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#104 Aldosterone antagonists in systolic heart failure – no longer an afterthought.

What is the role of aldosterone antagonists in patients with chronic systolic heart failure?

Aldosterone antagonists reduce mortality and hospitalizations in patients with congestive heart failure (Class II–IV). The benefit appears similar to β-blockers or ACE inhibitors. Close monitoring is required for those at risk of hyperkalemia.  

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Two randomized controlled trials: 
  • RALES:1 1,663 patients with Class III–IV heart failure on ACE inhibitors and diuretics. Given spironolactone or placebo. At 24 months: 
    • Statistically significant reduction in: 
      • Mortality: spironolactone 35%, placebo 46%, Number Needed to Treat (NNT) 10. 
      • Cardiovascular hospitalization: 32% vs. 40%, NNT 12. 
    • Adverse events: 
      • Gynecomastia/breast pain: spironolactone 10%, placebo 1%, Number Needed to Harm (NNH) 11. 
      • Serious hyperkalemia (potassium ≥6 mmol/L): not statistically different. 
  • EMPHASIS-HF:2 2,737 patients with Class II heart failure with majority on ACE inhibitors, and β-blockers. Given eplerenone or placebo. At 21 months: 
    • Statistically significant reduction in: 
      • Mortality: eplerenone 13%, placebo 16%, NNT 34. 
      • Cardiovascular hospitalization: 22% vs. 29%, NNT 15. 
    • Adverse events: 
      • Hyperkalemia (>5.5 mmol/L) increased with eplerenone 12%, placebo 7%, NNH 22. 
      • No difference in gynecomastia or renal failure. 
Two meta-analyses found similar results.3,4 
  • Aldosterone antagonists compare favourably to other agents used in congestive heart failure whose relative risk reductions for mortality are: 
    • Aldosterone antagonists1,2 ~25%. 
    • β-blockers5 ~29%. 
    • ACE inhibitors6,7 ~23%. 
  • Aldosterone antagonists are prescribed at less than half the rate of β-blockers and ACE inhibitors, and represent the greatest potential for increased systolic heart failure survival.8 
  • Titration to target doses of ACE inhibitors and β-blockers before adding aldosterone antagonists has been advocated,9 however the rates/doses of these medications were quite different in RALES and EMPHASIS-HF, yet they had similar outcomes. 
  • There is no head-to-head trial of spironolactone vs. eplerenone. Spironolactone ($12/month) could be used first and, if gynecomastia/breast pain develop, switch to eplereonone ($100/month). 

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  • Adrienne J Lindblad BSP ACPR PharmD
  • G. Michael Allan MD CCFP
  • Ricky D. Turgeon BSc(Pharm) ACPR PharmD

1. Pitt B, Zannad F, Remme WJ, et al. N Engl J Med. 1999; 341(10):709–17.

2. Zannad F, McMurray JJ, Krum H, et al. N Engl J Med. 2011; 364(1):11–21.

3. Ezekowitz JA, McAlister FA. Eur Heart J. 2009 Feb; 30(4):469–77.

4. Hu LJ, Chen YQ, Deng SB, et al. Br J Clin Pharmacol. 2013; 75(5):1202–12.

5. Bonet S, Agusti A, Arnau JM, et al. Arch Intern Med. 2000; 160:621–7.

6. Garg R, Yusuf S. JAMA. 1995 May 10; 273(18):1450–6.

7. Flather MD, Yusuf S, Kober L, et al. Lancet. 2000; 355:1575–81.

8. Fonarow GC, Yancy CW, Hernandez AF, et al. Am Heart J. 2011 Jun; 161(6):1024–30.

9. McKelvie RS, Moe GW, Ezekowitz JA, et al. Can J Cardiol. 2013; 29(2):168–81.

Authors do not have any conflicts of interest to declare.