Timing the First Postoperative Dose of Anticoagulants

The non-vitamin K antagonist oral anticoagulants (NOACs), rivaroxaban, apixaban, and dabigatran, have been shown in phase 3 trials to be effective for thromboprophylaxis in patients undergoing elective hip or knee arthroplasty. Results from prior studies suggested that the safety of anticoagulants in such patients was improved if the first postoperative dose was delayed for at least 6 h after surgery. The timing of the first postoperative dose of the NOACs tested in phase 2 studies differed among the three NOACs: dabigatran was started 1 to 4 h postoperatively, whereas rivaroxaban and apixaban were started at least 6 and 12 h, postoperatively, respectively. Our review of the timing of initiation of thromboprophylaxis in randomized trials provides three related lessons. First, clinical trials performed before the NOACs were evaluated demonstrated that delaying the first dose of prophylactic anticoagulation until after major surgery is effective and safe. Second, the optimal timing of the first dose of prophylactic anticoagulation after surgery depends on the dose that is selected. Third, the results of the phase 3 trials with NOACs for thromboprophylaxis support the concept that acceptable efficacy and safety can be achieved when the appropriate first postoperative dose of anticoagulant is delayed for at least 6 h after surgery. The non-vitamin K antagonist oral anticoagulants (NOACs), rivaroxaban, apixaban, and dabigatran, have been shown in phase 3 trials to be effective for thromboprophylaxis in patients undergoing elective hip or knee arthroplasty. Results from prior studies suggested that the safety of anticoagulants in such patients was improved if the first postoperative dose was delayed for at least 6 h after surgery. The timing of the first postoperative dose of the NOACs tested in phase 2 studies differed among the three NOACs: dabigatran was started 1 to 4 h postoperatively, whereas rivaroxaban and apixaban were started at least 6 and 12 h, postoperatively, respectively. Our review of the timing of initiation of thromboprophylaxis in randomized trials provides three related lessons. First, clinical trials performed before the NOACs were evaluated demonstrated that delaying the first dose of prophylactic anticoagulation until after major surgery is effective and safe. Second, the optimal timing of the first dose of prophylactic anticoagulation after surgery depends on the dose that is selected. Third, the results of the phase 3 trials with NOACs for thromboprophylaxis support the concept that acceptable efficacy and safety can be achieved when the appropriate first postoperative dose of anticoagulant is delayed for at least 6 h after surgery. Rivaroxaban, apixaban, and dabigatran are non-vitamin K antagonist oral anticoagulants (NOACs) that have been evaluated in phase 3 trials for prevention of VTE in patients undergoing elective hip or knee arthroplasty. The NOACs were first evaluated in phase 2 trials that examined two important variables: (1) total daily dose and (2) dose frequency (once daily [OD] or bid).1Eriksson BI Dahl OE Büller HR BISTRO II Study Group et al.A new oral direct thrombin inhibitor, dabigatran etexilate, compared with enoxaparin for prevention of thromboembolic events following total hip or knee replacement: the BISTRO II randomized trial.JThromb Haemost. 2005; 3: 103-111Abstract Full Text Full Text PDF PubMed Scopus (397) Google Scholar, 2Turpie AG Fisher WD Bauer KA OdiXa-Knee Study Group et al.BAY 59-7939: an oral, direct factor Xa inhibitor for the prevention of venous thromboembolism in patients after total knee replacement. A phase II dose-ranging study.J Thromb Haemost. 2005; 3: 2479-2486Abstract Full Text Full Text PDF PubMed Scopus (296) Google Scholar, 3Eriksson BI Borris L Dahl OE ODIXa-HIP Study Investigators et al.Oral, direct factor Xa inhibition with BAY 59-7939 for the prevention of venous thromboembolism after total hip replacement.J Thromb Haemost. 