Spironolactone discontinuation in patients with heart failure: complex interactions with loop diuretics. Letter regarding the article ‘Spironolactone dose in heart failure with preserved ejection fraction: findings from TOPCAT’

In a post-hoc analysis of TOPCAT,¹ 25% of patients with heart failure and preserved ejection fraction who took spironolactone discontinued the drug during the first year, mainly due to hyperkalaemia and worsening renal function. The discontinuation was associated with a higher risk of subsequent events including hospitalization for heart failure, cardiovascular death and all-cause mortality.¹ However, a concomitant use of alternative diuretics, in particular loop diuretics, should have been investigated in greater detail.

In patients with heart failure, a combined use of diuretics including mineralocorticoid receptor antagonists, loop diuretics and thiazides is a common therapeutic approach involving increased doses of diuretics with the progression of cardiorenal syndrome and development of diuretic resistance.^{2, 3} Both spironolactone use and its dose have been closely correlated with markers of heart failure severity such as left ventricular ejection fraction, cardiac troponin I levels and N-terminal pro brain natriuretic peptide levels.³ Patients with heart failure who receive higher doses of spironolactone often concomitantly use a loop diuretic.³ In a companion paper in the Journal,⁴ an additional analysis of the same TOPCAT Americas population confirmed that 76% of patients taking spironolactone also used loop diuretics. The adverse effects of loop diuretics include dehydration, hypovolaemia, hypokalaemia, hypomagnesaemia, hyponatraemia, and hypocalcaemia, which may lead to discontinuation or reduction in the diuretic dose.² Because of the tendency toward hypokalaemia, loop diuretics probably have affected potassium levels in 76% of the TOPCAT participants who concomitantly took both drugs. This could have produced an underestimation of the spironolactone effect on hyperkalaemia. In addition, the use of furosemide may cause hyponatraemia,^{2, 3} especially when combined with spironolactone,³ which may be an added reason for diuretic discontinuation or dose reduction.² We also reported that on average hyponatraemic patients have higher serum potassium.³

The second important issue is that loop diuretics may independently adversely affect renal function through activation of the renin–angiotensin–aldosterone system and renal vasoconstriction.^4-6 In a study involving stable patients with heart failure, the reduction of furosemide dose by 50% for 3 weeks was associated with a significant improvement in renal function and a trend toward plasma renin decrease among those with glomerular filtration rate <60 mL/min/1.73 m².⁵ In another study also involving patients with stable heart failure, a reduction of furosemide dose of ≥120 mg to a third of the baseline dose was associated with increased 2-year survival rates free of hospitalization or cardiac death and significantly less frequent deterioration of renal function.⁶ Given the frequency of the parallel use of spironolactone and loop diuretic in the TOPCAT population,⁴ without accounting for the data on loop diuretics, we cannot be completely sure that the decline in renal function is solely the result of higher spironolactone dosage, i.e. the effect could be overestimated.

Spironolactone and loop diuretics are often concomitantly used, which could have affected the TOPCAT results. A crosstalk among haemodynamic and neurohumoral effects of diuretic use on renal function and serum electrolyte levels should be further investigated in order to avoid spironolactone discontinuation in patients with heart failure.