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Original Investigation
November 18, 2020

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

Author Affiliations
  • 1Division of Cardiology, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas
  • 2Division of Cardiology, Northwestern University Feinberg School of Medicine, Chicago, Illinois
  • 3Division of Cardiology, Department of Medicine, Duke University, Durham, North Carolina
  • 4Duke Clinical Research Institute, Duke University, Durham, North Carolina
  • 5Department of Cardiology, Ziekenhuis Oost Limburg, Genk, Belgium
  • 6Doctoral School of Medicine and Life Sciences, Hasselt University, Diepenbeek, Belgium
  • 7Division of Nephrology, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas
  • 8Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio
JAMA Cardiol. Published online November 18, 2020. doi:10.1001/jamacardio.2020.5592
Key Points

Question  Is visit-to-visit variability in kidney function and serum electrolyte indexes associated with risk of adverse clinical outcomes among patients with chronic, stable heart failure with preserved ejection fraction?

Findings  This cohort study of patients with chronic heart failure with preserved ejection fraction suggests that higher visit-to-visit variability in creatinine, blood urea nitrogen, sodium, and potassium levels is significantly associated with a higher risk of adverse clinical outcomes independent of other potential confounders and changes in these parameters.

Meaning  In heart failure with preserved ejection fraction, visit-to-visit variability in laboratory indexes of kidney function and certain serum electrolytes may identify a higher-risk disease state with worse long-term clinical outcomes.

Abstract

Importance  Although kidney dysfunction and abnormalities in serum electrolyte levels are associated with poor clinical outcomes in patients with heart failure with preserved ejection fraction (HFpEF), the association of visit-to-visit variability in such laboratory measures with long-term outcomes is unclear.

Objective  To evaluate the associations of visit-to-visit variability in indexes of kidney function (creatinine and blood urea nitrogen [BUN] levels) and serum electrolyte (sodium, chloride, and potassium) with the risk of adverse clinical outcomes among patients with chronic, stable HFpEF.

Design, Setting, and Participants  This cohort analysis used data from the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial. All participants with 3 or more serial laboratory measurements who were event free within the first 4 months of enrollment were included. Data were analyzed from March 1, 2019, to January 31, 2020.

Main Outcomes and Measures  Adjusted associations between indexes of variability in serum laboratory measurements during the first 4 months of follow-up and risk of the primary composite outcome (a composite of aborted cardiac arrest, hospitalization for heart failure, or cardiovascular death) and all-cause mortality were assessed using Cox proportional hazards regression models.

Results  Of the 3445 patients enrolled in the TOPCAT trial (mean [SD] age, 68-69 [10] years; 49.7%-51.5% female), 2479 (BUN) to 3195 (potassium) were analyzed, depending on availability of serial measurements. Participants with higher laboratory variability in kidney function parameters were older, had more comorbidities, and had more severe symptoms of HFpEF. Higher visit-to-visit variability in BUN (hazard ratio [HR] per 1-SD higher average successive variability [ASV], 1.21; 95% CI, 1.10-1.33) and creatinine (HR per 1-SD higher ASV, 1.13; 95% CI, 1.04-1.22) were independently associated with a higher risk of the primary composite outcome as well as mortality independent of other baseline confounders, changes in kidney function, changes in medication dosages, and variability in other cardiometabolic parameters (systolic blood pressure and body mass index). The higher risk associated with greater variability in kidney function was consistent across subgroups of patients stratified by the presence of chronic kidney disease (CKD) at baseline (CKD: HR per 1-SD higher ASV, 1.39; 95% CI, 1.16-1.67 and no CKD: HR per 1-SD higher ASV, 1.13; 95% CI, 1.01-1.27), among placebo and spironolactone treatment arms separately (spironolactone arm: 1.30; 95% CI, 1.03-1.65 and placebo arm: HR per 1-SD higher ASV, 1.27; 95% CI, 1.04-1.56). Among serum electrolytes, variability in sodium and potassium measures were also significantly associated with a higher risk of primary composite events (sodium: HR per 1-SD higher ASV, 1.14; 95% CI, 1.01-1.30 and potassium: HR per 1-SD higher ASV, 1.21; 95% CI, 1.02-1.44).

Conclusions and Relevance  In HFpEF, visit-to-visit variability in laboratory indexes of kidney function and serum electrolytes is common and independently associated with worse long-term clinical outcomes.

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