The safest potassium range across different heart failure (HF) phenotypes has remained uncertain. A patient-level pooled analysis of 12 randomized controlled trials published in the European Heart Journal has now identified a potassium range associated with the lowest risk of mortality and heart failure events in both heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF).

Investigators analyzed data from 46,069 patients, including 32,346 with HFrEF and 13,723 with HFpEF. Baseline serum potassium concentrations were categorized into six groups ranging from <3.5 mmol/L to ≥5.5 mmol/L. Associations between potassium levels and clinical outcomes were assessed using categorical analyses and restricted cubic spline models.

Findings

• In HFrEF, serum potassium demonstrated a reverse J-shaped relationship with outcomes, with risk increasing substantially at lower potassium levels.
• Patients with potassium <3.5 mmol/L had a 49% higher risk of all-cause mortality compared with those with potassium levels of 4.0–4.5 mmol/L (adjusted HR 1.49; 95% CI 1.27–1.76).
• Hypokalemia was also associated with increased risks of cardiovascular death, sudden cardiac death, and pump failure death in HFrEF.
• The lowest incidence of all evaluated outcomes occurred within a potassium range of 4.2–5.0 mmol/L in both HFrEF and HFpEF populations.
• Mild hyperkalemia (5.0–5.5 mmol/L) was not associated with increased mortality or adverse heart failure outcomes in HFrEF, while HFpEF demonstrated a flatter U-shaped risk curve across potassium levels.

The investigators concluded that hypokalemia is strongly associated with adverse outcomes in HFrEF and should be actively avoided. Across both HFrEF and HFpEF populations, serum potassium concentrations between 4.2 and 5.0 mmol/L were associated with the most favorable clinical outcomes.