The clinical heart failure community was surprised recently by the MHRA’s advice on the use of spironolactone and other renin-angiotensin-aldosterone system drugs in heart failure and the subsequent risk of potentially fatal hyperkalaemia.
The MHRA recommended that clinicians “use the lowest effective doses of spironolactone and angiotensin converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB), if co-administration is considered essential” and said that “the same advice applies regarding concomitant use of eplerenone with ACEi or ARB in heart failure”.
Many perceived this advice to be confusing and contrary to the globally recognised evidence base in heart failure. Spironolactone and eplerenone are proven to be effective in improving outcomes in patients with heart failure, including both mortality and morbidity.
The recommendation that clinicians “use the lowest effective doses’’ is confusing. Two previous trials have shown that higher doses of renin-angiotensin-aldosterone inhibitors are associated with improved hard outcomes compared to lower doses.
In both eplerenone trials, the dose of the medication was increased to the target dose within four weeks of initiation and this remains the approved licensed method for using the drug. Therefore, what does ‘‘lowest effective doses’’ mean in a condition where higher doses are more clinically effective? The principle of target dosing is supported in all major heart failure guidelines.
The MHRA’s terms “hyperkalaemia” and “severe hyperkalaemia” also left uncertainty, as these terms have no universal definition and mean different things to different clinicians.
All mineralocorticoid receptor antagonists (MRA), ACEi, ARB and even beta-blockers are known to increase serum potassium levels, but all also improve mortality and morbidity in heart failure. This relationship is not fully understood and the survival benefit of MRAs in heart failure is not eliminated by the presence of hyperkalaemia.
A balanced approach to the management of hyperkalaemia is needed in heart failure. New national guidance on changes in potassium (and general renal function) during ACEi, ARB, diuretic and MRA treatment has been produced, which delivers some new clarity. It sets out overarching principles of interpreting potassium results and gives clear advice on how to manage episodes of hyperkalaemia.
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