Enoxaparin sodium

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 rag, 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 trims 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.

Key words: anticoagulant therapy; antithrombotic therapy; thromboprolyaxis: venous thromboembolism

Abbreviations: ASRA = American Society of Regional Anesthesia and Pain Management; FDA = Food and Drug Administration: LMWH = low molecular-weight heparin; NAFT = North American Fragmin Trial: rNAPc2 = recombinant nematode anticoagulant protein c2

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The development of effective and safe approaches for preventing venous thromboembolism following major orthopedic surgery, of the legs has been the subject of extensive clinical investigation over the past 25 years. This clinical research has identified several effective prophylactic approaches. In North America, it has become standard practice to use either adjusted doses of oral warfarin sodium or fixed doses of subcutaneous low-molecular-weight heparin (LMWH) administered once or twice daily. These two strategies are the preferred approaches recommended by the Sixth Consensus Conference on Antithrombotic Therapy of the American College of Chest Physicians.

The initial clinical trials comparing LMWH with warfarin prophyhtxis in patients undergoing hip replacement failed to demonstrate superior effectiveness of LMWH when treatment with it is commenced 12 to 2.4 h postoperatively, and the absolute rates of deep-vein thrombosis detected by mandatory venography at 7 to 14 days postoperatively were substantial, leading room for improvement. (1) Over the past few years, clinical trials have been conducted to determine if modifying the timing of the first dose of LMWH prophylaxis would improve antithrombotic effectiveness while maintaining a low, acceptable rate of bleeding complications. Thus, recent clinical research has focused on two long-standing controversial questions regarding the timing of the first dose of LMWH prophylaxis: (1) does administering the first dose of prophylaxis close to the time of surgery, either preoperatively or early postoperatively, result in improved effectiveness for preventing venous thromboembolism, and (2) does administering the first dose of prophylaxis close to the time of surgery increase clinically important bleeding complications? The objectives of this article are as follows: (1) to review the clinical paradigms for the timing of the first dose of prophylaxis, and provide a historical perspective oil this issue, (2) to review the recent clinical research evidence relating the timing of the first dose of LMWH to the efficacy and safety of prophylaxis, (3) to review the recent clinical research evidence relating the timing of the first dose of newer anticoagulants to the efficacy and safety of prophylaxis, and (4) to discuss the implications for patient care of the timing of the first anticoagulant dose with the various anticoagulants.

METHODOLOGIC APPROACH FOR REVIEW OF EVIDENCE FROM CLINICAL RESEARCH

The review of clinical research evidence focuses on studies of venous thromboembolism prophylaxis in patients undergoing major orthopedic surgery of the legs. Only those studies that meet accepted methodologic criteria are considered. These criteria include a randomized trial design, mandatory testing with venography to establish the presence or absence of deep-vein thrombosis, interpretation of the venograms without knowledge of the prophylaxis administered, and a sufficient number of patients to make valid conclusions.

To evaluate the relation between the timing of the first anticoagulant dose and the efficacy and safety of prophylaxis, the strength of the evidence is considered. The studies were evaluated regarding the methodologic strength for establishing a relationship between timing of the first anticoagulant dose, and the efficacy and safety of prophylaxis. The studies were assigned strength of evidence category from I (strongest) to IV (weakest) as follows: category I, direct comparison in a randomized trial with the same anticoagulant of different times for initiating the first dose of prophylaxis; category II, subgroup analysis from large randomized trials in which the first dose of anticoagulant was administered at different times during a predefined "window" (eg, 4 to 8 h postoperatively); category III, comparison across different randomized trials in which the first dose of LMWH prophylaxis was administered at different times, using the same comparative control group (such as oral anticoagulant prophylaxis); and category IV, randomized trials using new anticoagulants with or without a control group. Definitive conclusions are made only if supported by category I evidence.

