is effective in reducing BP when added to the
standard multi-drug regimen.
Key Points
Apparent treatment-resistant hypertension (aTRH) is
associated with multiple co-morbid conditions and
elevated aldosterone levels.
Drugs that block the mineralocorticoid receptor, such
as spironolactone and eplerenone, are often effective
fourth-line drugs in patients with aTRH.
1 Introduction
Resistant hypertension (RH) is defined as blood pressure
(BP) [140/90 mmHg despite three different antihyperten-
sive drugs, including a diuretic. RH is associated with an
increased risk of cardiovascular events, including stroke,
chronic renal failure, myocardial infarction, congestive
heart failure, aortic aneurysm, atrial fibrillation, and sudden
death [1, 2]. Preliminary studies of renal nerve ablation as a
therapy to control RH were encouraging [3–5]. However,
these results were not confirmed by the SYMPLICITY
HTN-3 trial (‘‘Renal Denervation in Patients with Uncon-
trolled Hypertension’’), a large multicenter, prospective,
randomized single-blind, and sham procedure control trial
[6]. Important differences between the earlier trials
and Symplicity 3 included the requirement for ambula-
tory BP measurements, a more stringent methodology to
& Daniel Glicklich
William H. Frishman
1 Department of Renal Transplantation, Westchester Medical
Center, Valhalla, NY, USA
2 Division of Cardiology, Westchester Medical Center,
Valhalla, NY, USA
3 Kidney Transplant Office, Department of Medicine,
New York Medical College, 40 Sunshine Cottage Road,
Valhalla, NY 10595, USA
Drugs (2015) 75:473–485
DOI 10.1007/s40265-015-0372-3
demonstrate BP differences, and the requirement for a
sham procedure as a control [7]. Further studies are un-
derway to determine the role of renal nerve ablation in
specific groups of patients with hypertension [8]. Mean-
while, attention has refocused on drug-related strategies to
control RH. Secondary forms of hypertension and associ-
ated conditions such as primary aldosteronism, obesity, and
sleep apnea are more common in patients with RH than in
the general hypertensive population [2, 9]. The pivotal role
of aldosterone in the pathogenesis of RH in many cases is
well-recognized [10, 11]. This article reviews the current
understanding and recommendations for the treatment of
RH, with particular focus on those drugs that block the
renin-angiotensin-aldosterone system.
2 Definitions
The term ‘resistant hypertension’ has often been informally
or loosely applied in the literature to describe patients with
difficult to control hypertension. However, RH or treat-
ment-RH was formally defined in 2003 by the US 7th Joint
National Committee on Prevention, Detection, Evaluation
and Treatment of Hypertension (JNC7) and by the Amer-
ican Heart Association [9, 12] as a failure to achieve a goal
BP of \140/90 mmHg despite adherence to maximally
tolerated doses of drugs from three antihypertensive drug
classes, including a diuretic. Thus, a patient with BP\140/
90 mmHg who is on four or more medications including a
diuretic has RH. This is, at present, perhaps the most
widely accepted definition of RH, but others have been
proposed [1]. The lack of BP control is most often due to
isolated systolic hypertension, especially in the elderly [2].
‘Pseudo-RH’ refers to patients who appear to qualify as
having RH due to issues such as non-adherence with
medication which may be difficult to detect without mea-
surement of drug concentrations [13], incorrect BP mea-
surement technique [2, 9], and white coat hypertension
[13]. Among patients with RH, the rate of medication non-
adherence was 8–40 % in studies using self-report ques-
tionnaires or pharmacy refill data, but was 50–60 % when
therapeutic drug monitoring from urine or serum was used
[14–16]. Ambulatory BP monitoring studies have shown
that as many as 35–50 % of patients with RH have white
coat hypertension [17–19], which has also been called of-
fice resistance [20].
The term ‘apparent treatment-RH’ (aTRH) has been
used to refer to patients whose BP is uncontrolled despite
taking at least three antihypertensive medications of dif-
ferent classes (including a diuretic) and includes those with
white coat hypertension and suboptimal medical adherence
[20]. A recent consensus conference on RH favored the use
of patients with aTRH in future clinical trials and
observational studies [1], perhaps due to concern regarding
the costs involved in excluding white coat hypertension
and medical non-adherence in large groups of patients. In
fact, most reported studies of RH do not carefully assess
medical non-adherence or possible white coat hyperten-
sion. Therefore, unless specified, aTRH is the focus of
discussion in this review.
3 Prevalence/Patient Characteristics
Prevalence data for aTRH, as available from retrospective
cohort studies, electronic medical record databases and
post hoc analyses from large outcome trials, are imprecise
and problematic. These indirect estimates of aTRH range
from 10 to 40 % of all hypertensive patients [2]. For ex-
ample, in one report the prevalence of aTRH increased
from 14 to 43 % during a 7-month period of observation
[21]. The true prevalence of aTRH remains unclear without
a large prospective well-designed cohort study in an un-
selected hypertensive population following forced titration
of antihypertensive medications [2].
