Hypokalemia and hyperkaliemia appear to increase the hospitalization risk for heart failure with preserved ejection fraction (HFpEF), but hypokalemia may be a better predictor of mortality from cardiovascular (CV) and non-CV causes, according to an analysis of the PARAGON-HF study published in the European Journal of Heart Failure.

This analysis included patients aged ≥50 years (mean age, 73±8 years) who presented with New York Heart Association Functional Class II through IV symptoms, preserved left ventricular ejection fraction (LVEF) ≥45%, evidence of structural heart disease, and elevated levels of natriuretic peptides.

Researchers measured serum potassium and creatinine concentrations at screening, during a run-in phase, at time of randomization, as well as 1 and 4 months after randomization. They also measured concentrations of serum potassium and creatinine in 4-month intervals. The primary objective of the study was to assess the association between serum potassium concentrations and a composite outcome of total, both first and recurrent, HF hospitalizations and CV death.

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Investigators defined hypokalemia as serum potassium <4 mmol/L (n=592), hyperkalemia as a serum potassium of >5 mmol/L (n=327), and normal potassium levels as 4 to 5 mmol/L (n=3877).

Patients who had higher potassium levels at baseline more often presented with an ischemic etiology (29.7% vs 36.5% vs 39.8%; P =.002), diabetes (41.6% vs 42.4% vs 52.3%; P =.002), and mineralocorticoid receptor antagonist treatment (22% vs 25.9% vs 32.1%; P =.003) compared with patients with normokalaemia and hyperkaliemia.

Researchers observed a higher risk for the primary composite outcome in patients with hypokalemia (adjusted hazard ratio [aHR], 1.55 [95% CI, 1.3-1.85]; P <.001) and hyperkalemia (aHR, 1.21 [95% CI, 1.02-1.44]; P =.025) compared with normokalaemia.

Compared with hyperkaliemia, hypokalemia held the strongest association with a higher risk for all-cause death (aHR, 1.51 [95% CI, 1.21-1.87]; P <.001), CV death (aHR, 1.42 [95% CI, 1.06-1.89]; P =.018), and non-CV death (aHR, 1.72 [95% CI, 1.2-2.48]; P =.003). A stronger association was found between hypokalemia and an increased risk for all-cause death and CV death in patients with impaired kidney function.

Limitations of this study included its post-hocdesign as well as the original study’s inclusion of only patients who could tolerate recommended valsartan and sacubitril/valsartan doses, which may limit the generalizability of the findings.

The investigators concluded that their results may ultimately “suggest that potassium disturbances are a more of a marker of HFpEF severity rather than a direct cause of death.”

Disclosure: Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.


Ferreira JP, Claggett BL, Liu J, et al. Serum potassium and outcomes in heart failure with preserved ejection fraction: a post-hoc analysis of the PARAGON-HF trial. Eur J Heart Fail. Published online February 20, 2021. doi:10.1002/ejhf.2134