title: Predictors of congestive heart failure after treatment with an endothelin receptor antagonist.
abstract: OBJECTIVE
  The Avosentan on Time to Doubling of Serum Creatinine, End Stage Renal Disease or Death (ASCEND) trial tested the renoprotective effect of the endothelin receptor antagonist avosentan in patients with diabetes and nephropathy, but the study was terminated due to an excess of congestive heart failure (CHF) events in the avosentan arms, likely due to fluid retention. The aim of this study was to identify risk markers of CHF after treatment with avosentan.
  
  
  METHODS
  In a post hoc analysis of the ASCEND trial (N=1392 participants), we assessed which baseline characteristics predicted CHF risk during avosentan treatment. Furthermore, postrandomization changes between baseline and the first available measurement of body weight and hemoglobin were examined as potential clinical indicators of fluid retention for their relationship with CHF development.
  
  
  RESULTS
  Relative to placebo, avosentan increased CHF risk (hazard ratio, 2.76; 95% confidence interval, 1.68 to 4.54). The avosentan-related CHF risk was higher with lower baseline cholesterol levels (P interaction=0.003) and concomitant statin use (P interaction=0.06), whereas it was lower with a lower estimated GFR (P interaction=0.04). Patients allocated to avosentan had a median body weight increase of 0.6 kg (interquartile range, 0.0 to 2.0 kg) and a median hemoglobin decrease of 1.4 g/dl (interquartile range, -2.1 to -0.7 g/dl) at the first postrandomization measurement. The body weight increase induced by avosentan was associated with CHF development (P interaction=0.04), whereas hemoglobin decrease was not (P interaction=0.64). The increase in body weight was particularly pronounced in patients with a cardiovascular disease history and in patients using statins.
  
  
  CONCLUSIONS
  In avosentan-treated patients, body weight increase, but not hemoglobin decrease, was associated with CHF development, indicating that close body weight monitoring could provide an early signal of CHF development in future trials with endothelin receptor antagonists.
authors.affiliation: Department of Clinical Pharmacology, University of Groningen, University Medical Center, Groningen, The Netherlands;, †King's College London School of Medicine, Guy's Hospital, London, United Kingdom;, ‡Quintiles Ltd., Strasbourg, France;, §Schwabing General Hospital, Munich, Germany;, ‖Department of Medicine IV, University of Erlangen, Erlangen, Germany, ¶KfH Kidney Centre, Munich, Germany.
authors.forename: Jamo
authors.initials: J
authors.lastname: Hoekman
authors.forename: Hiddo J
authors.initials: HJ
authors.lastname: Lambers Heerspink
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Viberti
authors.forename: Damien
authors.initials: D
authors.lastname: Green
authors.forename: Johannes F E
authors.initials: JF
authors.lastname: Mann
authors.forename: Dick
authors.initials: D
authors.lastname: de Zeeuw
mesh_terms: D000368:Aged; D015415:Biomarkers / Q000097:blood; D003404:Creatinine / Q000097:blood; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000150:complications / Q000175:diagnosis / Q000188:drug therapy* / Q000401:mortality; D003928:Diabetic Nephropathies / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy* / Q000209:etiology / Q000401:mortality / Q000503:physiopathology; D004311:Double-Blind Method; D065128:Endothelin Receptor Antagonists; D005260:Female; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006333:Heart Failure / Q000139:chemically induced* / Q000175:diagnosis; D006454:Hemoglobins / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D007676:Kidney Failure, Chronic / Q000097:blood / Q000175:diagnosis / Q000209:etiology / Q000401:mortality / Q000503:physiopathology / Q000517:prevention & control*; D008297:Male; D008875:Middle Aged; D011725:Pyridines / Q000009:adverse effects*; D011743:Pyrimidines / Q000009:adverse effects*; D017466:Receptors, Endothelin / Q000378:metabolism; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome; D015430:Weight Gain / Q000187:drug effects
chemical_list: D015415:Biomarkers; D065128:Endothelin Receptor Antagonists; D006454:Hemoglobins; D011725:Pyridines; D011743:Pyrimidines; D017466:Receptors, Endothelin; D003404:Creatinine; C484919:Avosentan