2006; 4: 121-128Abstract Full Text Full Text PDF PubMed Scopus (297) Google Scholar, 4Lassen MR Davidson BL Gallus A Pineo G Ansell J Deitchman D The efficacy and safety of apixaban, an oral, direct factor Xa inhibitor, as thromboprophylaxis in patients following total knee replacement.J Thromb Haemost. 2007; 5: 2368-2375Abstract Full Text Full Text PDF PubMed Scopus (344) Google Scholar, 5Eriksson BI Borris LC Dahl OE ODIXa-HIP Study Investigators et al.A once-daily, oral, direct factor Xa inhibitor, rivaroxaban (BAY 59-7939), for thromboprophylaxis after total hip replacement.Circulation. 2006; 114: 2374-2381Crossref PubMed Scopus (313) Google Scholar None of the phase 2 studies investigated the optimal timing of the first postoperative dose. Rather, in the phase 2 trials, each NOAC was given at a fixed time postoperatively, presumably with the plan of using the same timing of initial dosing in subsequent phase 3 studies. However, earlier studies with "older" anticoagulants had provided useful information about the relationship between the timing of the first postoperative dose and both efficacy and safety. In this commentary, we consider the lessons learned from earlier studies about the timing of the first postoperative dose of anticoagulant prophylaxis and review the timing of the first postoperative dose with the three NOACS in both the phase 2 dose-finding studies and phase 3 trials. Before the evaluation of the NOACs, phase 3 trials had been performed with vitamin K antagonists (VKAs), low-dose unfractionated heparin (LDUH), low-molecular-weight heparin (LMWH), and fondaparinux for VTE prevention in high-risk surgical patients (Table 1). The results of the phase 3 trials provided important information about the relationship between the first perioperative dose and both safety and efficacy of anticoagulant prophylaxis.TABLE 1RCTs of Older Anticoagulants Informing on the Effect of Timing of Preoperative and Postoperative Dose on Efficacy and SafetyStudy/YearPopulationInterventionControlEfficacy Outcome, Intervention vs ControlSafety Outcome, Intervention vs ControlBergqvist et al6Bergqvist D Burmark US Frisell 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. 1986; 73: 204-208Crossref PubMed Scopus (147) Google Scholar/1986Elective general abdominal surgery, n = 432LMWH 5,000 units, 2 h preoperatively, then 5,000 units dailyLDUH 5,000 units, 2 h preoperatively, then 5,000 units q12hDVT on radiolabeled fibrinogen uptake scan 4.3% vs 6.4% (P = ns)Hemorrhagic complications 11.6% vs 4.6% (P =. 007)Bergqvist et al7Bergqvist D Mätzsch T Burmark US et al.Low molecular weight heparin given the evening before surgery compared with conventional low-dose heparin in prevention of thrombosis.Br J Surg. 1988; 75: 888-891Crossref PubMed Scopus (124) Google Scholar/1988Elective general abdominal surgery, n = 1,040LMWH 5,000 units on the evening before surgery then ODLDUH 5,000 units, 2 h preoperatively, then 5,000 units q12hDVT on radiolabeled fibrinogen uptake scan 5.0% vs 9.7% (P =. 01)Hemorrhagic complications 5.9% vs 3.0% (P =. 03)Turpie et al8Turpie AG Levine MN Hirsh J et al.A randomized controlled trial of a low-molecular-weight heparin (enoxaparin) to prevent deep-vein thrombosis in patients undergoing elective hip surgery.N Engl J Med. 1986; 315: 925-929Crossref PubMed Scopus (461) Google Scholar/1986Elective hip replacement, n = 100Enoxaparin 30 mg bid, started 12-24 h postoperativelySaline placeboVenographic DVT 10.8% vs 51.3% (P =. 0002)Major bleeding 4.0% vs 4.0% (P = ns)Hull et al9Hull RD Pineo GF Francis C The North American Fragmin Trial Investigators et al.Low-molecular-weight heparin prophylaxis using dalteparin in close proximity to surgery vs warfarin in hip arthroplasty patients: a double-blind, randomized comparison.Arch Intern Med. 2000; 160: 2199-2207Crossref PubMed Scopus (254) Google Scholar/2000Elective hip arthroplasty, n = 1,472(A) Preoperative arm: dalteparin 2,500 units, 2 h preoperatively, then 2,500 units postoperatively at mean 6.6 h (B) Postoperative arm: dalteparin 2,500 units postoperatively, mean 6.6 h, followed by 5,000 units OD in both arms(C) warfarin INR 2.0-3.0Venographic DVT A vs C: 10.7% vs 24.0% (P ≤. 