Deep venous thrombosis (DVT) is one of the most common complications of total joint arthroplasty of the lower extremities.20 Management of risks associated with the dynamics of venous thromboembolic disease (VTED) remains varied for the orthopaedic surgeon performing lower extremity reconstruction. Among patients having total joint arthroplasty without pharmaceutical or mechanical prophylaxis, thromboembolic events detected by venography have been reported in 48% to 60% of cases.2,8 Peripheral venous stasis and endothelial injury during these surgical procedures contribute to the development of thromboembolic complications.11 Without the use of preventive measures, symptomatic pulmonary emboli are reported at levels as high as 10% and as low as 1.5% in knee arthroplasty, with fatal pulmonary embolism reported at 0.7%.10 The evidence that both devastating complications can occur with no premonitory clinical symptoms, additionally compounds the importance of this problem.
Treating a patient with suspected VTED, based on interpretation of clinical manifestations alone, can be difficult. Our controlled, prospective studies provide scientific quantitative answers to questions regarding effective clinical management strategies for VTED. All completed studies have been published in peer-reviewed journals making this information available and useful to practicing physicians. We have conducted randomized clinical trials using multiple low-molecular-weight heparins (LMWH)6,12 as comparators to decrease the risk of thrombosis. These controlled studies using LMWH compounds report VTED outcomes with and without continuation of prophylactic drugs administered after hospital discharge. Clinical studies we have performed using LMWH over the past 20 years have strengthened our ability to decrease the risk of VTED in orthopaedic surgery. Continued exploration of interventions, including new pharmacologic therapies13 and genetic factors, may increase the quality of outcomes.
We reviewed studies in which we have participated that led us to the conclusion the evidence for using LMWH to decrease VTED in patients having total knee arthroplasty should be the standard of practice as has been recognized by the American College of Chest Physicians (ACCP). Though this is not a comprehensive review of the literature, we think the articles presented here are representative of the literature available as evidence on which to base the practice of LMWH prophylaxis in total knee arthroplasty.
Enoxaparin versus Unfractionated Heparin
In our study of patients having total knee arthroplasty (TKA), fewer (p = 0.02) patients receiving 30 mg enoxaparin every 12 hours had venographic evidence of DVT than those receiving 5000 units of unfractionated heparin every 8 hours (25%, 56 of 228 versus 34%, 77 of 225, respectively).6 Pulmonary embolism (PE) occurred in two patients in the heparin group, and there were none in the enoxaparin group. Major bleeding events occurred with similar frequency in both groups.6 The efficacy and safety information from this study was considered by the United States Food and Drug Administration (FDA) when they approved the LMWH compound enoxaparin for prophylaxis in TKA.
Ardeparin versus Warfarin in TKA
We conducted a controlled multicenter clinical trial of three different dosages of ardeparin (25, 35, or 50 anti-Xa U/kg subcutaneously twice a day) compared with adjusted-dose warfarin. We determined 50 anti-Xa U/kg was the best of the three doses of ardeparin, with a 27% occurrence of DVT in 232 patients. Prevalence of DVT in the 222 patients receiving warfarin was 38% (p = 0.02). Although more overt bleeding occurred in the ardeparin group (8%) than in the warfarin group (4%), this difference was not notable.12
Ardeparin versus Placebo in THA or TKA (outpatient extended use)
We then examined a longer phase of prophylaxis. In a double-blind, randomized, multicenter clinical trial of 1195 patients published by Heit et al,14 we explored the use of extended treatment with ardeparin (Wyeth Ayerst, Philadelphia, PA) or placebo. While in the hospital, all patients received subcutaneous injections of ardeparin (50 anti-Xa U/kg) twice a day. After discharge, the patients were randomized to self-administered subcutaneous ardeparin (100 anti-Xa U/kg) or placebo once daily for 6 weeks. Efficacy was based on clinical symptoms of DVT with confirmation by duplex ultrasound or venography. Our results indicated a similar overall VTED rate with ardeparin and placebo (1.5% versus 2%, respectively). Major bleeding was the same (0.6%, two in each group) during the extended period in the ardeparin group as in the placebo group. These two studies were considered by the FDA during the approval process of ardeparin for prophylactic use in TKA.
