The primary end point, changes in compression ultrasound and perfusion lung scan findings, was similar in all idraparinux groups and did not differ from that in the warfarin group. There was a clear dose response for major bleeding in patients who had received idraparinux with an unacceptably high frequency in those receiving the 10-mg dose. Two patients, both of whom received 5 mg idrapa-rinux once weekly, experienced a fatal bleeding incident. Patients who received the lowest dose of idraparinux had less bleeding than those randomized to receive warfarin (p = 0.029). Based on these results, a once-weekly 2.5-mg dose of idraparinux will be used in phase III clinical trials.
A nonpeptidic arginine derivative, DX-9065a binds reversibly to the active site of factor Xa. Administered as a continuous IV infusion, a small phase II trial compared four different doses of DX-9065a with placebo in 73 stable patients with coronary artery disease to assess safety. There were no major bleeding incidents among patients receiving DX-9065a. Additional phase II studies are comparing DX-9065a therapy with heparin therapy in patients undergoing percutaneous coronary interventions Generic Cialis.
An orally active agent, DPC 906 must be administered twice daily. In a phase II dose-finding study, DPC 906 was compared with enoxaparin in patients undergoing knee arthroplasty. This study was stopped prematurely, but the results have yet to be published.
Activated protein C
Recombinant activated protein C, drotrecogin alfa (activated), was compared with placebo in 1,690 patients with severe sepsis. When given as an infusion of 24 g/kg/h over > 96 h, activated protein C produced a 19% reduction in mortality at 28 days (reduction, 30.8 to 24.7%; p = 0.005). The rate of major bleeding was higher with activated protein C therapy than with placebo (3.5% and 2%, respectively; p = 0.06). Based on these results and economic analyses supporting the benefits of recombinant activated protein C, this agent has been licensed in North America for the treatment of patients with severe sepsis.
Although promising results with protein C concentrates have been reported in patients with meningococcemia, additional studies are needed. For theoretical reasons, activated protein C may be a better choice than protein C in patients with severe sepsis because inflammatory cytokines down-regulate thrombomodulin expression on the endothelial surface. This phenomenon may explain the results of immunohistochemical analyses of skin biopsy specimens from patients with meningococcemia, which revealed reduced thrombomodulin staining.
A recombinant analog of the extracellular domain of thrombomodulin, soluble thrombomodulin binds thrombin and induces a conformation change in the active site of the enzyme that converts it into a potent activator of protein C.