title: Anticoagulant effects of idraparinux after termination of therapy for prevention of recurrent venous thromboembolism: observations from the van Gogh trials.
abstract: OBJECTIVE
  To gather information on anticoagulant effects after the termination of long-term therapy with idraparinux.
  
  
  METHODS
  The anticoagulant effects of idraparinux, a synthetic polymethylated analogue of its pentasaccharide, were analysed in 23 patients after termination of a 6- or 12-month therapy period for the prevention of recurrent venous thromboembolism (VTE). Plasma samples of patients initially randomized to 2.5 mg idraparinux (normal creatinine clearance) or 1.5 mg idraparinux (creatinine clearance < 30 ml/min) were investigated in the van Gogh trials. At 3-month intervals for up to 15 months following the termination of the therapy, the factor Xa-specific S2222 chromogenic substrate (aXa) assay and Heptest were used to determine various pharmacokinetic parameters and prothrombin-induced clotting time (PiCT), activated partial thromboplastin time (aPTT) and prothrombin time (PT) were determined.
  
  
  RESULTS
  Based on the aXa assay and Heptest, the half lives (t1/2) were 60.2 days and 107.7 days (p < 0.0001), maximum drug concentrations (Cmax) were 0.30 and 0.39 microg/l (p = 0.0016), areas under the activity time curve (AUC) were 33.7 and 38.0 microg/l per day (p = 0.0002), plasma clearances were 0.09 and 0.06 ml/min (p < 0.0001), mean residence times (MRT) were 75.4 and 121.9 (p < 0.0001) and volumes of distribution (Vdiss) were 7.4 and 8.61 (p = 0.1336), respectively. After 12 months of treatment (n = 18), the S2222 and Heptest results showed significantly higher Cmax and AUC, lower Vdiss and clearance and unchanged t1/2 and MRT values compared to 6 months of treatment (n = 5). The PiCT was prolonged for a period of 9 months. Coagulation times of aPTT and PT were not influenced. The results of these parameters did not differ between 12 and 6 months of treatment.
  
  
  CONCLUSIONS
  The data support reports on a non-ionic binding of idraparinux to antithrombin and other proteins. We suggest that these findings may explain some of the findings of the van Gogh Extension trial.
authors.affiliation: 4th Department of Medicine, University Hospital Mannheim, Theodor Kutzer Ufer 1-3, 68167 Mannheim, Germany. job.harenberg@med.ma.uni-heidelberg.de
authors.forename: Job
authors.initials: J
authors.lastname: Harenberg
authors.forename: Ingrid
authors.initials: I
authors.lastname: Jörg
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Vukojevic
authors.forename: Gerd
authors.initials: G
authors.lastname: Mikus
authors.forename: Christel
authors.initials: C
authors.lastname: Weiss
mesh_terms: D000925:Anticoagulants / Q000494:pharmacology*; D006207:Half-Life; D006801:Humans; D009844:Oligosaccharides / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D016032:Randomized Controlled Trials as Topic; D012008:Recurrence; D054556:Venous Thromboembolism / Q000517:prevention & control*
chemical_list: D000925:Anticoagulants; D009844:Oligosaccharides; C479958:idraparinux