Multiple factors have been associated with aTRH
(Table 1) [9, 22–34]. Individual patients with aTRH often
have several risk factors or associated factors. Secondary
Table 1 Associated conditions and secondary causes of apparent
treatment-resistant hypertension
References
Age [55 years [9]
African American [9]
Cigarette smoking [22]
Obesity [23–27]
Obstructive sleep apnea [27–31]
High-salt diet [32]
Chronic renal failure [33]
Heavy alcohol use [22]
Drug-induced [9, 34]
Non-steroid Anti-Inflammtory Drugs (NSAIDs)
Cocaine, amphetamines
Decongestants
Glucocorticoids
Erythropoietin
Cyclosporine
Natural licorice
Herbal compounds: ephedra, ma huang
Classical secondary causes of hypertension [13, 34]
Primary aldosteronism
Renal artery stenosis
Pheochromocytoma
Cushing’s disease
474 D. Glicklich, W. H. Frishman
forms of hypertension should be evaluated carefully in all
patients with aTRH. Appropriate testing should be per-
formed to exclude pseudo-RH. Primary hyperaldostero-
nism may be detected in as many as 20 % of patients with
aTRH [9, 34], obesity is common in patients with aTRH
[24–26], and obstructive sleep apnea (OSA) may be seen in
as many as 65 % of patients [29). Perhaps only 10 % of
patients with RH have no clear etiology or associated risk
factors [2]. Genetic and environmental factors yet to be
defined may be important in these patients.
4 Pathophysiology
The pathogenesis of RH is not well-defined and is clearly
multifactorial as patients with RH or aTRH are a hetero-
geneous group. Studies have shown that patients with RH
generally have an elevated systemic vascular resistance and
an expanded plasma volume with a normal cardiac output
[35–37]. In a predominantly African American population,
another study showed that aTRH patients had decreased
total arterial compliance index, increased systemic vascular
resistance, and relatively decreased cardiac index com-
pared to hypertensive patients without RH [21]. At least
mild elevations in plasma aldosterone levels and a relative
suppression of plasma renin levels have been documented
in most patients with aTRH [10, 36–39]. Aldosterone, via
mineralocorticoid receptor (MR)-dependent and indepen-
dent mechanisms, likely plays a central role in aTRH, as a
regulator of cellular and organ function, and is directly
involved in target organ damage in various cardiovascular
and renal diseases [40]. Primary aldosteronism is associ-
ated with an increased prevalence of cardiovascular dis-
eases [41]. Conversely, drugs that serve as MR antagonists
(MRAs) are effective in the treatment of aTRH, primary
aldosteronism, and a variety of cardiovascular diseases
[11]. The effects of aldosterone and MR activation in the
pathogenesis of hypertension and various disease states are
shown in Fig. 1.
A high-salt diet aids and abets hypertension and hy-
pertension-related organ damage in humans and many ex-
perimental models [2, 32]. Sodium chloride is necessary
for aldosterone-mediated MR activation in multiple rat
models of hypertension. Salt loading is also indispensable
in aldosterone-independent models of MR activation such
as the Dahl salt-sensitive hypertensive rat. Salt loading
directly leads to Rac1 activation, which leads to MR acti-
vation and increased transcriptional activity of MR-de-
pendent genes, independent of aldosterone. An inhibitor of
Rac1 reverses MR activation and reduces BP [42]. A high-
salt diet enhances aldosterone-mediated cardiac and renal
injury and fibrosis in a number of experimental models
[31]. In humans, sodium intake was directly correlated with
worsening albuminuria and loss of renal function [43, 44].
In another study, increased serum aldosterone levels were
correlated with daily urine sodium excretion and protein-
uria [45].
MRAs may exert their antihypertensive effects through
four different mechanisms: diuresis, reduction in sympa-
thetic tone, modulation of vascular tone, and reduction in
vascular stiffness [46]. In patients with RH and elevated
24-h urine aldosterone excretion started on spironolactone,
BP reduction was associated with a large diuretic effect as
indicated by substantial reductions in intracardiac heart
volumes and brain natriuretic peptide levels [34]. In pa-
tients with congestive heart failure, spironolactone reduced
sympathetic nerve activity by blocking aldosterone-
mediated decrease of synaptic noradrenaline (nore-
pinephrine) reuptake [47]. In human coronary arteries, al-
dosterone infusion increased the vasoconstriction response
Fig. 1 Effects of aldosterone
and mineralocorticoid activation
in the pathogenesis of
hypertension and various
disease states.CKD chronic
kidney disease, HR heart rate,
MR mineralocorticoid receptor,
NE norepinephrine
(noradrenaline), PAI
plasminogen activator inhibitor,
ROS reactive oxygen species,
upward arrow indicates an
increase, downward arrow
indicates a decrease [37].
Permission from Tamargo et al.
Mineralocorticoid Receptor Antagonists in Hypertension 475
to angiotensin II [48]. Spironolactone treatment in patients
with RH has been associated with decreased plasma en-
dothelin-1 levels [49]. Vascular stiffness is an important
determinant of systolic hypertension and is independently
associated with increased mortality in patients with hy-
pertension [46]. Spironolactone reduced pulse wave ve-
locity, augmentation index, and systolic BP in patients with
essential hypertension [50].
5 Associated Conditions
5.1 Obesity
Obesity is very common [24], and 75 % of the prevalence
of hypertension may be directly related to obesity [25].
