Cardiology

Aldosterone Receptor Antagonists

General

Aldosterone

Aldosterone is a hormone secreted by the adrenal gland (zona glomerulosa). Aldosterone was first identified by Simpson and Tait approximately 5 decades ago. Aldosterone was classified as a mineralocorticoid hormone as it was found to play a major role in sodium reabsorption and potassium excretion.

The aldosterone secretion is stimulated mainly by angiotensin II (decreased renal perfusion --> renin secretion --> angiotensin I --> angiotensin II --> aldosterone). The main site of action of aldosterone is mineralocorticoid receptors in renal epithelial cells within the principal cells of the distal tubule and the collecting ducts.

The primary action of aldosterone is sodium and water retention, while aldosterone may also promote myocardial fibrosis and induce cardiac hypertrophy and remodeling. Furthermore, aldosterone can directly alter endothelial function by reducing nitric oxide availability and stimulating a vascular inflammatory response.

The three major trials of aldosterone receptor antagonists in heart failure are:

Aldosterone in heart failure

Plasma aldosterone levels were noted to be very elevated in patients with heart failure. This is likely secondary to activation of the renin-angiotensin-aldosterone system (RAAS).

Aldosterone exerts a deleterious effect on a failing heart through multiple mechanisms.

1. Sodium and fluid retention

2. Endothelial dysfunction

3. Left ventricular hypertrophy

4. Myocardial fibrosis

Elevated aldosterone levels have been associated with increased mortality.

Aldosterone Receptor Antagonists (ARAs) in heart failure

Aldosterone receptor antagonists are proven to be beneficial in heart failure patients even if they are already on angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs). The dose, mechanisms, and indications are discussed in other sections below. But we can start with reviewing the major trials of ARAs.

Clinical trials of ARAs in heart failure

1. RALES

2. EPHESUS

3. EMPHASIS-HF

1. RALES Trial (Randomized ALdactone Evaluation Study)

This is the first major clinical trial of ARAs in heart failure, published in 1999. This is a double-blinded, randomized placebo control trial comparing spironolactone and a placebo. This trial enrolled 1,663 patients with New York Heart Association (NYHA) class III or IV heart failure symptoms and an ejection fraction (EF) of 35% or less. Exclusion criteria included patients with creatinine >2.5 mg/dL and potassium >5.0 mmol/L.

This study was discontinued early as the 24-month interim analysis showed significant mortality benefit with spironolactone. There was an approximately 30% reduction in both all cause mortality and cardiac mortality. Lower risk of sudden cardiac death and death from progressive heart failure was attributable to the above results. Antiandrogenic effects, such as gynecomastia and breast pain, were observed in about 10% of patients in the spironolactone group.

2. EPHESUS (Eplerenone Post-acute myocardial infarction Heart failure Efficacy and SUrvival Study)

This is the next major mortality trial in the world of ARAs. This is also a multicenter, randomized, double-blinded study that enrolled 6,642 patients who were found to have an EF of 40% or less after acute myocardial infarction with either clinical signs of heart failure or history of diabetes.

This study also excluded patients with creatinine >2.0 mg/dL and potassium >5.0 mmol/L. The mean follow-up was 16 months on this event-driven trial.

A 15% reduction in all cause mortality and a 13% reduction in cardiac mortality was observed in the eplerenone group. There was significant reduction in sudden cardiac death and heart failure hospitalization. Serious hyperkalemia was significantly higher in the eplerenone group (5.5%). Antiandrogenic side effects such as gynecomastia was not similar among the two groups. Twenty-five percent of all deaths in this study happened within the first 30 days after randomization, which emphasizes the need for early initiation of ARAs after acute myocardial infarction, when indicated.

3.EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization And Survival Study in Heart Failure)

This is the recently published major trial of ARAs. This randomized, double-blinded trial enrolled 2,737 patients with an EF of 35% or less with NYHA class II symptoms.

These patients were randomized to eplerenone and a placebo. Patients with a glomerular filtration rate (GFR) <30 ml/min were excluded and those with a GFR between 30 and 49 ml/min were given alternate day dosing. The inclusion criteria was made very specific to achieve higher event rates and is beyond the scope of this review. (See "Articles to read" section)

The primary endpoint was death from cardiovascular causes or heart failure hospitalizations. The median follow-up was 21 months. The primary endpoint occurred less frequently in the eplerenone group as did all-cause mortality and cardiovascular mortality. Although the Kaplan-Meier curve for all-cause mortality showed separation only after a year, the one for heart failure hospitalizations showed separation within weeks. The incidence of hyperkalemia was significantly higher in the eplerenone group. There was no difference between groups with antiandrogenic symptoms.

