Kwong Louis M, Muntz James E
Department of Orthopaedic Surgery, Harbor/UCLA Medical Center, Torrance, California 90509, USA.
Am J Orthop (Belle Mead NJ). 2002 Nov;31(11 Suppl):16-20.
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.
磺达肝癸钠是一种独特的抗血栓药物，它能选择性抑制Xa因子，从而抑制凝血酶的生成，但不影响凝血酶分子的活性。在涉及7433例患者的4项III期临床试验中，证实了其在预防大型骨科手术后（即髋关节和膝关节置换术以及髋部骨折）静脉血栓栓塞方面的疗效和安全性。相对于低分子肝素依诺肝素，磺达肝癸钠使静脉血栓栓塞风险总体降低了55%，且未增加临床相关出血的发生率，两种药物的该发生率均较低。然而，磺达肝癸钠导致出血指数≥2的明显出血发生率更高。根据4项III期试验方案，磺达肝癸钠的首剂给药时间为术后6±2小时，依诺肝素则遵循制造商的建议，即在术前12小时或术后12至24小时给药。事后分析探讨了首剂给药时间是否可以解释所观察到的两种药物在疗效和安全性上的差异。对III期试验数据的事后分析表明，磺达肝癸钠的卓越疗效不受首剂给药时间的影响。这些分析还表明，术后6小时内早期使用磺达肝癸钠与出血指数≥2的发生率增加有关。因此，当按照制造商推荐的方案使用磺达肝癸钠时，即不早于术后6小时给药，出血指数≥2的发生率会降至与依诺肝素组相似的水平。磺达肝癸钠相对于依诺肝素的卓越疗效是其独特的作用机制、临床药理学和剂量选择的结果，而非首次给药的早期时间。
