The Use of Aldosterone Receptor Blockers in the Treatment of Hypertension

Abstract

The emerging role of aldosterone in hypertension and cardiovascular diseases has prompted a renewal of interest in therapeutic approaches designed to interfere with the action of this mineralocorticoid hormone. While spironolactone has long been used for this purpose, side effects, largely attributable to the interaction of this agent with non‐mineralocorticoid steroid receptors, has reduced the enthusiasm for its use. Eplerenone, a specific aldosterone receptor blocker with a lower incidence of the sex hormone‐related side effects than spironolactone, has been used in several recent clinical trials in hypertension and congestive heart failure. This review will highlight the major findings from these studies.

The renin‐angiotensin‐aldosterone system has long been recognized as playing a major role in cardiovascular disease by its involvement in the pathophysiology and maintenance of essential hypertension, some forms of secondary hypertension, and the pathophysiology of congestive heart failure (CHF) and other forms of cardiovascular disease. During the past three decades, the emphasis has been placed on renin and angiotensin II in terms of the physiology and treatment of these disorders, with little focus on the role of aldosterone. From a therapeutic standpoint, the mineralocorticoid receptor antagonist spironolactone has been available for over 40 years, but its use has been limited because of side effects, many of which are related to the ability of spironolactone to interact with sex hormone receptors as well as the mineralocorticoid receptor. The development of eplerenone, a selective aldosterone receptor blocker with greater specificity for the mineralocorticoid receptor, less than 1% affinity for the progesterone receptor, and less than 0.1% affinity for the androgen receptor, ¹ and thus potentially producing a lower incidence of sex hormone‐related side effects than with spironolactone, has renewed interest in this therapeutic approach, i.e., blocking the effects of aldosterone.

In addition to the long‐recognized effects of aldosterone to stimulate sodium and water reabsorption by the distal nephron in exchange for potassium and hydrogen ions, and thus to play a major role in the development and maintenance of hypertension by expansion of extracellular fluid volume and diminution of body potassium stores, aldosterone has also been shown to induce left ventricular hypertrophy (LVH); induce fibrosis of myocardial, vascular, and renal tissues; and promote magnesium loss. ² , ³ The plasma aldosterone concentration has been found to be directly related to mortality in severe CHF. ³ , ⁴

The use of angiotensin‐converting enzyme (ACE) inhibitors and, more recently, angiotensin receptor blockers (ARBs) in the treatment of hypertension and CHF assume that aldosterone as well as angiotensin II levels will be reduced or their effects blocked. However, recent studies, such as the Randomized Evaluation Of Strategies for Left Ventricular Dysfunction (RESOLVD) trial ⁵ , ⁶ utilizing ACE inhibitors or angiotensin receptor blocking (ARB) drugs ⁷ have demonstrated a lack of persistent suppression of aldosterone with these agents. Aldosterone levels, which had initially decreased with the initiation of ACE inhibitors, were found to be back to baseline levels or above initial levels at the end of the study. ⁵ , ⁶ It has been suggested that non‐renin mediated sources of angiotensin II generation and/or increased intracellular potassium concentration may have contributed to the rise in aldosterone in these studies despite inhibition of the ACE or blockade of its receptor. ⁷

Aldosterone has been shown to be involved in the process of LVH; in the canine model of CHF, eplerenone has been shown to cause reversal of LVH and remodeling of the left ventricle. ⁸ Moreover, these effects on the myocardium are independent of blood pressure (BP) reduction, thus establishing a role for selective ARB in preventing or possibly reversing cardiovascular injury. ⁹ Recent observations have further suggested that aldosterone blockade can also lead to an improvement in endothelial function, ¹⁰ as well as having an anti‐fibrotic effect on the heart, aorta, and vasculature. ⁹

Observations from recent studies with the specific aldosterone blocker, eplerenone, in hypertensive patients will be reviewed. These observations include a dose‐ranging comparison of eplerenone with placebo and spironolactone, a comparison of antihypertensive efficacy between eplerenone and losartan in black and white hypertensives and in subjects with low‐renin hypertension, combination studies with ACE inhibitors and ARBs, studies in diabetics with proteinuria, in CHF, and in isolated systolic hypertension.