TIMING OF THE FIRST DOSE OF PROPHYLAXIS: CLINICAL PARADIGMS AND HISTORICAL PERSPECTIVE

The accepted timing of the first dose of prophylaxis was established as being 2 h preoperatively in the 1970s by clinical trials (2,3) with low-dose unfractionated heparin in general surgical patients. When LMWH was introduced in the early 1980s, studies by Bergqvist et al (4) in general surgical patients reported high rates of perioperative bleeding when the first dose of 5,000 U (anti-Xa) was administered 2 h preoperatively. Excessive bleeding was also reported when the first dose was lowered to 2,500 U. Consequently, it became standard practice in Europe to administer the first dose of LMWH 12 h preoperatively. In the meantime, a placebo-controlled randomized trial performed by Turpie et al (5) in patients undergoing hip replacement reported a 70% relative risk reduction in venous thrombosis without excessive bleeding when the first dose of LMWH (enoxaparin, 30 mg) was started 12 to 24 h postoperatively and then continued twice daily. These clinical trial results set the stage for a longstanding controversy between North America and Europe regarding the dosing regimens of LMWH for venous thrombosis prophylaxis. Historically, orthopedic surgeons in North America have begun prophylaxis postoperatively, usually delayed for at least 12 h after surgery to allow hemostasis of the surgical wound. In contrast, European orthopedic surgeons convinced anticoagulant prophylaxis 12 h preoperatively. Although the European approach aims to optimize antithrombotic effectiveness, based on the recognition that venous thrombosis may originate at the time of surgery or early postoperatively, it is uncertain whether this aim is achieved with the 12-h preoperative dose. The North American approach, in contrast, has been driven by a stronger concern for bleeding, and reinforced by the results of a number of clinical trials in major orthopedic surgery that established the effectiveness of postoperative initiation of LMWH prophylaxis. (1,5,6) The historically stronger concern about bleeding among North American surgeons is probably related, at least in part, to previous clinical experience in North America with intensive oral anticoagulant therapy (target international normalized ratio, 3.0 to 4.5), which was associated with a high rate ([greater than or equal to] 20%) of clinically important bleeding complications. (7)

Because of the difference in clinical practice between North America and Europe, the clinical development of the LMWH enoxaparin in the early 1980s for the prevention of venous thromboembolism after hip or knee replacement surgery utilized different regimens for North America and Europe. In Europe, the first dose of enoxaparin (40 mg) was administered preoperatively the evening before surgery, and prophylaxis was continued postoperatively as a once-daily regimen of the same dose. In North America, the clinical trials (5,6) evaluated a regimen in which the first dose was delayed until 12 to 24 h postoperatively, based on the concept that this approach would minimize the potential for bleeding complications. However, since it was recognized that venous thrombi may form perioperatively before prophylaxis is started, a regimen was evaluated that included a larger total daily dose of enoxaparin (60 mg per 24 h administered in divided doses of 30 mg bid), based in part on the concept that larger doses of anticoagulant would inhibit the growth of thrombi that may finance before the first dose of prophylaxis is administered, and enable natural lysis of these thrombi to occur, and also on the view that the 3-h half-life of subcutaneous LMWH required twice-daily dosing.

The widespread introduction of LMWH into clinical practice in the early 1990s coincided with the increasing use of neuraxial anesthetic techniques in patients undergoing major orthopedic surgery. This change in anesthesia practice included the increased use of single-injection spinal anesthesia, as well as the increased use of indwelling epidural catheters. In the United States, drag safety surveillance by the Food and Drug Administration (FDA) documented reports of spinal hematoma and paralysis occurring in orthopedic surgical patients who had received neuraxial anesthesia techniques and received LMWII for the prevention of venous thromboembolism. In 1997, Ilorlocker and Heit (8) investigated all case reports of spinal hematoma reported through 1996 by reviewing the literature and contacting the manufacturers of LMWH. Of the 24 identified cases of spinal hematoma associated with LMWH, 18 cases (75%) involved the use of a continuous epidural catheter, 1 case occurred after a single-dose epidural, 3 cases occurred with a single spinal technique (1 of these cases occurred after a failed epidural), and the remaining 2 cases did not specify the technique. Fifteen of the 24 identified cases were associated with the use of enoxaparin as a 30 mg bid regimen (the most common regimen in North America), 3 cases with enoxaparin at 40 mg qd, 2 cases with nadroparin once or twice daily, 1 case with mono-embolex, and in 3 cases the drug was unspecified. The neurologic outcome included paralysis in 17 of the 24 reported cases.

The FDA issued a "black-box" warning for the use of LMWH in patients receiving neuraxial anesthesia. (10) It is noteworthy that the European during regulatory agencies did not receive a proportionately similar number of reports of spinal hematoma associated with LMWH use in patients receiving neuraxial anesthesia. It is possible that the differences in reported episodes of spinal hematoma between North America and Europe were due to the different regimens of LMWH used, and/or to variances in anesthesia practice, patient differences, and differences in adverse event surveillance or reporting. The use of neuraxial anesthetic techniques has important implications for the tuning of the first dose of anticoagulant prophylaxis. This issue is discussed in more detail under the subheading "Clinical Implications of Timing of the First Dose of Prophylaxis for the Use of Neuraxial Anesthesia," including the recently released recommendations of the American Society of Regional Anesd/esia and Pain Management (ASRA). (10)

Thus, both the concern about bleeding complications of the surgical wound and, more recently, the risk of the potentially devastating complication of spinal hematoma in patients receiving neuraxial anesthesia has resulted in a change in labeling requested by the FDA and a strong preference among North American orthopedic surgeons for the initiation of LMWH prophylaxis to be delayed for at least 12 h and up to 24 h postoperatively or, alternately, to use warfarin prophylaxis because of the delayed onset of its anticoagulant effect.

