title: Prophylaxis against deep vein thrombosis in critically ill patients with severe renal insufficiency with the low-molecular-weight heparin dalteparin: an assessment of safety and pharmacodynamics: the DIRECT study.
abstract: BACKGROUND
  Use of low-molecular-weight heparins is avoided in patients with renal insufficiency because of concerns about an excessive anticoagulant effect and increased bleeding risk. To challenge this premise, we evaluated if deep vein thrombosis (DVT) prophylaxis with dalteparin sodium confers an excessive anticoagulant effect in critically ill patients with severe renal insufficiency.
  
  
  METHODS
  We conducted a multicenter, single-arm clinical trial of DVT prophylaxis with dalteparin sodium, 5000 IU once daily in critically ill patients with a creatinine clearance lower than 30 mL/min (to convert to milliliters per second, multiply by 0.0167). Bioaccumulation was defined by a trough anti-Xa level higher than 0.40 IU/mL, measured twice weekly. The pharmacodynamic properties of dalteparin were assessed by serial anti-Xa levels measured on days 3, 10, and 17.
  
  
  RESULTS
  We enrolled 156 patients with a mean (SD) creatinine clearance of 18.9 (6.5) mL/min; 18 were excluded because they died or were discharged before testing (n = 3) or had prevalent DVT (n = 15). Of 138 patients included, the median (interquartile range [IQR]) duration of dalteparin exposure was 7 (4-12) days. In 120 patients who had at least 1 trough anti-Xa level (427 total measurements), no patient had bioaccumulation (0%; 95% confidence interval [CI]: 0%-3.0%); the median (IQR) trough anti-Xa level was undetectable (<0.10 IU/mL [<0.10 to <0.10 IU/mL]). Based on serial measurements, peak anti-Xa levels were 0.29 to 0.34 IU/mL and trough levels were lower than 0.06 IU/mL. Deep vein thrombosis occurred in 7 of 138 patients (5.1%; 95% CI, 2.5%-10.1%); major bleeding occurred in 10 patients (7.2%; 95% CI, 4.0%-12.8%), all with trough anti-Xa levels of 0.18 IU/mL or lower.
  
  
  CONCLUSIONS
  In critically ill patients with severe renal insufficiency, DVT prophylaxis with dalteparin sodium, 5000 IU once daily, is not associated with an excessive anticoagulant effect due to drug bioaccumulation and is unlikely to contribute to bleeding.
  
  
  BACKGROUND
  clinicaltrials.gov Identifier: NCT00138099.
authors.affiliation: Department of Medicine, McMaster University, Hamilton, Ontario, Canada. jdouket@mcmaster.ca
authors.forename: James
authors.initials: J
authors.lastname: Douketis
authors.forename: Deborah
authors.initials: D
authors.lastname: Cook
authors.forename: Maureen
authors.initials: M
authors.lastname: Meade
authors.forename: Gordon
authors.initials: G
authors.lastname: Guyatt
authors.forename: William
authors.initials: W
authors.lastname: Geerts
authors.forename: Yoanna
authors.initials: Y
authors.lastname: Skrobik
authors.forename: Martin
authors.initials: M
authors.lastname: Albert
authors.forename: John
authors.initials: J
authors.lastname: Granton
authors.forename: Paul
authors.initials: P
authors.lastname: Hébert
authors.forename: Guiseppe
authors.initials: G
authors.lastname: Pagliarello
authors.forename: John
authors.initials: J
authors.lastname: Marshall
authors.forename: Robert
authors.initials: R
authors.lastname: Fowler
authors.forename: Andreas
authors.initials: A
authors.lastname: Freitag
authors.forename: Christian
authors.initials: C
authors.lastname: Rabbat
authors.forename: David
authors.initials: D
authors.lastname: Anderson
authors.forename: Nicole
authors.initials: N
authors.lastname: Zytaruk
authors.forename: Diane
authors.initials: D
authors.lastname: Heels-Ansdell
authors.forename: Mark
authors.initials: M
authors.lastname: Crowther
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000925:Anticoagulants / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D016638:Critical Illness; D017985:Dalteparin / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D051436:Renal Insufficiency, Chronic / Q000150:complications*; D012720:Severity of Illness Index; D016896:Treatment Outcome; D020246:Venous Thrombosis / Q000150:complications / Q000188:drug therapy* / Q000517:prevention & control*
chemical_list: D000925:Anticoagulants; D017985:Dalteparin