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.
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.
Douketis
James
J
Department of Medicine, McMaster University, Hamilton, Ontario, Canada. jdouket@mcmaster.ca
Cook
Deborah
D
Meade
Maureen
M
Guyatt
Gordon
G
Geerts
William
W
Skrobik
Yoanna
Y
Albert
Martin
M
Granton
John
J
Hébert
Paul
P
Pagliarello
Guiseppe
G
Marshall
John
J
Fowler
Robert
R
Freitag
Andreas
A
Rabbat
Christian
C
Anderson
David
D
Zytaruk
Nicole
N
Heels-Ansdell
Diane
D
Crowther
Mark
M
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*
D000925:Anticoagulants; D017985:Dalteparin