There is a direct linear relationship between magnitude of
weight gain and increases in BP [23]. Conversely, weight
loss is associated with a decrease in BP [51–53]. Obesity is
also commonly associated with aTRH. It is clear that pa-
tients with central obesity have higher levels of aldosterone
[26]. Adipokines produced by adipose tissue, including
angiotensinogen and 12,13,epoxy-9-keto-10 (trans)-oc-
tadecenoic acid, directly stimulate aldosterone production
from adrenal cells [54]. High circulating leptin levels in
humans have been associated with increased BP in patients
with RH [38]. In another study, 44 patients with aTRH
were found to have elevated aldosterone levels associated
with decreased adiponectin levels [39]. OSA, which is
often seen in obese patients, is itself associated with
elevated serum aldosterone levels and is very common in
aTRH [27]. MRAs have been shown to be effective in
treating hypertension in obesity [26].
5.2 Obstructive Sleep Apnea
OSA is characterized by recurrent episodes of partial or
complete upper airway obstruction during sleep, and is
very common in patients with aTRH [30]. In fact, one
study from a hypertension referral clinic reported that
OSA was the most common secondary form of hyper-
tension, seen in 64 % of 125 patients over a 2-year period
[29]. Stimulation of the sympathetic nervous system may
be the main mechanism by which BP increases in OSA,
with increased peripheral vascular resistance, greater car-
diac output, and stimulation of the renin-angiotensin-al-
dosterone system [40]. Patients with OSA have elevated
aldosterone levels and the severity of OSA directly cor-
relates with aldosterone levels [30]. In 12 patients with
OSA and RH, 8 weeks of spironolactone 25–50 mg/day
led to improvement in OSA as measured by serial
polysomnography, and also led to significant reductions in
weight and clinic and ambulatory BP. This suggests that
aldosterone-mediated fluid retention may be an important
mediator of OSA severity, perhaps involving nocturnal
fluid shifts [55].
5.3 Chronic Renal Failure
aTRH is probably common in chronic renal failure, but its
prevalence has not been well-studied. A recent prospective,
multicenter study of 436 patients with chronic kidney
disease, stages 2–5, found that 22.9 % of the patients had
true RH, with efforts made to exclude white coat hyper-
tension and medication non-adherence [56]. Aldosterone
levels increase as glomerular filtration rate decreases and
chronic kidney disease is considered a state of relative
hyperaldosteronism [33]. Excessive salt intake and aldos-
terone together have been well-documented to play a
central role in the progression of experimental chronic re-
nal failure. MR antagonism has been shown to decrease
renal injury in these models. In humans, MR antagonism
has been shown to decrease proteinuria and slow progres-
sion of renal disease in diabetic and non-diabetic patients
over the short-term. However, there are no long-term
studies of MRA in humans with chronic renal failure [33].
Although ACE inhibitors (ACEIs) or angiotensin receptor
blockers (ARBs) have been used for years to slow the
progression of chronic renal failure [57], patients with
chronic kidney disease on ACEIs or ARBs commonly
show evidence of increased aldosterone levels, thought to
be related to aldosterone breakthrough. MRAs are effective
in reducing BP, left ventricular mass, and proteinuria in
this setting [33].
6 Treatment
6.1 Lifestyle Modifications
A number of lifestyle changes can lower hypertension. The
JNC7 report in 2003 [12] emphasized dietary sodium re-
striction (no more than 6 g of sodium chloride per day), a
high-fiber diet rich in fruits and vegetables and low in
saturated fat, moderation of alcohol intake to no more than
two drinks per day, weight loss if overweight, and 30 min
per day of aerobic exercise. In 2008 the American Heart
Association issued a statement that all patients with aTRH
should be regularly counseled to follow these recommen-
dations [9]. Patients should also be strongly encouraged to
take their BP at home daily, as this enhances adherence to
the medical regimen and has been shown to be associated
with lower BP [9, 58]. Smoking cessation should be em-
phasized [22].
Patients with aTRH appear to be very salt sensitive and
sodium restriction may be a particularly important aspect
476 D. Glicklich, W. H. Frishman
of therapy. A randomized crossover study showed that
patients with aTRH on a low-sodium diet (3 g of sodium
chloride per day) for 1 week had a reduction in systolic and
diastolic BP of 22.7 and 9.1 mmHg, respectively, com-
pared to 7 days on a high-salt diet (15 g of sodium chloride
per day) [59].
6.2 Drug Therapy
For patients with aTRH, a recent consensus conference [1],
the 8th Joint National Committee on Prevention, Detection,
Evaluation and Treatment of Hypertension (JNC8) [60],
and the European Society of Hypertension [61] recom-
mended that a diuretic, ACEI, or ARB and calcium channel
blocker (CCB) combination be used to maximally tolerated
doses before starting a ‘fourth-line’ drug such as an MRA
(Tables 2 and 3) [12]. There is significant disconnect be-
tween evidence-based recommendations for diuretic ther-
apy and the actual clinic practice and usage of diuretics
[19], as discussed below. Although the best fourth-line
drug for aTRH has not been extensively investigated [12], a
number of studies summarized in Table 4 show that MR
antagonism was effective in reducing BP when added to a
multi-drug regimen such as that discussed above. There
have been four relatively small randomized control trials;
the rest of the evidence supporting the use of MR an-
tagonism in aTRH is from observational data. In contrast,
to date there are no studies of b-blockers, a-blockers,
central sympatholytic drugs, or direct vasodilators as
fourth- or fifth-line drugs for the treatment of aTRH.