DOSE‐RESPONSE TRIALS IN ESSENTIAL HYPERTENSION

In a multicenter, 8‐week trial in 417 essential hypertensive patients eplerenone 50, 100, or 400 mg o.d. or 25, 50 or 200 mg b.i.d. was compared with spironolactone 50 mg b.i.d. or placebo. ¹¹ All doses of eplerenone, whether given once or twice daily, produced reductions in both systolic and diastolic pressures that were significantly (p<0.05) greater than with placebo. The eplerenone‐induced reduction in BP was dose‐dependent; response to 100 mg of eplerenone was about 75% of that observed with 100 mg of spironolactone. The rate of adverse events reported with eplerenone was similar to that of placebo. A dose‐dependent rise in plasma renin activity was noted in patients treated with eplerenone that was less in the patients treated with <400 mg of eplerenone than seen with 100 mg of spironolactone. Similar increases in plasma aldosterone concentrations were also observed in the active treatment groups compared with those receiving placebo. Small increases in mean serum potassium levels were seen in most of the active treatment groups. At least one serum potassium measurement that exceeded 5.5 mmol/L was seen in 17 patients equally distributed among all treatment groups, including placebo. No symptoms that could be related to the increased potassium values were reported, nor did this finding require drug discontinuation for any subject.

In this 8‐week active drug treatment study, the only sex‐hormone‐related side effect, intermenstrual bleeding, was reported in one patient in the spironolactone treatment group. Specifically, no reports of impotence or gynecomastia were reported in any of the participants in the study. ¹¹ It should be emphasized that the duration of active treatment (8 weeks) may not have been sufficiently long to exclude the possibility of this sex‐hormone‐related side effect with eplerenone. This study provided evidence of a dose‐dependent antihypertensive efficacy of eplerenone but also to a single dose of spironolactone in comparison to placebo.

In another study employing 24‐hour ambulatory BP monitoring eplerenone (25, 50, 100, or 200 mg) was compared with placebo. ¹² All doses of eplerenone were significantly more effective in reducing BP than placebo. In this study one subject receiving placebo and one subject in the 200‐mg/d eplerenone group had a serum potassium level >5.5 mmol/L. There were no dose‐dependent increases in mean serum potassium in the eplerenone‐treated groups while significant (p<0.01) dose‐dependent increases in plasma renin and aldosterone were observed. ¹² The frequency of side effects reported with eplerenone was not significantly greater than those reported for placebo in this study ¹² ; no sex‐hormone‐related side effects were reported. ¹¹

COMPARATIVE TRIALS IN ESSENTIAL HYPERTENSION

Several studies have compared eplerenone to losartan. In a population of 348 black hypertensives and 203 white hypertensives double‐blind randomization to placebo, eplerenone 50 mg/d or losartan 50 mg/d for 12 weeks of active drug therapy was conducted with dose titration if needed to achieve BP control of <140/90. ¹³ Eplerenone was significantly (p<0.001) more effective in reducing systolic and diastolic BP than placebo in the entire population as well as in black or white subgroups. Eplerenone was more effective (p<0.001) in reducing systolic and diastolic pressure in the black hypertensive subgroup than losartan, but no significant differences between eplerenone and losartan in the antihypertensive efficacy were observed in the white subgroup. There were no differences in the incidence of serum potassium values >5.5 mmol/L among the three groups, placebo, eplerenone, or losartan. Adverse report frequencies also did not differ among the three treatment groups, however, significantly (p<0.001) more subjects in the placebo and losartan groups were discontinued from the study because of treatment failure than in the eplerenone group. ¹³

In another trial of 168 hypertensives with low renin levels, eplerenone in doses of 100 to 200 mg/d was compared with losartan, 50 to 100 mg/d. ¹⁴ After 8 weeks of monotherapy, if the BP was not <140/90 on the higher titration dose of assigned drug, hydrochlorothiazide, 12.5 to 25 mg/d, was added if needed to achieve BP goals. After the 8‐week monotherapy period, eplerenone lowered both systolic (p<0.001) and diastolic pressure (p<0.017) significantly more than losartan. After the addition of hydrochlorothiazide, these differences were no longer apparent since diuretic combination therapy with both assigned drugs resulted in similar BP reductions, however, significantly (p<0.05) more losartan‐treated patients (56.5%) required the addition of hydrochlorothiazide than those assigned to eplerenone (32.5%). The BP response in the losartan group was inversely related to the baseline renin levels as those with the highest renin levels had a better response to losartan than those with the lowest renin levels. This relationship was not seen in response to eplerenone.