Enoxaparin versus Placebo in THA or TKA (extended use)
To further examine treatment duration, we conducted a randomized, double-blind, parallel group multicenter clinical study in which all patients received enoxaparin (30 mg, twice a day) for 7 to 10 days. Then 873 patients were randomized to self-administered enoxaparin (40 mg, once daily) or placebo as outpatients for 21 days. Analyzing hips and knees together, venographic incidence of DVT was higher (p < 0.001) in the placebo group (95 of 432 patients, 22%) than in the enoxaparin group (56 of 441, 13%). Three PE occurred in the placebo group (0.6%) and no PE occurred in the enoxaparin group. Because hip and knee arthroplasties differ in the incidence of DVT, the groups also were considered separately. The incidence of DVT in the hip arthroplasty group was greater at 23% (49 of 221 patients) for placebo than at 8% (18 of 224 patients) for enoxaparin-treated patients (p < 0.001). In the knee arthroplasty group, DVT rate was higher at 21% (46 of 221 patients) for placebo than at 18% (38 of 217 patients) for enoxaparin-treated patients, but not substantially higher. At 3 months, two patients in the enoxaparin group had clinically symptomatic DVT, and one patient randomized to placebo died of a probable PE. No increased incidence of bleeding was reported with the use of enoxaparin during the study, with a bleeding rate of 2.7% (six patients) for enoxaparin and a bleeding rate of 3.7% (eight patients) for placebo.7
Oral Thrombin Inhibitor, Ximelagatran for VTED Prophylaxis in TKA
Most surgeons and patients prefer oral anticoagulants to injectable anticoagulants because of ease of administration. Oral anticoagulants become more attractive if laboratory monitoring and dose adjustment are not required. The most common oral agent, warfarin, has an effectiveness equal to or less than heparin or LMWH, requires laboratory monitoring, has a delayed onset of action, and requires professional management to oversee dosing schedules. A safe, effective oral agent that requires no monitoring would be beneficial and well received by patients and physicians.
We initiated a study to investigate a novel oral direct thrombin inhibitor that seemed to offer an alternative to subcutaneous injection and/or warfarin prophylaxis. A multicenter, randomized, parallel group study in patients having TKA was performed to investigate the safety and efficacy of four different dosages (8, 12, 18, and 24 mg) of oral ximelagatran given every 12 hours compared with enoxaparin 30 mg given subcutaneously every 12 hours. Efficacy was determined by venography. The 24-mg dosage was more efficacious, with 16.8% (16 of 95) of patients having thrombosis develop compared with 23.7% (23 of 97) of patients in the enoxaparin group. The bleeding rate was similar in both treatment groups (nine of 127 in the ximelagatran group and 10 of 125 in the enoxaparin group).13 This oral anticoagulant has not been approved by the FDA for use, but other novel oral anticoagulants are being developed and studied.
Outpatient Compliance with Subcutaneous Self-injection of Enoxaparin after TJA
In 1998, the FDA allowed extended use of enoxaparin 40 mg once daily for an additional 14 days after the initial 7 to 10 days of enoxaparin 30 mg given every 12 hours. The potential of lower compliance and satisfaction with self-injection versus oral medication has been identified as a concern. We conducted an independent study examining patients' ability to alter doses and to complete the extended use of self-injection after hospital discharge. Consecutive patients who provided signed consent to participate were included in this study. Our hospital nursing staff gave routine instruction for self-administering the drug to 50 patients before hospital discharge. Patients self-injected enoxaparin 30 mg twice a day for 7 days. Patients were then converted to enoxaparin 40 mg, self-administered once daily for 14 days. Phone interviews conducted by an independent reviewer indicated 100% of the patients were given instructions before discharge and understood the purpose of the injections. We found 88% were able to self-inject. Of patients completing the study, 92% (37 of 40) were able to comply with both regimens. Two patients not included in this group were unable to comply with a dosing change, but did not experience adverse effects. No patients experienced clinical symptoms of DVT or PE.5
Effectiveness of Once Daily Administration of Enoxaparin 40 mg sc for VTED Prevention after TKA
The ease of once daily injections and the European published data indicate enoxaparin 40 mg once daily is effective in preventing DVT. Therefore, Pulido et al21 evaluated the use of enoxaparin 40 mg subcutaneously once daily for 7 days for the prevention of DVT in our practice. Efficacy was based on DVT detected by duplex ultrasound performed on postoperative Day 3 and Day 21. Fifty-five patients with 60 surgically treated lower extremities completed the study. On postoperative Day 3, 10 of 55 patients were found to have DVT; seven clots were distal to the knee and three clots were proximal to the knee. On Day 21, seven of 55 patients had clots (five distal and two proximal to the knee) seen using ultrasound (Table 1).5 Three clots seen on the ultrasounds performed on Day 3 had resolved by Day 21 (two distal and one proximal). No new clots had formed and no patients experienced symptomatic PE through Day 21. These results compared favorably with the incidence reported in the literature.
