- RALES demonstrated a 30% reduction in all-cause mortality with spironolactone, without a significant increase in the risk of serious hyperkalemia or renal failure as had been hypothesized. - This prompted the subsequent EPHESUS study (2003), which investigated the aldosterone antagonist eplerenone in the treatment of LV dysfunction complicating acute MI, as well as the EMPHASIS-HF study (2011), investigating eplerenone in the treatment of moderate HFrEF with mild symptoms. Both were positive trials, reinforcing the benefits of aldosterone antagonism in HF. - The mechanism by which aldosterone antagonists improve survival is not well understood. However, it is clear that plasma concentrations of aldosterone in HF patients reach exceptionally high levels, some 20 times that of normal. - The aldosterone axis regulates hemodynamics, cardiac remodeling, and natriuresis. The natriuretic property of spironolactone is seen predominantly at high doses. That RALES used low-dose spironolactone suggests that its principal mechanism in prolonging survival has more to do with its effects on cardiac remodeling, and less with natriuresis.