Adjusted doses of oral
warfarin sodium or fixed doses of subcutaneous
low-molecular-weight heparin (
LMWH) are the standard approaches for preventing
venous thromboembolism following major
orthopedic surgery of the legs. In recent years, new
anticoagulants have been compared with either
LMWH or
warfarin. The optimal timing for the first dose of
LMWH prophylaxis and of the new
anticoagulants is controversial. Recent clinical trials of
LMWH and of newer
anticoagulants have provided new information on the relationship between the timing of the first
anticoagulant dose and the efficacy and safety of thromboprophylaxis after major
orthopedic surgery. These data on the optimal timing of initiating prophylaxis come from limited direct randomized comparisons of different timing with the same
anticoagulant, subgroup analysis of large studies with a single
anticoagulant, indirect comparisons across studies in systematic reviews, and single randomized trials comparing different
anticoagulants. In the direct comparison of the same
anticoagulant, preoperative initiation of the same regimen of
LMWH (
dalteparin) increased major
bleeding, without improved antithrombotic efficacy compared to the early postoperative regimen.
Fondaparinux, 2.5 mg, begun 6 h postoperatively is more effective and as safe as the currently approved regimens of
enoxaparin begun either 12 h preoperatively, or 12 to 24 h postoperatively, in patients undergoing major
orthopedic surgery. In a subgroup analysis of several large randomized trials,
fondaparinux, 2.5 mg, begun < 6 h postoperatively was associated with increased major
bleeding, without improved efficacy. The results of indirect comparisons also favor the use of a 6-h postoperative starting time for the first dose, while the single randomized trials comparing different
anticoagulants performed to date are not helpful in establishing an optimal time for the first dose. The aggregate clinical research evidence supports the following general conclusions about the relationship between the timing of the first
anticoagulant dose and the efficacy and safety of prophylaxis: (1) preoperative initiation is not required for good efficacy and, when begun within 2 h of surgery, increases major
bleeding; (2) initiation at 6 h postoperatively is effective and not associated with increased major
bleeding; (3) initiation < 6 h postoperatively increases major
bleeding, without improved efficacy; thus, 6 h appears to be the threshold for early postoperative administration; and (4) initiation 12 to 24 h postoperatively may be less effective than initiation at 6 h, but further randomized trials comparing the same
anticoagulant initiated at different times postoperatively (
eg, 6 h vs 12 h) are required to establish definitively the optimal timing of the first
anticoagulant dose.