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

glicklichd@wcmc.com

William H. Frishman

William_Frishman@nymc.edu

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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