6.3 Diuretics
There is general agreement that diuretic therapy be part of
a multi-drug regimen to control aTRH [12, 60]. Most pa-
tients with RH have an expanded plasma volume [9, 35].
Studies have shown that diuretic use is associated with
improved BP control [12, 62]. Dietary salt restriction is
critical to enable successful diuretic therapy. However, the
exact mechanisms for the persistent antihypertensive ef-
fects of most diuretics such as thiazides are unclear [63].
The main classes of diuretic agents include thiazide, loop,
and potassium-sparing diuretics. Hydrochlorothiazide is by
far the most widely used diuretic agent, with numerous
formulations commercially available that combine it with a
range of other agents, including potassium-sparing diuret-
ics, ACEIs, and ARBs [64]. Taking a pill with several
medications compounded together may enhance medica-
tion adherence [65]. Combination therapy with thiazide and
potassium-sparing diuretics has been shown to effectively
reduce BP, limit abnormalities in serum potassium, and
reduce cardiovascular events in several large multicenter
hypertension treatment trials [65].
Not all thiazide diuretics are equally efficacious. It is
indeed curious that while hydrochlorothiazide is by far the
most commonly used, it is not the most effective thiazide
diuretic for lowering BP or decreasing cardiovascular dis-
ease. Chlorthalidone, a longer-acting thiazide diuretic, was
clearly recommended over hydrochlorothiazide in the 2008
American Heart Association position statement on RH [9]
and by the International Society on Hypertension in Blacks
Consensus Statement [66]. Over a 20-year period, a num-
ber of large randomized clinical hypertension trials which
used chlorthalidone-based regimens have shown a reduc-
tion in cardiovascular disease events, including the
Hypertension Detection and Follow-up Program (HDFP)
[67], MRFT (Multiple Risk Factor Intervention Trial) [68],
Systolic Hypertension in the Elderly Program (SHEP) [69],
and ALLHAT (Antihypertensive and Lipid-Lowering
Treatment to Prevent Heart Attack Trial) [70]. In contrast,
hydrochlorothiazide-based therapy was less effective than
other study drugs [71, 72]. A small blinded comparison
study showed that chlorthalidone 25 mg/day lowered BP
more effectively than hydrochlorothiazide 50 mg/day,
particularly at night, as assessed by ambulatory BP
monitoring [73]. However, there are few long-term head-
to-head comparison trials of various classes of thiazide-
type diuretics [1]. Chlorthalidone has a duration of action
at least twice as long as hydrochlorothiazide and is ap-
proximately 1.5–2.0 times as potent a diuretic. Despite
information supporting the use of chlorthalidone, less than
3 % of hypertensive patients were managed with this drug
in a Veterans Administration study [74]. A partial expla-
nation for this may be that no combination medications
include chlorthalidone [65].
In patients with chronic kidney disease, with a
glomerular filtration rate of \40 cc/min, loop diuretics
such as furosemide, bumetanide, or torsemide may be more
effective than thiazides [9].
Amiloride and triamterene are potassium-sparing di-
uretics that block luminal membrane epithelial sodium
channels in the distal tubule and collecting duct. The re-
duction in sodium reabsorption hyperpolarizes the tubular
epithelial apical membrane and reduces the electro-
chemical gradient for potassium secretion, an effect that is
aldosterone independent [40]. These drugs, by themselves,
have a weak antihypertensive effect. They are commonly
administered with thiazide or loop diuretics to prevent
potassium and magnesium loss and increase natriuresis
[63]. In obese black patients with uncontrolled hyperten-
sion despite a thiazide or loop diuretic and CCB, amiloride
10 mg was compared with spironolactone 25 mg in a
randomized placebo-controlled double-blinded trial.
Treatment with amiloride was more effective in lowering
BP than spironolactone. However, the amiloride group had
significantly elevated aldosterone and endothelin-1 levels
Mineralocorticoid Receptor Antagonists in Hypertension 477
Table 2 First-line three-drug treatment with diuretic therapy for apparent treatment-resistant hypertension [13]
Drug Dosing range
(mg/day)
Daily
dosing
Adverse effects Special indication Level of
evidence
Diuretics Hyponatremia, hypokalemia, volume
depletion, renal dysfunction,
glucose intolerance, DM,
hyperuricemia, gout
Initial therapy for Black and elderly
patients with isolated systolic
hypertension
High
Thiazide
Chlorthalidone 12.5-25 1
Indapamide 1.25–5 1
HCTZ 12.5–50 1
Metolazone 2.5–10 1
Loop diuretics Hypokalemia, volume depletion,
renal dysfunction
CHF, advanced CKD Moderate
Furosemide 20–160 2
Torsemide 2.5–80 1–2
Bumetanide 0.5–2.0 2
Ethacrynic acid 25–100 2
Potassium-sparing diuretics Hyperkalemia, volume depletion,
renal dysfunction
None Moderate
Amiloride 5–20 1
Triamterene 25–100 1
CCBs All CCBs: Raynaud’s phenomenon,
angina pectoris, vasospastic angina
Moderate
Dihydropyridine Lower-extremity edema, gingival
hyperplasia
Initial therapy for Black and elderly
patients with isolated systolic
hypertension
High
Amlodipine 2.5–10 1
Felodipine 2.5–20 1–2
Isradipine CR 2.5–20 2
Nicardipine SR 30–120 2
Nifedipine XL 30–120 1
Nisoldipine 10–40 1–2
Non-dihydropyridine Lower-extremity edema, gingival
hyperplasia, heart block,
bradycardia, CHF
Supraventricular tachycardia Moderate
Diltiazem CD 120–540 1
SR 120–480 1
ACEIsa Cough, hyperkalemia, angioedema CHF, CKD High
Benazepril 10–80 1–2
Captopril 25–150 2
Enalapril 2.5–40 2
Fosinopril 10–80 1–2
Lisinopril 5–80 1–2
Moexipril 7.5–30 1
Perindopril 4–16 1
Quinapril 5–80 1–2
Ramipril 2.5–20 1
Trandolapril 1–8 1
ARBs Hyperkalemia CHF, CKD High
Azilsartan 40–80 1
Candesartan 8–32 1
Eprosartan 400–800 1–2
Irbesartan 150–300 1–2
Losartan 25–100 2
Olmesartan 5–40 1
Telmisartan 20–80 1
Valsartan 80–320 1–2
ACEIs ACE inhibitors, ARBs angiotensin receptor blockers, CCBs calcium channel blockers, CHF congestive heart failure, CKD chronic kidney disease,
CR controlled release, DM diabetes mellitus, HCTZ hydrochlorothiazide, SR sustained release, CD and XL extended releasea Should not be used in combination with ARBs
478 D. Glicklich, W. H. Frishman
compared to the spironolactone group [75]. There are no
studies comparing amiloride or triamterene with spirono-
lactone or eplerenone as add-on therapy in aTRH.
