The low-molecular-weight heparin dalteparin was found to be no better than unfractionated heparin in preventing proximal leg deep vein thrombosis among critically ill adults, according to an international study published online March 22 in the New England Journal of Medicine.
Rates of venous thrombosis, venous thromboembolism, major bleeding, and death also were similar with the two agents. Although dalteparin was associated with significantly fewer pulmonary emboli and significantly less heparin-induced thrombocytopenia, these were not primary outcomes, and "caution is warranted in making inferences about nominally significant findings in secondary outcomes," said Dr. Deborah Cook and her coinvestigators in the Prophylaxis for Thromboembolism in Critical Care Trial (PROTECT). The study was published online simultaneously with its presentation at the International Symposium on Intensive Care and Emergency Medicine in Brussels.
The study was done because two previous randomized trials comparing the two types of heparin were inconclusive. PROTECT was conducted in 67 ICUs within academic or community hospitals in Australia, Brazil, Canada, Saudi Arabia, the United Kingdom, and the United States. A total of 3,746 patients were randomly assigned in equal numbers to receive either dalteparin or unfractionated heparin to prevent thromboembolism.
Approximately three-fourths of the study subjects were medical patients and the remainder were surgical patients. Ninety percent required mechanical ventilation and 45% required vasopressors.
"Throughout the trial, the rates of cointerventions with drugs or devices that influence bleeding or thrombotic risk were similar in the two groups," noted Dr. Cook of the departments of medicine and clinical epidemiology and biostatistics at McMaster University, Hamilton, Ont., and her colleagues.
Twice a week until discharge, the study subjects underwent ultrasonography of the proximal venous system in the leg at 1-cm intervals to detect deep vein thrombosis (DVT). Compressibility was documented at the common femoral, proximal, middle, and distal superficial femoral and popliteal veins, and at the venous trifurcation.
Even though screening compression ultrasonography has limitations in this regard, it was chosen because "classic signs and symptoms of DVT do not develop in comatose, recumbent, critically ill patients." Moreover, it is safe, noninvasive, readily available, and recommended for such research, the investigators said.
The median duration of the use of both drugs was 7 days.
The primary end point – incident proximal leg DVT – developed in 96 (5.1%) of the patients receiving dalteparin, compared with 109 (5.8%) of those receiving unfractionated heparin, a nonsignificant difference.
However, "the confidence interval around the hazard ratio for the primary end point was fairly wide, so it did not exclude either a 32% benefit or a 23% harm associated with dalteparin, as compared with unfractionated heparin. Thus, the result for the primary outcome was not clinically directive," the researchers said (N. Engl. J. Med. 2011 March 22 [doi:10.1056/NEJMoa1014475]).
The rates of venous thrombosis, venous thromboembolism, major bleeding, and death also were similar between the two groups.
Patients in the dalteparin group had significantly fewer pulmonary emboli (1.3% vs. 2.3% of patients) and significantly less heparin-induced thrombocytopenia (0.3% vs. 0.6% of patients), but these outcomes must be interpreted with caution, given the small numbers, Dr. Cook and her associates said.
These study findings were consistent in further adjusted analyses of the data, as well as in sensitivity analyses and a per-protocol analysis.
"Our results might have been different if the study enrollment had been larger or if we had used different drugs or doses," they noted.
The PROTECT study was funded by the Canadian Institutes of Health Research, the Australian and New Zealand College of Anesthetists Research Foundation, and the Heart and Stroke Foundation of Canada. Study drugs were provided by Pfizer and Eisai. The investigators reported ties to numerous industry sources.