Prognostic value of hyperkalemia and mineralocorticoid receptor antagonist use in heart failure: a national registry study
K Berge, T Ovrebotten, H Nahoui, H Schirmer, T Omland, L Gullestad, R Mo, S Orn, D Atar, P L MyhreAbstract
Background
Mineralocorticoid receptor antagonists (MRA) are cornerstones of heart failure (HF) therapy, but increase serum potassium levels, potentially resulting in hyperkalemia. Whether hyperkalemia during MRA treatment confers different prognostic implications compared to hyperkalemia from other causes remains unknown.
Purpose
To evaluate prevalence, predictors, and prognostic significance of hyperkalemia in real-world HF patients, and to test the hypothesis that the prognostic impact of hyperkalemia differs between MRA users and non-users.
Methods
We analysed data from the Norwegian HF Registry (2013-2025), capturing nearly all patients attending HF outpatient clinics during guideline-directed medical therapy (GDMT) optimization. Mortality data were obtained from the Norwegian Cause of Death Registry. Missing data were handled using multiple imputation. Predictors and prognostic associations were assessed using logistic and Cox regression with restricted cubic splines, adjusting for variables in the Table. Effect modification by MRA on the association between hyperkalemia and mortality was evaluated through interaction analyses.
Results
Among 23,658 patients, 7.4% had hyperkalemia at the final follow-up visit, including 6.5% with mild (5.1–5.5 mmol/L), 0.9% with moderate (5.6–6.0 mmol/L), and 0.1% with severe (>6.0 mmol/L) hyperkalemia. Compared to normokalemic (3.6–5.0 mmol/L) patients, those with hyperkalemia were older, more often male, had lower eGFR, and more comorbidities (Table). Independent predictors of hyperkalemia included reduced eGFR (OR 0.75 per 10 ml/min/1.73m², 95% CI 0.73–0.78), diabetes (OR 1.45 [1.30–1.63]), current smoking (OR 1.34 [1.17–1.54]), COPD/asthma (OR 1.26 [1.12–1.43]), and male sex (OR 1.38 [1.22–1.56]). MRA use was not associated with hyperkalemia (OR 1.02 [0.91–1.14]). During median follow-up of 1061 (526–1935) days, 24.4% of patients died, including 27.8% with hyperkalemia and 23.8% with normokalemia, p<0.001. Restricted cubic spline analysis demonstrated a U-shaped association between potassium and mortality (p-for-nonlinearity<0.001), with lowest risk at 4.5 mmol/L (Figure). In unadjusted analyses, MRA users had lower mortality across all potassium levels (Figure panel A). However, after multivariable adjustment, the curves overlapped with no significant interaction between hyperkalemia and MRA use on mortality (p-interaction=0.75, Figure panel B).
Conclusions
In this large real-world HF cohort, moderate and severe hyperkalemia after GDMT optimization was uncommon and associated with only a modest increase in mortality risk. Although MRA users had lower mortality across all potassium levels in unadjusted analyses, this association was attenuated after adjustment for baseline characteristics. These findings suggest that hyperkalemia can be avoided through careful titration of GDMT in HF clinics and that hyperkalemia carries similar prognostic implications regardless of MRA treatment status.For image description, please refer to the figure legend and surrounding text.For image description, please refer to the figure legend and surrounding text.