Thromboprophylaxis dosing: the relationship between timing of first administration, efficacy, and safety

A unique antithrombotic agent, fondaparinux, selectively inhibits factor Xa and, therefore, thrombin generation, without affecting activity of the thrombin molecule. Its efficacy and safety in preventing venous thromboembolism following major orthopedic surgery, that is, hip and knee replacement and hip fracture, were demonstrated in 4 phase III clinical trials involving 7433 patients. Fondaparinux produced an overall 55% reduction in the risk of venous thromboembolism relative to the low-molecular-weight heparin enoxaparin without increasing the incidence of clinically relevant bleeding, which was similarly low for both agents. However, the incidence of overt bleeding with a bleeding index > or = 2 was higher for fondaparinux. First-dose timing according to the protocol for the 4 phase III trials was fondaparinux, 6 +/- 2 hours postoperatively, and enoxaparin, following the manufacturers' recommendations--either 12 hours preoperatively or 12 to 24 hours postoperatively. Whether the first-dose timing may explain the observed differences in efficacy and safety between the drugs was addressed in post-hoc analyses. Post-hoc analyses of the phase III trial data indicate that the superior efficacy of fondaparinux is maintained independent of the timing of the first dose. These analyses also indicate that administration of fondaparinux earlier than 6 hours postoperatively is associated with an increased incidence of a bleeding index > or = 2. Thus, when fondaparinux is administered according to the manufacturers recommended regimen, that is, not earlier than 6 hours postoperatively, the incidence of a bleeding index > or = 2 decreases to a rate similar to that found in the enoxaparin group. The superior efficacy of fondaparinux relative to enoxaparin is the result of its unique mechanism of action, clinical pharmacology, and dose selection rather than early timing of first administration.