title: Minimal dose for effective clinical outcome and predictive factors for responsiveness to carvedilol: Japanese chronic heart failure (J-CHF) study.
abstract: BACKGROUND
  In chronic heart failure (CHF), it remains unclear whether the minimal dose of beta-blockade is related to survival benefits and which parameter predicts morbidity and mortality. We sought to determine the minimal dose related to survival benefits by comparing the efficacy and safety of three doses of carvedilol and the best predictive parameter for effective outcomes in Japanese patients with CHF.
  
  
  METHODS
  In this prospective, randomized, stratified trial, 364 patients with mild to moderate CHF were assigned to a daily carvedilol dose of 2.5, 5, or 20mg, plus optimal standard therapy.
  
  
  RESULTS
  During the mean 3-year follow-up, resting heart rate (HR) and BNP were significantly reduced with dose-response relations in the early period but without dose-response relations in the late period. The LVEF and the LVDd were increased and decreased, respectively, without a dose-response relation. No significant difference was seen in the composite primary endpoint of all-cause mortality and hospitalization for cardiovascular diseases and heart failure. Multivariate analysis indicated early decreases in HR and BNP predicted long-term outcomes. However, adverse events increased dose-dependently. Among 237 polymorphisms in 87 heart failure-related genes, the osteopontin G-156 del genotype was associated with an event-free survival rate (Wilcoxon test, P=0.030).
  
  
  CONCLUSIONS
  A low carvedilol dose is effective if the HR and/or plasma BNP has been reduced. Carvedilol therapy should be guided by reductions in HR and/or BNP, especially by initial HR reduction, but not only by its dose. OPN might be a surrogate genetic marker for long-term event-free survival.
authors.affiliation: Department of Cardiovascular Medicine, National Hospital Organization, Hokkaido Medical Center, Sapporo, Japan. okamotoh@med.hokudai.ac.jp
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Okamoto
authors.forename: Masatsugu
authors.initials: M
authors.lastname: Hori
authors.forename: Masunori
authors.initials: M
authors.lastname: Matsuzaki
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Tsutsui
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Yamazaki
authors.forename: Ryozo
authors.initials: R
authors.lastname: Nagai
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Yoshikawa
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Fujio
authors.forename: Shinpei
authors.initials: S
authors.lastname: Nonen
authors.forename: Junichi
authors.initials: J
authors.lastname: Azuma
authors.forename: Tohru
authors.initials: T
authors.lastname: Izumi
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Ohashi
authors.forename: Akira
authors.initials: A
authors.lastname: Kitabatake
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use*; D000368:Aged; D044466:Asian People / Q000208:ethnology; D002227:Carbazoles / Q000627:therapeutic use*; D000077261:Carvedilol; D002908:Chronic Disease; D005260:Female; D005500:Follow-Up Studies; D006333:Heart Failure / Q000175:diagnosis* / Q000188:drug therapy* / Q000208:ethnology; D006801:Humans; D008297:Male; D008875:Middle Aged; D011237:Predictive Value of Tests; D011412:Propanolamines / Q000627:therapeutic use*; D011446:Prospective Studies; D016896:Treatment Outcome
chemical_list: D000319:Adrenergic beta-Antagonists; D002227:Carbazoles; D011412:Propanolamines; D000077261:Carvedilol