Efficacy and safety of mineralocorticoid receptors in mild to moderate arterial hypertension

doi:10.1016/j.ijcard.2014.10.150

International Journal of Cardiology

Volume 200, 1 December 2015, Pages 8-11

https://doi.org/10.1016/j.ijcard.2014.10.150 Get rights and content

Abstract

The mineralocorticoid receptor antagonists have been shown to have favourable safety and cost-effectiveness profiles across a broad range of clinical indications, including heart failure, primary aldosteronism and resistant hypertension. The clinical biology of the first aldosterone blocker, i.e. spironolactone, and its effects in several organ systems has been well elucidated from multiple studies. The range of adverse effects experienced with spironolactone has led to its modification and the consequent synthesis of eplerenone. Scientific evidence accumulated so far supports the role of eplerenone as first-choice drug in heart failure, with lower prevalence rates of sex-related adverse effects associated with eplerenone as compared to spironolactone. In Europe, eplerenone is currently marketed only in some countries and only with the indication of heart failure, whereas its clinical efficacy and safety in mild to moderate hypertension is said to be uncertain. A review of available scientific evidence, however, discloses that 11 randomized clinical trials assessing eplerenone in > 3500 hypertensives have been reported so far. The results of these studies clearly show that eplerenone is an effective antihypertensive agent when used alone or in combination with other medications. In doses ranging from 25 to 100 mg daily, eplerenone monotherapy results in a dose-dependent reduction in clinic blood pressure. As compared to placebo, eplerenone reduces significantly blood pressure from baseline. In general, 100 mg daily eplerenone has a blood pressure lowering that is 50 to 75% that of spironolactone. Eplerenone results in a greater reduction in blood pressure as compared with losartan, and comparison between eplerenone and amlodipine shows that both treatments decrease systolic blood pressure to a similar extent but eplerenone is better tolerated. In conclusion, there is now evidence that eplerenone can play an important role in the treatment of mild to moderate arterial hypertension and therefore scientific experts and regulatory authorities should support its wider use in clinical practice worldwide.

Introduction

Hypertension is one of the most important preventable causes of premature morbidity and mortality worldwide. Indeed, it is a major risk factor for ischaemic and haemorrhagic stroke, myocardial infarction, heart failure, chronic kidney disease and cognitive decline [1]. Indeed, arterial hypertension can lead to left ventricular hypertrophy and remodelling of resistance arteries, both of which are associated with adverse cardiovascular outcomes [2]. Most cases of hypertension have no known cause and are termed essential hypertension. Secondary causes of hypertension account for approximately 10% of cases, and treatment of secondary hypertension generally involves treating the underlying cause [2]. Whatever the aetiology, it is clear that controlling high arterial pressure improves life expectancy and is an important component of primary prevention of cardiovascular disease.

Section snippets

The clinical biology of aldosterone in hypertension

The renin–angiotensin–aldosterone system plays an essential role in blood pressure control through regulation of fluid and electrolyte balance [3]. Angiotensin II, i.e. the main effector of the renin–angiotensin system, acts on the type I angiotensin II receptor thus increasing blood pressure by a combination of vasoconstriction, increased cardiac output, vascular remodelling and increased aldosterone secretion. Aldosterone plays an important role in electrolyte homeostasis. It acts on

Mineralocorticoid receptor antagonism in hypertension: initial experiences

The effects of aldosterone on sodium retention and the importance of sodium restriction in blood pressure regulation has been the background for assessing the therapeutic role of agents able to block the mineralocorticoid receptors in arterial hypertension.

Mineralocorticoid receptor antagonists provide effective antihypertensive treatment in most patients with low renin forms of hypertension, particularly in blacks, elderly patients, and diabetics [11], [12]. Mineralocorticoid receptor

Spironolactone as antihypertensive agent

The first mineralocorticoid receptor antagonist used in hypertension was spironolactone, which was introduced in 1960 and still remains commonly used 50 years later [15]. Spironolactone acts in the aldosterone-sensitive distal tubular site of the nephron by indirect inhibition of sodium reabsorption through the epithelial sodium channel and stimulation of potassium retention. Because of these mechanisms of action, the drug is classified as a potassium-sparing diuretic. Although the principal

Eplerenone in mild to moderate arterial hypertension

The selective mineralocorticoid receptor antagonist eplerenone has been repeatedly tested in patients with arterial hypertension, and there is now evidence that it is effective and well tolerated for lowering blood pressure in patients with mild to moderate hypertension and diverse comorbidities, including left ventricular hypertrophy and diabetes mellitus [11], [12]. Indeed, many open-label and randomized controlled trials have highlighted the antihypertensive effect of eplerenone when

Future perspectives on the role of eplerenone in mild-to-moderate hypertension

There is increasing convergence for multiple clinical indications of mineralocorticoid receptor antagonists, as various reports from varied clinical settings, including hypertension, have attested the efficacy and safety of these agents. At present, however, mineralocorticoid receptor antagonists have been incorporated into various national and international treatment guidelines on heart failure, whilst they are poorly considered by hypertension recommendations [34], [35]. Specifically,

Conflict of interest for all authors

None.

