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Evevident
Original paper
1999NEJMCardiology

RALES

The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators

RCTHFrEF

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Overview

In severe HFrEF, spironolactone reduced mortality and HF hospitalizations when added to standard therapy.

Clinical takeaway

RALES established mineralocorticoid receptor antagonism as disease-modifying therapy in symptomatic HFrEF, while making hyperkalemia/renal monitoring essential.

Key result

All-cause mortality was lower with spironolactone (RR 0.70; 95% CI 0.60-0.82).

Practice impact

MRAs became part of guideline-directed medical therapy for HFrEF with appropriate renal function and potassium.

Evidence

Study design

Randomized, double-blind, placebo-controlled trial.

Enrollment

1,663

Follow-up

Mean 24 months; stopped early for efficacy.

Geography

Multinational

Clinical question

Does spironolactone improve survival in severe HFrEF?

Population

  • Patients with severe chronic heart failure (NYHA class III-IV) and left ventricular ejection fraction <=35% on an ACE inhibitor and loop diuretic.

Intervention

Spironolactone 25 mg daily added to standard therapy.

Comparator

Placebo added to standard therapy.

Primary outcome

All-cause mortality.

Spironolactone reduced all-cause mortality by 30% compared with placebo when added to standard heart-failure therapy.

Relative risk / 0.7 / CI 95% CI 0.60-0.82 / p=<0.001

Key results

  • All-cause mortality: 35% with spironolactone vs 46% with placebo; RR 0.70; 95% CI 0.60-0.82; p<0.001 (30% relative reduction).
  • Hospitalization for worsening heart failure was 35% lower with spironolactone (RR 0.65; 95% CI 0.54-0.77).
  • Gynecomastia or breast pain occurred in 10% of men on spironolactone vs 1% on placebo.
  • Serious hyperkalemia was uncommon in the trial but is a key real-world risk.

Harms

  • Gynecomastia or breast pain occurred in 10% of men treated with spironolactone versus 1% with placebo.
  • Serious hyperkalemia was uncommon in the trial but is a key real-world risk, especially outside the trial's monitoring conditions.

Clinical Use

When to cite

  • When adding mineralocorticoid receptor antagonists to symptomatic HFrEF while monitoring potassium and kidney function.

Practice impact

  • MRAs became part of guideline-directed medical therapy for HFrEF with appropriate renal function and potassium.

Applicability

  • Most applicable to patients with severe chronic heart failure and reduced ejection fraction on background ACE inhibitor and loop diuretic.

Limitations

  • Pre-ARNI/SGLT2 era; background therapy differs from contemporary GDMT.
  • Requires careful potassium and renal monitoring; real-world hyperkalemia rates exceeded the trial after publication.
  • Enrolled predominantly severe (NYHA III-IV) heart failure.

Common misinterpretations

  • Do not assume the trial's low hyperkalemia rate transfers to routine practice; real-world use requires potassium and creatinine monitoring.
  • RALES studied severe HFrEF; EPHESUS and EMPHASIS-HF extended MRA evidence to post-MI and milder heart failure.

Related evidence

PARADIGM-HF - Same Disease

Citation

Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med. 1999;341(10):709-717. doi:10.1056/NEJM199909023411001

Blockade of aldosterone receptors by spironolactone, in addition to standard therapy, substantially reduces the risk of both morbidity and death among patients with severe heart failure.