01) B vs C: 13.1% vs 24.0% (P ≤. 01)Adjudicated major bleeding A vs B vs C: 6.7% vs 5.7% vs 4.1%Colwell et al10Colwell Jr, CW Kwong LM Turpie AG Davidson BL Flexibility in administration of fondaparinux for prevention of symptomatic venous thromboembolism in orthopaedic surgery.J Arthroplasty. 2006; 21: 36-45Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar/2006Elective hip or knee arthroplasty, n = 2,046Delayed fondaparinux 2.5 mg started morning after surgery, followed by 2.5 mg dailyStandard fondaparinux 2.5 mg started 8 h ± 2 h postoperatively, followed by 2.5 mg dailySymptomatic VTE 2.0% vs 1.9% (P =. 89)Major bleeding 1.2% vs 0.7% (P=.19)INR = international normalized ratio; LDUH = low-dose unfractionated heparin; LMWH = low-molecular-weight heparin; ns = nonsignificant; OD = once daily; RCT = randomized controlled trial. Open table in a new tab INR = international normalized ratio; LDUH = low-dose unfractionated heparin; LMWH = low-molecular-weight heparin; ns = nonsignificant; OD = once daily; RCT = randomized controlled trial. In the earlier trials of subcutaneous LDUH, the first dose of the drug (5,000 units) was given 2 h before surgery followed by 5,000 units every 8 to 12 h thereafter until the patient was ambulatory.11Gallus AS Hirsh J Tutle RJ et al.Small subcutaneous doses of heparin in prevention of venous thrombosis.N Engl J Med. 1973; 288: 545-551Crossref PubMed Scopus (354) Google Scholar, 12Prevention of fatal postoperative pulmonary embolism by low doses of heparin. An international multicentre trial..Lancet. 1975; 2: 45-51PubMed Google Scholar, 13Clagett GP Salzman EW Prevention of venous thromboembolism in surgical patients.N Engl J Med. 1974; 290: 93-96Crossref PubMed Scopus (31) Google Scholar, 14Gruber UF Saldeen T Brokop T et al.Incidences of fatal postoperative pulmonary embolism after prophylaxis with dextran 70 and low-dose heparin: an international multicentre study.BMJ. 1980; 280: 69-72Crossref PubMed Scopus (101) Google Scholar The rationale for giving the first dose preoperatively was based on the results of radiolabeled fibrinogen leg scanning, which revealed that small thrombi often formed during surgery.12Prevention of fatal postoperative pulmonary embolism by low doses of heparin. An international multicentre trial..Lancet. 1975; 2: 45-51PubMed Google Scholar It seemed logical, therefore, to modulate coagulation during surgery, a conclusion that dominated thinking for decades despite the fact that VKAs were effective for VTE prophylaxis even though they failed to produce a measurable anticoagulant effect for at least 2 days after surgery. These two apparently conflicting positions can be reconciled by the thesis that small thrombi, formed during or soon after surgery, can be prevented from growing into larger clinically important thrombi by a level of anticoagulation that would not be tolerated during or immediately after surgery. When LMWH was first introduced for VTE prophylaxis, the first dose was given 2 h preoperatively based on experience with LDUH. However, this practice was abandoned after Bergqvist and colleagues6Bergqvist D Burmark US Frisell 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. 1986; 73: 204-208Crossref PubMed Scopus (147) Google Scholar reported the results of a randomized trial comparing dalteparin with LDUH. Both subcutaneously administered anticoagulants were initiated in doses of 5,000 units 2 h preoperatively and continued postoperatively (Table 1). Dalteparin and LDUH were similarly effective in preventing postoperative VTE, but dalteparin caused more bleeding (11.6% vs 4.6%, P =.007).6Bergqvist D Burmark US Frisell 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. 