Authorship

All authors had access to and participated in writing this manuscript.

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Eplerenone Reduces Atrial Fibrillation Burden Without Preventing Atrial Electrical Remodeling
2017, Journal of the American College of Cardiology
Citation Excerpt :
However, the fibrosis level achieved in the sheep model at 7 days persistent AF is substantially lower compared with human persistent AF (8,34). Another limitation is that although EPL can benefit patients with mild-to-moderate arterial hypertension (35), we have not evaluated the effects on arterial blood pressure in our model. Importantly, except for comparing the effects of EPL versus SP, the experimental conditions were practically the same as in the previous 2 papers (8,16).
The aldosterone inhibitor eplerenone (EPL) has been shown to reduce the incidence of atrial fibrillation (AF) in patients with systolic heart failure, but the mechanism is unknown.
This study hypothesized that by reducing atrial dilation and fibrosis in the absence of heart failure, EPL also reduces AF burden and prevents AF perpetuation.
The authors conducted a randomized controlled study in 34 sheep that were atrially tachypaced (13 ± 1 week). They compared daily oral EPL (n = 19) versus sugar pill (SP) treatment (n = 15) from the start of tachypacing. The endpoint was a continuous 7-day stretch of persistent AF (n = 29) or completion of 23 weeks tachypacing (n = 5).
EPL significantly reduced the rate of left atrial dilation increase during AF progression. Atria from EPL-treated sheep had less smooth muscle actin protein, collagen-III expression, interstitial atrial fibrosis, and cell hypertrophy than SP-treated sheep atria did. However, EPL did not modify the AF-induced increase in the rate of dominant frequency and ion channel densities seen under SP treatment, but rather prolonged the time to persistent AF in 26% of animals. It also reduced the degree of fibrillatory conduction, AF inducibility, and AF burden.
In the sheep model, EPL mitigates fibrosis and atrial dilation, modifies AF inducibility and AF complexity, and prolongs the transition to persistent AF in 26% of animals, but it does not prevent AF-induced electrical remodeling or AF persistence. The results highlight structural remodeling as a central upstream target to reduce AF burden, and the need to prevent electrical remodeling to avert AF perpetuation.
Prevalence and characteristics of patients with resistant hypertension and chronic kidney disease
2016, Nefrologia
Citation Excerpt :
In addition, 18.8% of our patients were treated with spironolactone, i.e. a figure well above the 3% of patients enrolled in the NHANES1 or the 9% in the Spanish register of hypertensive patients in primary care.11 Aldosterone antagonists are the standard in controlling BP and proteinuria in patients with refractory HTN, and this fact has been demonstrated in several studies.12,13 In more recent studies like SYMPLICITY HTN-3,14 conducted in highly selected patients with refractory HTN, that assess the efficacy of renal sympathetic denervation, one quarter of the patients received such treatment.
Resistant hypertension (RH) is a common problem in patients with chronic kidney disease (CKD). A decline in the glomerular filtration rate (GFR) and increased albuminuria are associated with RH; however, there are few published studies about the prevalence of this entity in patients with CKD.
To estimate the prevalence of RH in patients with different degrees of kidney disease and analyse the characteristics of this group of patients.
A total of 618 patients with hypertension and CKD stages I–IV were enrolled, of which 82 (13.3%) met the criteria for RH.
RH prevalence increased significantly with age, the degree of CKD and albuminuria. The prevalence of RH was 3.2% in patients under 50 years, 13.8% between 50 and 79 years and peaked at 17.8% in patients older than 80 years. Renal function prevalence was 4%, 15.8% and 18.1% in patients with an estimated glomerular filtration rate (GFR) of >60, 30–59 and <30 ml/min/1.73 m², respectively, and 8.9%, 15.9% and 22.5% for a urine albumin to creatinine ratio (UACR) <30, 30–299 and >300 mg/g respectively. In a logistic regression model, the characteristics associated with resistant hypertension were age, history of cardiovascular disease, GFR, albuminuria and diabetes mellitus. A total of 47.5% of patients with resistant hypertension had controlled BP (<140/90 mmHg) with 4 or more antihypertensive drugs. These patients were younger, with better renal function, less albuminuria and received more aldosterone antagonists.
RH prevalence increases with age, the degree of CKD and albuminuria. Strategies such as treatment with aldosterone receptor antagonists are associated with better blood pressure control in this group of patients, leading to reduced prevalence.
La hipertensión arterial (HTA) resistente en un problema frecuente en pacientes con enfermedad renal crónica (ERC). El descenso del filtrado glomerular (FGe) y el incremento en la albuminuria se asocian a HTA resistente, sin embargo, hay pocos estudios publicados sobre la prevalencia de esta entidad en los pacientes con ERC.
