Hypokalemia, Hyperkalemia May Indicated HFpEF Severity

test tubes with red liquid on top of lab test results
Researchers examined the association between serum potassium concentration and outcomes in patients with heart failure with preserved ejection fraction.

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.

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