RELATION BETWEEN TIMING OF FIRST DOSE OF LMWH AND EFFECTIVENESS AND SAFETY OF PROPHYLAXIS

Category I Evidence

To our knowledge, the only category I study is the North American Fragmin Trial (NAFT). (11) This trial was designed to determine if administering the first dose of LMWH early (4 to 6 h) postoperatively in a modified dose (one half the usual dose) would be similarly effective to administering the first dose preoperatively, but with less major bleeding. The NAFT study compared three prophylactic regimens in a randomized, double-blind trial: (1) dalteparin, 2,500 U administered within 2 h b preoperatively, then 2,500 U at 4 to 6 h postoperatively, followed by 5,000 U qd beginning the next clay; if neuraxial anesthesia was used, the preoperative dose was administered after the spinal puncture and only if this procedure was uncomplicated; (2) dalteparin, 2,500 U begma 4 to 6 b postoperatively, followed by 5,000 U qd beginning the next day; or (3) warfarin sodium begun postoperatively the evening after surgery, and adjusted to maintain the international normalized ratio between 2.0 to 3.0. Prophylaxis was continued in each group until venography was performed an average of 6 days postoperatively. (11)

The rates of all deep-vein thromboses for the preoperative dalteparin, postoperative dalteparin, and warfarin regimens, respectively, were as follows: 11% (36 of 337 patients), 13% (44 of 336 patients), and 24% (81 of 338 patients) [p < 0.001]. The rates of proximal-vein thromboses for the preoperative dalteparin, postoperative dalteparin, and warfarin regimens, respectively, were as follows: 0.8% (3 of 354 patients), 0.8% (3 of 358 patients), and 3.0% (11 of 363 patients) [p < 0.05]. The results indicate that the use of a preoperative dose does not result in a clinically important improvement in effectiveness compared to the regimen in which the first close of dalteparin is administered 6 h postoperatively. The results also indicate that both regimens of dalteparin begun in close proximity to surgery, were more effective than warfarin at reducing both all deep-vein thromboses and proximal-vein thromboses. (11)

The NAFT study (11) also provided data regarding the relationship between tuning of the first dose of LMWH and safety for clinically important bleeding; the study evaluated major bleeding, minor bleeding, and serious bleeding, using a central adjudication committee who were blind to the treatment group. Because the central adjudication of bleeding evaluates only the information contained within the case report forms and lacks the input of clinical assessment by the surgeon or physician investigator at the bedside, this double-blind study also evaluated major bleeding as assessed by the clinical investigator, in which the physician at the site determined if the bleeding is clinically important based on clinical assessment of the patient at the bedside. Bleeding was classified as major if it was clinically overt and associated with a decrease in hemoglobin level of [greater than or equal to] 2 g/dL or required transfusion of [greater than or equal to] 2 U of blood or packed RBCs, or if it was intracranial, intraspinal, intraocular, or retroperitoneal. Bleeding was classified as minor if it was clinically overt but did not meet the other criteria for major bleeding. Serious bleeding was defined as the requirement for transfusion of > 5 U of blood or packed RBCs perioperatively, or transfusion of > 7 U at any time after surgery, or total blood loss of > 3,500 mL.

The rates for centrally adjudicated major bleeding for the preoperative dalteparin, postoperative dalteparin, and warfarin, respectively, were as follows: 8.9% (44 of 496 patients), 6.6% (32 of 487 patients), and 4.5% (22 of 489 patients) [p < 0.05 for preoperative dalteparin compared with warfarin]. The corresponding rates for major bleeding ms assessed by the physician investigator were as follows: 3.6% (18 of 496 patients), 2.5% (12 of 487 patients), and 3.1% (15 of 489 patients). The corresponding rates for serious bleeding were 2.0%, 1.0%, and 1.6%. Complicated wound hematoma, defined as hematoma resulting in reoperation, wound infection, wound dehiscence, or persistent drainage, or resulting in prolongation of the hospital stay, occurred in 0.4% of patients in each of the dalteparin groups and in 0.2% of patients receiving warfarin. (11)

The results indicate that preoperative dalteparin is associated with an increase in centrally adjudicated major bleeding compared with warfarin prophylaxis. Of interest is the finding that although warfarin therapy was not begun until the evening after surgery, the centrally adjudicated major bleeding rate in the warfarin group on the day of surgery and first postoperative day was 4.1%; this bleeding rate, therefore, reflects the usual bleeding associated with the surgery. Major bleeding as assessed by the physician investigator was not increased for the postoperative dalteparin regimen (2.,5%) compared with warfarin (3.1%). Serious bleeding or minor bleeding was also not increased by the postoperative dalteparin regimen.

