Serum potassium in the PARADIGM-HF trial

Eur J Heart Fail. 2020 Nov;22(11):2056-2064. doi: 10.1002/ejhf.1987. Epub 2020 Sep 29.


Aims: The associations between potassium level and outcomes, the effect of sacubitril-valsartan on potassium level, and whether potassium level modified the effect of sacubitril-valsartan in patients with heart failure and a reduced ejection fraction were studied in PARADIGM-HF. Several outcomes, including cardiovascular death, sudden death, pump failure death, non-cardiovascular death and heart failure hospitalization, were examined.

Methods and results: A total of 8399 patients were randomized to either enalapril or sacubitril-valsartan. Potassium level at randomization and follow-up was examined as a continuous and categorical variable (≤3.5, 3.6-4.0, 4.1-4.9, 5.0-5.4 and ≥5.5 mmol/L) in various statistical models. Hyperkalaemia was defined as K+ ≥5.5 mmol/L and hypokalaemia as K+ ≤3.5 mmol/L. Compared with potassium 4.1-4.9 mmol/L, both hypokalaemia [hazard ratio (HR) 2.40, 95% confidence interval (CI) 1.84-3.14] and hyperkalaemia (HR 1.42, 95% CI 1.10-1.83) were associated with a higher risk for cardiovascular death. However, potassium abnormalities were similarly associated with sudden death and pump failure death, as well as non-cardiovascular death and heart failure hospitalization. Sacubitril-valsartan had no effect on potassium overall. The benefit of sacubitril-valsartan over enalapril was consistent across the range of baseline potassium levels.

Conclusions: Although both higher and lower potassium levels were independent predictors of cardiovascular death, potassium abnormalities may mainly be markers rather than mediators of risk for death.

Keywords: Hyperkalaemia; Hypokalaemia; Mineralocorticoid receptor antagonists; Outcomes; Potassium; Sacubitril-valsartan.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aminobutyrates* / therapeutic use
  • Angiotensin Receptor Antagonists / therapeutic use
  • Angiotensin-Converting Enzyme Inhibitors / therapeutic use
  • Biphenyl Compounds* / therapeutic use
  • Drug Combinations
  • Enalapril* / therapeutic use
  • Female
  • Heart Failure* / blood
  • Heart Failure* / drug therapy
  • Heart Failure* / physiopathology
  • Humans
  • Male
  • Potassium* / blood
  • Randomized Controlled Trials as Topic
  • Stroke Volume / drug effects
  • Valsartan* / therapeutic use
  • Ventricular Function, Left


  • Aminobutyrates
  • Angiotensin Receptor Antagonists
  • Angiotensin-Converting Enzyme Inhibitors
  • Biphenyl Compounds
  • Drug Combinations
  • Enalapril
  • Valsartan
  • Potassium
  • sacubitril and valsartan sodium hydrate drug combination