TY - JOUR
T1 - 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
AU - Segar, Matthew W.
AU - Patel, Ravi B.
AU - Patel, Kershaw V.
AU - Fudim, Marat
AU - Devore, Adam D.
AU - Martens, Pieter
AU - Hedayati, S. Susan
AU - Grodin, Justin L.
AU - Tang, W. H.Wilson
AU - Pandey, Ambarish
N1 - Funding Information:
reported receiving support from grant KL2TR001424 from the National Institutes of Health’s National Center for Advancing Translational Sciences. Dr K. V. Patel reported receiving T32 postdoctoral training grant 5T32HL125247-03 from the National Heart, Lung, and Blood Institute during the conduct of the study. Dr Fudim reported receiving personal fees from Daxor, AxonTherapies, Edwards Lifesciences, and Galvani outside the submitted work. Dr DeVore reported receiving grants from the American Heart Association, Amgen, AstraZeneca, Bayer, Intra-Cellular Therapies, American Regent Inc, the National Heart, Lung, and Blood Institute, Novartis, and the Patient-Centered Outcomes Research Institute; personal fees from Amgen, AstraZeneca, Bayer, CareDx, InnaMed, LivaNova, Mardil Medical, Novartis, Procyrion, scPharmaceuticals, and Zoll; and nonfinancial support from Abbott outside the submitted work. Dr Martens reported receiving a research grant from Vifor Pharma, research support
Funding Information:
from grant 1127917N from the Fonds Wetenschappelijk Onderzoek, and consulting fees from AstraZeneca, Bayer, Boehringer Ingelheim, Novartis, and Vifor Pharma during the conduct of this study. Dr Hedayati reported receiving support from grant R01DK124379 from the National Institute of Diabetes and Digestive and Kidney Diseases and from the Yin Quan-Yuen Distinguished Professorship in Nephrology from the University of Texas Southwestern, Dallas, during the conduct of this study. Dr Grodin reported receiving personal fees from Pfizer, Eidos, and Alnylam outside the submitted work. Dr Tang reported receiving personal fees from Sequana Medical AG, Springer Nature, Owkin Inc, and the American Board of Internal Medicine and grants from the National Heart Institute outside the submitted work. Dr Pandey reported serving on the advisory board of Roche Diagnostics. No other disclosures were reported.
Publisher Copyright:
© 2021 American Medical Association. All rights reserved.
Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/1
Y1 - 2021/1
N2 - 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..
AB - 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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U2 - 10.1001/jamacardio.2020.5592
DO - 10.1001/jamacardio.2020.5592
M3 - Article
C2 - 33206129
AN - SCOPUS:85096649523
VL - 6
SP - 68
EP - 77
JO - JAMA Cardiology
JF - JAMA Cardiology
SN - 2380-6583
IS - 1
ER -