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Serum potassium in the PARADIGM-HF trial
João Pedro Ferreira1,2, Ulrik M Mogensen3, Pardeep S Jhund2
1National Institute of Health and Medical Research, Centre for Clinical Multidisciplinary Research, INSERM U1116, University of Lorraine, Regional University Hospital of Nancy, French Clinical Research Infrastructure Network Investigation Network Initiative-Cardiovascular and Renal Clinical Trialists, Nancy, France.
Insights
Both high and low potassium levels increase cardiovascular death risk in heart failure patients. Sacubitril-valsartan showed consistent benefits across all potassium levels, with no overall effect on potassium. Potassium levels appear to be risk markers, not mediators.
Area of Science:
- Cardiology
- Clinical Pharmacology
Background:
- Potassium levels are crucial in cardiovascular health.
- Abnormal potassium (hyperkalemia and hypokalemia) is common in heart failure.
- The impact of potassium on heart failure outcomes and treatment response needs clarification.
Purpose of the Study:
- To investigate the association between potassium levels and outcomes in heart failure with reduced ejection fraction (HFrEF).
- To determine the effect of sacubitril-valsartan on potassium levels.
- To assess if potassium levels modify the efficacy of sacubitril-valsartan compared to enalapril in HFrEF patients.
Main Methods:
- Analysis of data from the PARADIGM-HF trial involving 8399 patients with HFrEF.
- Potassium levels were analyzed as continuous and categorical variables (hypokalemia ≤3.5 mmol/L, hyperkalemia ≥5.5 mmol/L).
- Outcomes included cardiovascular death, sudden death, pump failure death, non-cardiovascular death, and heart failure hospitalization.
Main Results:
- Both hypokalemia and hyperkalemia were associated with increased risk of cardiovascular death compared to normal potassium levels (4.1-4.9 mmol/L).
- Potassium abnormalities showed similar associations with other adverse outcomes like sudden death, pump failure death, and hospitalizations.
- Sacubitril-valsartan demonstrated consistent benefits across the spectrum of baseline potassium levels and did not significantly alter potassium levels overall.
Conclusions:
- Abnormal potassium levels (both high and low) are independent predictors of cardiovascular death in HFrEF patients.
- Potassium abnormalities may serve as indicators of risk rather than direct causes of mortality.
- The therapeutic advantages of sacubitril-valsartan in HFrEF are not influenced by baseline potassium status.
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.
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