RALES

Published

Pitt B, et al. "The effect of spironolactone on morbidity and mortality in patients with severe heart failure". New England Journal of Medicine. 1999. 341(10):709-717.
PubMed • Full text • PDF

Clinical Question

In patients with HFrEF and NYHA class III-IV symptoms, does spironolactone reduce mortality?

Bottom Line

In patients with HFrEF (EF<35%) and NYHA III-IV symptoms, spironolactone led to a 30% reduction in all-cause mortality.

Major Points

RALES was the first of a series of trials to prospectively study aldosterone antagonists' mortality benefits in HFrEF. Patients with NYHA class III-IV ischemic or nonischemic HF and EF <35% were randomized to spironolactone or placebo, with a majority of patients receiving a background of loop diuretics, ACE inhibitors, and digoxin. 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.

Guidelines

AHA/ACCF Heart Failure Guidelines (2013, adapted)

• Aldosterone antagonists recommended if NYHA class II-IV, LVEF ≤35% unless contraindicated (class I, level A)
  • If NYHA class II, should have prior CV hospitalization or elevated BNP (or analogous test)
• Aldosterone antagonists recommended after MI if LVEF ≤40% with HF symptoms or DM unless contraindicated (class I, level B)
• Aldosterone antagonists harmful if creatinine >2.5 mg/dL in men or >2.0 mg/dL in women (GFR <30 mL/min/1.73 m²) or potassium ≥5.0 mEq/L (class III, level B)

Design

• Multicenter, double-blinded, parallel-group, randomized, placebo-controlled trial
• N=1,663
  • Spironolactone (n=822)
  • Placebo (n=841)
• Setting: 195 centers in 15 countries
• Enrollment: March 1995 to December 1996
• Mean follow-up: 2 years
• Primary outcome: All-cause mortality

Population

Inclusion Criteria

• NYHA class IV HF within 6 months prior to enrollment
• NYHA class III or IV at time of enrollment
• Treatement with an ACE inhibitor (if tolerated) and a loop diuretic
• LVEF <35% within 6 months prior to enrollment without a significant intercurrent event

Exclusion Criteria

• Primary operable valvular heart disease other than mitral or tricuspid regurgitation with clinical symptoms as a result of LV dysfunction
• Congenital heart disease
• Unstable angina
• Primary hepatic failure
• Active cancer
• Life threatening disease other than HF
• History of heart transplant
• Anticipated heart transplant
• Creatinine >2.5 mg/dL (221 umol/L)
• Potassium >5 mEq/L (>5mmol/L)

Baseline Characteristics

• Mean age: 65 years in each
• White race: 86% vs. 87%
• Male: 73% in each
• BP: 122/75 vs. 123/75 mmHg
• HR: 81 bpm in each
• NYHA class:
  • II: 0.4% vs. 0.5%
  • III: 69% vs. 72%
  • IV: 31% vs. 27%
• LVEF 25% vs. 26%
• Ischemic HF: 54% vs. 55%
• Medications:
  • Loop diuretics: 100% in each
  • ACE inhibitors: 94% vs. 95%
    • Mean dose captopril: 62mg/d vs. 63mg/d
    • Mean dose enalapril: 17mg/d vs. 14mg/d
    • Mean dose lisinopril: 13mg/d vs. 16mg/d
  • Digoxin: 72% vs. 75%
  • Aspirin: 37% vs. 36%
  • KCl: 27% vs. 29%
  • Beta-blockers: 10% vs. 11%

Interventions

• Randomized to spironolactone 25mg daily or placebo
• After eight weeks the dose could be increased to 50 mg daily if no hyperkalemia but worsening HF
• If patents developed hyperkalemia the dose could be decreased to 25mg every other day (after adjusting other medications appropriately)
• Follow up evaluations and laboratory studies were performed every 4 weeks for the first 12 weeks then every three months for up to a year, then every six months until the study concluded
• Additional laboratory tests were performed at weeks 1 and 5
• Patients with a dose increase to 50mg had potassium checked at week 9
• All patients, regardless of their status, remained in the study, though study medication was held in instances of:
  • Serious hyperkalemia
  • Serum creatinine >4 mg/dL (353 umol/L)
  • Intercurrent illness
  • Any condition in which such a course was deemed medically necessary

Outcomes

Comparisons are spironolactone vs. placebo.

Primary Outcomes

All-cause mortality

35% vs. 46% (RR 0.70; 95% CI 0.59-0.82; P<0.001)

Secondary Outcomes

CV mortality

27% vs. 37% (RR 0.69; 95% CI 0.58-0.82; P<0.001)

CV hospitalization

62% vs. 90% (RR 0.70; 95% CI 0.59-0.82; P<0.001)

CV mortality or hospitalization

RR 0.68; 95 CI 0.59-0.78; P<0.001

Change in NYHA class

Improvement: 41% vs. 33%

No change: 21% vs. 18%

Worsening or death: 38% vs. 48%

Subgroup Analysis

Favored spironolactone when adjusted for LVEF, HF etiology, renal function, age, ACE inhibitor use, and digoxin use.

Adverse events

Gynecomastia or mastalgia

10% vs. 1% (P<0.001)

Additionally, spironolactone was associated with:

• Creatinine rise by 0.05 to 0.10 mg/dL (4.4-8.8 umol/L)
• Potassium rise by 0.30 meq/L
• Per the authors, neither was clinically significant.
• There were no difference in the rates of serious hyperkalemia between the two groups.

Funding

Funding provided by Searle, makers of Aldactone (the brand name of spironolactone).