PURPOSE: The XPRESS study was a large phase 3B study designed to assess 28-day mortality and relative incidence of venous thrombotic events (VTE) in patients treated with Drotrecogin alfa activated (DAA) with or without prophylactic heparin.
METHODS: From December 2002 to July 2005, adult patients with high risk severe sepsis were enrolled. DAA at 24 microgram/kilogram/hour for a planned 96 hour infusion was administered to each patient. The study drug was unfractionated heparin (5000 units subcutaneously twice a day), enoxaparin (40 mg subcutaneously per day) or placebo in a 1:1:2 randomization scheme. Lower extremity ultrasound was performed between days 4-6.
RESULTS: A total of 1935 patients received DAA and study drug. A total of 959 patients were randomized to placebo and 976 to heparin (478 to low molecular weight heparin and 498 to unfractionated heparin). During Study Days 0-6, 4.6% of combined heparin patients and 5.1% of placebo patients experienced a VTE, p=0.60; during Study Days 0-28, 5.7% of combined heparin patients and 7.0% of placebo patients experienced a VTE, p=0.26. During both time periods, lower extremity DVT was the most common VTE and pulmonary embolism and central venous thrombosis were rare. Subgroups with the highest incidence of VTE included: previous VTE, age >75, recent surgery and patients on baseline heparin randomized to placebo. In patients on baseline heparin, the rates of VTE over Study Days 0-28 in the heparin versus placebo groups were 5.3% and 8.1% respectively.
CONCLUSION: The rate of VTE in this population treated with DAA was relatively low compared to recent ICU-based studies. There was no statistical difference between the combined heparin and placebo groups.
CLINICAL IMPLICATIONS: It is uncertain whether DAA alone provides adequate VTE prophylaxis. However, given the increase in VTE in patients on baseline heparin randomized to placebo, prophylactic heparin should not be discontinued unless the clinical situation dictates that the risks of heparin outweigh any potential benefit.
DISCLOSURE: Mitchell Levy, Other Principle investigator for the XPRESS study and compensated for travel and consultation for the study.