The PROTECT Study: Dalteparin versus Unfractionated Heparin

Patients in the intensive care unit (ICU) are at risk for venous thromboembolism, a serious complication of critical illness, as well as the need for life support measures, sedation, analgesia and paralysis, central venous catheterization, and other procedures. In 2 randomized thromboprophylaxis trials involving critically ill patients, researchers found a benefit of either unfractionated heparin or low-molecular-weight heparin versus placebo; 2 other trials comparing low-molecular-weight heparin with unfractionated heparin had inconclusive results. To compare the effect of dalteparin, a low-molecular-weight heparin, with the effect of unfractionated heparin in critically ill patients, researchers recently conducted PROTECT (Prophylaxis for Thromboembolism in Critical Care Trial), a multicenter, randomized study. They reported study results online in the New England Journal of Medicine [2011; 10.1056/NEJMoa1014475]. The primary outcome was proximal leg deep vein thrombosis in critically ill patients; secondary outcomes were rates of pulmonary embolism, venous thromboembolism, bleeding, heparin-induced thrombocytopenia, and death. Proximal leg deep thrombosis was diagnosed on compression ultrasonography performed within 2 days following admission, twice weekly, and as clinically indicated. Additional testing for venous thromboembolism was performed as clinically indicated. Study data were analyzed according to the intention-to-treat principle. The trial, begun in May 2006 and completed in 4 years, was conducted in 567 ICUs in academic and community hospitals in Canada, Australia, Brazil, Saudi Arabia, the United States, and the United Kingdom. The researchers randomly assigned 3764 patients to receive either subcutaneous dalteparin at a dose of 5000 IU once daily plus placebo (n=1873) or unfractionated heparin at a dose of 5000 IU twice daily (n=1873). No patients were lost to follow-up. Participants were at least 18 years of age, weighed at least 45 kg, and were expected to remain in the ICU at least 3 days. The 2 groups were similar at baseline: 76% of the admissions were medical, 90% of the patients required mechanical ventilation, and 45% required vasopressors. Prevalent proximal deep vein thrombosis identified at initial screening was present in 3.5% of those receiving dalteparin and in 3.4% of those receiving unfractionated heparin. The rates of cointerventions with drugs or devices that influence bleeding or thrombotic risk were also similar in the 2 groups throughout the trial. In both groups, the median duration of exposure to a study drug was 7 days. There was no significant difference in the 2 groups in the rate of proximal leg deep vein thrombosis. Incident proximal leg deep vein thrombosis occurred in 5.1% (96/1873) of the group receiving dalteparin and in 5.8% (109/1873) of the patients in the group receiving unfractionated heparin (hazard ratio in the dalteparin group, 0.92; 95% confidence interval [CI], 0.68-1.23; P=.57). There was a significant difference in the number of patients who developed pulmonary embolism: 1.3% (n=24) of the patients in the dalteparin group versus 2.3% (n=43) of those in the unfractionated heparin group (hazard ratio, 0.51; 95% CI, 0.30-0.88; P=.01). Rates of other deep vein thromboses or any venous thromboembolism were similar in both groups. There was a trend toward a lower rate of the composite outcome of any venous thromboembolism or death for patients in the dalteparin group (28.3%; n=530) compared with the group receiving unfractionated heparin (31.4%; n=589); however, the difference was not significant (hazard ratio, 0.89; 95% CI, 0.79-1.01; P=.07). In summary, the researchers said, “Among critically ill patients with medical or surgical admissions, dalteparin as compared with unfractionated heparin did not decrease the incidence of proximal deep vein thrombosis. It is possible that in a larger trial, such a difference might have been detected. There was a significant reduction in the secondary end point of pulmonary embolism in the dalteparin group.”