6.4 Mineralocorticoid Receptor Antagonists
The first report of the effect of add-on MR antagonism in
patients with RH was an open-label uncontrolled trial of 25
patients, most of whom had uncontrolled BP despite three
or more drugs, no apparent secondary cause, and normal
renal function [76] (Table 4). Spironolactone 1 mg/kg/day
administered for 1 month decreased mean 24-h ambulatory
BP measurement from 152/86 to 128/76 mmHg. After
3 months of MR antagonism, 23 of 25 patients had con-
trolled BP and the mean number of antihypertensive pa-
tients was reduced from 3.2 to 2.1. No patient had to stop
spironolactone due to adverse effects. Another prospective
uncontrolled study compared the effect of spironolactone
12.5–50 mg/day in 34 primary aldosteronism patients and
42 patients with RH [77]. All patients had uncontrolled BP
while taking at least three drugs including a diuretic, ACEI,
or ARB. After 6 weeks of spironolactone, BP decreased by
21/14 mm Hg, an effect sustained at 6 months of follow-
up. BP reduction was similar in patients with and without
primary aldosteronism.
A small retrospective study of spironolactone add-on
therapy in patients with uncontrolled hypertension despite
at least two other antihypertensive drugs showed a sub-
stantial reduction in BP of 23/12.5 mmHg compared to
other add-on agents where BP decreased by 7.6/5.8 mmHg
[78]. A large retrospective study of the ASCOT-BPLA
(Anglo-Scandinavian Cardiac Outcome Trial–blood pres-
sure lowering arm) showed that the 1411 patients who
received spironolactone 25–50 mg/day as add-on therapy
after three-drug combinations failed to achieve goal BP had
a significant decrease in BP of 21.9/9.5 mmHg [79].
In another report, 119 patients seen at a hypertension
referral clinic had spironolactone 25–50 mg/day added to a
C3-drug regimen (n = 100) or two-drug regimen (n = 19)
[80]. A similar response to spironolactone was seen as in
other studies, with BP decreased by 21.7/8.5 mmHg. Very
similar observations were made by another group in 175
patients taking a median of four drugs who then had
spironolactone 25–100 mg/day added to their drug regi-
men, with BP declining by 19/9 mmHg [81].
In a prospective crossover study, 42 patients with un-
controlled BP despite taking at least three drugs including a
diuretic and ACEI or ARB compared the effect of dual
blockade with ACEI and ARB versus ACEI or ARB and
spironolactone [82]. During the 3-month period on
spironolactone, office BP was reduced by 32.2/10.9 mmHg,
ambulatory BP measurements showed a reduction of
20.8/8.8 mmHg, and 56.4 % of the patients achieved
goal BP. In comparison, while on an ACEI and ARB, BP
decreased to 12.9/2.2 mmHg and the ambulatory BP
measurements showed a reduction of 7.1/4.7 mmHg.
Changes between the groups were highly significant
(p \ 0.001).
There are four prospective, randomized, double-blind,
placebo-controlled trials of spironolactone in patients with
RH. In the ASPIRANT (addition of spironolactone in pa-
tients with arterial hypertension) trial, all 117 patients had
uncontrolled BP on at least three drugs including a diuretic
[83]. Exclusion criteria included BP [180/110 mmHg,
estimated glomerular filtration rate \40 cc/min, hypona-
tremia, porphyria, pregnancy or lactation, hypersensitivity
to spironolactone, or ongoing MRA usage prior to the
study. After 2 months on spironolactone, serial ambulatory
BP measurements showed a decrease in BP of 9.8/3 mmHg
versus placebo (p \ 0.01). Adverse effects led to discon-
tinuation of placebo in one patient and spironolactone in
two patients. Subsequent to the study, 24 % of the par-
ticipants were found to have secondary causes of hyper-
tension, including 17 with primary aldosteronism, six with
renovascular hypertension, three with OSA, and two with
intrinsic renal disease.
