Novel Therapies for Heart Failure: Vasopressin and Selective Aldosterone Antagonists

Sandeep A. Kamath, MD; S. Raja Laskar, MD; 2Clyde W. Yancy, MD


CHF. 2005;11(1):21-27. 

In This Article

Selective Aldosterone Antagonism

Aldosterone is a steroid hormone that plays a critical role in the homeostasis of sodium, potassium and volume. Aldosterone is secreted primarily by cells of the zona glomerulosa in the adrenal cortex in response to elevated levels of angiotensin II and serum potassium. Aldosterone facilitates the reabsorption of sodium in exchange for potassium in the distal segments of the nephron as well as in a variety of other organs including sweat and salivary glands and the colon.

Although once considered solely an endocrine hormone, aldosterone is now thought to be produced in a paracrine fashion as well. Aldosterone is produced in endothelial and vascular smooth muscle cells in the heart and blood vessels.[33–35] One stimulus for this local release of aldosterone is tissue injury. Aldosterone has several actions in this regard: increased production of cytokines, activation of macrophages at sites of repair,[33,36] and stimulation of fibroblast growth and production of type I and III collagen, which govern scar formation.[33,37] Aldosterone may contribute to tissue repair post-myocardial infarction (MI).[33,38]

Aldosterone levels are elevated in CHF. The importance of aldosterone in the pathogenesis of CHF and other edematous states is demonstrated by the ability of an aldosterone-receptor antagonist to ameliorate edema in patients with these conditions.[33] Beyond the development of edema, chronic elevation of aldosterone levels may have adverse long-term effects as well. In animal models, chronic elevation of aldosterone can cause increased fibrosis in the atria and ventricles.[39,40] The addition of an aldosterone antagonist in these models attenuated the development of cardiac fibrosis. Based upon this experimental data and preliminary clinical data, two large-scale clinical trials have been undertaken. The protean effects of aldosterone on cardiovascular disease are summarized in Figure 3.

Role of aldosterone in cardiovascular disease. Reproduced with permissionfrom McMahon EG. Recent studies with eplerenone, a novel selective aldosteronereceptor antagonist. Curr Opin Pharmacol . 2001;1:190–196.

The RALES (Randomized Aldactone Evaluation Study) trial enrolled a total of 1663 patients from 195 centers in 15 countries with NYHA class III/ IV HF and LVEF of <35%. Patients were randomized to spironolactone 25 mg/d or placebo. Both groups received standard therapy for HF. The trial was discontinued prematurely at a mean follow-up of 24 months because interim analysis determined that spironolactone was efficacious. When compared with standard therapy, the addition of spironolactone resulted in a 30% reduction in all-cause mortality (Figure 4), a 31% reduction in death from cardiac causes, a 36% reduction in death from HF, and a 31% reduction in sudden cardiac death. Treatment with spironolactone resulted in a 30% decline in hospitalization for cardiac causes, with a 35% decline in hospitalizations for worsening CHF compared with placebo. The decline in sudden cardiac death rates with spironolactone was attributed to a decline in myocardial fibrosis and the prevention of hypokalemia and hypomagnesemia associated with diuretic use. Spironolactone was well tolerated with a low incidence of serious hyperkalemia. Of note, patients were excluded from the study with renal insufficiency (serum creatinine [Cr] >2.5 mg/dL) or serum potassium >5.0 mg/dL. The only major adverse effect noted was a 10% incidence of gynecomastia or breast pain in men.[41]

Kaplan-Meier analysis of the probability of survival among patients in the placebo group and patients in the spironolactone group (RALES). Reproduced with permission from N Engl J Med. 1999;341:709–717.41

A substudy of RALES provided evidence that spironolactone ameliorates the progressive myocardial fibrosis seen in chronic HF. Markers of collagen synthesis were measured serially in 261 patients within the larger RALES trial. One marker, procollagen type III N-terminal peptide (PIIINP) was found to correlate with an increased rate of death and rehospitalization. At 6 months, patients in the placebo group had PIIINP levels that were nearly the same or higher than baseline values. Those patients deriving a survival benefit from spironolactone therapy had a decrease in PIIINP levels from baseline (Figure 5). In contrast, those patients in the spironolactone group that failed to benefit from therapy had an increase or no change in PIIINP levels, similar to the placebo group.[42]

Kaplan-Meier survival according to procollagen type III N-termi-nal peptide (PIIINP) levels. Reproduced with permission from Circulation . 2000;102:2700–2706.42

The RALES investigators recently evaluated the use of the selective aldosterone antagonist eplerenone in patients following acute MI complicated by LV dysfunction and HF. Eplerenone is a selective antagonist of the aldosterone receptor and does not affect glucocorticoid, progesterone, or androgen receptors. In the EPHESUS trial (Eplerenone Post-acute MI Heart failure Efficacy and Survival Study), a total of 6642 patients underwent randomization to either placebo or eplerenone at 25 mg/d, titrated to 50 mg/d, plus standard therapy post-MI. To be eligible, patients had to be 3–14 days post-acute MI, have a post-MI EF of ≤ 40%, and demonstrate clinical evidence of HF (diabetic subjects needed only to have LV dysfunction). Major exclusion criteria were a serum Cr >2.5 mg/dL and serum potassium >5.0 mg/dL. The primary end points of the study were all-cause mortality and death from cardiovascular causes or hospitalization for HF, acute MI, stroke, or ventricular arrhythmia. Eplerenone therapy resulted in reductions in both primary end points (15% and 17%, respectively) as well as a 21% decline in the incidence of sudden cardiac death (Figure 6).[43] For the patients with a left ventricular ejection fraction <0.30 status post-MI, the reduction in sudden death was >30%. In contrast to spironolactone, there was no difference in the incidence of gynecomastia compared with placebo. The EPHESUS trial suggests that selected patients with LV dysfunction following MI may benefit from aldosterone antagonism as adjunctive therapy for post-MI LV dysfunction.

EPHESUS Trial: Cumulative incidence of overall mortality. Reproduced with permission from N Engl Med. 2003;348:1309–1321.43

There are risks associated with the use of aldosterone antagonists, most notably the risk of hyperkalemia in the setting of renal insufficiency. In the EPHESUS trial, the incidence of serious hyperkalemia was 1.6%. This was buffeted by a much greater protection from the risks of hypokalemia. As well, the risks of hyperkalemia appear to be ever-present and may be higher than the risk noted in published clinical trials where rigorous follow-up was the norm.[44] For spironolactone, a serum Cr >2.5 mg/dL should represent a contraindication to its use,[45] and for eplerenone, a serum Cr >2.5 mg/dL should likewise represent a contraindication.[46] In our opinion, diabetic patients with a type IV renal tubular acidosis should also avoid the use of aldosterone antagonists even if the serum Cr is <2.0 mg/dL. Once these agents are started, careful monitoring of the serum potassium levels is recommended.

Aldosterone antagonism has emerged as a treatment option for severe CHF and for those with HF post-MI. Whether aldosterone antagonism should be prescribed in all patients with HF is unclear, however, in carefully selected patients, aldosterone antagonism appears appropriate. A remaining question to be answered is whether aldosterone antagonists used early in the course of HF will result in delayed disease progression. In addition, the mechanisms which underlie the ability of aldosterone antagonism to reduce the incidence of sudden cardiac death need to be further explored, as new pharmacologic strategies to prevent sudden cardiac death may emerge.