1986; 73: 204-208Crossref PubMed Scopus (147) Google Scholar In an attempt to reduce peri-operative bleeding, a second trial compared 5,000 units of dalteparin initiated 12 h preoperatively and continued OD postoperatively with LDUH in patients undergoing general abdominal surgery. There was a trend toward a lower risk of postoperative VTE in patients receiving dalteparin compared with LDUH (5.5% vs 8.3%; P =.08), but dalteparin was again associated with more bleeding than LDUH (6.7% vs 2.7%, P =.03).7Bergqvist D Mätzsch T Burmark US et al.Low molecular weight heparin given the evening before surgery compared with conventional low-dose heparin in prevention of thrombosis.Br J Surg. 1988; 75: 888-891Crossref PubMed Scopus (124) Google Scholar However, because the majority of bleeding was considered clinically insignificant, and (presumably) because of the greater importance placed upon the trend for lower VTE rates and the convenience of OD vs bid dosing, LMWH, given 12 h preoperatively, became standard practice in Europe (Table 1). In the early 1980s, Turpie and colleagues8Turpie AG Levine MN Hirsh J et al.A randomized controlled trial of a low-molecular-weight heparin (enoxaparin) to prevent deep-vein thrombosis in patients undergoing elective hip surgery.N Engl J Med. 1986; 315: 925-929Crossref PubMed Scopus (461) Google Scholar performed a randomized trial in patients undergoing elective hip surgery in North American centers; patients were randomized to receive LMWH bid (enoxaparin 30 mg bid) or placebo with the first dose of study drug given 12 to 24 h after surgery (Table 1).8Turpie AG Levine MN Hirsh J et al.A randomized controlled trial of a low-molecular-weight heparin (enoxaparin) to prevent deep-vein thrombosis in patients undergoing elective hip surgery.N Engl J Med. 1986; 315: 925-929Crossref PubMed Scopus (461) Google Scholar The rationale for starting enoxaparin postoperatively was based on three considerations. First, Bergqvist and colleagues6Bergqvist D Burmark US Frisell 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. 1986; 73: 204-208Crossref PubMed Scopus (147) Google Scholar7Bergqvist D Mätzsch T Burmark US et al.Low molecular weight heparin given the evening before surgery compared with conventional low-dose heparin in prevention of thrombosis.Br J Surg. 1988; 75: 888-891Crossref PubMed Scopus (124) Google Scholar had shown that an early preoperative dose caused excessive bleeding during and soon after surgery. Second, North American orthopedic surgeons were particularly concerned about mitigating peri-operative bleeding complications. Third, VKAs started postoperatively were shown to be effective and safe for VTE prophylaxis despite their delayed anticoagulant effect.15Coventry MB Nolan DR Beckenbaugh RD "Delayed" prophylactic anticoagulation: a study of results and complications in 2,012 total hip arthroplasties.J Bone Joint Surg Am. 1973; 55: 1487-1492Crossref PubMed Scopus (172) Google Scholar The study by Turpie and colleagues8Turpie AG Levine MN Hirsh J et al.A randomized controlled trial of a low-molecular-weight heparin (enoxaparin) to prevent deep-vein thrombosis in patients undergoing elective hip surgery.N Engl J Med. 1986; 315: 925-929Crossref PubMed Scopus (461) Google Scholar showed that postoperative initiation of enoxaparin at a dose of 30 mg bid was highly effective at reducing the risk of DVT (enoxaparin vs placebo: 10.8% vs 51.3%, P =.0002) without increasing the risk of major bleeding (enoxaparin vs placebo: 4.0% vs 4.0%, Pvalue not reported).8Turpie AG Levine MN Hirsh J et al.A randomized controlled trial of a low-molecular-weight heparin (enoxaparin) to prevent deep-vein thrombosis in patients undergoing elective hip surgery.N Engl J Med. 1986; 315: 925-929Crossref PubMed Scopus (461) Google Scholar Two subsequent randomized trials compared enoxaparin 30 mg bid and 40 mg OD with enoxaparin 10 mg OD16Spiro TE Johnson GJ Christie MJ Enoxaparin Clinical Trial Group et al.Efficacy and safety of enoxaparin to prevent deep venous thrombosis after hip replacement surgery.Ann Intern Med. 1994; 121: 81-89Crossref PubMed Scopus (116) Google Scholar or LDUH 5,000 units tid17Colwell Jr, CW Spiro TE