title: Comparison between the impact of morning and evening doses of rivaroxaban on the circadian endogenous coagulation rhythm in healthy subjects.
abstract: ESSENTIALS: It is unknown whether single rivaroxaban doses should best be administered in the morning or evening. Circadian rhythm of coagulation/fibrinolysis was measured after morning or evening intake of rivaroxaban. Evening intake of rivaroxaban leads to prolonged exposure to rivaroxaban concentrations. Evening intake of rivaroxaban better matches the morning hypofibrinolysis.
  
  
  BACKGROUND
  A circadian variation of the endogenous coagulation system exists with hypercoagulability and hypofibrinolysis and a corresponding peak of cardiovascular thromboembolic events in the morning. So far, no information is given as to whether single daily doses of the new oral anticoagulant drug rivaroxaban should best be administered in the morning or the evening.
  
  
  METHODS
  Sixteen healthy male or female volunteers with a mean age of 26 ± 7 years were included in this randomized, controlled, analyst-blinded cross-over clinical trial. All subjects were given three morning and three evening single doses of 10 mg rivaroxaban. Circadian rhythms of prothrombin fragment 1 + 2, plasminogen activator inhibitor, and plasmin-antiplasmin complex were measured before any medication intake, as well as after morning or evening medication intake. Rivaroxaban concentrations were determined by an anti-activated factor X assay and liquid chromatography-mass spectrometry.
  
  
  RESULTS
  Concentrations of rivaroxaban were higher 12 h after evening intake of rivaroxaban than 12 h after morning intake (53.3 ng mL(-1) [95% confidence interval 46.0-67.8] vs. 23.3 ng mL(-1) [19.4-29.1, respectively]). Rivaroxaban intake in the evening reduced morning F1+2 concentrations better at 8:00 AM than did administration on awakening (85 ± 25 nmol L(-1) vs. 106 ± 34 nmol L(-1) , CI: 9.4-32.1). In addition, this suppression effect was longer lasting after evening intake.
  
  
  CONCLUSIONS
  Evening intake of rivaroxaban leads to prolonged exposure to rivaroxaban concentrations and better matches the morning hypofibrinolysis. These results might help to further improve the efficacy and safety of rivaroxaban treatment.
authors.affiliation: Division of Angiology, Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria.
authors.forename: S
authors.initials: S
authors.lastname: Brunner-Ziegler
authors.affiliation: Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.
authors.forename: B
authors.initials: B
authors.lastname: Jilma
authors.affiliation: Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.
authors.forename: C
authors.initials: C
authors.lastname: Schörgenhofer
authors.affiliation: Division of Angiology, Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria.
authors.forename: F
authors.initials: F
authors.lastname: Winkler
authors.affiliation: Clinical Institute of Medical, Chemical Laboratory Diagnostics, Medical University of Vienna, Vienna, Austria.
authors.forename: P
authors.initials: P
authors.lastname: Jilma-Stohlawetz
authors.affiliation: Division of Angiology, Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria.
authors.forename: R
authors.initials: R
authors.lastname: Koppensteiner
authors.affiliation: Clinical Institute of Medical, Chemical Laboratory Diagnostics, Medical University of Vienna, Vienna, Austria.
authors.forename: P
authors.initials: P
authors.lastname: Quehenberger
authors.affiliation: Central Institute for Medical and Chemical Laboratory Diagnostics, Innsbruck, Austria.
authors.forename: C
authors.initials: C
authors.lastname: Seger
authors.affiliation: Central Institute for Medical and Chemical Laboratory Diagnostics, Innsbruck, Austria.
authors.forename: G
authors.initials: G
authors.lastname: Weigel
authors.affiliation: Central Institute for Medical and Chemical Laboratory Diagnostics, Innsbruck, Austria.
authors.forename: A
authors.initials: A
authors.lastname: Griesmacher
authors.affiliation: Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.
authors.forename: M
authors.initials: M
authors.lastname: Brunner
mesh_terms: D000328:Adult; D001777:Blood Coagulation / Q000187:drug effects*; D001780:Blood Coagulation Tests; D002853:Chromatography, Liquid; D002940:Circadian Rhythm; D004334:Drug Administration Schedule; D016903:Drug Monitoring / Q000379:methods; D065427:Factor Xa Inhibitors / Q000008:administration & dosage* / Q000097:blood; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D013058:Mass Spectrometry; D011237:Predictive Value of Tests; D000069552:Rivaroxaban / Q000008:administration & dosage* / Q000097:blood; D013997:Time Factors; D055815:Young Adult
chemical_list: D065427:Factor Xa Inhibitors; D000069552:Rivaroxaban
keywords: blood coagulation; chronotherapy; circadian rhythm; prothrombin activation fragment F1+2; rivaroxaban