In conclusion, the NAFT study (11) demonstrates that a postoperative regimen of the LMWH dalteparin, begun early postoperatively (mean, 6 h), is more effective than warfarin for preventing deep-vein thrombosis, including proximal-vein thrombosis. This regimen did not increase clinically important bleeding complications by comparison to warfarin prophylaxis. The preoperative regimen did not produce a clinically important improvement in effectiveness compared to the early postoperative regimen, but did increase the rate of centrally adjudicated major bleeding.

Category II Evidence

The only category II analysis is derived from the results of clinical trials (12-17) with fondaparinux. Fondaparinux is a synthetic factor Xa inhibitor that has been evaluated in a clinical development program with > 7,000 patients undergoing major orthopedic surgery, which included hip replacement, knee replacement, or surgery for fractured hip. (17) The program included four phase III, randomized, double-blind trialsra-17 comparing fondaparinux, 2.5 rag, administered subcutaneously 4 to 8 h after surgery with enoxaparin in the approved regimens of either 30 nag bid begun 12 to 24 h postoperatively (for North America) or 4(1 nag qd begun 12 h preoperatively (for Europe and the rest of the world). In the phase III program, the regimen of fondaparinux, 2.5 rag, begun 6 h postoperatively resulted in relative risk reductions of > 50% for all deep-vein thrombosis and also for proximal-vein thrombosis. (17) Major bleeding occurred in 2.7% of 3,616 patients who received fondaparinux, and in 1.7% of 3,621 patients receiving enoxaparin (p = 0.1108) (17); bleeding requiring reoperation, occurring in a critical organ or leading to death, did not differ between these two regimens (two patients receiving enoxaparin and none receiving fondaparinux had such bleeding).

The relationship between timing of the first dose of fondapafinux and the efficacy and safety of prophylaxis has been evaluated by subgroup analysis (category II evidence) of the > 3,000 patients who received this drug in the phase III studies)s The efficacy' of the fondaparinux regimen was not improved by initiating the first dose < 6 h postoperatively. The incidence of all venous thromboembolism was 6.4% (62 of 964 patients) among those who began fondaparinux therapy < 6 h postoperatively, compared with 7.0% (115 of 1,635 patients) in those receiving the first dose [is greater than or equal to] 6 h after surgery (p = 0.57). (18) In contrast, major bleeding was increased when the first dose of fondaparinux was administered < 6 h postoperatively. The rate of major bleeding was 3.2% (42 of 1,300 patients) in those receiving the first dose of fondaparinux < 6 h postoperatively, compared to 2.1% (46 of 2,171 patients) for those who received the first dose at [is greater than or equal to] 6 (p - 0.045). The first dose of fondaparinnx was administered between 6 h and 9 h postoperatively in 95% of parents. Few patients received the first dose of fondaparinux > 9 h postoperatively. Thus, initiation of prophylaxis with fondaparinux, 2.5 nag, between 6 h and 9 h postoperatively was more effective than enoxaparin therapy, begun either 12 h preoperatively or 12 to 24 h postoperatively, with a similar incidence of major bleeding. Since the initial dose of enoxaparin was administered later than the initial dose of fondaparinux, it is possible that the observed superior efficacy of fondaparinux over enoxaparin, and the observed results for major bleeding, were contributed to, at least in part, by the difference in timing of administration of the two anticoagulants.

The reported increase in bleeding index without an increase in clinically severe bleeding is similar to the NAFT study, (11) which reported a lower rate of major bleeding as assessed by the physician investigator at the bedside, than for centrally adjudicated major bleeding. Thus, the increase in major bleeding with fondaparinux compared to enoxaparin (from 1.7 to 2.7%) resulted from bleeding associated with a bleeding index of [greater than or equal to] 2 without increasing the need for reoperation or the frequency of other important clinical consequences (17); many such bleeds are not considered clinically important by orthopedic surgeons. However, since the bleeding index is likely a valid and sensitive surrogate marker of the potential to cause major clinically important bleeding, the results from both the NAFT study (11) and the fondaparinux program (12-17) suggest the doses chosen for the first dose at 6 h postoperatively are at the threshold of safety.

Category III Evidence

The relation between tinting of the first dose of LMWH and antithrombotic effectiveness has also been assessed by recent systematic reviews of the literature. (19,20) Because the quantitative analyses in these reviews are based on comparisons across studies, possible confounding factors such as differences between patients or the specific LMWH used cannot be completely ruled out, and definitive conclusions are not made based on these analyses (category III evidence as defined earlier).

