Authors
Pitt B, Zannad F, Remme WJ, et al.
Title
The effect of spironolactone on morbidity and mortality in patient with severe heart failure
References
N Engl J Med 1999;341:709-17
Background
ACE inhibitor (ACEi) incompletely block the renin-angiotensin-aldosterone system and aldosterone plays a significant pathogenetic role in HF. With a potential for important hyperkalemia, a role of concomitant ACEi and aldosterone-receptor blocker therapy was explored in this landmark study.
Purpose
To determine whether spironolactone, when added to ACEi and loop diuretic therapy, improves mortality rates and clinical outcomes in patients with severe heart failure (NYHA Class IV)
Design
  • Randomized, double-blind, placebo-controlled trial
  • 1663 patients with NYHA class III or IV symptoms, (mean age of 65), LVEF ≤35% within the previous 6 months, receiving treatment with a loop diuretic as well as with an ACEi (if tolerated)
  • treatment with digitalis and vasodilators permitted; oral potassium supplementation recommended serum potassium <3.5 mmol/L
Exclusion Criteria
  • valvular heart disease, congenital heart disease, unstable angina
  • hepatic failure, active cancer or other life-threatening disease
  • serum creatinine >221 umol/L and potassium >5 mmol/L
  • potassium sparing diuretics
Follow-Up
24 months (stopped early, as spironolactone demonstrated efficacy)
Treatment Regimen
  • Spironolactone 25 mg once daily vs. placebo (increased to 50 mg once daily after 8 wks if heart failure progressed and no hyperkalemia)
  • hyperkalemia = serum potassium ≥ 6 mmol/L; dose decreased to 25 mg every other day if it developed, but adjustment with concomitant medications (ie ACE inhibitor) encouraged first; spironolactone withheld if serious hyperkalemia, serum creatinine >354 umol/L, medically necessary
  • serum potassium every four weeks for first 12 weeks, then every 3 months for the remainder of the year, then every 6 months until completion of study; also at week 9 if increased to 50 mg
Results

Primary Endpoints

Death from any cause: 35% (spironolactone) vs. 46% (placebo); relative risk 0.70 (0.6-0.82), p<0.001.

Secondary Endpoints (see study for complete list)

  • CV death: 27.5% (spironolactone) vs. 37.3% (placebo), relative risk 0.69 (0.58-0.82), <0.001; due to decrease in sudden death and death from progressive heart failure
  • Cardiac hospitalization: 30% risk reduction with spironolactone, relative risk 0.70 (0.59-0.82), <0.001
  • Combined CV death or cardiac hospitalization: 32% risk reduction in spironolactone; relative risk 0.68 (0.59-0.78), <0.001
  • Change in NYHA class (p<0.001):
    • Spironolactone: 41% improved, 21% no change, 38% worsened
    • Placebo: 33% improved, 18% no change, 48% worsened
  • Adverse events: with spironolactone, slight serum creatinine and potassium increase vs. no change in placebo (p<0.001); serious hyperkalemia was not significant (p=0.42)
  • gynecomastia: 1% (placebo) vs. 10% (spironolactone), p<0.001; higher rates of discontinuation in spironolactone (10 vs. 1, p=0.006)
Summary
When added to standard therapy of ACEi and loop diuretic, spironolactone significantly reduces death from any cause and risk for cardiovascular hospitalization in patients with NYHA class III or IV as compared to placebo.