Aldosterone receptor blockade
in the heart failure continuum

BRIGITTE STANEK

Vienna, Austria

STANEK B. Aldosterone receptor blockade in the heart failure continuum. Cardiol 2004;13(6):372–375
Morbidity and mortality associated with heart failure remain high despite the use of angiotensin-converting enzyme-inhibitors and ß-blockers. Increased survival was demonstrated in RALES and, more recently, in EPHESUS, using aldosterone receptor blockade in addition to these drugs. The mechanisms of action of aldosterone that might build the basis for the benefits of aldosterone blockade are increasingly understood. Potentially, aldosterone may induce electrolyte disturbances, autonomic imbalance, vasculopathy, and myocardial hypertrophy and fibrosis. All these effects are detrimental in patients with heart failure, as they may accelerate the progression of the underlying disease.The fact that these pathophysiological considerations are clinically substantiated by the positive findings in RALES and EPHESUS strongly indicates that aldosterone receptor blockers should be an integral part of the heart failure treatment triad.
Key words: Heart failure – Systolic dysfunction – Aldosterone – Spironolactone – Eplerenone


STANEK B. Blokáda aldosterónového receptora pri zlyhaní srdca. Cardiol 2004;13(6):372–375
Chorobnosť a úmrtnosť spojená so zlyhaním srdca je stále vysoká, a to aj napriek užívaniu ACE inhibítorov a betablokátorov. Zvýšený počet prežitia bol dokázaný v štúdii RALES a nedávno v štúdii EPHESUS pri použití blokády aldosterónového receptora. Stále viac a viac poznávame mechanizmus činnosti aldosterónu, čo by mohlo tvoriť základ pre benefit blokády aldosterónu. Do úvahy treba brať aj možnosť, že aldosterón môže vyvolať elektrolytové poruchy, autonómnu nerovnováhu, vaskulopatiu, hypertrofiu myokardu a fibrózu. Sú to škodlivé účinky pre pacientov so zlyhaním srdca, pretože môžu urýchliť zhoršenie skrytej choroby. Skutočnosť, že tieto patofyziologické javy možno klinicky dokázať pozitívnymi nálezmi v štúdiách RALES a EPHESUS naznačuje, že blokáda aldosterónového receptora by mala byť integrálnou súčasťou liečebnej triády pri zlyhaní srdca.
Kľúčové slová: zlyhanie srdca – systolická dysfunkcia – aldosterón – spironolaktón – eplerenón

Five years ago, the RALES study showed that aldosterone receptor blockade with spironolactone provides additional benefits in morbidity and mortality over angiotensin converting enzyme (ACE) inhibitors in patients with severe, late stage, heart failure (1).
Meanwhile, the efficacy of eplerenone, a new selective aldosterone receptor antagonist, was proven in the EPHESUS study involving post-myocardial infarction patients presenting with early stage left-ventricular systolic dysfunction (2).
Together the positive findings in EPHESUS and RALES support the concept of an important pathophysiologic role for aldosterone in the heart failure continuum. These two large trials provide good evidence for a cardioprotective effect of aldosterone blockade in patients with left ventricular dysfunction.

Experimental background

It is commonly accepted that persistent activation of the renin-angiotensin-aldosterone system (RAAS) is a stressful cardiovascular condition promoting myocardial jeopardy and injury. Angiotensin II was the first factor to be recognized as a key peptide in this deleterious neurohumoral cascade (3). More recently a pathogenetic role for the mineralcorticoid aldosterone emerged which appears to be independent of angiotensin II stimulation (4). Although ACE inhibitors and angiotensin receptor blockers counteract the deleterious effects of angiotensin II, these agents do not block aldosterone at the receptor site. This is essential, because plasma aldosterone which falls acutely with the introduction of an ACE inhibitor returns towards pre-treatment levels with chronic therapy. Aldosterone has a broad range of cardiovascular effects. Besides the classic actions on electrolyte metabolism leading to fluid retention and edema, aldosterone increases sympathetic activity (5). When mineralcorticoid- receptors were detected in the vasculature it became evident that aldosterone can act directly on all three layers of the arterial blood vessel (6). Unfortunately, regarding aldosterone’s actions in the vessel wall, again pathogenic aspects predominate. These include endothelial dysfunction, proliferation of vascular smooth muscle cells and perivascular fibrosis (6 – 8). Furthermore, aldosterone was demonstrated to be involved in end-organ damage concerning heart and kidney (9). In particular, fibrosis of the myocardium leads to myocardial stiffness, resulting in ventricular diastolic dysfunction. Myocardial fibrosis may interfere with ventricular excitation and produce arrhythmias. In experimental myocardial infarction, pharmacologic inhibition of aldosterone’s action at the receptor site was demonstrated to protect against subsequent myocardial fibrosis (10). Furthermore, aldosterone receptor blockade inhibited the progression of ventricular remodeling and preserved ventricular function in experimental heart failure (11).

