Aldosterone antagonists in the management of heart failure

NICE suggest with respect to use of mineralocorticoid receptor antagonists (MRA) in treating heart failure with reduced ejection fraction (1)

• an MRA (e.g. spironolactone, eplerenone) should be offered, in addition to an ACE inhibitor (or ARB) and beta-blocker, to people who have heart failure with reduced ejection fraction if they continue to have symptoms of heart failure
  
  
• measure serum sodium and potassium, and assess renal function, before and after starting an MRA and after each dose increment
  
  
• blood pressure must be measured before and after after each dose increment of an MRA
  
  
• once the target, or maximum tolerated, dose of an MRA is reached, monitor treatment monthly for 3 months and then at least every 6 months, and at any time the person becomes acutely unwell
  
  
• note that in the 2018 guidance the addition of an MRA is a primary intervention (and not suggested as requiring specialist advice)

For patients who have had an acute MI and who have symptoms and/or signs of heart failure and left ventricular systolic dysfunction, treatment with an aldosterone antagonist licensed for post-MI treatment should be initiated within 3-14 days of the MI, preferably after ACE inhibitor therapy (2)

Notes:

• in consideration of the use of aldosterone antagonists in the management of heart failure:
  • there is a risk of developing hyperkalaemia when spironolactone is combined with an ACE inhibitor - therefore the combination should be used with caution in those with advanced age and/or reduced renal function.
    • in the RALES study (3) revealed that the addition of spironolactone to ACE inhibitor therapy led to an increased mean serum potassium concentration of 0.3mmol per litre - this increase was not found to be clinically important (NB patients with high serum potassium at baseline were excluded)
  • eplerenone is a more selective aldosterone antagonist and is less likely to cause sexual side effects than spironolactone (4)
    • in the EPHESIS study, eplerenone was shown to improve survival compared with placebo when added to existing medical therapy within 3-14 days following acute MI. Patients (n=6,632) were required to have reduced LVEF (<40%) and diabetes or clinical signs of heart failure
    • during a mean follow up of 16 months, 14.4% of patients receiving eplerenone and 16.7% of patients receiving placebo died (RR 0.85; 95%CI 0.75 to 0.96; NNT=43; P=0.008)
    • rates of severe hyperkalaemia were significantly higher with eplerenone than with placebo (5.5% vs. 3.9%; NNT=63; P=0.002)
  • aldosterone blockage and left ventricular function - systematic review (5)
    • review revealed a 20% reduction in all-cause mortality with the use of aldosterone blockade in a clinically heterogeneous group of clinical trial participants with heart failure and post-MI
      • also showed 3.1% improvement in ejection fraction

An an individual patient level meta-analysis concluded (6):

• steroidal MRAs reduce the risk of cardiovascular death or heart failure hospitalisation in patients with HFrEF and non-steroidal MRAs reduce this risk in patients with HFmrEF (heart failure with mildly reduced ejection fraction) or HFpEF (heart failure with preserved ejection fraction)

Reference:

• NICE (September 2018).Chronic heart failure in adults: diagnosis and management
• NICE (May 2013). Secondary prevention in primary and secondary care for patients following a myocardial infarction
• NEJM 1999; 341: 709-17.
• MeReC Bulletin 2008; 18 (3):1-9.
• Ezekowitz JA, McAlister FA.Aldosterone blockade and left ventricular dysfunction: a systematic review of randomized clinical trials. Eur Heart J. 2009 Feb;30(4):469-77.
• Jhund PS et al. Mineralocorticoid receptor antagonists in heart failure: an individual patient level meta-analysis. Lancet September 1st 2024.