Trowbridge AA Enoxaparin Clinical Trial Group et al.Use of enoxaparin, a low-molecular-weight heparin, and unfractionated heparin for the prevention of deep venous thrombosis after elective hip replacement. A clinical trial comparing efficacy and safety.J Bone Joint Surg Am. 1994; 76: 3-14Crossref PubMed Scopus (222) Google Scholar within 24 h after elective hip replacement surgery. The first study showed that enoxaparin 30 mg bid (11% vs 25%, P≤.001) and 40 mg OD (14% vs 25%, P =.02) were more effective than enoxaparin 10 mg OD at preventing VTE.16Spiro TE Johnson GJ Christie MJ Enoxaparin Clinical Trial Group et al.Efficacy and safety of enoxaparin to prevent deep venous thrombosis after hip replacement surgery.Ann Intern Med. 1994; 121: 81-89Crossref PubMed Scopus (116) Google Scholar A comparison between enoxaparin 30 mg bid and 40 mg OD demonstrated similar rates of VTE (11% vs 14%, P >.2) and bleeding (13% vs 11%, Pvalue not reported). The second study showed that enoxaparin 30 mg bid was more effective than both LDUH 5,000 units bid (6% vs 15%, P =.03) and enoxaparin 40 mg OD (6% vs 21%, P =.0003) at preventing VTE. Rates of bleeding were similar with enoxaparin 30 mg bid and both LDUH 5,000 units bid (12% vs 12%, Pvalue not reported) and enoxaparin 40 mg OD (10% vs 12%, Pvalue not reported). Based on these results, the enoxaparin 30-mg bid regimen and not the 40-mg OD regimen was initially approved by the US Food and Drug Administration and widely adopted by North American orthopedic surgeons. In an attempt to refine the peri-operative timing of the first dose of anticoagulant, Hull and associates9Hull RD Pineo GF Francis C The North American Fragmin Trial Investigators et al.Low-molecular-weight heparin prophylaxis using dalteparin in close proximity to surgery vs warfarin in hip arthroplasty patients: a double-blind, randomized comparison.Arch Intern Med. 2000; 160: 2199-2207Crossref PubMed Scopus (254) Google Scholar performed a randomized trial evaluating the relative efficacy and safety of two regimens of dalteparin given in close proximity to surgery (Table 1). They compared three groups: preoperative dalteparin (2,500 units started within 2 h of surgery, then 2,500 units at least 4 h postoperatively, followed by 5,000 units OD), postoperative dalteparin (2,500 units started at least 4 h postoperatively, then 5,000 units OD), and VKA prophylaxis. The results showed lower rates of VTE with both preoperative and postoperative dalteparin compared with VKA (10.7% and 13.1% vs 24.0%, respectively; P ≤.001 for both comparisons). However, the rate of major bleeding was significantly higher with preoperative dalteparin than with postoperative dalteparin (2.2% vs 0.8%; Pvalue not reported) or VKA (2.2% vs 0.4%; P=.01). The next important series of studies that informed on the timing of the first postoperative dose included four randomized trials comparing enoxaparin with fondaparinux in patients undergoing major orthopedic surgery. Two trials18Eriksson BI Bauer KA Lassen MR Turpie AG 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: 1298-1304Crossref PubMed Scopus (653) Google Scholar19Lassen MR Bauer KA Eriksson BI Turpie AG European Pentasaccharide 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: 1715-1720Abstract Full Text Full Text PDF PubMed Scopus (496) Google Scholar compared fondaparinux (2.5 mg OD starting 6 h after surgery) with enoxaparin (40 mg OD starting 12 h preoperatively; the common European dosing regimen), while the other two trials compared fondaparinux (2.5 mg OD starting 6 h after surgery) with enoxaparin (30 mg bid starting 12-24 h after surgery; the common North American dosing regimen).20Bauer KA Eriksson BI Lassen MR Turpie AG Steering Committee of the Pentasaccharide in Major Knee Surgery Study Fondaparinux compared with enoxaparin for the prevention of venous thromboembolism after elective major knee surgery.N Engl J Med. 2001; 345: 1305-1310Crossref PubMed Scopus (646) Google Scholar21Turpie AG Bauer KA Eriksson BI Lassen MR