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An Assessment of Safety and Pharmacodynamics: The DIRECT Study

James Douketis, MD, FRCPC; Deborah Cook, MD, MSc, FRCPC; Maureen Meade, MD, FRCPC; Gordon Guyatt, MD, FRCPC; William Geerts, MD, FRCPC; Yoanna Skrobik, MD, FRCPC; Martin Albert, MD, FRCPC; John Granton, MD, FRCPC; Paul Hébert, MD, FRCPC; Guiseppe Pagliarello, MD, FRCSC; John Marshall, MD, FRCSC; Robert Fowler, MD, FRCPC; Andreas Freitag, MD, FRCPC; Christian Rabbat, MD, FRCPC; David Anderson, MD, FRCPC; Nicole Zytaruk, MSc; Diane Heels-Ansdell, MSc; Mark Crowther, MD, MSc, FRCPC; for the Canadian Critical Care Trials Group

Arch Intern Med. 2008;168(16):1805-1812.

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.

Conclusion  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.

Trial Registration  clinicaltrials.gov Identifier: NCT00138099

Author Affiliations: Departments of Medicine (Drs Douketis, Cook, Meade, Guyatt, Freitag, Rabbat, and Crowther) and Clinical Epidemiology and Biostatistics (Drs Douketis, Cook, Meade, and Guyatt and Mss Zytaruk and Heels-Ansdell), McMaster University, Hamilton, Ontario, Canada; Department of Medicine (Drs Geerts, Granton, and Fowler), Interdepartmental Divisions of Critical Care (Drs Granton, Marshall, and Fowler) and Surgery (Dr Marshall), University of Toronto, Toronto, Ontario, Canada; Department of Medicine, Université de Montréal, Montréal, Quebec, Canada (Drs Skrobik and Albert); Department of Critical Care, University of Ottawa, Ottawa, Ontario, Canada (Drs Hébert and Pagliarello); and Department of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada (Dr Anderson).

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