Clinical background

Based on the stimulation of adrenergic activity, of vascular and cardiac fibrosis and of structural remodeling, aldosterone is considered a clinically important pathogenetic factor in the setting of coronary heart disease, hypertension and heart failure (12, 13). In patients with anterior myocardial infarction, aldosterone inhibition with spironolactone was reported to limit collagen synthesis and to prevent progressive left ventricular enlargement (14). According to these observations, the characteristic progressive course of ischemic dilated cardiomyopathy might be partly attributed to sustained aldosterone production.
In uncontrolled hypertension which may be associated with diastolic and systolic ventricular dysfunction due to increased ventricular mass, aldosterone plasma levels are frequently elevated. Moreover, a recent study demonstrated that aldosterone is synthesized in the ventricles of hypertensive patients (15). Increases in wall tension or stretching of the heart secondary to hypertension might be the stimuli for this cardiac aldosterone production, which increased proportionally with escalations in diastolic blood pressure. Aldosterone blockade with eplerenone produced a regression of myocardial hypertrophy which was comparable to that obtained with an ACE inhibitor. Importantly, both regimens combined had a greater effect than either agent alone (16).
Thus, there is good evidence that aldosterone is involved in the development of left ventricular hypertrophy (17 – 19). Accordingly, by interfering with aldosterone’s actions, improvement of diastolic dysfunction is expected to occur.

Aldosterone receptor blockade in severe, late stage, heart failure

The RALES study, conducted in 15 countries, was a multicenter, randomized, double-blind, placebo controlled trial of 1663 New York Heart Association Class III or IV heart failure patients (1). A standard treament regimen including an ACE inhibitor and a diuretic with or without digoxin was compared to this regimen plus the nonselective aldosterone blocker spironolactone (mean daily dose 26 mg).
The Data Safety Monitoring concluded that the results obtained with spironolactone were so significant that the trial was prematurely terminated. After a mean follow-up of 2 years, there were 372 deaths in the placebo group and 283 deaths in the spironolactone group, representing a 27% decrease in mortality. 91% placebo-treated and 81% spironolactone treated patients had at least one non-fatal hospitalization.
Under the conditions of RALES, aldosterone receptor blockade appeared a key factor to greater reduction of mortality associated with severe heart failure. The findings in RALES were a major surprise to many cardiologists who thought that ACE inhibitors alone would adequately block aldosterone release. Because of the global nature of the RALES study and the large number of study sites in Europe, spironolactone was approved in many European countries and is now indicated as adjunctive therapy of all patients with severe heart failure.
Importantly, in mild NYHA II heart failure or in patients with asymptomatic left ventricular dysfunction, the benefit – risk ratio of spironolactone has not yet been evaluated. Therefore, in the treatment of heart failure spironolactone is currently confined to patients with advanced disease (NYHA III-IV).

Aldosterone blockade in early stage left ventricular systolic dysfunction

The data obtained with aldosterone blockade in RALES were extended in the EPHESUS trial to patients who had sustained a myocardial infarction in the previous 3 – 14 days (2). Patients were eligible if ejection fraction was less than 40% (mean 33%). Optimal post-infarction heart failure therapy was administered in all of them, including an ACE inhibitor in 87%, beta-blocker in 75%, diuretic in 61%, aspirin in 89% and statins in 47%. The trial was randomized and double-blind and compared the new selective aldosterone antagonist eplerenone (initially 25 mg/day titrated to 50 mg/day after 4 weeks) and placebo. Co-primary endpoints were all-cause mortality and the composite of cardiovascular death or hospitalisations. Addition of eplerenone to background therapy reduced mortality by a further 15% and cardiovascular death or hospitalisation by 13% (Table 1). Besides the main results, a number of findings of EPHESUS have been discussed in the literature in the context of previous trials (20).
Firstly, the issue of prognosis in the EPHESUS population: Early mortality was 10% by 6 months in the placebo group. Then, annual mortality was approximately 6%. Thus, prognosis after 6 months in EPHESUS was comparable to the SOLVD prevention population with an annual mortality of 5%. However, this low mortality was only achieved in EPHESUS with the combined use of ACE inhibitors and beta-blockers, so the population risk was probably intrinsically higher than in the SOLVD prevention trial. Interestingly, patients with a past history of hypertension had significantly greater mortality benefits.
Secondly, the issue of mode of death: In fact, sudden death was the most common mode of death in EPHESUS. In the patient subgroup with ejection fraction < 30% (i.e. the MADIT II population) eplerenone reduced sudden death by 33%.
If death due to acute myocardial infarction and sudden death are considered together, then more than 70% of lives were saved by eplerenone through its impact on sudden death. Thirdly, background therapy in EPHESUS: Patients receiving ACE inhibitiors and beta blockers had greater benefit from eplerenone (20% reduction in mortality). There was no adverse interaction with baseline aspirin use.
Finally, regarding the issue of safety, patients randomised to eplerenone were less likely to get respiratory infections (presumably due to a reduction in pulmonary congestion). While the risk of serious hyperkalemia (> 6 mmol/l) was increased, the risk of hypokalemia (< 3.5 mmol/l) was lowered in the eplerenone group. Most importantly, eplerenone appeared free of feminising side effects such as gynaecomastia (Table 1).
Taken together, aldosterone receptor blockade with eplerenone prolonged survival in patients with left ventricular dysfunction early after acute myocardial infarction. It is tempting to interpret this result in favor of a specific role of aldosterone blockade in the treatment of mild (NYHA II) chronic heart failure as well. Clinical studies of eplerenone targeting such patients are underway.

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