Hull et al (9) identified the randomized trials comparing LMWH regimens begun at different times relative to surgery with oral anticoagulant prophylaxis in patients undergoing total hip replacement. The LMWH regimens in which the first dose was administered either 12 h before surgery or 12 to 24 h after surgery were not more effective than prophylaxis with oral anticoagulants. The LMWH regimens in which the first dose was administered either within 2 h preoperatively or at 4 to 6 h postoperatively were more effective than oral anticoagulant prophylaxis. The relative risk reductions were 43 to 55% for all deep-vein thromboses (from 25% to 11 to 13%) and 72% for proximal-vein thromboses (from 3.0 to 0.8%). (19) The major bleeding rates for the LMWH regimens were 1.2% for the 12-h preoperative regimen, 2.2% and 8.9% for the two studies that included a preoperative regimen administered within 2 h of surgery, 6.6% for the postoperative regimen commenced at 4 to 6 h, and 2.8% for the regimen begun 18 to 24 h postoperatively; the major bleeding rate for the oral anticoagulant control group in each of these studies ranged from 1.5 to 4,5%.19

In their analysis, Strebel et al (20) reported that perioperative regimens of LMWH, administered either within 2 h preoperatively or 4 to 6 h postoperatively, were associated with a decreased incidence of proximal-vein thrombosis (from 5 to 2%), compared to the regimens begun 12 to 48 h postoperatively (relative risk reduction, 60%). The pooled major bleeding rates were, 1% for the regimen begun 12 h preoperatively; 7% for the perioperative regimens (which include a first dose either within 2 h preoperatively or within 4 to 6 h, postoperatively), and 3% for the postoperative regimen begun 12 to 24 h after surgery. (20)

In summary, the aggregate evidence from clinical research supports the concept that there is a time window to give the first dose of LMWH in order for it to be optimally effective. Administering the first dose 12 h before surgery is probably too early, and administering the first dose -> 12 h after surgery is probably too late from optimal effectiveness (category III evidence). Administering the first dose within 2 h preoperatively results in increased major bleeding and does not improve efficacy compared to administering the first dose 6 h postoperatively (category I evidence). This regimen of dalteparin uses a dose of 2,500 U for the first dose, which is one half the usual dose of 5,000 U approved by regulatory affairs agencies for patients at high risk of venous thromboembolism. It is likely that the dose of LMWH used as the first dose is an important variable for safety, and too large a dose administered 6 h postoperatively may be expected to increase clinically important bleeding. The concept of using a lower-than-usual dose administered early postoperatively will probably translate to other LMWHs such as enoxaparin or tinzaparin. However, the modified regimens for these heparins should be evaluated by clinical trials before they are considered for clinical use. Finally, a randomized trial that directly compares different times of postoperative initiation (eg, 6 h vs 12 h) of the same LMWH is required to establish definitively the timing of dm first dose that optimizes the risk-benefit of this prophylaxis.

CLINICAL IMPLICATIONS OF TIMING OF THE FIRST ANTICOAGULANT DOSE OR USE OF NEURAXIAL ANESTIIESIA

Administering the first dose of LMWH postoperatively has the advantage that the anticoagulant is not "on board" at the time of spinal puncture for neuraxial anesthesia. In the NAFT study, (11) there were no cases of spinal hematoma among the 482 patients who received neuraxial anesthesia and were administered the modified regimens of dalteparin (either preoperatively or postoperatively). The average time of administering the first dose of dalteparin postoperatively after neuraxial anesthesia was 9 h. (11)

The ASRA has issued new guidelines (10) for neuraxial anesthesia in patients receiving prophylaxis with LMWH. For once-daily regimens, such as dalteparin, the recommended timing of the first postoperative dose is 6 to 8 h postoperatively, with the next dose to be given not sooner than 24 h later, (10) Indwelling neuraxial catheters can be maintained. However, the catheter should be removed a minimum of 10 to 12 h after the previous dose of LMWH, and subsequent doses of LMWH should be delayed until at least 2 h after catheter removal. (10) The use of a first dose of dalteparin of 2,500 U administered between 6 h and 9 h postoperatively is expected to provide antithrombotic protection consistent with the clinical trial results reviewed earlier in this article, and is also consistent with the ASRA guidelines. (10)

If a twice-daily regimen is used, such as enoxaparin, 30 mg bid, the ASRA guidelines (10) recommend the first dose should not be administered < 24 h postoperatively, and indwelling neuraxial catheters should be removed before LMWH therapy is commenced. The first dose should 'also be delayed until at least 24 h if there is blood during needle or catheter placement (for either once- or twice-daily regimens). (10)

Category IV Evidence

Clinical trials with three other anticoagulants with different mechanisms of action support a relationship between the timing of the first dose and the effectiveness and safety of venous thromboembolism prophylaxis. However, these studies did not directly compare the same anticoagulant therapy begun at different times, and therefore provide category IV evidence.