In the second study, 119 patients with type 2 diabetes
who had uncontrolled hypertension despite at least three
antihypertensives, including a diuretic and ACEI or ARB,
were given spironolactone 25–50 mg/day over a 4-month
period [84]. Exclusion criteria were office BP [180/
110 mmHg, severe heart failure, arrhythmias, glycosylated
hemoglobin [10 %, known secondary hypertension, esti-
mated glomerular filtration rate\50 cc/min, intolerance to
spironolactone, pregnancy, and oral contraception. In the
spironolactone-treated group, serial ambulatory BP mea-
surements showed a reduction of BP of 8.9/3.7 mmHg
versus placebo (p \ 0.001), 36 % of the spironolactone-
treated group achieved a goal BP of \130/80 mmHg
compared with 12 % of the placebo group. One patient
discontinued MRA due to hyperkalemia (serum potassium
5.7 mmol/L) and one patient due to hypotension.
The third study was a prospective, randomized, double-
blind, placebo-controlled, parallel-group trial of 155 pa-
tients that compared LCI699, a new aldosterone synthetase
inhibitor, with various dosages of eplerenone and placebo
[85]. All patients had uncontrolled BP despite taking at
least three drugs including a diuretic. Exclusion criteria
were a history of stroke, myocardial infarction, congestive
heart failure, angina, angioplasty, coronary artery bypass
surgery, a significant conduction abnormality, cardiac
valve disease, secondary hypertension, creatinine clearance
\50 cc/min, poorly controlled diabetes, pregnant or lac-
tating women, and prior recent use of a potassium-sparing
diuretic. After 2 months, patients with eplerenone showed
a significant reduction in BP of 9.9/2.9 mmHg versus
Mineralocorticoid Receptor Antagonists in Hypertension 479
placebo. None of the groups taking graded dosages of
LCI699 showed a significant drop in BP versus placebo.
In the fourth study, a prospective, randomized controlled
trial, 41 patients with chronic renal disease and RH taking
at least three drugs including a diuretic were randomized
and assigned to receive spironolactone 25–50 mg/day or
placebo. Other secondary forms of hypertension had been
excluded. After 4 months of follow-up, patients on
spironolactone had a significantly greater decrease in BP
than placebo, -36/12 mmHg (p \ 0.05). One patient tak-
ing an MRA developed mild hyperkalemia, defined as
serum potassium [5.5 mEq/L [86].
A CCB, ARB, or ACEI and a diuretic is a commonly
prescribed and recommended combination in RH [57]. A
Table 3 Fourth- and fifth-line drug therapy for apparent treatment-resistant hypertension [13]
Drug Dosing
range
(mg/day)
Daily
dosing
Adverse effects Special indication Level of
evidence
Fourth-line drug therapy
MRA Hyperkalemia, volume depletion,
renal dysfunction
CHF, post-myocardial infarction with left
ventricular dysfunction, primary
aldosteronism
High
Spironolactone 12.5–400 1–2
Eplerenone 25–100 1–2
Fifth-line drug therapy
Direct renin
inhibitors
Hyperkalemia, diarrhea None High
Aliskiren 75–300 1
b-Blockers Bradycardia, heart block,
bronchospasm, fatigue, depression
Myocardial infarction, CHF High
Acebutolol 200–800 2
Atenolol 25–100 1
Betaxolol 5–20 1
Bisoprolol 2.5–20 1
Metoprolol T 50–450 2
Metoprolol S 50–200 1–2
Nadolol 20–320 1
Nebivolol 5–20 1
Pindolol 10–60 2
Propranolol 40–180 2
Propranolol LA 60–180 1–2
Timolol 20–60 2
Labetalol 200–2400 2
Carvedilol 6.25–50 2
a-Blockers Nasal congestion, dizziness,
orthostatic hypotension
Pheochromocytomaa Moderate
Doxazosin 1–16 1
Prazosin 1–40 2–3
Terazosin 1–20 1
Phenoxybenzamine 20–120 2
Central
sympatholytics
Drowsiness, orthostatic hypotension,
depression
None Moderate
Clonidine 0.2–1.2 2–3
Clonidine patch 0.1–0.6 Weekly
Guanfacine 1–3 1
Methyldopa 250–1000 2
Direct vasodilators Reflex tachycardia, lower extremity
edema, drug-induced lupus