In previous studies with spironolactone, using doses of 25 to 50 mg/d, as many as 25% of men reported sexual dysfunction and 7%‐10% experienced gynecomastia with an increase in the occurrence of this side effect to 52% with doses in excess of 150 mg/d. ¹⁵ , ¹⁶ , ¹⁷

COMBINATION THERAPY WITH ACE INHIBITORS OR ARBs

While the previous studies have concentrated on monotherapy with eplerenone alone or with the addition of hydrochlorothiazide, a recent study ¹⁸ examined the benefit of adding eplerenone to an angiotensin receptor antagonist when the BP reduction with the latter agent alone was not adequate. In this study the ACE inhibitor or ARB was continued and subjects were randomly assigned to eplerenone, 50 mg/d, increasing to 100 mg/d after 2 weeks if needed to reduce diastolic pressure <90 mm Hg, or to placebo, for 8 additional weeks. Systolic pressure was significantly reduced after the addition of eplerenone to either ACE inhibitors or ARBs; diastolic pressure was significantly reduced in the eplerenone plus ARB group. One subject in the eplerenone plus ACE inhibitor group demonstrated a serum potassium value >5.5 mmol/L on one occasion, but subsequent measurements in that subject were within the normal range. The number of adverse events did not differ between subjects assigned to eplerenone from that seen in the placebo group.

ALDOSTERONE ANTAGONISTS IN DIABETES MELLITUS AND PROTEINURIA—OR IN PATIENTS WITH CHF

In other combination studies in patients with type II diabetes mellitus with proteinuria, the addition of eplerenone to ACE inhibitors was shown to reduce proteinuria. When doses of eplerenone >100 mg o.d. were administered to subjects with renal impairment in this study, several cases of hyperkalemia were observed. In subjects with CHF to whom eplerenone was added to the existing treatment regimen, a reduction in LVH was observed, ¹⁹ however, the most dramatic findings with eplerenone in CHF were reported in the Eplerenone Post‐Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) trial. ²⁰ Based on the positive results with spironolactone in the Randomized Aldactone Evaluation Study (RALES) trial, ¹⁵ eplerenone was examined for its efficacy in CHF in the EPHESUS trial ²⁰ by randomly assigning over 6500 patients with CHF to eplerenone 25–50 mg/d or placebo in addition to existing optimal medical therapy. A significant (p<0.0008) reduction in death was observed in the eplerenone group compared with the placebo group. Serious hyperkalemia (potassium >6.0 mmol/L) was significantly (p<0.002) more frequent in the eplerenone group (5.5%) than with placebo while hypokalemia (potassium <3.5 mmol/L) was significantly (<0.001) lower in the eplerenone group than with placebo (13.1%).

EFFICACY AND TOLERABILITY IN SYSTOLIC HYPERTENSION

Among 269 subjects>50 years with an elevation of systolic pressure who were randomly assigned to receive eplerenone 50 mg/d or amlodipine 2.5 mg/d with subsequent titration to a maximum of 200 mg/d eplerenone or 10 mg/d amlodipine to achieve a reduction in systolic pressure to 140 mm Hg or below, no differences in BP reduction were seen between the two groups. ²¹ Thus it would appear from this study that eplerenone was as effective in reducing BP in this population as amlodipine, generally conceded to be one of the more efficacious agents for this group. A Quality of Life and a Symptom Distress questionnaire was applied which showed significant (<0.03) worsening in the amlodipine group compared with the eplerenone group. Thus far, there have been no specific trials comparing eplerenone to a thiazide diuretic in patients with isolated systolic hypertension.

SUMMARY

The studies presented herein provide evidence of the efficacy and tolerability of a selective ARB in a variety of hypertensive populations. These populations include unselected essential hypertensives, in black and white subgroups, in type II diabetics with proteinuria, and in patients with LVH and CHF. They appear to confirm the efficacy and tolerability of eplerenone in hypertensive patients. Multiple factors, including cost, will influence physicians in their choices of antihypertensive agents.

Disclosure: The author has been the recipient of research grant support from Pharmacia for participation in some of the research studies described herein and presented data from these studies at the American Society of Hypertension annual meetings in 2002 and 2003.