Eriksson et al (21) reported that recombinant hirudin (desirudin) therapy begun 30 rain preoperatively was more effective than the European regimen of enoxaparin therapy begun 12 h preoperatively. The regimen of desirudin reduced all deep-vein thromboses from 26 to 18% (relative risk reduction, 28%) and proximal-vein thromboses from 7.5 to 4.5% (relative risk reduction, 40%). Perioperative blood loss, transfusion requirements, serious bleeding, and wound hematomas all occurred with similar frequency in the two treatment groups. (21)

Melagatran, and its oral pro-drug formulation ximelagatran, are direct thrombin inhibitors that have been evaluated in several randomized trials (22-25) for the prevention of venous thromboembolism alter elective hip or knee replacement. The Melagatran for Thrombin Inhibition in Orthopedic Surgery I and II studies (22,23) were randomized, dose-ranging, clinical trials in which different regimens of melagatran followed by oral ximelagatran were compared with subcutaneous LMWH (dalteparin) in patients undergoing hip or knee replacement. The melagatran/ximelagatran regimens were administered as subcutaneous injections of melagatran begun immediately before surgery but after induction of regional anesthesia (if used), a second injection within 12 h postoperatively, then twice-daily injections for another day or two, followed by twice-daily oral ximelagatran. The dalteprin group received 5,000 U qd begun the evening before surgery. The larger Melagatran fur Thrombin Inhibition in Orthopedic Surgery II study (23) documented a dose-response relationship for both the antithrombotic efficacy and severe bleeding of the melagatran/ximelagatran regimens. The highest dose regimen of melagatran 3 mg/ximelagatran 24 mg was more effective than the dalteparin regimen, reducing deep-vein thrombosis from 28 to 15% (p < 0.01), but with an incidence of severe bleeding of .5.0% compared to 2.3% for dalteparin. The rates of severe bleeding for the four melagatran/ximelagatran regimens from lowest to highest dose were 1.1%, 2.1%, 2.9%, and 5.0% (p < 0.01). The corresponding rates of deep-vein thrombosis were 39%, 24%, 24%, and 15% (p < 0.01). Thus, at doses that did not increase severe bleeding, the melagatran/ximelagatran regimen was not more effective than the dalteprin regimen begun the evening before surgery.

Two additional randomized trials evaluated melagatran/ ximelagatran compared with either warfarin prophylaxis (24) or LMWH (enoxaparin). (25) Francis et al (24) compared treat-merit with ximelagatran, 24 mg bid, begun the morning after surgery, with warfarin begun the evening of the day of surgery in patients undergoing total knee replacement. Deep-vein thrombosis occurred in 19% (53 of 276 patients) who received ximelagatran, compared with 26% (67 of 261 patients) who received warfarin (p = 0.07). Major bleeding occurred in 1.7% of patients receiving ximelagatran and ill 0.9% receiving warfarin (p > 0.05). Eriksson et al (25) compared the regimen of melagatran, 3 mg, begun 4 to 12 h postoperatively followed by ximelagatran, 24 mg bid, with enoxaparin, 40 mg qd, begun 12 h preoperatively in a study of > 2,.200 patients undergoing hip or knee replacement. The melagatran/ximelagatran regimen was marginally less effective than the enoxaparin regimen; the incidences of deep-vein thrombosis were 3] % and 27%, respectively (p = 0.053).

Taken together, the clinical trials with melagatran/ ximelagatran indicate that a regimen of this direct thrombin inhibitor begun immediately preoperatively can achieve greater antithrombotic efficacy than LMWH (dalteparin) begun the evening before surgery.2a However, the doses required to achieve this improved efficacy probably increase clinically important bleeding. Postoperative initiation of the same regimen 4 to 12 h airier surgery was marginally less effective than LMWH (enoxaparin) therapy begun 12 preoperatively. (25) In patients undergoing knee replacement, treatment with ximelagatran, 24 mg bid, begun the morning after surgery, was at least as effective as warfarin, and possibly more effective, but the absolute incidence of thrombosis remains high (19%). (24)

Lee et al, (26) in a dose-finding study in patients undergoing knee replacement, reported that lower doses of recombinant nematode anticoagulant protein c2 (rNAPc2) begun 1 h postoperatively were associated with lower rates of all deep-vein thrombosis than larger doses of rNAPc2 begun [greater than or equal to] 12 h postoperatively. The 1-h postoperative lower-dose regimen was not associated with an increased rate of major bleeding, whereas the 12-h postoperative regimen appeared to be associated with increased mahor bleeding as the dose of rNAPc2 increased. (26)