Estimar la prevalencia de la HTA resistente en pacientes con diferentes grados de enfermedad renal y analizar sus características.
Se incluyó a 618 pacientes con HTA y ERC estadios i-iv, de los cuales 82 (13,3%) cumplían criterios de HTA resistente.
La prevalencia de HTA resistente se incrementó de forma significativa con la edad, el grado de ERC y la albuminuria. La prevalencia de HTA resistente fue del 3,2% en pacientes menores de 50 años, del 13,8% entre 50 y 79 años, y alcanzó el 17,8% en mayores de 80 años. En relación con la función renal, la prevalencia fue del 4, del 15,8 y del 18,1%, en pacientes con filtrado glomerular estimado (FGe) de >60, de 30-59 y de <30 ml/min/1,73 m², respectivamente y de 8,9, 15,9 y 22,5% para índice albúmina/creatinina urinario (UACR) < 30, 30-299 y > 300 mg/g, respectivamente. En un modelo de regresión logística las características que se asociaron con la HTA resistente fueron la edad, el antecedente de enfermedad cardiovascular, el FGe, la albuminuria y la diabetes mellitus. El 47,5% de los pacientes con HTA resistente tenían la PA controlada (<140/90 mmHg) con 4 o más fármacos antihipertensivos. Estos pacientes eran más jóvenes, con mejor función renal, menos albuminuria y recibían con más frecuencia antagonistas de la aldosterona.
La prevalencia de HTA resistente aumenta con la edad, el grado de ERC y la albuminuria. Estrategias como el tratamiento con antagonistas de receptores de aldosterona se asocian con un mejor control tensional en este grupo de pacientes y disminuyen su prevalencia.
Diuretics
2016, Side Effects of Drugs Annual
Citation Excerpt :
Studies suggest that eplerenone administered at100 mg daily has a blood pressure lowering that is 50–75% that of spironolactone, and comparison between eplerenone and amlodipine shows that both treatments decrease systolic blood pressure to a similar extent but eplerenone is better tolerated. The authors concluded that there is no evidence that eplerenone can play an important role in the treatment of mild to moderate arterial hypertension and therefore scientific experts and regulatory authorities should support its wider use in clinical practice worldwide [31r]. Hyperkalemia is a commonly known adverse effect of spironolactone.
This is an updated comprehensive review of the adverse effects of diuretics for the year 2015. This review includes five different groups of diuretics: carbonic anhydrase inhibitors (CAI) with a primary focus on acetazolamide as the only current CAI still used for its diuretic effect. Loop diuretics (furosemide, bumetanide, torsemide, azosemide, and ethacrynic acid), thiazide and thiazide-like diuretics (hydrochlorothiazide, chlorthalidone, chlorothiazide and indapamide), aldosterone receptor antagonists (spironolactone and eplerenone) and the osmotic diuretic, mannitol. Intravenous infusion of furosemide in acute heart failure has shown to be associated with acute kidney injury (AKI), especially with high doses and longer duration of therapy. However, this therapy continues to prove in being very effective at decreasing symptomatic dyspnea in this patient population. This publication also reviews thiazide and thiazide-like diuretics and their effects on the metabolic, electrolyte and hemodynamic parameters. Gynecomastia and vaginal bleeding continue to be a recurrent adverse effect of spironolactone as well as new evidence indicating that combination therapy with sulfamethoxazole–trimethoprim may lead to sudden death due to hyperkalemia. Inhaled mannitol still remains a possible treatment option for patients with cystic fibrosis.
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Efficacy and safety of mineralocorticoid receptors in mild to moderate arterial hypertension

Abstract

Introduction

Section snippets

The clinical biology of aldosterone in hypertension

Mineralocorticoid receptor antagonism in hypertension: initial experiences

Spironolactone as antihypertensive agent

Eplerenone in mild to moderate arterial hypertension

Future perspectives on the role of eplerenone in mild-to-moderate hypertension

Conflict of interest for all authors

Authorship

Am. J. Hypertens.

Am. J. Med.

J. Am. Soc. Hypertens.

Lancet

Am. J. Cardiol.

J. Am. Coll. Cardiol.

Clin. Ther.

Am. J. Hypertens.

Am. J. Cardiol.

Am. Heart J.

Impact of high-normal blood pressure on the risk of cardiovascular disease

N. Engl. J. Med.

Initial treatment of hypertension

N. Engl. J. Med.

The renin–angiotensin aldosterone system: pathophysiological role and pharmacologic inhibition

J. Manag. Care Pharm.

Aldosterone and arterial hypertension

Nat. Rev. Endocrinol.

Aldosterone, hypertension, and cardiovascular disease: an endless story

Hypertension

Reconsidering the roles of the mineralocorticoid receptor

Hypertension

Multimarker approach to evaluate correlates of vascular stiffness: the Framingham Heart Study

Circulation