title: Relevance of Changes in Serum Creatinine During a Heart Failure Trial of Decongestive Strategies: Insights From the DOSE Trial.
abstract: BACKGROUND
  Worsening renal function (WRF) is a common endpoint in decompensated heart failure clinical trials because of associations between WRF and adverse outcomes. However, WRF has not universally been identified as a poor prognostic sign, challenging the validity of WRF as a surrogate endpoint. Our aim was to describe the associations between changes in creatinine and adverse outcomes in a clinical trial of decongestive therapies.
  
  
  RESULTS
  We investigated the association between changes in creatinine and the composite endpoint of death, rehospitalization or emergency room visit within 60 days in 301 patients in the Diuretic Optimization Strategies Evaluation (DOSE) trial. WRF was defined as an increase in creatinine >0.3 mg/dL and improvement in renal function (IRF) as a decrease >0.3 mg/dL. When examining linear changes in creatinine from baseline to 72 hours (the coprimary endpoint of DOSE), increasing creatinine was associated with lower risk for the composite outcome (HR = 0.81 per 0.3 mg/dL increase, 95% CI 0.67-0.98, P = .026). Compared with patients with stable renal function (n = 219), WRF (n = 54) was not associated with the composite endpoint (HR = 1.17, 95% CI = 0.77-1.78, P = .47). However, compared with stable renal function, there was a strong relationship between IRF (n = 28) and the composite endpoint (HR = 2.52, 95% CI = 1.57-4.03, P < .001).
  
  
  CONCLUSIONS
  The coprimary endpoint of the DOSE trial, a linear increase in creatinine, was paradoxically associated with improved outcomes. This was driven by absence of risk attributable to WRF and a strong risk associated with IRF. These results argue against using changes in serum creatinine as a surrogate endpoint in trials of decongestive strategies.
authors.affiliation: Department of Medicine, Cardiovascular Division, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania.
authors.forename: Meredith A
authors.initials: MA
authors.lastname: Brisco
authors.affiliation: Department of Medicine, Cardiovascular Division, Medical University of South Carolina, Charleston, South Carolina.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Zile
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Hanberg
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut; Program of Applied Translational Research, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: F Perry
authors.initials: FP
authors.lastname: Wilson
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut; Program of Applied Translational Research, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Chirag R
authors.initials: CR
authors.lastname: Parikh
authors.affiliation: Department of Medicine, Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Steven G
authors.initials: SG
authors.lastname: Coca
authors.affiliation: Section of Heart Failure and Transplantation, The Cleveland Clinic Foundation, Cleveland, Ohio.
authors.forename: W H Wilson
authors.initials: WH
authors.lastname: Tang
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut; Program of Applied Translational Research, Yale University School of Medicine, New Haven, Connecticut. Electronic address: jeffrey.testani@yale.edu.
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Testani
mesh_terms: D000368:Aged; D015415:Biomarkers / Q000097:blood; D002423:Cause of Death; D003404:Creatinine / Q000097:blood*; D018450:Disease Progression; D018572:Disease-Free Survival; D004232:Diuretics / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D005665:Furosemide / Q000627:therapeutic use*; D005919:Glomerular Filtration Rate / Q000187:drug effects*; D006333:Heart Failure / Q000097:blood* / Q000175:diagnosis / Q000188:drug therapy* / Q000401:mortality; D006801:Humans; D007262:Infusions, Intravenous; D007677:Kidney Function Tests; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D015996:Survival Rate; D016896:Treatment Outcome
chemical_list: D015415:Biomarkers; D004232:Diuretics; D005665:Furosemide; D003404:Creatinine
keywords: Worsening in renal function; acute decompensated heart failure; cardio-renal syndrome; improvement in renal function; renal dysfunction