CONCLUSION

A regimen of the LMWH dalteparin begun early (6 h) postoperatively is more effective than warfarin for preventing venous thromboembolism after total hip replacement, without an increase in major bleeding. Preoperative initiation of the same LMWH regimen did not produce a clinically important efficacy advantage over early postoperative initiation, and resulted in increased major bleeding. Treatment with fondaparinux, 2.5 rag, begun 6 h postoperatively is more effective and as safe as the currently approved regimens of enoxaparin begun either 1.2 h preoperatively, or 12 to 24 h postoperatively, in patients undergoing major orthopedic surgery. The same dose of fondaparinux begun < 6 h postoperatively was associated with increased major bleeding, without improved efficacy.

These clinical trial findings, together with the aggregate data from systematic reviews and emerging results of clinical trials with new anticoagulants, support the following general conclusions about the relationship between the l i ruing of the first anticoagulant dose, and the efficacy and safety, of thromboprophylaxis after major orthopedic surgery of the legs: (1) preoperative administration is not required to achieve good efficacy, and when begun within 2 h of surgery, increases major bleeding; (2) initiation between 6 h and 9 h postoperatively is effective and not associated with increased major bleeding; (3) initiation < 6 h postoperatively increases major bleeding, without improved efficacy; therefore, 6 h appears to be the threshold for early postoperative initiation; and (4) initiation 12 to 24 h postoperatively may be less effective than initiation at 6 h. A randomized trial comparing the same anticoagulant initiated at either 6 h or 12 h postoperatively is required to unequivocally determine if initiating prophylaxis at 12 h will retain the efficacy of earlier initiation, but with a reduced rate of major bleeding.

REFERENCES

(1) Geerts W, Heft JA, Clagett GP. et al. Prevention of venous thromboembolism. Chest 2001; 119:139S-175S

(2) Gallus A, Hirsh J, Tuttle B., et al. Small subcutaneous doses of heparin in the prevention of venous thrombosis. N Engl J Med 1973; 288:545-551

(3) Kakkar V, Corrigan T, Fossard D, et al. Prevention of fatal postoperative pulmonary embolism by low doses of subcutaneous heparin: an international multicentre trial. Lancet 1975; 2:45-51

(4) Bergqvist D, Burmack US, Erisell J, et al. Low-molecular-weight-heparin once daily compared with conventional low-dose heparin twice daily: a prospective double-blind multicentre trial on prevention of postoperative thrombosis. Br J Surg i986:73:204-208

(5) Turpie A, Levine M, Hirsh J, et al. A randomize at controlled trial of a low-molecular-weight heparin (enoxaparin) to prevent deep-vein thrombosis in patients undergoing elective hip surgely. N Engl J Med 1986; 315:925-929

(6) Leclerc J, Geerts W, Desjardins L, et al. Prevention of deep-vein thrombosis after major knee surgery,: a randomized: double-blind trial comparing a low-molecular-weight heparin fragment (enoxaparin) to placebo. Thromb Haemost 1992; 67:417-423

(7) Hirsh J, Dalen J, Anderson D, et al. Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range. Chest 20111; 119:(suppl):8S-21S

(8) Horlocker TT. Heit JA. Low-molecular-weight-heparin: biochemistry, pharmacology, perioperative prophylaxis regimens and guidelines for regional anesthetic management. Anesth Amdg 1997; 85:874-885

(9) Lumpkin MM. FDA alert: FDA public health advisory. Anesthesiology 1998; 88:27A 2SA

(10) American Society of Regional Anesthesia and Pain Management. Regional anesthesia in the anticoagulated patient: defining the risks; anesthetic management of the patient receiving low-molecular weight heparin (LMWH). Availableat: http://www.asra.com. Accessed November 17, 2003

(11) Hull R, Pineo G, Francis C, et al. Low-molecular-weight heparin prophylaxis using dalteparin in close proximity to surgery vs warfarin in hip arthroplastty patients: a double blind, nmdomized comparison: North American Fragmin Trial Investigators. Arch Intern Med 2000; 160:2199-2207

(12) Turpie AC, Callus AS, Hock JA, for the Pentasaccharide Investigators. A synthetic pentasaccharide for the prevention of deep-vein thrombosis after total hip replacement. N Engl J Med 2001; 344:619-625

(13) Batter JA, Eriksson BI, Lassen MR, et al, for the Steering Committee of the Pentasaccharide in Major Knee Surgery Study. Fondaparinux compared with enoxaparin for the prevention of venous thromboembolism alter elective major knee surgery. N Engl J Med 2001; 345:1305-1319

