Dalteparin versus unfractionated heparin in critically ill patients

N Engl J Med. 2011 Apr 7;364(14):1305-14. doi: 10.1056/NEJMoa1014475. Epub 2011 Mar 22.


Background: The effects of thromboprophylaxis with low-molecular-weight heparin, as compared with unfractionated heparin, on venous thromboembolism, bleeding, and other outcomes are uncertain in critically ill patients.

Methods: In this multicenter trial, we tested the superiority of dalteparin over unfractionated heparin by randomly assigning 3764 patients to receive either subcutaneous dalteparin (at a dose of 5000 IU once daily) plus placebo once daily (for parallel-group twice-daily injections) or unfractionated heparin (at a dose of 5000 IU twice daily) while they were in the intensive care unit. The primary outcome, proximal leg deep-vein thrombosis, was diagnosed on compression ultrasonography performed within 2 days after admission, twice weekly, and as clinically indicated. Additional testing for venous thromboembolism was performed as clinically indicated. Data were analyzed according to the intention-to-treat principle.

Results: There was no significant between-group difference in the rate of proximal leg deep-vein thrombosis, which occurred in 96 of 1873 patients (5.1%) receiving dalteparin versus 109 of 1873 patients (5.8%) receiving unfractionated heparin (hazard ratio in the dalteparin group, 0.92; 95% confidence interval [CI], 0.68 to 1.23; P=0.57). The proportion of patients with pulmonary emboli was significantly lower with dalteparin (24 patients, 1.3%) than with unfractionated heparin (43 patients, 2.3%) (hazard ratio, 0.51; 95% CI, 0.30 to 0.88; P=0.01). There was no significant between-group difference in the rates of major bleeding (hazard ratio, 1.00; 95% CI, 0.75 to 1.34; P=0.98) or death in the hospital (hazard ratio, 0.92; 95% CI, 0.80 to 1.05; P=0.21). In prespecified per-protocol analyses, the results were similar to those of the main analyses, but fewer patients receiving dalteparin had heparin-induced thrombocytopenia (hazard ratio, 0.27; 95% CI, 0.08 to 0.98; P=0.046).

Conclusions: Among critically ill patients, dalteparin was not superior to unfractionated heparin in decreasing the incidence of proximal deep-vein thrombosis. (Funded by the Canadian Institutes of Health Research and others; PROTECT ClinicalTrials.gov number, NCT00182143.).

Publication types

  • Comparative Study
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anticoagulants / adverse effects
  • Anticoagulants / therapeutic use*
  • Critical Illness / mortality
  • Critical Illness / therapy*
  • Dalteparin / adverse effects
  • Dalteparin / therapeutic use*
  • Female
  • Hemorrhage / chemically induced
  • Heparin / adverse effects
  • Heparin / therapeutic use*
  • Humans
  • Incidence
  • Injections, Subcutaneous
  • Kaplan-Meier Estimate
  • Male
  • Middle Aged
  • Pulmonary Embolism / epidemiology
  • Pulmonary Embolism / prevention & control
  • Thrombocytopenia / chemically induced
  • Thromboembolism / prevention & control
  • Venous Thrombosis / epidemiology
  • Venous Thrombosis / prevention & control*


  • Anticoagulants
  • Heparin
  • Dalteparin

Associated data

  • ClinicalTrials.gov/NCT00182143