Differences between drugs within the class

Choice of ARAs

The two commonly used aldosterone receptor antagonists are spironolactone and eplerenone.

Spironolactone: Five decades ago, Cella tried to combine the elements of progesterone and digoxin for the antimineralocorticoid and cardiotonic effect, respectively, thereby developing a nonselective aldosterone receptor antagonist called spironolactone. Spironolactone is very helpful in hypertension and heart failure management. But the main limiting factor is its progestational and antiandrogenic side effects.

Eplerenone: To overcome this limitation, a selective aldosterone receptor antagonist was developed in 1987 by Grob. Although the antiandrogenic action is negligible, no significant difference in drug efficacy was noted in clinical trials. There are no large-scale, head-to-head comparison trials between spironolactone and eplerenone in the heart failure population. The factors influencing the choice between these two agents in clinical practice would be:

1. Selectivity to receptors (antiandrogenic side effects)

2. Price difference: Although both drugs are available in generic form, the cost of eplerenone tablets is at least three to four times higher than spironolactone tablets.

Why not just ACE/ARB?

The concept of 'aldosterone escape'

Heart failure management has changed considerably over last 3 decades. When neurohormonal hypothesis was introduced, multiple new classes of medications that interfere with RAAS emerged.

For many years, it was believed that the aldosterone levels were sufficiently suppressed along with RAAS blockade by angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs). But in the last decade, this was proven to be wrong.

One of the studies showed that elevated aldosterone levels were noted in up to 38% of patients while on chronic ACE inhibitor (ACEI) therapy. This was noted even in patients who are on dual blockade, both ACEI and ARB.

Although the aldosterone levels are lower at 17 weeks of therapy, they trend back up at 43 weeks after initiation of ACE and ARB. This phenomenon is called "aldosterone escape." The etiology of this escape is unclear.

Angiotensin II gets "reactivated" during chronic ACEI therapy. This could be the reason for aldosterone escape as angiotensin II is a potent stimulator of aldosterone, but aldosterone escape happens in a higher proportion of patients.

Aldosterone escape has been noted with both high and low dose ACE inhibition. Aldosterone escape can thereby reduce the benefits of ACE inhibitors and ARBs. This is the rationale for using aldosterone receptor antagonists (ARAs) in heart failure.

Administration

Dose

The following dose was recommended in the American College of Cardiology (ACC)/American Heart Association (AHA) guidelines for heart failure management (last update from 2009). The recommended starting dose is 12.5 mg/day of spironolactone or 25 mg/day of eplerenone; the dose may be doubled if tolerated by the patient. The guidelines also recommend close monitoring of serum potassium and renal function in 3 to 7 days after initiation of therapy.

Pharmacologic action

Mechanisms of aldosterone receptor antagonists

There are multiple mechanisms through which ARAs can cause beneficial effects in heart failure:

1. Both spironolactone and eplerenone have a good antihypertensive effect. The antihypertensive effect is dose related.

2. ARAs reduce the volume status and pulmonary congestion, which could be the primary mechanism for reduction in heart failure hospitalizations.

3. Aldosterone could be a stimulant of myocardial fibrosis. Spironolactone significantly suppressed elevation of procollagen III N-terminal propeptide (PIIINP), a biochemical marker of myocardial fibrosis after myocardial infarction.

4. Spironolactone prevented post infarction left ventricular (LV) remodeling, even in patients receiving an ACE inhibitor.

5. Myocardial fibrosis is a known substrate for ventricular arrhythmias. Spironolactone is shown to decrease the incidence of ventricular arrhythmias. This finding correlates with the decreased incidence of sudden cardiac death in recent trials.

Indications and contraindications

AHA guidelines: (Class I, Level B)

Updated guidelines for management of heart failure from American College of Cardiology (ACC) and American Heart Association (AHA) was published in 2013, and the guidelines-based recommendations are as follows:

Indications

ARAs are recommended (class I) for patients with NYHA class II-IV symptoms, decreased ejection fraction (EF ≤ 35%), and normal renal function and potassium levels. Patients with NYHA class II symptoms should have elevated BNP or recent heart failure hospitalizaiton.