(14) Eriksson B1, Bauer KA, Lassen MR, et al, for the Steering Committee of the Pentasaccharide in Hip-Fracture Surgery Study. Fondaparinux compared with enoxaparin for the prevention of venous thromboembolism after hip-fracture surgery. N Engl J Med 2001; 345:1298-1304

(15) Turpie AG, Bauer KA, Eriksson BI, et al, for the Pentathlon 2900 Study Steering Committee. Postoperative fondaparinux versus postoperative enoxaparin for prevention of venous thromboembolism after elective hip-replacement surgery: a randomised double blind trial. Lancet 2002; 359:1721-1726

(16) Lassen MR, Bauer KA, Eriksson BI, et al, for the European Pentasaccharide Hip Elective Surgery Study (EPHESUS) Steering Committee. Postoperative fondaparinux versus preoperative enoxaparin for prevention of venous thromboembolism in elective hip-replacement surgery: a randomised double-blind comparison. Lancet 2002; 359:1715-1720

(17) Turpie AG, Bauer KA, Eriksson BI, et al, for the Steering Committees of the Pentasaccharide Orthopedic Prophylaxis Studies. Fondaparinux vs enoxaparin for the prevention of venous thromboembolism in major orthopedic surgery: a meta-analysis of 4 randomized double-blind studies. Arch Intern Med 2002; 162:1833-18410

(18) Turpie A, Bauer K, Eriksson B, et al. Effect on efficacy and safety of the timing of the first administration of fondaparinux in the prophylaxis of venous thromboembolism following major orthopedic surgery. Presented at the Seventh Annual Meeting of the European Hematology Association, Florence, Italy, 2002

(19) Hun R, Pineo G, Stein P, et al. Timing of initial administration of low-molecular-weight heparin prophylaxis against deep vein thrombosis in patients following elective hip arthroplasty: a systematic review. Arch Intern Med 2001; 161:1952-1960

(20) Strebel N, Prins M, Aguelli G, et al. Preoperative or postoperative start of prophylaxis for venous thromboembolism with low-molecular-weight heparin in elective hip surgery? Arch Intern Med 2002; 162:1451-1456

(21) Eriksson B, Willie-Jorgensen P, Kalebo P, et al. A comparison of recombinant hirudin with a low molecular-weight heparin to prevent thromboembolic complications after total hip replacement. N Engl J Med 1997; 337:1329-1335

(22) Eriksson B, Arfwidsson A, Frison L, et al. A dose-ranging study of the oral direct thrombin inhibitor ximelagatran, and its subcutaneous form, melagatran, compromised with dalteparin in the prophylaxis of thromboembolism after hip or knee replacement: METHRO I. Thromb and Haemost 20112; 37:231-237

(23) Eriksson B, Bergqvist D, Kalebo P, et ad. Ximelagatran and melagatran compared with dalteparin prevention of venous thromboembolism after total hip or knee replacement: the METHRO II randomised trial. Lancet 2002; 360:1441-1447

(24) Francis C, Davidson B, Bcrkowitz S, et al. Ximelagatran versus warfarin for the prevention of venous thromboembolism after total knee arthroplasty: a randomized double-blind trial. Ann Intern Med 2002; 137:648-655

(25) Eriksson B, Agnelli G, Cohen A, et al. Direct thrombin inhibitor melagatran followed by oral ximelagatran in comparison with enoxaparin for prevention of venous thromboembolism after total hip or knee replacement. Thromb Haemost 2003; 89:288-296

(26) Lee A, Agnelli G, Bullet H, et al, A dose response study of the recombinant factor VII/tissue factor inhibitor rNAPc2 in the prevention of postoperative venous thromboembolism in patients undergoing total knee replacement. Circulation 20111:104:74-78

* From the College of Public Health (Dr. Raskob), Department of Biostatistics and Epidemiology, and College of Medicine, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK; and the Henderson Research Centre (Dr. Hirsh), Department of Medicine. McMaster University, Hamilton, ON, Canada.

Dr. Raskob has consulted with, participated as a speaker or received honoraria from Sanofi-Synthelabo Organon the, Astra-Zeneca, Pharmion, Aventis Pharmacia and has received an honorarium from the American College of Chest Physicians for the preparation of this article.

Dr. Hirsh is a member of the Sanofi-Synthelabo International Advisory Board.

Reproduction of this article is prohibited without written permission from the American College of Crest Physicians (e mail: permissioos@ehestnet.org).

Correspondence to: Gary E. Baskob, PhD, College of Public Health, University of Oklahoma Health Sciences Center, 801 NE Thirteenth St, Boom 139. Oklahoma City, OK 73104; e-mail: gary:retskoh@ouhsc.edu

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