Patients with both heart failure and preserved ejection fraction (HFpEF) who experience greater visit-to-visit variability in kidney function, serum potassium, and/or serum sodium may be at greater risk for cardiovascular events and death, according to new study findings.

Investigators calculated average successive variability (ASV), the mean absolute difference between successive laboratory values, for 3445 patients in the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) trial. Each standard deviation (SD) increase in ASV in blood urea nitrogen (BUN) and creatinine was significantly associated with a 21% and 13% higher risk, respectively, for the primary composite outcome of aborted cardiac arrest, heart failure hospitalization, or cardiovascular death, Ambarish Pandey, MD, MSCS, of the University of Texas Southwestern Medical Center in Dallas, Texas, and colleagues reported in JAMA Cardiology. Patients with and without chronic kidney disease had a significant 39% and 13% higher risk for the primary outcome per 1-SD higher ASV in BUN and a 21% and 15% higher risk per 1-SD higher ASV in creatinine, respectively. Placebo and spironolactone recipients had a 30% and 27% increased risk for the composite per ASV increment, respectively. The observed relationship was independent of changes in kidney function, medication dosages, systolic blood pressure, and body mass index.

Dr Pandey’s team also found that greater variability in serum sodium and potassium was significantly associated with a significant 14% and 21% higher risk of the primary composite outcome per 1-SD higher ASV in these electrolytes, respectively.

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The study’s secondary outcome was all-cause mortality. The risk of dying from any cause increased significantly by 15%, 16%, 14%, 10%, and 19% for each 1-SD higher ASV in BUN, creatinine, sodium, potassium, and chloride, respectively, the investigators reported.

Visit-to-visit fluctuations might help to better identify a patient population that has less kidney reserve to withstand subtle perturbations, according to Dr Pandey and colleagues. Such patients with HFpEF may benefit from “more aggressive” monitoring for clinical deterioration.

“Taken together, these findings suggest significant prognostic importance of substantial fluctuations in both kidney function and electrolytes among patients with HFpEF in identifying future risk of adverse events,” they stated.

The investigators acknowledged that they could not rule out reverse causation and, in an accompanying editorial, Sanjiv J. Shah, MD, of Northwestern University in Chicago, Illinois, made note of this:

“It may be that patients with increased visit-to-visit variability in kidney function and electrolytes have the cardiorenal syndrome even when the estimated glomerular filtration rate is normal and could benefit from implantable hemodynamic monitoring to guide therapy.”

Dr Shah encouraged future research on novel risk markers in HFpEF and other diseases to improve risk prediction and elucidate biological mechanisms, disease progression, and potential therapeutic targets.

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


Segar MW, Patel RB, Patel KV, et al. Association of visit-to-visit variability in kidney function and serum electrolyte indexes with risk of adverse clinical outcomes among patients with heart failure with preserved ejection fraction. JAMA Cardiol. 2021;6(1):68-77. doi:10.1001/jamacardio.2020.5592

Shah SJ. Risk marker fatigue—Is there an actionable outcome? JAMA Cardiol. 2021;6(1):78. doi:10.1001/jamacardio.2020.5616