Contraindications

Creatinine should be 2.5 mg/dL or less in men or 2.0 mg/dL or less in women, and potassium should be <5.0 mEq/L.

Dose

As given above in dose section

Monitoring

Guidelines recommend close monitoring of serum potassium and renal function measurement in 3 to7 days after initiation of therapy. Also advised is monthly laboratory tests for first 3 months and closer monitoring if an ACEI or ARB is added later.

Caution

If monitoring for hyperkalemia or renal dysfunction is not anticipated to be feasible, the risks may outweigh the benefits of aldosterone antagonists.

ESC Guidelines: (Class I, Level B)

Very similar to AHA guidelines.

  • LVEF less than or equal to 35%.

  • Moderate to severe symptoms (NYHA functional class II-IV).

  • An optimal dose of a beta-blocker and an ACEI or an ARB

Contraindications

  • Serum potassium >5 mmol/L

  • Serum creatinine >2.5 mg/dL

  • Concomitant use of drugs that may increase serum potassium level (potassium supplements, nonsteroidal antiinflammatory drugs, both ACEI and ARBs, high doses of either ACEI or ARB)

  • Conditions that can lead to dehydration (e.g., diarrhea, excessive diuretics) or acute illness should warrant reduction or even withholding of ARAs.

Undesirable effects

Adverse effects

The most feared adverse effect is hyperkalemia.

Other adverse effects

1. Antiandrogenic effects like breast pain, gynecomastia, and impotence

2. Reversible decline in GFR

3. Upper gastrointestinal side effects

Risk factors for hyperkalemia

The two most common risk factors for development of hyperkalemia are:

1. Chronic kidney disease—lower the GFR, higher the risk

2. Concomitant use of other drugs that could cause hyperkalemia—ACEI, ARBs, NSAIDs, potassium sparing diuretics, etc.

Alternative approaches

Special circumstances

Heart failure with preserved ejection fraction: This condition is also commonly called as "diastolic heart failure." Despite multiple trials, no treatment has shown to have a mortality benefit in this group of patients. One of the recently published studies showed improvement in diastolic function with ARAs without improvement in exercise capacity. Recently published TOPCAT trial did not show any mortality benefit but showed slight reduction in heart failure hospitalization. Hospitalization secondary to any cause was not different among groups and significant increase in rate of hyperkalemia was noted in the ARA group.

Diabetes and CKD: Patient with chronic kidney disease (CKD) could have high aldosterone levels without RAAS stimulation. In a small study, ARAs have shown to decrease proteinuria and even progression of CKD. In patients with diabetic nephropathy, a similar antiproteinuric effect was noted with spironolactone.

Elderly:ARAs are not advisable when GFR is <30 ml/min/1.73 m2. In elderly patients, please use GFR instead of creatinine.

Conclusion

Aldosterone receptor antagonists have clearly shown to have survival advantage in multiple recent trials. Thereby they play a major role in current medical management of heart failure along with beta-blockers, ACEI, and/or ARBs. However, use of ARAs has been limited by side effects, especially hyperkalemia. Close monitoring of patients to prevent hyperkalemia during ARA therapy is vital.

What's the Evidence

Pitt, B, Zannad, F, Remme, WJ. "The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized aldactone evaluation study investigators". N Engl J Med. vol. 341. 1999. pp. 709-17.

Pitt, B, Remme, W, Zannad, F. "Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction". N Engl J Med. vol. 348. 2003. pp. 1309-21.

Zannad, F, McMurray, JJ, Krum, H. "Eplerenone in patients with systolic heart failure and mild symptoms". N Engl J Med. vol. 364. 2011. pp. 11-21.

Yancy, CW, Jessup, M, Bozkurt, B. "American College of Cardiology Foundation; American Heart Association Task Force on Practice Guidelines. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines". J Am Coll Cardiol. vol. 62. 2013. pp. e147-239.

McMurray, JJ1, Adamopoulos, S, Anker, SD. "ESC Committee for Practice Guidelines. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC". Eur J Heart Fail. vol. 14. 2012. pp. 803-69.

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