(hydralazine)
None Moderate
Hydralazine 10–200 2
Minoxidil 2.5–100 1
CHF congestive heart failure, LA slow release, MRA mineralocorticoid receptor antagonist, T tartrate, S succinatea Should be considered the first-line drug therapy in the presence of special indication
480 D. Glicklich, W. H. Frishman
Ta
ble
4E
ffec
to
fad
d-o
nm
iner
alo
cort
ico
idre
cep
tor
anta
go
nis
tth
erap
yin
resi
stan
th
yp
erte
nsi
on
Yea
ran
d
refe
ren
ces
Po
pu
lati
on
nS
tud
yd
esig
nM
RA
(dai
lyd
ose
)F
oll
ow
-up
(mo
nth
s)
Mea
nre
du
ctio
nin
BP
(mm
Hg
)
20
03
[77
]1
9U
nco
ntr
oll
edB
P,
3d
rug
s2
5P
rosp
ecti
ve,
un
con
tro
lled
Sp
iro
no
lact
on
e1
mg
/kg
32
3/1
0
20
03
[78
]U
nco
ntr
oll
edB
Po
nC
2d
rug
s(3
4/7
6
had
PA
)
76
Pro
spec
tiv
e,u
nco
ntr
oll
ed,
op
en-l
abel
Sp
iro
no
lact
on
e1
2.5
–5
0m
g6
25
/12
20
05
[79
]B
lack
pts
;B
Pu
nco
ntr
oll
edo
n2
dru
gs
amil
ori
de
vs
spir
on
ola
cto
ne
98
Ran
do
miz
ed,
do
ub
le-b
lin
d,
pla
ceb
o-
con
tro
lled
,p
aral
lel
gro
up
s
Sp
iro
no
lact
on
e2
5m
g;
amil
ori
de
10
mg
2.2
57
.3/3
.3v
s.1
2.2
/4.8
amil
ori
de
20
06
[80
]U
nco
ntr
oll
edB
Po
nC
2d
rug
s4
2R
etro
spec
tiv
eS
pir
on
ola
cto
ne
12
.5–
25
mg
32
3.2
/12
.5
20
07
[81
]U
nco
ntr
oll
edB
Po
nC
3d
rug
s
(AS
CO
T-B
PL
A)
14
11
Ret
rosp
ecti
ve,
mu
ltic
ente
rS
pir
on
ola
cto
ne
25
–5
0m
g1
52
1.9
/9.5
20
07
[82
]U
nco
ntr
oll
edB
Po
nC
3d
rug
sin
10
0
pts
,C
2d
rug
sin
19
pts
Pro
spec
tiv
e,u
nco
ntr
oll
ed,
op
en-l
abel
Sp
iro
no
lact
on
e2
5–
50
mg
62
1.7
/8.5
20
10
[83
]U
nco
ntr
oll
edB
Po
n4
dru
gs,
seri
al
AB
PM
17
5P
rosp
ecti
ve,
un
con
tro
lled
,o
pen
-lab
elS
pir
on
ola
cto
ne
25
–1
00
mg
15
16
/9
20
10
[84
]U
nco
ntr
oll
edB
Po
nC
3d
rug
s,se
rial
AB
PM
,se
rial
AB
PM
com
par
edw
ith
MR
A?
AC
EI
or
AR
Bw
ith
AC
EI
?A
RB
42
Pro
spec
tiv
e,cr
oss
ov
er,
op
en-l
abel
Sp
iro
no
lact
on
e2
5–
50
mg
62
1/9
vs.
6/2
.5o
nA
CE
I?
AR
B
20
11
[85
]U
nco
ntr
oll
edB
Po
nC
3d
rug
s,se
rial
AB
PM
,A
BP
M(A
SP
IRA
NT
tria
l)
11
7P
rosp
ecti
ve,
ran
do
miz
ed,
do
ub
le-
bli
nd
,p
lace
bo
-co
ntr
oll
ed,
par
alle
l-
gro
up
Sp
iro
no
lact
on
e2
5m
g2
9.8
/3
20
11
[88
]P
tsw
ith
CR
F,
un
con
tro
lled
BP
on
C3
dru
gs
41
Pro
spec
tiv
e,ra
nd
om
ized
,p
lace
bo
-
con
tro
lled
Sp
iro
no
lact
on
e2
5–
50
mg
43
6/1
2
20
13
[86
]T
yp
e2
DM
,u
nco
ntr
oll
edB
Po
nC
3
dru
gs,
seri
alA
BP
M
11
9P
rosp
ecti
ve,
ran
do
miz
ed,
do
ub
le-
bli
nd
,p
lace
bo
-co
ntr
oll
ed
Sp
iro
no
lact
on
e2
5–
50
mg
48
.9/3
.7
20
13
[87
]U
nco
ntr
oll
edB
Po
nC
3d
rug
s1
53
Pro
spec
tiv
e,ra
nd
om
ized
,d
ou
ble
-
bli
nd
,p
lace
bo
-co
ntr
oll
ed,
par
alle
l
gro
up
,co
mp
ared
LC
I69
9w
ith
eple
ren
on
e
Ep
lere
no
ne
10
0m
g2
9.9
/2.9
eple
ren
on
e4
.3/1
.2L
C1
69
9
AB
PM
amb
ula
tory
blo
od
pre
ssu
rem
easu
rem
ent,
AC
EI
AC
Ein
hib
ito
r,A
RB
ang
iote
nsi
nre
cep
tor
blo
cker
(an
tag
on
ist)
,A
SC
OT
-BP
LA
An
glo
-Sca
nd
inav
ian
Car
dia
cO
utc
om
eT
rial
—b
loo
d
pre
ssu
relo
wer
ing
arm
,A
SP
IRA
NT
add
itio
no
fsp
iro
no
lact
on
ein
pat
ien
tsw
ith
arte
rial
hy
per
ten
sio
n,
BP
blo
od
pre
ssu
re,
CR
Fch
ron
icre
nal
fail
ure
,M
RA
min
eral
oco
rtic
oid
rece
pto
ran
tag
on
ist,
PA
pri
mar
yal
do
ster
on
ism
,p
tsp
atie
nts
Mineralocorticoid Receptor Antagonists in Hypertension 481
number of commonly used dihydropyridine CCBs compete
for aldosterone binding to the MR [87, 88]. The non-di-
hydropyridine CCBs have no effect on MR. The dihy-
dropyridine CCBs that most strongly bind to MR include
felodipine, nimodipine, and nitrendipine. Thus, some of the
BP-lowering effects of certain CCBs may be attributed to
inhibition of MR. A number of drug companies have po-
tential new molecules in the dihydropyridine family with
MR-blocking properties, but no effect on other steroidal
receptors [89]. An example is lercandipine, a CCB with
enhanced MRA activity shown in a clinical trial [90].