Fondaparinux Compared with Enoxaparin for Prevention of VTE after TKA
In a double-blind study of patients having elective knee arthroplasty, fondaparinux, part of a new class of synthetic antithrombotics, was compared with enoxaparin. The primary outcome efficacy was DVT detected by bilateral venogram by Day 11, documented symptomatic DVT, or documented symptomatic PE. Efficacy outcome was assessed in 724 patients. Fondaparinux had a lesser (p < 0.001, risk reduction 54%) DVT incidence of 12.5% (45 of 361) than enoxaparin, with a DVT incidence of 27.1% (98 of 361) in patients having TKA. Incidence of PE was lower in the fondaparinux group (0.2%) than in the enoxaparin group (0.8%). Overt bleeding with a bleeding index of 2 or more occurred more frequently (p = 0.006) in the fondaparinux group, but no difference was observed in bleeding leading to death or reoperation. Total bleeding in the fondaparinux group was greater at 4.8% (25 of 517) than in the enoxaparin group at 3.9% (20 of 517). Fondaparinux 2.5 mg given once daily was more effective (p < 0.001) in preventing DVT than enoxaparin 30 mg given twice daily.1
Flexibility in Administration of Fondaparinux for Prevention of Symptomatic VTED in Orthopaedic Surgery
Despite well-controlled clinical trials with clearly defined dosing schedules, the timing of administering the first dose of fondaparinux may vary in clinical practice. Dosing flexibility allows the clinician a much larger window in which to begin VTED prophylaxis, ensuring safety and efficacy by “tailoring” the dose of fondaparinux to the patient's situation and to the hospital's routine drug-dispensing schedule. Based on the incidence of symptomatic VTED, this 2046 patient cohort study evaluated the flexibility of two dosing regimens: Group 1-1003 patients with fondaparinux initiated on the day of lower extremity reconstruction surgery; or Group 2-997 patients with fondaparinux initiated on the morning after surgery. Group 1 and Group 2 each had an incidence of 11 DVT for 1.1% in each group. The incidence of PE was similar with Group 1 having 9 (0.9%) and Group 2 having 10 (1.0%). Fourteen major and 14 minor bleeding events occurred in the early initiation group and seven major and 20 minor bleeding events occurred in the delayed initiation group. Four deaths occurred in the early initiation group and one death occurred in the delayed initiation group; no deaths were related to VTED or bleeding.4 Delaying the first dose of fondaparinux until the morning after surgery did not change clinical efficacy and may reduce major bleeding rates, providing an additional option to orthopaedic surgeons for patients undergoing total joint arthroplasty.
The National Institutes of Health (NIH) 1986 recommendations underscore the importance of prophylaxis after knee arthroplasty, and the ACCP guidelines include algorithms for prophylaxis based largely on the controlled studies we discussed.3,9,10 The cost of the agents varies dramatically, depending upon the contracts with the hospital. We have no information on the individual cost structure and have no information with respect to what mechanical devices cost. The duration of prophylaxis from a review of the trials and the acceptance of the ACCP Guidelines suggest up to 10 days is a valid length of prophylaxis for knee replacement patients.
We note our review of LMWH studies is not comprehensive but rather is based on the authors' participation in these studies. However, the studies we reviewed are published and the data reviewed here is presented in those publications.
Major bleeding remains a concern in any prospective, randomized study. The definition of major or minor bleeding is contained in each study design. By maintaining the same definition for each wing of the comparison studies, one should be able to compare bleeding rates, both major and minor. Reoperation falls into the major bleeding category. One would expect the risk of major bleeding events in the patients with mechanical devices to be in the same basic range as placebos, if one includes the definition of 2 g decrease or more of hemoglobin. In a study by Levine et al,19 the major bleeding rate was 2.4% for patients with compression stockings and 2.5% for patients treated with ardeparin. Leclerc et al18 reported overall bleeding in a placebo group undergoing TKA at 8% (5 of 65) and major bleeding at 2% (1 of 65) compared with an enoxaparin group with 6% (4 of 66) overall bleeding and no major bleeding. There are no data within the studies to compare range of motion (ROM) with and without major bleeding. Because the rates of major bleeding were similar, the ROM should not have been affected.
In patients receiving neuraxial anesthesia, LMWH should be used with caution. Guidelines for the use of neuraxial anesthesia and LMWH were first published in 199816 and since then only 13 cases of spinal hematoma have been reported by MedWatch or published case report.17 If using twice daily dosing of LMWH, the indwelling catheter should be removed prior to the initiation of LMWH and the first dose should be given at least 2 hours after removal of the catheter. For single daily dosing, one author recommends removing the catheter a minimum of 10 to 12 hours after the last dose of LMWH and the next dose should occur a minimum of 2 hours after catheter removal.15
The two placebo and low-molecular-weight heparin comparison trials in total knee arthroplasties18,19 of which we are aware demonstrated a substantial reduction in DVT. One study by Leclerc et al18 reduced (p < 0.0001) DVT from 65% with placebo to 19% with enoxaparin. A study by Levine et al19 reported a reduction (p < 0.001) in VTED with 30% in the ardeparin group and 59% in the placebo group.
Based on the studies highlighted within this submission,3,10 LMWH and synthetic pentasaccharide appear effective prophylaxis drugs for VTED. The occurrence of VTED has been decreased by use of LMWH and by use of the synthetic pentasaccharide in TKA and adequate safety has been documented.
In this limited group of studies of LMWH in TKA, the results appear to favor the use of LMWH for DVT prophylaxis after surgery. The risks of deep venous thrombosis and pulmonary embolism in orthopaedic practice are well recognized. This risk has stimulated historical and contemporary research efforts. The limited controlled clinical studies described provide scientific data to assist the orthopaedic surgeon to maintain an evidence-based practice.
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