Mineralocorticoid receptor antagonists (MRAs) in HFrEF or post-MI LV dysfunction (EPHESUS, EMPHASIS, RALES)

EPHESUS: Pitt B, et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 2003;348:1309-21.

EMPHASIS-HF: Zannad F, et al. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med 2011;364:11-21.

RALES: Pitt B, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med 1999;341:709-17.

Bottom-line:

  • In patients with HFrEF with NYHA functional class 2-4, MRAs reduced the risk of death (NNT 18-60 per year) and hospitalization (NNT 24-30 per year), but increased the risk of hyperkalemia.

  • Proper monitoring of renal function & serum potassium (e.g. 1 week after start/dose change, monthly x3 months, then q3-6 months) is critical to ensure that harms do not outweigh benefits of this important therapy.

Patients, Interventions, Controls & Duration of Follow-Up

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Results

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Generalizability & internal validity

  • RALES set the indication for mineralocorticoid antagonists in HFrEF NYHA class III-IV; EPHESUS expanded it to HFrEF or LV dysfunction+diabetes post-MI; EMPHASIS-HF further expanded the indication to HFrEF NYHA II with high risk for HF hospitalization. 
  • Assessed together, these 3 trials evaluated MRAs in all stages in a varity of etiologies for HFrEF, as early as 3 days post-MI, with background therapy ranging from the full gamut to only ACEI + diuretic therapy.
  • Trials employed routine monitoring for renal & potassium abnormalities:
    • EPHESUS: Serum potassium  48h after treatment start, then at weeks 1, 4, 5, 12 of treatment, then q3 months
    • RALES: Serum potassium q4 weeks x3 months, then q3 months x1 year, then q6 months
  • Internal validity: Low risk of bias in all 3 trials