Evidence suggests that MRAs may be underutilized in
patients with uncontrolled aTRH. No more than one in four
patients with uncontrolled aTRH takes an MRA [20, 91].
Part of this is likely related to concerns about adverse ef-
fects. Breast tenderness and gynecomastia with spirono-
lactone affected 6–10 % of patients in the ASCOT-BPLA
trial [79], but these adverse effects are not a problem with
eplerenone. There is a risk of hyperkalemia, e.g., serum
potassium[5.2 mEq/L, with MRA therapy in patients with
diabetes, those aged over 65 years of age, and in patients
taking NSAIDs. Such patients should be started on a low-
dose MRA such as spironolactone 12.5 mg daily or
eplerenone 25 mg daily, cautioned to avoid NSAIDs, and
monitored carefully. Specifically, serum potassium levels
should be checked 7–10 days after initiating MRA therapy
in these patients. If serum potassium is over 6 mEq/L, the
MRA should be stopped and oral kayexalate with sorbitol
or intravenous therapy for hyperkalemia administered, with
confirmation of normal serum potassium. Patients with a
serum potassium level 5.3–6.0 mEq/L can usually be easily
managed with one of more of the following: increased dose
of a thiazide or loop diuretic, sodium bicarbonate
650–1300 mg with meals, low-potassium diets, and lower
doses of MRAs [20, 91].
6.5 Aliskiren
Aliskiren, the only direct renin inhibitor available, has been
shown to be an effective antihypertensive when used alone
or in combination with other drugs, particularly a diuretic
and/or CCB [90, 92]. A meta-analysis of randomized
control trials using aliskiren in combination with an ACEI
or ARB showed that there was a significant increased risk
of hyperkalemia [93]. ASPIRE (Aliskiren Study in Post-MI
Patients to Reduce Remodeling), a multicenter trial of
aliskiren in cardiovascular disease, showed that the patients
on aliskiren had a higher rate of adverse events [94]. The
ALTITUDE (aliskiren trial in type 2 diabetes using cardio-
renal endpoints) trial was designed to determine whether
the addition of aliskiren to conventional treatment includ-
ing an ARB or ACEI in patients with type 2 diabetes re-
duced cardiovascular and renal morbidity and mortality
versus placebo. This trial was stopped prematurely because
of an increase in adverse events and no clear benefits in
patients randomly assigned to aliskiren [94]. These results,
along with the other studies mentioned, strongly suggest
that aliskiren should not be used in combination with an
ARB or ACEI. The role of aliskiren for the treatment of
RH is uncertain, but it has been reported as useful in a
small observational study [92].
6.6 New Drugs
There are few new classes of drugs that have recently been
marketed for the treatment of hypertension. Several al-
dosterone synthetase inhibitors have been tested in animal
models and one is being evaluated in a clinical trial. Al-
dosterone synthetase is an enzyme of the cytochrome P450
system with steroid 18-hydroxylase, 18-oxidase, and 11b-
hydroxylase properties. Inhibition of aldosterone syn-
thetase in experimental animals modestly reduced elevated
BP and reduced end-organ damage related to high an-
giotensin II and aldosterone. The aldosterone synthetase
inhibitor LCI699 has been tested in patients with primary
aldosteronism and primary hypertension with initial en-
couraging results [95, 96]. A prospective, randomized,
double-blinded, placebo-controlled trial showed that
eplerenone was more effective than three different doses of
LCI699 in patients with RH [85].
Other agents such as natriuretic peptide receptor A
agonists, angiotensin II type 2 receptor agonists, dual
inhibitors with angiotensin-1R blockade, and neutral
endopeptidase inhibitors are all in early clinical trials
[90, 97].
7 Conclusion
aTRH is associated with significantly increased cardio-
vascular morbidity and mortality. A number of co-morbid
and predisposing factors may be present in any one indi-
vidual with aTRH. Hyperaldosteronism seems to be a
common theme in aTRH, linking a number of these pre-
disposing factors. Therefore, the rationale to use of an
MRA as a fourth-line drug in aTRH seems clinically sound.
Although there is some evidence from several randomized
controlled trials, most of the data supporting MRA use in
aTRH derives from observational series or retrospective
data. MRAs also have at least potential primary cardio-
vascular benefits in patients with underlying left ventricular
hypertrophy, congestive heart failure, or coronary artery
disease. We therefore recommend that MR antagonism be
considered for use in patients with aTRH, with careful
clinical monitoring to detect and treat hyperkalemia if
it occurs. Large randomized controlled, parallel-group
482 D. Glicklich, W. H. Frishman
studies are needed to determine the best add-on therapy in
patients with aTRH.
Acknowledgments No external funding was used in the preparation
of this manuscript. Neither of the authors have any conflicts of interest
that might be relevant to the contents of this review.
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