PENTATHALON 2000 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: 1721-1726Abstract Full Text Full Text PDF PubMed Scopus (476) Google Scholar A meta-analysis of all four studies (N = 7,344) showed that fondaparinux was more effective than enoxaparin in reducing the incidence of asymptomatic DVT detected by mandatory venography (6.8% vs 13.7%, P≤.001), but there was no difference in the incidence of symptomatic VTE (0.6% vs 0.4%, P =.25) or in fatal pulmonary embolism (0.1% vs 0.1%, no Pvalue reported) and fondaparinux was associated with an increased rate of major bleeding (2.7% vs 1.7%, P =.008).22Turpie AG Bauer KA Eriksson BI Lassen MR 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: 1833-1840Crossref PubMed Scopus (751) Google Scholar Although compared with enoxaparin, fondaparinux reduced the rate of asymptomatic DVT, it did not replace LMWH for thromboprophylaxis in patients undergoing major orthopedic surgery, presumably because of the high concern placed on bleeding by orthopedic surgeons and because it did not reduce the rate of symptomatic events. Two secondary analyses were performed to investigate the influence of timing of the first postoperative dose of fondaparinux on safety and efficacy. The first reported that the bleeding risk was significantly increased in patients who were given their first dose earlier than 6 h after surgery compared with later than 6 h (3.2% vs 2.1%, P =.045).23Turpie AG, Bauer K, Eriksson B. 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: Seventh Annual Meeting of the European Hematology Association; 2002; Florence, Italy.Google Scholar The second reported that the risk of postoperative bleeding was related to the timing of the first postoperative dose (over a 3-9 h postoperative window), while the efficacy of fondaparinux was not affected by timing.10Colwell Jr, CW Kwong LM Turpie AG Davidson BL Flexibility in administration of fondaparinux for prevention of symptomatic venous thromboembolism in orthopaedic surgery.J Arthroplasty. 2006; 21: 36-45Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar Although the results of these post hoc analyses are not definitive, their findings are supported by the results of a large randomized trial (N = 2,046) comparing standard postoperative administration of fondaparinux (at 8 h) with delayed administration (the morning after surgery), which showed similar rates of symptomatic VTE in both arms (2.0% vs 1.9%, P =.89) and a trend for increased major bleeding in the standard arm (1.2% vs 0.7%, P =.19) (Table 1). Several conclusions can be drawn from these earlier studies. First, prophylactic doses of LMWH administered 2 h before surgery cause more bleeding than LDUH. Second, anticoagulants are effective when started 12 h or more after surgery. Third, there is a strong suggestion that starting treatment with anticoagulants within 6 h of surgery increases the risk of bleeding without improving efficacy compared with a later start. Fourth, in the context of designing trials for regulatory approval, enoxaparin 30 mg bid starting 12 h postoperatively is a formidable comparator, both in terms of efficacy and safety. Table 2 details the timing of the first postoperative dose of the NOACs in phase 2 and phase 3 studies. Rivaroxaban was tested in three phase 22Turpie AG Fisher WD Bauer KA OdiXa-Knee Study Group et al.BAY 59-7939: an oral, direct factor Xa inhibitor for the prevention of venous thromboembolism in patients after total knee replacement. A phase II dose-ranging study.J Thromb Haemost. 2005; 3: 2479-2486Abstract Full Text Full Text PDF PubMed Scopus (296) Google Scholar3Eriksson BI Borris L Dahl OE ODIXa-HIP Study Investigators et al.Oral, direct factor Xa inhibition with BAY 59-7939 for the prevention of venous thromboembolism after total hip replacement.J Thromb Haemost. 2006; 4: 121-128Abstract Full Text Full Text PDF PubMed Scopus (297) Google Scholar5Eriksson BI Borris LC Dahl OE ODIXa-HIP Study Investigators et al.A once-daily, oral, direct factor Xa inhibitor, rivaroxaban (BAY 59-7939), for thromboprophylaxis after total hip replacement.Circulation. 2006; 114: 2374-2381Crossref PubMed Scopus (313) Google Scholar and four phase 3 studies,24Eriksson BI Borris LC Friedman RJ RECORD1 Study Group et al.Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty.NEngl JMed. 2008; 358: 2765-2775Crossref PubMed Scopus (1312) Google Scholar, 25Kakkar AK Brenner B Dahl OE RECORD2 Investigators et al.Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial..Lancet. 2008; 372: 31-39Abstract Full Text Full Text PDF PubMed Scopus (994) Google Scholar, 26Lassen MR Ageno W Borris LC RECORD3 Investigators et al.Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty.N Engl J Med. 2008; 358: 2776-2786Crossref PubMed Scopus (1235) Google Scholar, 27Turpie AG Lassen MR Davidson BL RECORD4 Investigators et al.Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): a randomised trial.Lancet. 2009; 373: 1673-1680Abstract Full Text Full Text PDF PubMed Scopus (896) Google Scholar apixaban in one phase 24Lassen MR Davidson BL Gallus A Pineo G Ansell J Deitchman D The efficacy and safety of apixaban, an oral, direct factor Xa inhibitor, as thromboprophylaxis in patients following total knee replacement.J Thromb Haemost. 2007; 5: 2368-2375Abstract Full Text Full Text PDF PubMed Scopus (344) Google Scholar and three phase 3 studies,28Lassen MR Gallus AS Pineo GF Raskob GE Late breaking clinical trial: The ADVANCE-2 Study: a randomized double-blind trial comparing apixaban with enoxaparin for thromboprophylaxis after total knee replacement.J Thromb Haemost. 2009; (LB-MO-005.)Google Scholar, 29Lassen MR Raskob GE Gallus A Pineo G Chen D Hornick P ADVANCE-2 investigators Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): a randomised double-blind trial.Lancet. 2010; 375: 807-815Abstract Full Text Full Text PDF PubMed Scopus (718) Google Scholar, 30Lassen MR Gallus A Raskob GE Pineo G Chen D Ramirez LM ADVANCE-3 Investigators Apixaban versus enoxaparin for thromboprophylaxis after hip replacement.N Engl J Med. 2010; 363: 2487-2498Crossref PubMed Scopus (686) Google Scholar and dabigatran in two phase 21Eriksson BI Dahl OE Büller HR BISTRO II Study Group et al.A new oral direct thrombin inhibitor, dabigatran etexilate, compared with enoxaparin for prevention of thromboembolic events following total hip or knee replacement: the BISTRO II randomized trial.JThromb Haemost. 2005; 3: 103-111Abstract Full Text Full Text PDF PubMed Scopus (397) Google Scholar31Eriksson BI Dahl OE Ahnfelt L et al.Dose escalating safety study of a new oral direct thrombin inhibitor, dabigatran etexilate, in patients undergoing total hip replacement: BISTRO I.J Thromb Haemost. 2004; 2: 1573-1580Abstract Full Text Full Text PDF PubMed Scopus (196) Google Scholar and four phase 3 studies,32Eriksson BI Dahl OE Rosencher N RE-MODEL Study Group et al.Oral dabigatran etexilate vs. subcutaneous enoxaparin for the prevention of venous thromboembolism after total knee replacement: the RE-MODEL randomized trial.J Thromb Haemost. 2007; 5: 2178-2185Abstract Full Text Full Text PDF PubMed Scopus (943) Google Scholar, 33Eriksson BI Dahl OE Rosencher N RE-NOVATE Study Group et al.Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomised, double-blind, non-inferiority trial.Lancet. 2007; 370: 949-956Abstract Full Text Full Text PDF PubMed Scopus (1062) Google Scholar, 34Ginsberg JS Davidson BL Comp PC RE-MOBILIZE Writing Committee et al.Oral thrombin inhibitor dabigatran etexilate vs North American enoxaparin regimen for prevention of venous thromboembolism after knee arthroplasty surgery.J Arthroplasty. 2009; 24: 1-9Abstract Full Text Full Text PDF PubMed Scopus (583) Google Scholar, 35Eriksson BI Dahl OE Huo MH RE-NOVATE II Study Group et al.Oral dabigatran versus enoxaparin for thromboprophylaxis after primary total hip arthroplasty (RE-NOVATE II*). A randomised, double-blind, non-inferiority trial.Thromb Haemost. 2011; 105: 721-729Crossref PubMed Scopus (374) Google Scholar although only one of the ph